Point-of-Care Testing in Patients with Hereditary Disorders of Primary Hemostasis: A Narrative Review

• Abstract
• Methods
• Definitions
• Statistical Analysis
• Results
• Mechanism of Action of the Point-of-Care Tests
• Platelet Function Analyzer (PFA-100, PFA-200)
• Total Thrombus Formation Analysis System
• Multiplate
• Viscoelastic Tests
• Clot Signature Analyzer
• Impact-R/Cone and Plate(let) Analyzer
• Results of the Point-of-Care Tests in Patients with Hereditary Disorders of Primary Hemostasis
• Platelet Function Analyzer (PFA-100, PFA-200)
• Total Thrombus Formation Analysis System
• Multiplate
• Viscoelastic Assays (Thromboelastography and Rotational Thromboelastometry)
• Discontinued Assays
• Clot Signature Analyzer
• Impact-R (Cone and Plate(let) Analyzer)
• Novel Assays
• General Discussion and Study Limitations
• Conclusion
• References

Abstract

Inherited disorders of primary hemostasis, such as von Willebrand disease and congenital platelet disorders, can cause extensive, typically mucocutaneous bleeding. Assays to diagnose and monitor these disorders, such as von Willebrand factor activity assays and light transmission aggregometry, are performed in specialized hemostasis laboratories but are commonly not available in local hospitals. Due to the complexity and relative scarcity of these conventional assays, point-of-care tests (POCT) might be an attractive alternative in patients with hereditary bleeding disorders. POCTs, such as thromboelastography, are increasingly used to assess hemostasis in patients with acquired hemostatic defects, aiding clinical decision-making in critical situations, such as during surgery or childbirth. In comparison, the use of these assays in patients with hereditary hemostasis defects remains relatively unexplored. This review aims to give an overview of point-of-care hemostasis tests in patients with hereditary disorders of primary hemostasis. A summary of the literature reporting on the performance of currently available and experimental POCTs in these disorders is given, and the potential utility of the assays in various use scenarios is discussed. Altogether, the studies included in this review reveal that several POCTs are capable of identifying and monitoring severe defects in the primary hemostasis, while a POCT that can reliably detect milder defects of primary hemostasis is currently lacking. A better understanding of the strengths and limitations of POCTs in assessing hereditary defects of primary hemostasis is needed, after which these tests may become available for clinical practice, potentially targeting a large group of patients with milder defects of primary hemostasis.

Hemostasis is accomplished by a complex system, involving many interacting cells and proteins that constitute a delicate balance between hypo- and hypercoagulation. Inherited disorders of platelets or proteins involved in primary hemostasis can cause excessive, typically mucocutaneous bleeding. Von Willebrand disease (VWD) is the most common inherited bleeding disorder, with approximately 1:1000 people expressing a symptomatic bleeding tendency.[1] The prevalence of platelet function disorders (PFD) is less well known. A recent study reported an estimated prevalence of PFDs of 1:3000, based on the findings in a genome database.[2]

While most patients with primary hemostasis disorders experience mild bleeding symptoms, some suffer from severe bleeding that can result in life-threatening situations in which rapid medical intervention is paramount. Making a timely and accurate diagnosis of these patients is challenging. This requires testing that is only performed in specialized clinical hemostasis laboratories.

Commonly used assays to finalize a diagnosis include light transmission aggregometry (LTA) and flow cytometry,[3] both of which are most often performed in platelet-rich plasma (PRP), necessitating blood samples to be differentially centrifuged prior to analysis, adding to the time required to perform these assays. When results are available, interpretation calls for an intricate understanding of the mechanisms underlying blood hemostasis, which is not common knowledge for most physicians.[4] As a result, misdiagnosis or significant delay between the onset of bleeding symptoms and diagnosis is common.[5]

Availability of easy-to-perform assays with high specificity that rapidly inform on the potency of primary hemostasis could aid not only in the prevention of a diagnostic delay, but also in tailoring treatment in patients with an established diagnosis during a bleed or perioperatively. This would be especially useful in resource-limited countries where specialized laboratories and treatment products are scarce.[6]

A wide range of assay methodologies has been employed in an effort to meet the need for such easy-to-perform assays. In some of these assays, hemostasis is assessed in whole blood under circumstances of shear stress (e.g., platelet function analyzer [PFA-100/PFA-200], total thrombus formation analysis system [T-TAS], clot-signature analyzer). Other assays, such as the Multiplate and Plateletworks, measure the reactivity of platelets and von Willebrand factor (VWF) in whole blood to specific agonists. A third category of assays evaluates global hemostasis by measuring thrombin generation or the viscoelastic properties of blood as a clot is formed, both of which are influenced by primary hemostasis. All three categories of assays are utilized as point-of-care tests (POCT) in the general population. Specific assays were found helpful to guide treatment during and after surgery[7] or labor[8] or in the care of trauma patients.[9] Additionally, POCTs of secondary hemostasis are commonly employed in monitoring anticoagulation.[10] However, due to the rarity of congenital bleeding disorders, performing sufficiently powered studies to validate such POCTs in these disorders is difficult. Furthermore, as many available POCTs are poorly standardized, aggregating results of small studies is problematic. Consequently, uncertainty regarding the validity of POCTs in hereditary bleeding disorders persists. In this review, our aim is to provide a comprehensive summary of all available POCTs used to diagnose and monitor hereditary disorders of primary hemostasis, with the main focus on VWD and PFDs.

Methods

PubMed was searched for articles that described the use of POCTs in patients with hereditary disorders of primary hemostasis published before June 12, 2023 ([Supplementary Material], available in online version only). Articles that were available in English of any study type except narrative reviews were included.

Articles solely focusing on bleeding time without comparative analysis with other POCTs were excluded from our analysis. However, to enrich the breadth of our findings, we incorporated one review discussing the utility of bleeding time during the final drafting of the article.

Definitions

PFD not otherwise specified was defined as a bleeding tendency in combination with abnormal aggregation in LTA but without the diagnosis of a specific platelet disorder. Mild quantitative VWD was defined as a diagnosis of VWD type 1 or “low VWF” in combination with a bleeding tendency.

Statistical Analysis

In the calculation of overall assay sensitivity, studies were weighted according to the number of patients included. Calculations were performed with Microsoft Excel.

Graphs were created using R version 4.1.3. [Fig. 1] was created using Lucidchart. Other figures were created with Adobe Illustrator 2023.

Results

After an extensive literature research, 186 articles were included in this review. A flowchart of the articles included in this review is presented in [Fig. 1].

Various POCTs to assess primary hemostasis have been employed over the years. Bleeding time, first described approximately 3,000 years ago by Huang Ti,[11] has long been considered a fundamental tool in this regard. In this test, hemostasis is evaluated by creating a small cut in the skin of the patient and monitoring the time it takes until bleeding stops. Many variations of the bleeding time have been developed over the years, with later methods trying to automate and standardize the technique, to reduce variability in test results. Among these revised methods, the Ivy and Template bleeding time are notable for their extensive use in the past century. Nevertheless, patient discomfort and interoperator variability remained persistent problems in all these techniques. Rodgers and Levin stated in their extensive review in 1990 that there are no clear criteria for the use of bleeding time, as there was no evidence that it could accurately predict bleeding and aid in monitoring the effect of treatment.[12]

Several laboratory methods have been described in an attempt to mimic bleeding time in vitro. For example, in the capillary thrombometer whole blood was pumped back and forth through a glass column until clot formation resulted in occlusion of the tube.[13] [14] Similarly, whole blood was passed through a woven polyethylene terephthalate[15] or glass fiber[16] filter to measure “filter bleeding time.” These methods showed promising results to detect severe primary hemostasis disorders but did not find widespread use. Nowadays, bleeding time has mostly been replaced by the PFA-100 and PFA-200. This device is reported to be more sensitive in patients with VWD compared with bleeding time. However, for other primary hemostasis defects, diagnostic performance is comparable to bleeding time ([Fig. 2]).[17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] Other devices that hold resemblance to the bleeding time, such as the T-TAS, clot signature analyzer (CSA), cone and plate(let)/impact-R analyzer (CPA), and experimental microfluidic flow chambers,[38] have been used specifically in patients with hereditary primary hemostasis disorders. Multiplate and viscoelastic assays employ different methods to assess hemostasis and have also been studied in these patients. In this review, the mechanism of action of these POCTs is first described ([Fig. 3] and [Table 1]). Next, articles describing the results of their use in hereditary disorders of primary hemostasis will be discussed.

Interestingly, several available point-of-care (POC) hemostasis assays have never been studied in patients with congenital primary hemostasis defects: the Global Thrombosis Test, Hemodyne analyzer, Plateletworks, Ultegra Rapid Platelet Function Assay and its follow-up the Verifynow, ReoRox, Sonoclot, and the Quantra Hemostasis Analyzer. Some of these tests utilize methods that were able to identify patients with inherited primary bleeding disorders. For instance, in Plateletworks, platelet count measured before and after addition of agonists determines the platelet activation to these agonists. While this method holds promise in patients with hereditary platelet disorders,[39] Plateletworks has never been validated in these patients.

Mechanism of Action of the Point-of-Care Tests

An overview of characteristics of the assay techniques is depicted in [Table 1]. A schematic representation of the mechanism of the assays is shown in [Fig. 3].

Platelet Function Analyzer (PFA-100, PFA-200)

The PFA-100 system was first described in 1995 as a follow-up of the Thrombostat-4000,[40] building upon a technique to assess primary hemostasis as described by Kratzer and Born in 1985.[41] Citrated whole blood is inserted into one of two different cartridges and aspirated through a 150-µm aperture in a collagen and either epinephrine (EPI) or adenosine diphosphate (ADP)-coated membrane. This procedure generates a shear force of 5,000 to 6,000/seconds, presumably activating VWF. The closure time, the time until the aperture is closed, is a marker of the potency of primary hemostasis.[40] An updated version of the PFA-100, the PFA-200, was released mid-2010s. While the user interface has been changed significantly, test results were shown to be similar to the older model.[42] [43] Furthermore, an additional cartridge designed to test P2Y12 function has been created (INNOVANCE PFA P2Y). Development of this cartridge was incentivized by the need for a convenient assay to measure the effect of P2Y12-inhibiting drugs.

Total Thrombus Formation Analysis System

This device was introduced in 2011 as a method to assess thrombus formation under high and low shear force. Two distinct chips are used: the PL-chip with a collagen-coated flow-chamber, aimed to assess platelet function in whole blood under conditions of high shear force. The second chip called the AR-chip is coated with tissue thromboplastin, with the main goal to assess factor-based coagulation in whole blood containing corn trypsin inhibitor. In both chips, whole blood is perfused through a channel, while the pressure within this channel is continuously monitored. The time to reach predefined pressure levels serves as a surrogate for the onset of thrombus formation and subsequent channel occlusion. These parameters constitute the main outcomes of the assay.

Multiplate

A technique called multiple electrode aggregometry is used. This assay was first described in 2004 in an abstract on the 10^th Erfurt Conference on Platelets by Calatzis et al[44] as an improvement of the method that was described by Cardinal and Flower in 1979.[45] The reactivity of platelets in whole blood to different agonists is assessed by continuously measuring the electrical impedance in the test cell following addition of these agonists. As platelets adhere to two pairs of electrodes, the electrical impedance increases, thereby reflecting the platelet responsiveness to the added agonist.

Viscoelastic Tests

Testing of the viscoelastic properties of blood over time informs on entire coagulation process from initiation to fibrinolysis. Hartert described this technology as early as in 1948.[46] Technologic advancement has rekindled interest in this technique at the end of the 20^th century. Two viscoelastic techniques have been studied extensively in patients with hereditary bleeding disorders: thromboelastography (TEG) and rotational thromboelastometry (ROTEM). In both TEG and ROTEM, plasma or citrated whole blood is placed in a heated cuvette in which a pin is suspended. In TEG, the cuvette rotates, whereas in ROTEM, the pin rotates. As coagulation occurs and fibrin networks are formed, the viscoelasticity of the sample increases. In TEG, the increasing viscoelasticity leads to a higher conveyance of the rotating cuvette with blood to the pin. This, in turn, causes the pin to track the movements of the cuvette more closely. An electromagnetic transducer monitors the movement of the pin. In contrast, in ROTEM the movement of the rotating pin is increasingly impeded as the viscoelasticity of the blood rises, resulting in diminished rotation of the pin. The detection is achieved optically in a commonly used ROTEM platform (ROTEM delta). For both TEG and ROTEM, the viscoelasticity of the sample over time is depicted in characteristic curves, from which several parameters can be identified. The most commonly used parameters and their definitions are outlined in [Fig. 4]. Depending on the agent added to initiate coagulation, various assays are recognized ([Table 1]).

Modifications of TEG and ROTEM have been developed to specifically assess platelet function: TEG Platelet Mapping and ROTEM Platelet Analysis. In TEG Platelet Mapping, the maximal amplitude (MA) obtained after addition of different agonists and inhibitors of hemostasis is compared. While this method involves relatively many steps for a POCT, it has shown promise in a POC setting for trauma patients[47] and cardiac surgery patients.[48] Firstly, a standard kaolin TEG is performed to determine the maximal clot strength after activation of platelets by contact pathway-mediated generation of thrombin (MA_thrombin). MA in this assay represents the clot strength that can be attained after maximal platelet stimulation. Secondly, the clot strength due to fibrin network formation without platelet activation is determined (MA_fibrin). This is accomplished by adding reptilase and FXIII to heparinized blood. Reptilase converts fibrinogen to fibrin in a thrombin-independent manner, whereas heparin prevents the activation of thrombocytes by thrombin. This last assay is repeated in the presence of either arachidonic acid (AA) or ADP, to assess the clot strength that is reached after stimulation of platelets by these agents (MA_AA and MA_ADP). The results of the assays are compared to determine platelet aggregation after stimulation with AA or ADP as a percentage of maximal platelet aggregation (Equation 1), or the percentage of AA or ADP receptors inhibited (100% − percentage of aggregation).

The ROTEM platelet module takes a different approach and measures impedance aggregometry in response to AA, ADP, and thrombin receptor-activating peptide simultaneously with conventional ROTEM analysis.

Clot Signature Analyzer

The pressure over time in two oil-filled pressure chambers connected to distinct channels perfused with whole blood is examined.[49] One of these channels is coated with collagen. Flow of blood through the channels causes pressure to build up in the pressure chambers. Consequently, as the channels occlude due to thrombus formation, the pressure in the pressure chambers decreases to zero. The time until the pressure drops to 50% in the collagen channel (collagen-induced thrombus formation time) and to 10% in the uncoated channel (clotting time—CT) are two of the main outcomes of the assay. A unique feature of this assay is that the channel not coated with collagen is punctured with a needle to mimic vascular injury. As a result, the flow to the associated pressure chamber declines, resulting in a temporary decrease in pressure, until blood coagulation restores the continuity of the channel. The time from puncturing the channel until recovery of pressure is called the platelet hemostasis time and constitutes the third main outcome of this assay. In fact, this “tube bleeding time” was used to successfully detect Glanzmann thrombasthenia (GT) prior to release of the CSA.[50]

Impact-R/Cone and Plate(let) Analyzer

Blood is placed in a polystyrene well and shear force is applied with a circulating Teflon cone. After 2 minutes, the well is washed and stained. The amount of adhered and aggregated platelets as determined by surface coverage and the average size of adhered particles are calculated by a computer.

In the next section, an overview of studies reporting on the use of these assays in patients with hereditary disorders of primary hemostasis is presented.

Results of the Point-of-Care Tests in Patients with Hereditary Disorders of Primary Hemostasis

Platelet Function Analyzer (PFA-100, PFA-200)

Apart from being influenced by aberrations in primary hemostasis, this assay's main outcome is reported to be influenced by several physiological parameters, such as platelet and hematocrit level,[32] [43] [51] blood group,[52] time during the day,[36] age (neonates having shorter closure time),[53] and physical exercise.[54] Currently, PFA-100 is one of the most used POC hemostasis assays in patients with suspected hereditary disorders of primary hemostasis.[55] However, a Worldwide Survey of ISTH members found that only 58% of all responding hemostasis laboratories were using the PFA-100.[3]

PFA-100 is extensively studied in patients with (suspected) VWD.[17] [18] [19] [21] [22] [23] [24] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [43] [51] [52] [53] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] Favaloro et al reported an overall sensitivity of 83.2% and 91.5% of the ADP and EPI cartridge respectively in a review in 2008.[79] A current analysis including all articles published before and after 2008 yielded similar test performance outcomes, as shown in [Fig. 5] and [Supplementary Table S1] (available in online version only). Two recent large retrospective studies incorporating the data of over 10 years of experience confirmed the high diagnostic value of PFA-100 in detecting VWD.[43] [52] Normal PFA-100 results are especially rare in patients with abnormal VWF function or a lower quantity of large molecular VWF multimers.[24] [26] [32] [35] [60] [78] [80] [81] In cases of mild type 1 VWD the false-negative rate is higher. Sap et al reported a sensitivity of only 29%, specifically in this group of patients.[77] However, all patients diagnosed with VWD type 1 in this study had (near)-normal VWF:Ag levels, whereas VWF:RCo levels were markedly decreased. Accordingly, the patients' VWF profile was more in line with type 2 VWD, raising questions about the precise VWD diagnoses of patients in this study. Only patients with VWD type 2N consistently exhibited normal test results,[24] [26] [67] unless VWF levels were also low. This observation aligns with expectations, since PFA is not able to detect secondary hemostasis defects, such as FVIII deficiency, which is the main outcome of type 2N VWD.[24] [53] [56] [80] As the PFA primarily functions as a screening tool, it does not contribute to identifying the specific subtype of VWD in any given patient.[28] Nor can the PFA-100 distinguish VWD from PFDs. However, comparison of PFA-100 results before and after administration of DDAVP has been used to help differentiate patients with severe type 1 and classical type 2 VWD.[81]

The diagnostic utility of the PFA-100 has been studied in a variety of diseases other than VWD. An overview of the published literature on test results in primary hemostasis disorders other than VWD is presented in [Fig. 6] and [Supplementary Table S2] (available in online version only). Karger et al found a pooled sensitivity of 82.5% and 66.9% of EPI and ADP cartridge, respectively, for detecting primary hemostasis defects.[82] Individuals diagnosed with severe PFDs, such as GT[17] [24] [26] [27] [31] [37] [51] [55] [57] [60] [66] [68] [75] [83] [84] [85] [86] and Bernard–Soulier syndrome (BSS),[51] [55] [60] [75] [87] consistently exhibited prolonged closure time with both cartridges. In fact, blood of GT patients was not able to occlude the PFA-100's aperture even after transfusion of normal pooled platelets.[85] It was suggested that the patients' GPIIbIIIa-deficient platelets compete with the transfused platelets for adhesion to the membrane. However, once adhered, the patients' platelets lack the capacity to aggregate effectively, resulting in the inability to form a stable blood clot and obstruct the PFA's aperture.

In patients with milder bleeding disorders, such as platelet secretion disorders or storage pool disorders (SPD), diagnosis can be missed when solely relying on PFA-100.[17] [20] [24] [25] [26] [30] [31] [32] [33] [36] [51] [55] [57] [60] [65] [66] [68] [84] [88] [89] [90] [91] [92] [93] [94] [95] On the whole, the EPI cartridge demonstrates greater sensitivity than the ADP cartridge in detecting primary hemostasis defects. In practice, isolated prolongation of the closure time in the EPI cartridge is often attributed to drug-induced COX-1 inhibition such as that caused by aspirin. This pattern is also frequently observed in patients with mild VWD or PFDs. Using both cartridges simultaneously offers the benefit of providing information on the severity of the underlying disorder. If only the EPI cartridge shows abnormal results, a diagnosis of severe VWD or PFD is unlikely.

The added value of the INNOVANCE P2Y cartridge in patients with hereditary disorders of primary hemostasis is uncertain. While it showed improved sensitivity for moderate–severe P2Y12 defects in a small study,[94] the detection rate of PFDs and VWD did not increase by adding this cartridge to the diagnostic protocol.[66]

The PFA-100 has also been used to detect primary hemostasis disorders prior to surgery. In a meta-analysis on preoperative screening for bleeding disorders in pediatric patients, PFA-100 performed best of the screening methods studied, which also included several questionnaires, bleeding time, and activated partial thromboplastin time.[96] However, the authors stated that given the general lack of high-quality studies, care should be taken to draw firm conclusions. The largest included study in this meta-analysis found low diagnostic value of PFA in screening unselected preoperative patients and argued it had led to unnecessary delay of surgical procedures.[97] While this study reported false-positive results to be problematic, others found insufficient sensitivity to be the largest problem in preoperative screening.[84] Conversely, Koscielny et al reported the PFA-100 to be useful in screening before surgery: they were able to reduce perioperative blood product use by utilizing PFA-100 in a protocol to detect hemostasis defects in unselected patients scheduled for surgery and to monitor treatment prior to surgery.[98]

Apart from identifying patients with VWD or PFDs, PFA-100 has been used to monitor treatment in patients with hereditary bleeding disorders. The extent of normalization of closure time correlates with the increase in VWF activity (including VWF:RCo) and VWF:Ag in patients with VWD type 1 treated with DDAVP.[18] [22] [23] [34] [66] [80] [99] [100] [101] In patients with type 2 VWD, however, closure time remained prolonged after DDAVP in the subset of patients with normalization of VWF:Ag, possibly due to a persistent lack of high molecular VWF multimers.[80] [81] [99] [102] Monitoring treatment with plasma-derived VWF (pd-VWF) concentrate with PFA-100 is unreliable, as most concentrates do not contain high molecular weight VWF multimers.[18] [23] [71] [99] [103] In contrast, a few recent studies suggested that monitoring treatment with recombinant VWF concentrate is promising, as this product does contain high molecular weight VWF multimers and can lead to correction of prolonged PFA CTs.[104] [105]

While most studies assessed the validity of PFA-100 in monitoring treatment compared with conventional assays, there is limited literature on the correlation with clinical outcomes. Some studies reported that PFA-100 results correlated with the severity of bleeding tendency.[31] [64] [106] This finding was not, however, confirmed by others.[25] [107] [108] [109] The correlation between the change in closure time after treatment with clinical outcomes is even less clear. Weston et al reported that DDAVP might prevent bleeding even in patients with unchanged closure time.[110] Similarly, Hanebutt et al noted that all three patients in whom closure time did not shorten after DDAVP administration did not experience subsequent bleeding complications.[100] Accordingly, questions surrounding the validity of PFA-100 to monitor treatment remain.

Some patients with clinically elevated bleeding tendency have abnormal PFA-100 results, while test results in all other hemostasis studies are normal. Heubel-Moenen et al showed significant abnormalities in extensive multiparameter microfluidic assays in a subset of these patients.[111] In some cases, the test results exhibited abnormalities to a comparable extent as observed in patients with GT. The authors hypothesized that these patients have multifactorial defects in shear-dependent mechanisms of primary hemostasis, which cannot be detected with traditional static hemostasis assays.

Taken altogether, the suboptimal sensitivity in patients with mild PFDs hampers the utility of PFA-100 in assessing patients with suspected hereditary bleeding disorders and has compelled several authors and the ISTH Platelet Physiology Subcommittee to advise against using PFA-100 in screening for hereditary bleeding disorders.[30] [33] [59] [112] [113] We, however, concur with the conclusions of Favaloro et al who recently stated that the main purpose of the PFA-100/200 is to rapidly exclude VWD.[42]

Total Thrombus Formation Analysis System

Ogiwara et al were the first to describe the use of this device in patients with hereditary bleeding disorders.[114] They showed that all five tested patients with various types of VWD had impaired thrombus formation in the PL-chip. Of interest, thrombus formation was also abnormal in one patient diagnosed with VWD type 2N. However, as the VWF:RCo of this patient was 32 IU/dL, the cause of this result might have been low VWF activity in addition to low FVIII activity levels. Later studies confirmed high sensitivity of T-TAS in patients with VWD, especially in patients with deficiency of high molecular weight multimers.[115] [116] Additionally, a correlation between bleeding tendency and T-TAS outcomes was found in patients with VWD type 1.[117] However, sensitivity in those with mild VWD type 1 and (VWF: Ag > 25%) was limited.[115] As such, it was questioned whether T-TAS has added value over PFA-100 in patients with VWD. Charpy et al performed the only study that directly compared both assays.[68] While this small study reported a relatively low sensitivity of PFA-100 (75%), the sensitivity of PL-chip was even lower (42%). An explanation for the low sensitivities might be that all patients with VWF:GP1bR < 50% were considered to have VWD in this study. As such, many included patients did not exhibit a bleeding tendency; the median ISTH Bleeding Assessment Tool score in patients with VWF:GP1bR level of 30 to 39% was just one.

T-TAS has two notable advantages over PFA-100 in patients with VWD. Nakajima et al reported that the AR-chip of the T-TAS provides the possibility to identify patients with VWD type 2N and assess their bleeding risk.[118] Furthermore, the AR-chip showed normalization of test outcomes after infusion of pd-VWD/FVIII concentrate, in contrast to the PFA-100.[119] T-TAS might therefore be more suitable to monitor treatment with pd-VWD/FVIII concentrate.

Superiority of T-TAS over PFA-100 appears more clearly in patients with mild PFDs, although only a few relevant studies are available. Similarly to PFA-100, results of T-TAS were abnormal in all patients with GT or BSS.[116] In addition, the diagnostic performance of T-TAS was better in mild thrombocytopathies compared with PFA-100. T-TAS test results were abnormal in 80 to 100% of patients with δ-SPD[120] [121] and in 70 to 82% of patients with abnormalities in (lumi-)LTA.[68] [122] Nonetheless, a sensitivity of 70% still limits the general utility of this assay as a screening tool.

Multiplate

In VWD, using ristocetin as an activating agent, diagnostic performance of Multiplate in most studies was excellent in all patients, except in those patients with a mild subtype 1.[64] [123] [124] Similar to PFA-100 and T-TAS, sensitivity was notably lower in patients with mild type 1 VWD.[64] [65] However, Valarche et al reported normal Multiplate results even in patients with VWD type 2A and 2M.[76] Notably, four out of five patients with normal results in this study had a VWF activity of ≥40%, which could potentially account for the observed low sensitivity. An advantage of multiplate compared with other POCTs is the ability to identify patients with VWD type 2B, in whom increased aggregation to low-dose ristocetin was seen.[64] [76] However, a study by Nakajima et al raised doubts about the technique's reliability, as none of the three tested patients with VWD type 2B demonstrated increased aggregation in response to low-dose ristocetin.[116]

The ability of Multiplate to simultaneously measure the response to different agonists is especially interesting. In theory, it could allow differentiation of various platelet disorders, whereas other POCTs only measure general platelet function. Multiplate consistently showed abnormal results in patients with GT and BSS,[84] [86] [125] [126] demonstrating high agreement with results obtained by LTA. However, limited sensitivity in patients with mild PFDs was seen. Only 40% of patients with abnormalities in LTA were identified with Multiplate in one study.[84] In another study, only 20% of pediatric patients with mild bleeding disorders had abnormal Multiplate results.[65] In this last study, the addition of Multiplate to a protocol for screening in patients with a suspected bleeding disorder did not increase sensitivity of the screening protocol and was therefore deemed ineffective. Lastly, Al Ghaithi et al reported that Multiplate only identified 3 out of 20 patients with PFDs detected by lumi-LTA.[127] This outcome is not surprising, as the Multiplate much alike conventional LTA does not measure ATP release.

Insufficient sensitivity in mild platelet disorders seems to restrict the usability of this device in patients with (suspected) hereditary bleeding disorders. Interestingly, some limitations might have been resolved in a different system, the Chrono-log Whole Blood Lumi-Aggregometer (Chrono-log Corporation), as this platform does allow for performing concurrent whole blood impedance aggregometry and ATP release measurements. Using this system, reduced ATP secretion was found in a patient with Hermansky–Pudlak syndrome (HPS—a genetic syndrome characterized by albinism and absence of platelet delta granules).[128] Further reports on the use of the Chrono-log Whole Blood Lumi-Aggregometer in patients with hereditary bleeding disorders are limited to studies describing its use in the screening of patients with heavy menstrual bleeding.[129] [130] Conclusions, however, cannot be drawn from these studies regarding the diagnostic performance of the device, as conventional lumi-aggregometry in plasma was not performed in these studies.

Viscoelastic Assays (Thromboelastography and Rotational Thromboelastometry)

The lack of high shear stress in TEG and ROTEM is thought to hamper their utility in assessing primary hemostasis disorders, especially in VWD. Nonetheless, several studies have described the use of these techniques in these disorders, with varying success.

In VWD, prolonged coagulation initiation (R-time or CT) and decreased propagation (K-time and CFT) have been observed.[131] [132] [133] However, the test parameters were found to correlate with FVIII activity levels but not with VWF activity levels[132] and the tracings normalized in VWD type 3 patients after suppletion with FVIII concentrates[131]; these abnormalities are therefore likely explained at least in part by FVIII deficiency and not by the alterations in VWF-mediated hemostasis.

Interestingly, while overall it is thought that TEG and ROTEM produce similar, although not interchangeable results, studies using ROTEM reported lower sensitivity in patients with VWD compared with TEG. Strikingly, even some patients with VWD type 2 or 3 exhibited normal results with ROTEM.[132] [134] [135] This difference in performance was clearly seen in a study involving 100 VWD patients, whose hemostasis was tested with both TEG and ROTEM.[132]

Relatively many studies described the use of TEG and ROTEM in patients with PFDs. However, the vast majority of these studies consists of case reports involving patients undergoing surgical procedures[136] [137] [138] [139] [140] [141] [142] [143] [144] [145] or during peripartum care.[146] [147] [148] [149] [150] [151] [152]

In GT, viscoelastic assays unequivocally have shown decreased clot strength (MA/maximal clot firmness).[126] [153] [154] [155] [156] Using TEG Platelet Mapping, it was even possible to identify a GT patient with a mild bleeding phenotype from four other patients with more severe bleeding tendencies,[83] which suggests that this technique might be an attractive method to monitor GT patients. Utility of viscoelastic assays to monitor treatment in GT is further supported by the observation that maximal clot strength improved after treatment with platelet transfusions,[157] [158] fibrinogen,[154] [155] and recombinant factor XIII.[154] Addition of recombinant factor VIIa (rFVIIa) did not normalize clot strength despite adequate clinical outcome in one study, which suggests limited utility of viscoelastic assays altogether in monitoring rFVIIa treatment in GT.[159] This last study is an exception on the general lack of studies correlating the changes in test results after treatment with clinical outcomes, despite anecdotal evidence suggesting that hemostasis might still be impaired in spite of normalization of test results.[143]

In BSS, clot strength is mostly unaltered, but the coagulation propagation phase is affected (increased K-time/CFT and decreased α angle).[126] [153] Only one study reported the effects of treatment on viscoelastic assays in BSS: rFVIIa improved the initiation and propagation phase, whereas fibrinogen improved maximal clot strength in addition to increasing the propagation.[150]

In contrast to the results of the assays in these severe platelet disorders, blood of patients with mild bleeding disorders often produces normal tracings. As such, the added value of these assays was found to be limited in screening for mild bleeding disorders.[135]

Hypothetically, addition of TEG Platelet Mapping and the ROTEM platelet module could improve the diagnostic value of TEG and ROTEM. However, their use in patients with hereditary disorders is exclusively reported in small (case) studies,[126] [143] [145] [147] [153] obstructing the formulation of definite conclusions regarding their utility.

Discontinued Assays

The CSA and Impact-R (CPA) have previously been used in patients with hereditary bleeding disorders. However, these systems are not commercially available nowadays. Nonetheless, the lessons learned with these systems might prove valuable in developing novel testing platforms.

Clot Signature Analyzer

The CSA was successfully used to monitor two patients with HPS during labor. However, a subsequent larger study reported insufficient sensitivity of the assay in patients with HPS.[160] The latest study on CSA in patients with hereditary bleeding disorders was performed by Fricke et al in 2004, who studied the diagnostic accuracy of CSA in a large group of patients with various hemostasis defects.[161] Sensitivity was high in patients with VWD (91%) and coagulation factor deficiencies (92%), while it was lower in patients with various PFDs (69%). Regarding VWD patients, only patients with type 1 VWD had false-negative results. Specificity was acceptable, with 89% of healthy controls showing normal results. Since 2004 there have been no additional publications using CSA in patients with hereditary bleeding disorders.

Impact-R (Cone and Plate(let) Analyzer)

Platelet deposition was found to be highly dependent on surface immobilization of plasma VWF on the polystyrene plate[162] and proved to be useful in detecting VWD, GT, and afibrinogenemia.[163] In a trial involving pediatric patients with diverse primary hemostasis defects, the assay demonstrated a notable capacity to reliably rule out bleeding disorders, with a sensitivity of 90%. However, the specificity was comparatively lower at 67.5%.[164] A modification of the assay was later proposed, performing the Cone and Plate(let) assay both before and after the addition of platelet agonists to the sample.[165] This modification might allow for differentiation of different PFDs, but further studies confirming its validity in patients with PFDs are lacking.

Novel Assays

A full overview of new POC techniques to monitor coagulation is outside the scope of this review. However, some novel assays have shown promising results specifically in patients with hereditary bleeding disorders and will be discussed briefly.

In several novel devices, hemostasis was monitored by perfusing whole blood through microfluidic channels. Some experimental flow chamber devices were tested in patients with VWD or suspected primary hemostasis disorders.[38] [166] [167] [168] In these microfluidic devices, whole blood was perfused through capillaries with varying shear stress, owing to the specific geometry of the capillaries. Video microscopy was used to monitor the area of the capillaries covered by a growing thrombus, reflecting hemostatic potency. These assays showed high sensitivity even in patients with VWD type 1, signifying potential added value over currently available POCTs. In the device of Grabowski et al, blood is incubated with anti-GPIIb and ALEXA 555-conjuncted anti-mouse antibodies. Using epifluorescence this device was able to monitor total volume of thrombus formation in addition to monitoring the area covered. Twenty-four patients with low VWF were evaluated with this assay. None of the patients with normal platelet adhesion in this device developed clinical bleeding, whereas 7/16 patients with low platelet adhesion did. Therefore, this assay might have a role in predicting bleeding tendency in patients with VWD or low VWF, although its utility as a POCT is limited by the need for incubation prior to testing.[169]

Another device that optically measures clot formation in flow chambers was called the clotMAT.[170] In this device, micropillars are placed inside the channels. As blood perfuses the channels, clots are formed between these micropillars. In addition to optically monitoring the clot formation, this device also measured the contractile force of the clot and the clot stiffness. Early experiments with plasma of type 2A VWD patients showed that these additional measurements could provide more insight in the hemostatic status of these patients. However, further validation is needed.

General Discussion and Study Limitations

In this narrative review of available POCTs, aggregated data result in a remarkable lack of an outstanding POCT that is able to detect mild hereditary disorders of primary hemostasis, whereas sensitivity of all assays was excellent in severe disorders, such as GT, BSS, and severe VWD. Unfortunately, most patients referred for an increased bleeding tendency in developed countries will harbor mild hemostatic defects, and therefore, we believe that currently available POCTs are of limited value in screening patients with suspected bleeding disorders.

Several factors are likely to contribute to the suboptimal performance of the POCTs. An ideal POCT should assess hemostasis under (near-)physiological circumstances, incorporating all mechanical forces,[171] proteins, and cells that contribute to hemostasis in vivo. However, deviations from this ideal scenario are apparent across all discussed POCTs.

First, the effects of endothelial cells and the subendothelial matrix are not incorporated in any of the assays. Although in PFA, T-TAS and CSA platelets are exposed to collagen to resemble in vivo platelet adhesion, these methodologies do not comprehensively address the hemostatic functions attributed to the endothelium.[172]

In addition, Multiplate and viscoelastic assays are conducted under static conditions. The crucial role of high shear rate in unfolding VWF and subsequent platelet adhesion is thus neglected in these assays,[173] with the outcome that these assays show low sensitivity in mild quantitative VWF disorders. Interestingly, even in the assays that harbor higher shear rates such as PFA-100 and T-TAS, mild VWD is often missed. It should be noted that in all assays the shear rates applied were still low when compared with the shear rates observed in vascular injuries, thus deviating from in vivo conditions.[174]

Lastly, the use of citrated blood samples in most POCTs is a cause for concern. Beyond its role in inhibiting thrombin generation, the nonphysiological low ionized calcium environment induced by citrate significantly impairs platelet function. Immediately after blood draw, platelet reactivity was lower in citrated whole blood[175] and citrated PRP[176] compared with samples anticoagulated with other agents. Relatively small increases in citrate concentration further blunted platelet reactivity in LTA.[177] Paradoxically, reactivity to the weak platelet agonist ADP can be increased by using citrated blood,[178] due to augmented thromboxane A₂ production[179] and decreased ectonucleotidase activity.[180] While this effect might be beneficial in the detection of mild PFDs, it constitutes an artifact that deviates from the physiological in vivo situation. Additionally, there are concerns regarding the stability of citrated samples. Platelet function begins to deteriorate rapidly in citrated PRP as early as 2 hours after blood drawing, while it remains relatively preserved in PRP anticoagulated with heparin,[176] hirudin, or benzylsulfonyl-d-Arg-Pro-4-amidinobenzylamide (BAPA, a dual inhibitor of FXa and thrombin).[181] Platelet function shows similar deterioration in citrated whole blood samples and samples treated with hirudin,[182] while the samples treated with heparin[176] or BAPA[183] have shown greater stability. BAPA-treated samples even showed stable PFA results for up to 24 hours after blood draw.[183]

Given these limitations of the current generation of POCTs and the unsatisfactory results in patients with mild hemostatic defects, negative assay results do not reliably exclude an underlying disorder, and positive results require follow-up testing to make a definite diagnosis. Therefore, the ability of POCTs to significantly affect clinical decision-making is limited. However, we do not exclude a potential use of these assays in appropriate settings, as the findings of this review suggest the capability of these POCTs in monitoring primary hemostasis perioperatively. Also, some devices, such as the PFA, may be useful for quick exclusion of VWD. Most importantly, it is crucial that any assay result in medicine is considered in conjunction with the clinical data of the individual patient. As such, while not being able to perfectly rule out any disorder, these POCTs might still aid clinicians in diagnostic decision-making and in personalizing treatment.

Several studies assessed the influence of prohemostatic treatment on POCT results and suggested utility of these assays in monitoring. However, it might be premature to conclude that such monitoring strategies are beneficial, as trials correlating the results of POCTs after treatment with meaningful clinical outcomes are lacking. Alternatively, POCTs might provide valuable information in emergency situations when specialized hemostasis testing is unavailable. To this end, TEG and ROTEM are nowadays frequently used to steer treatment of patients with acquired coagulopathy in the emergency department or operating theatre. While numerous case reports suggest utility of POCTs in patients with hereditary bleeding disorders of primary hemostasis during surgery, no clinical prospective trials have been performed on this subject.

We acknowledge that definitive conclusions are difficult to draw from the presented data due to several limitations in methodology of the available studies and results. Firstly, due to the rare nature of many of the inherited disorders of primary hemostasis, most of the included studies only described a limited number of patients. We opted to include these articles to provide preliminary evidence and offer directions for future research. However, the importance of exercising care in drawing conclusions based on these small-scale studies should not be understated. Moreover, aggregation of the small studies to provide more substantial evidence is complicated due to the high variability in the methodology and definitions used in these studies. For instance, patients with a bleeding tendency, VWF:Ag 30 to 50%, with normal VWF activity/Ag ratios, are classified as VWD type 1 patients by the current ASH ISTH NHF WFH (American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, World Federation of Hemophilia) 2021 guidelines.[184] Historically, these patients were considered to have “low VWF” and were not diagnosed with VWD. To allow for summation of the available literature, we decided to combine all patients with mild quantitative VWF defects in one group to calculate overall assay performance. Nevertheless, this approach comes at the cost of reduced homogeneity within this group. Furthermore, while relatively many studies described the use of viscoelastic assays, aggregation of these studies is complicated, due to considerable variability in the assay protocols.

Secondly, we calculated the overall assay performance of the PFA-100 in an explorative fashion and did not perform a true systematic meta-analysis. As such, we weighted studies solely based on number of patients included and did not consider study quality in the calculation of the overall sensitivity.

Thirdly, several researchers were involved in multiple studies included in this review. This poses a risk that patients are included multiple times.

Lastly, we provided a detailed description of studies that used POCTs in patients with hereditary disorders of primary hemostasis but did not incorporate the vast amount of literature on these assays in other disorders. Extrapolation of results of this additional literature might have aided in substantiating conclusions and identifying additional uses of POCTs, such as differentiating between different types of bleeding disorders.

Conclusion

Overall, POC testing for primary hemostasis is a dynamic field and specific problems of the current generation of devices might be solved by future improvements and inventions. In recent years, discoveries in microfluidics[185] have paved the way for a new generation of “Lab on a Chip” devices to assess hemostasis.[186] These advancements have enabled the development of platforms that could potentially revolutionize the care for patients with hereditary platelet disorders, such as a disk-shaped device that automatically generates PRP from inserted whole blood and subsequently performs LTA.[187] Additionally, future assays performed with whole blood in microchannels coated with endothelial cells under high shear forces could provide the means for more realistic in vitro hemostasis testing.[188] It remains to be seen how effectively these innovative devices will translate from the laboratory setting to real-world clinical applications, ultimately filling the yet unmet need for a truly reliable and easy-to-use primary hemostasis assay.

Conflict of Interest

A.P.B. is an employee of Enzyre BV. W.V.H. is the founder and stockholder of Enzyre BV. Enzyre BV has contracts with Takeda and Novo Nordisk. W.V.H. has received travel support from Takeda for Enzyre-related meetings. S.S. declares no conflict of interest.

• References

• 1 Bowman M, Hopman WM, Rapson D, Lillicrap D, James P. The prevalence of symptomatic von Willebrand disease in primary care practice. J Thromb Haemost 2010; 8 (01) 213-216
  PubMedSearch in Google Scholar
• 2 Oved JH, Lambert MP, Kowalska MA, Poncz M, Karczewski KJ. Population based frequency of naturally occurring loss-of-function variants in genes associated with platelet disorders. J Thromb Haemost 2021; 19 (01) 248-254
  PubMedSearch in Google Scholar
• 3 Gresele P, Harrison P, Bury L. et al. Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey. J Thromb Haemost 2014; 12 (09) 1562-1569
  PubMedSearch in Google Scholar
• 4 Pilsczek FH, Rifkin WD, Walerstein S. Overuse of prothrombin and partial thromboplastin coagulation tests in medical inpatients. Heart Lung 2005; 34 (06) 402-405
  PubMedSearch in Google Scholar
• 5 Noris P, Schlegel N, Klersy C. et al; European Hematology Association – Scientific Working Group on Thrombocytopenias and Platelet Function Disorders. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Haematologica 2014; 99 (08) 1387-1394
  PubMedSearch in Google Scholar
• 6 Hagembe J, Baumann A, Haffar A, Pierce GF, Toulon P. Development of a target product profile (TTP) for haemophilia point-of-care (POC) diagnostic devices for low-resource countries and remote settings. Haemophilia 2023; 29 (02) 671-673
  PubMedSearch in Google Scholar
• 7 Woźniak MJ, Abbasciano R, Monaghan A. et al. Systematic review and meta-analysis of diagnostic test accuracy studies evaluating point-of-care tests of coagulopathy in cardiac surgery. Transfus Med Rev 2021; 35 (01) 7-15
  PubMedSearch in Google Scholar
• 8 Collins P. Point-of-care coagulation testing for postpartum haemorrhage. Best Pract Res Clin Anaesthesiol 2022; 36 (3-4): 383-398
  PubMedSearch in Google Scholar
• 9 Caspers M, Holle JF, Limper U, Fröhlich M, Bouillon B. Global coagulation testing in acute care medicine: back to bedside?. Hamostaseologie 2022; 42 (06) 400-408
  Thieme ConnectPubMedSearch in Google Scholar
• 10 Barcellona D, Fenu L, Marongiu F. Point-of-care testing INR: an overview. Clin Chem Lab Med 2017; 55 (06) 800-805
  PubMedSearch in Google Scholar
• 11 Owen CA. A History of Blood Coagulation. Mayo Foundation for Medical;; 2001
  Search in Google Scholar
• 12 Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16 (01) 1-20
  PubMedSearch in Google Scholar
• 13 Kadota RP, Bowie EJ, Emslander HC, Fass DN, Ilstrup DM. The capillary thrombometer revisited. Haemostasis 1987; 17 (1-2): 25-31
  PubMedSearch in Google Scholar
• 14 Kadota RP, Emslander HC, Sawada Y, Fass DN, Katzmann JA, Bowie EJ. The capillary thrombometer and von Willebrand factor. Thromb Res 1987; 45 (03) 235-248
  PubMedSearch in Google Scholar
• 15 Uchiyama S, Stropp JQ, Claypool DA, Didisheim P. Filter bleeding time: a new in vitro test of hemostasis. II. Application to the study of von Willebrand disease and platelet function inhibitors. Thromb Res 1983; 31 (01) 117-125
  PubMedSearch in Google Scholar
• 16 Boda Z, Tornai I, Rak K. Studies of the platelet filter test (shear dependent platelet aggregation) in patients with uncommon haemorrhagic disorders. Blood Coagul Fibrinolysis 1996; 7 (02) 162-164
  PubMedSearch in Google Scholar
• 17 Cariappa R, Wilhite TR, Parvin CA, Luchtman-Jones L. Comparison of PFA-100 and bleeding time testing in pediatric patients with suspected hemorrhagic problems. J Pediatr Hematol Oncol 2003; 25 (06) 474-479
  PubMedSearch in Google Scholar
• 18 Cattaneo M, Federici AB, Lecchi A. et al. Evaluation of the PFA-100 system in the diagnosis and therapeutic monitoring of patients with von Willebrand disease. Thromb Haemost 1999; 82 (01) 35-39
  PubMedSearch in Google Scholar
• 19 Chen YC, Yang L, Cheng SN, Hu SH, Chao TY. von Willebrand disease: a clinical and laboratory study of sixty-five patients. Ann Hematol 2011; 90 (10) 1183-1190
  PubMedSearch in Google Scholar
• 20 Dargaud Y, Bordet JC, Trzeciak MC, Mazet M, Dechavanne M, Negrier C. Inherited bleeding disorder due to familial type 2 platelet cyclo-oxygenase deficiency. Thromb Res 2005; 116 (06) 483-489
  PubMedSearch in Google Scholar
• 21 Dean JA, Blanchette VS, Carcao MD. et al. von Willebrand disease in a pediatric-based population–comparison of type 1 diagnostic criteria and use of the PFA-100 and a von Willebrand factor/collagen-binding assay. Thromb Haemost 2000; 84 (03) 401-409
  PubMedSearch in Google Scholar
• 22 Franchini M, Gandini G, Manzato F, Lippi G. Evaluation of the PFA-100 system for monitoring desmopressin therapy in patients with type 1 von Willebrand's disease. Haematologica 2002; 87 (06) 670
  PubMedSearch in Google Scholar
• 23 Fressinaud E, Veyradier A, Sigaud M, Boyer-Neumann C, Le Boterff C, Meyer D. Therapeutic monitoring of von Willebrand disease: interest and limits of a platelet function analyser at high shear rates. Br J Haematol 1999; 106 (03) 777-783
  PubMedSearch in Google Scholar
• 24 Fressinaud E, Veyradier A, Truchaud F. et al. Screening for von Willebrand disease with a new analyzer using high shear stress: a study of 60 cases. Blood 1998; 91 (04) 1325-1331
  CrossrefPubMedSearch in Google Scholar
• 25 Harrison C, Khair K, Baxter B, Russell-Eggitt I, Hann I, Liesner R. Hermansky-Pudlak syndrome: infrequent bleeding and first report of Turkish and Pakistani kindreds. Arch Dis Child 2002; 86 (04) 297-301
  PubMedSearch in Google Scholar
• 26 Kerényi A, Schlammadinger A, Ajzner E. et al. Comparison of PFA-100 closure time and template bleeding time of patients with inherited disorders causing defective platelet function. Thromb Res 1999; 96 (06) 487-492
  PubMedSearch in Google Scholar
• 27 Mammen EF, Comp PC, Gosselin R. et al. PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 1998; 24 (02) 195-202
  PubMedSearch in Google Scholar
• 28 Nitu-Whalley IC, Lee CA, Brown SA, Riddell A, Hermans C. The role of the platelet function analyser (PFA-100) in the characterization of patients with von Willebrand's disease and its relationships with von Willebrand factor and the ABO blood group. Haemophilia 2003; 9 (03) 298-302
  PubMedSearch in Google Scholar
• 29 Penas N, Pérez-Rodríguez A, Torea JH. et al. von Willebrand disease R1374C: type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia). Am J Hematol 2005; 80 (03) 188-196
  PubMedSearch in Google Scholar
• 30 Philipp CS, Miller CH, Faiz A. et al. Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time. Haemophilia 2005; 11 (05) 497-503
  PubMedSearch in Google Scholar
• 31 Podda GM, Bucciarelli P, Lussana F, Lecchi A, Cattaneo M. Usefulness of PFA-100 testing in the diagnostic screening of patients with suspected abnormalities of hemostasis: comparison with the bleeding time. J Thromb Haemost 2007; 5 (12) 2393-2398
  PubMedSearch in Google Scholar
• 32 Posan E, McBane RD, Grill DE, Motsko CL, Nichols WL. Comparison of PFA-100 testing and bleeding time for detecting platelet hypofunction and von Willebrand disease in clinical practice. Thromb Haemost 2003; 90 (03) 483-490
  PubMedSearch in Google Scholar
• 33 Quiroga T, Goycoolea M, Muñoz B. et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004; 2 (06) 892-898
  PubMedSearch in Google Scholar
• 34 Rand ML, Carcao MD, Blanchette VS. Use of the PFA-100 in the assessment of primary, platelet-related hemostasis in a pediatric setting. Semin Thromb Hemost 1998; 24 (06) 523-529
  PubMedSearch in Google Scholar
• 35 Schlammadinger A, Kerenyi A, Muszbek L, Boda Z. Comparison of the O'Brien filter test and the PFA-100 platelet analyzer in the laboratory diagnosis of von Willebrand's disease. Thromb Haemost 2000; 84 (01) 88-92
  PubMedSearch in Google Scholar
• 36 Wuillemin WA, Gasser Ka, Zeerleder SS, Lämmle B. Evaluation of a platelet function analyser (PFA-100) in patients with a bleeding tendency. Swiss Med Wkly 2002; 132 (31-32): 443-448
  PubMedSearch in Google Scholar
• 37 Srichumpuang C, Sosothikul D. Comparison between bleeding time and PFA-200 to evaluate platelet function disorder in children. J Pediatr Hematol Oncol 2021; 43 (05) e748-e749
  PubMedSearch in Google Scholar
• 38 Brazilek RJ, Tovar-Lopez FJ, Wong AKT. et al. Application of a strain rate gradient microfluidic device to von Willebrand's disease screening. Lab Chip 2017; 17 (15) 2595-2608
  PubMedSearch in Google Scholar
• 39 Cheeseman JE, Mills SP, Hardisty RM. Platelet aggregometry on whole blood: the use of the ELT 8/ds blood cell counter in the investigation of bleeding disorders. Clin Lab Haematol 1984; 6 (03) 265-272
  PubMedSearch in Google Scholar
• 40 Kundu SK, Heilmann EJ, Sio R, Garcia C, Davidson RM, Ostgaard RA. Description of an in vitro platelet function analyzer–PFA-100. Semin Thromb Hemost 1995; 21 (Suppl. 02) 106-112
  PubMedSearch in Google Scholar
• 41 Kratzer MA, Born GV. Simulation of primary haemostasis in vitro. Haemostasis 1985; 15 (06) 357-362
  PubMedSearch in Google Scholar
• 42 Favaloro EJ, Pasalic L, Lippi G. Towards 50 years of platelet function analyser (PFA) testing. Clin Chem Lab Med 2022; 61 (05) 851-860
  PubMedSearch in Google Scholar
• 43 Favaloro EJ. Utility of the platelet function analyser (PFA-100/200) for exclusion or detection of von Willebrand disease: a study 22 years in the making. Thromb Res 2020; 188: 17-24
  PubMedSearch in Google Scholar
• 44 Abstracts from the 10th Erfurt Conference on Platelets. June 20-23, 2004. Erfurt, Germany. Platelets 2004; 15 (08) 479-517
  PubMedSearch in Google Scholar
• 45 Cardinal DC, Flower RJ. The 'electronic platelet aggregometer' [proceedings]. Br J Pharmacol 1979; 66 (01) 138P
  PubMedSearch in Google Scholar
• 46 Hartert H. [Blood clotting studies with thrombus stressography; a new investigation procedure]. Klin Wochenschr 1948; 26 (37-38): 577-583
  PubMedSearch in Google Scholar
• 47 Connelly CR, Yonge JD, McCully SP. et al. Assessment of three point-of-care platelet function assays in adult trauma patients. J Surg Res 2017; 212: 260-269
  PubMedSearch in Google Scholar
• 48 Agarwal S, Johnson RI, Shaw M. Preoperative point-of-care platelet function testing in cardiac surgery. J Cardiothorac Vasc Anesth 2015; 29 (02) 333-341
  PubMedSearch in Google Scholar
• 49 Li CK, Hoffmann TJ, Hsieh PY, Malik S, Watson WC. The xylum clot signature analyzer: a dynamic flow system that simulates vascular injury. Thromb Res 1998; 92 (6, Suppl 2): S67-S77
  PubMedSearch in Google Scholar
• 50 Muga KM, Melton LG, Gabriel DA. A flow dynamic technique used to assess global haemostasis. Blood Coagul Fibrinolysis 1995; 6 (01) 73-78
  PubMedSearch in Google Scholar
• 51 Harrison P, Robinson MS, Mackie IJ. et al. Performance of the platelet function analyser PFA-100 in testing abnormalities of primary haemostasis. Blood Coagul Fibrinolysis 1999; 10 (01) 25-31
  PubMedSearch in Google Scholar
• 52 Ardillon L, Ternisien C, Fouassier M. et al. Platelet function analyser (PFA-100) results and von Willebrand factor deficiency: a 16-year 'real-world' experience. Haemophilia 2015; 21 (05) 646-652
  PubMedSearch in Google Scholar
• 53 Carcao MD, Blanchette VS, Dean JA. et al. The platelet function analyzer (PFA-100): a novel in-vitro system for evaluation of primary haemostasis in children. Br J Haematol 1998; 101 (01) 70-73
  PubMedSearch in Google Scholar
• 54 Kumar R, Bouskill V, Schneiderman JE. et al. Impact of aerobic exercise on haemostatic indices in paediatric patients with haemophilia. Thromb Haemost 2016; 115 (06) 1120-1128
  PubMedSearch in Google Scholar
• 55 Perez Botero J, Pruthi RK, Majerus JA. et al. Practice patterns in the diagnosis of inherited platelet disorders within a single institution. Blood Coagul Fibrinolysis 2017; 28 (04) 303-308
  PubMedSearch in Google Scholar
• 56 Favaloro EJ, Facey D, Henniker A. Use of a novel platelet function analyzer (PFA-100) with high sensitivity to disturbances in von Willebrand factor to screen for von Willebrand's disease and other disorders. Am J Hematol 1999; 62 (03) 165-174
  PubMedSearch in Google Scholar
• 57 Buyukasik Y, Karakus S, Goker H. et al. Rational use of the PFA-100 device for screening of platelet function disorders and von Willebrand disease. Blood Coagul Fibrinolysis 2002; 13 (04) 349-353
  PubMedSearch in Google Scholar
• 58 Casonato A, Galletta E, Daidone V. The elusive and heterogeneous pattern of type 2M von Willebrand disease: a diagnostic challenge. Eur J Haematol 2018
  PubMedSearch in Google Scholar
• 59 Naik S, Teruya J, Dietrich JE, Jariwala P, Soundar E, Venkateswaran L. Utility of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia. Pediatr Blood Cancer 2013; 60 (07) 1184-1187
  PubMedSearch in Google Scholar
• 60 Harrison P, Robinson M, Liesner R. et al. The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction. Clin Lab Haematol 2002; 24 (04) 225-232
  PubMedSearch in Google Scholar
• 61 Nitu-Whalley IC, Lee CA, Hermans C. Reassessment of the correlation between the von Willebrand factor activity, the PFA-100, and the bleeding time in patients with von Willebrand disease. Thromb Haemost 2001; 86 (02) 715-716
  PubMedSearch in Google Scholar
• 62 Veyradier A, Gervaise A, Boyer-Neumann C, Wolf M, Fernandez H. Screening for bleeding disorders in women with menorrhagia using a platelet function analyzer. J Thromb Haemost 2006; 4 (02) 483-485
  PubMedSearch in Google Scholar
• 63 Gursel T, Biri A, Kaya Z, Sivaslıoglu S, Albayrak M. The frequency of menorrhagia and bleeding disorders in university students. Pediatr Hematol Oncol 2014; 31 (05) 467-474
  PubMedSearch in Google Scholar
• 64 Nummi V, Lassila R, Joutsi-Korhonen L, Armstrong E, Szanto T. Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function. Int J Lab Hematol 2018; 40 (03) 304-311
  PubMedSearch in Google Scholar
• 65 Haas T, Cushing MM, Varga S, Gilloz S, Schmugge M. Usefulness of multiple electrode aggregometry as a screening tool for bleeding disorders in a pediatric hospital. Platelets 2019; 30 (04) 498-505
  PubMedSearch in Google Scholar
• 66 Koessler J, Ehrenschwender M, Kobsar A, Brunner K. Evaluation of the new INNOVANCE® PFA P2Y cartridge in patients with impaired primary haemostasis. Platelets 2012; 23 (08) 571-578
  PubMedSearch in Google Scholar
• 67 Veyradier A, Fressinaud E, Boyer-Neumann C, Trossaert M, Meyer D. von Willebrand factor ristocetin cofactor activity correlates with platelet function in a high shear stress system. Thromb Haemost 2000; 84 (04) 727-728
  PubMedSearch in Google Scholar
• 68 Charpy J, Chaghouri PE, Benattar N. et al. Evaluation of the potential utility of the total thrombus-formation analysis system in comparison to the platelet function analyser in subjects with primary haemostatic defects. Br J Haematol 2020; 191 (01) e7-e10
  PubMedSearch in Google Scholar
• 69 Favaloro EJ. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study of 148 patients–a rebuttal. J Thromb Haemost 2004; 2 (12) 2280-2282 , author reply 2283–2285
  PubMedSearch in Google Scholar
• 70 Favaloro EJ, Patterson D, Denholm A. et al. Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis. Br J Haematol 2007; 139 (04) 623-626
  PubMedSearch in Google Scholar
• 71 Favaloro EJ, Lloyd J, Rowell J. et al. Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (high purity)] in people with von Willebrand disorder. A randomised cross-over, multi-centre study. Thromb Haemost 2007; 97 (06) 922-930
  PubMedSearch in Google Scholar
• 72 Akin M, Karapinar DY, Balkan C, Ay Y, Kavakli K. Resemblance to vWD types and laboratory diagnosis of obligatory carriers of type 3 von Willebrand disease. Clin Appl Thromb Hemost 2011; 17 (06) E21-E24
  PubMedSearch in Google Scholar
• 73 Perel JM, Just S, Rowell J, Williams B, Kennedy GA. Utility of the PFA-100 analyser in the evaluation of primary haemostasis in a paediatric population. Int J Lab Hematol 2007; 29 (06) 480-481
  PubMedSearch in Google Scholar
• 74 Bakr S, Almutairi AA, Dawalibi A, Owaidah M, Almughiyri AA, Owaidah T. Screening hemostatic defects in Saudi University students with unexplained menorrhagia: a diagnosis, which could be missed. Blood Coagul Fibrinolysis 2021; 32 (04) 278-284
  PubMedSearch in Google Scholar
• 75 Cakı Kılıç S, Sarper N, Zengin E, Aylan Gelen S. Screening bleeding disorders in adolescents and young women with menorrhagia. Turk J Haematol 2013; 30 (02) 168-176
  PubMedSearch in Google Scholar
• 76 Valarche V, Desconclois C, Boutekedjiret T, Dreyfus M, Proulle V. Multiplate whole blood impedance aggregometry: a new tool for von Willebrand disease. J Thromb Haemost 2011; 9 (08) 1645-1647
  PubMedSearch in Google Scholar
• 77 Sap F, Kavaklı T, Kavaklı K, Dizdarer C. The prevalence of von Willebrand disease and significance of in vitro bleeding time (PFA-100) in von Willebrand disease screening in the İzmir region. Turk J Haematol 2013; 30 (01) 40-47
  PubMedSearch in Google Scholar
• 78 Geevar T, Dave RG, Mathews NS. et al. Laboratory characterization of obligate carriers of type 3 von Willebrand disease with a potential role for platelet function analyzer (PFA-200). Int J Lab Hematol 2022; 44 (03) 603-609
  PubMedSearch in Google Scholar
• 79 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34 (08) 709-733
  PubMedSearch in Google Scholar
• 80 Favaloro EJ, Kershaw G, Bukuya M, Hertzberg M, Koutts J. Laboratory diagnosis of von Willebrand disorder (vWD) and monitoring of DDAVP therapy: efficacy of the PFA-100 and vWF:CBA as combined diagnostic strategies. Haemophilia 2001; 7 (02) 180-189
  PubMedSearch in Google Scholar
• 81 Akin M, Karapinar DY, Balkan C, Ay Y, Kavakli K. An evaluation of the DDAVP infusion test with PFA-100 and vWF activity assays to distinguish vWD types in children. Clin Appl Thromb Hemost 2011; 17 (05) 441-448
  PubMedSearch in Google Scholar
• 82 Karger R, Donner-Banzhoff N, Müller HH, Kretschmer V, Hunink M. Diagnostic performance of the platelet function analyzer (PFA-100) for the detection of disorders of primary haemostasis in patients with a bleeding history-a systematic review and meta-analysis. Platelets 2007; 18 (04) 249-260
  PubMedSearch in Google Scholar
• 83 Callaghan MU, Chitlur MB, Fleming P, Rajpurkar M, Lusher JM. Thromboelastogram platelet mapping accurately predicts bleeding phenotype in Glanzmann thrombasthenia. Blood 2008; 112 (11) 4560-4560
  PubMedSearch in Google Scholar
• 84 Moenen FCJI, Vries MJA, Nelemans PJ. et al. Screening for platelet function disorders with multiplate and platelet function analyzer. Platelets 2019; 30 (01) 81-87
  PubMedSearch in Google Scholar
• 85 Al-Battat S, Rand ML, Bouskill V. et al. Glanzmann thrombasthenia platelets compete with transfused platelets, reducing the haemostatic impact of platelet transfusions. Br J Haematol 2018; 181 (03) 410-413
  PubMedSearch in Google Scholar
• 86 Albanyan A, Al-Musa A, AlNounou R. et al. Diagnosis of Glanzmann thrombasthenia by whole blood impedance analyzer (MEA) vs. light transmission aggregometry. Int J Lab Hematol 2015; 37 (04) 503-508
  PubMedSearch in Google Scholar
• 87 Bragadottir G, Birgisdottir ER, Gudmundsdottir BR. et al. Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome–a case control study. Am J Hematol 2015; 90 (02) 149-155
  PubMedSearch in Google Scholar
• 88 Acharya S, Barraclough J, Ibrahim MS. et al. The usefulness of the platelet function analyser (PFA-100) in screening for underlying bleeding disorders in women with menorrhagia. J Obstet Gynaecol 2008; 28 (03) 310-314
  PubMedSearch in Google Scholar
• 89 Sladky JL, Klima J, Grooms L, Kerlin BA, O'Brien SH. The PFA-100 ® does not predict delta-granule platelet storage pool deficiencies. Haemophilia 2012; 18 (04) 626-629
  PubMedSearch in Google Scholar
• 90 Santos XM, Bercaw-Pratt JL, Yee DL, Dietrich JE. Recurrent menorrhagia in an adolescent with a platelet secretion defect. J Pediatr Adolesc Gynecol 2011; 24 (02) e35-e38
  PubMedSearch in Google Scholar
• 91 Rolf N, Knoefler R, Bugert P. et al. Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families. Br J Haematol 2009; 144 (03) 416-424
  PubMedSearch in Google Scholar
• 92 Knöfler R, Lohse J, Stächele J. et al. Significance of platelet function diagnostics for clarification of suspected battered child syndrome. Hamostaseologie 2014; 34 (Suppl. 01) S53-S56
  PubMedSearch in Google Scholar
• 93 Lasne D, Baujat G, Mirault T. et al. Bleeding disorders in Lowe syndrome patients: evidence for a link between OCRL mutations and primary haemostasis disorders. Br J Haematol 2010; 150 (06) 685-688
  PubMedSearch in Google Scholar
• 94 Scavone M, Germanovich K, Femia EA, Cattaneo M. Usefulness of the INNOVANCE PFA P2Y test cartridge for the detection of patients with congenital defects of the platelet P2Y₁₂ receptor for adenosine diphosphate. Thromb Res 2014; 133 (02) 254-256
  PubMedSearch in Google Scholar
• 95 Kaufmann J, Adler M, Alberio L, Nagler M. Utility of the platelet function analyzer in patients with suspected platelet function disorders: diagnostic accuracy study. TH Open 2020; 4 (04) e427-e436
  PubMedSearch in Google Scholar
• 96 Guay J, Faraoni D, Bonhomme F, Borel Derlon A, Lasne D. Ability of hemostatic assessment to detect bleeding disorders and to predict abnormal surgical blood loss in children: a systematic review and meta-analysis. Paediatr Anaesth 2015; 25 (12) 1216-1226
  PubMedSearch in Google Scholar
• 97 Roschitz B, Thaller S, Koestenberger M. et al. PFA-100 closure times in preoperative screening in 500 pediatric patients. Thromb Haemost 2007; 98 (01) 243-247
  PubMedSearch in Google Scholar
• 98 Koscielny J, von Tempelhoff GF, Ziemer S. et al. A practical concept for preoperative management of patients with impaired primary hemostasis. Clin Appl Thromb Hemost 2004; 10 (02) 155-166
  PubMedSearch in Google Scholar
• 99 van Vliet HH, Kappers-Klunne MC, Leebeek FW, Michiels JJ. PFA-100 monitoring of von Willebrand factor (VWF) responses to desmopressin (DDAVP) and factor VIII/VWF concentrate substitution in von Willebrand disease type 1 and 2. Thromb Haemost 2008; 100 (03) 462-468
  PubMedSearch in Google Scholar
• 100 Hanebutt FL, Rolf N, Loesel A, Kuhlisch E, Siegert G, Knoefler R. Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders. Haemophilia 2008; 14 (03) 524-530
  PubMedSearch in Google Scholar
• 101 Akin M. Response to low-dose desmopressin by a subcutaneous route in children with type 1 von Willebrand disease. Hematology 2013; 18 (02) 115-118
  PubMedSearch in Google Scholar
• 102 Favaloro EJ, Thom J, Patterson D. et al. Potential supplementary utility of combined PFA-100 and functional von Willebrand factor testing for the laboratory assessment of desmopressin and factor concentrate therapy in von Willebrand disease. Blood Coagul Fibrinolysis 2009; 20 (06) 475-483
  PubMedSearch in Google Scholar
• 103 Meskal A, Vertessen F, Van der Planken M, Berneman ZN. The platelet function analyzer (PFA-100) may not be suitable for monitoring the therapeutic efficiency of von Willebrand concentrate in type III von Willebrand disease. Ann Hematol 1999; 78 (09) 426-430
  PubMedSearch in Google Scholar
• 104 Pekrul I, Kragh T, Turecek PL, Novack AR, Ott HW, Spannagl M. Sensitive and specific assessment of recombinant von Willebrand factor in platelet function analyzer. Platelets 2019; 30 (02) 264-270
  PubMedSearch in Google Scholar
• 105 Trossaërt M, Flaujac C, Jeanpierre E. et al. Assessment of primary haemostasis with a new recombinant von Willebrand factor in patients with von Willebrand disease. Haemophilia 2020; 26 (02) e44-e48
  PubMedSearch in Google Scholar
• 106 Castaman G, Tosetto A, Goodeve A. et al. The impact of bleeding history, von Willebrand factor and PFA-100(®) on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM-1VWD. Br J Haematol 2010; 151 (03) 245-251
  PubMedSearch in Google Scholar
• 107 Ortel TL, James AH, Thames EH, Moore KD, Greenberg CS. Assessment of primary hemostasis by PFA-100 analysis in a tertiary care center. Thromb Haemost 2000; 84 (01) 93-97
  PubMedSearch in Google Scholar
• 108 Favaloro EJ, Zafer M, Nair SC, Hertzberg M, North K. Evaluation of primary haemostasis in people with neurofibromatosis type 1. Clin Lab Haematol 2004; 26 (05) 341-345
  PubMedSearch in Google Scholar
• 109 Tanous O, Steinberg Shemer O, Yacobovich J. et al. Evaluating platelet function disorders in children with bleeding tendency - a single center study. Platelets 2017; 28 (07) 676-681
  PubMedSearch in Google Scholar
• 110 Weston H, Just S, Williams B, Rowell J, Kennedy GA. PFA-100 testing for pretherapeutic assessment of response to DDAVP in patients with von Willebrand's disease. Haemophilia 2009; 15 (01) 372-373
  PubMedSearch in Google Scholar
• 111 Heubel-Moenen FCJI, Brouns SLN, Herfs L. et al. Multiparameter platelet function analysis of bleeding patients with a prolonged platelet function analyser closure time. Br J Haematol 2022; 196 (06) 1388-1400
  PubMedSearch in Google Scholar
• 112 Hayward CP, Harrison P, Cattaneo M, Ortel TL, Rao AK. Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006; 4 (02) 312-319
  PubMedSearch in Google Scholar
• 113 Favaloro EJ. Clinical utility of closure times using the platelet function analyzer-100/200. Am J Hematol 2017; 92 (04) 398-404
  PubMedSearch in Google Scholar
• 114 Ogiwara K, Nogami K, Hosokawa K, Ohnishi T, Matsumoto T, Shima M. Comprehensive evaluation of haemostatic function in von Willebrand disease patients using a microchip-based flow chamber system. Haemophilia 2015; 21 (01) 71-80
  PubMedSearch in Google Scholar
• 115 Daidone V, Barbon G, Cattini MG. et al. Usefulness of the total thrombus-formation analysis system (T-TAS) in the diagnosis and characterization of von Willebrand disease. Haemophilia 2016; 22 (06) 949-956
  PubMedSearch in Google Scholar
• 116 Nakajima Y, Yada K, Ogiwara K. et al. A microchip flow-chamber assay screens congenital primary hemostasis disorders. Pediatr Int 2021; 63 (02) 160-167
  PubMedSearch in Google Scholar
• 117 Nogami K, Ogiwara K, Yada K. et al. Assessing the clinical severity of type 1 von Willebrand disease patients with a microchip flow-chamber system. J Thromb Haemost 2016; 14 (04) 667-674
  PubMedSearch in Google Scholar
• 118 Nakajima Y, Nogami K, Yada K. et al. Evaluation of clinical severity in patients with type 2N von Willebrand disease using microchip-based flow-chamber system. Int J Hematol 2020; 111 (03) 369-377
  PubMedSearch in Google Scholar
• 119 Ågren A, Holmström M, Schmidt DE, Hosokawa K, Blombäck M, Hjemdahl P. Monitoring of coagulation factor therapy in patients with von Willebrand disease type 3 using a microchip flow chamber system. Thromb Haemost 2017; 117 (01) 75-85
  PubMedSearch in Google Scholar
• 120 Minami H, Nogami K, Ogiwara K, Furukawa S, Hosokawa K, Shima M. Use of a microchip flow-chamber system as a screening test for platelet storage pool disease. Int J Hematol 2015; 102 (02) 157-162
  PubMedSearch in Google Scholar
• 121 Lecchi A, La Marca S, Padovan L, Boscarino M, Peyvandi F, Tripodi A. Flow-chamber device (T-TAS) to diagnose patients suspected of platelet function defects. Blood Transfus 2023
  PubMedSearch in Google Scholar
• 122 Al Ghaithi R, Mori J, Nagy Z. et al. Evaluation of the total thrombus-formation system (T-TAS): application to human and mouse blood analysis. Platelets 2019; 30 (07) 893-900
  PubMedSearch in Google Scholar
• 123 Nakajima Y, Nogami K, Yada K. et al. Whole blood ristocetin-induced platelet impedance aggregometry does not reflect clinical severity in patients with type 1 von Willebrand disease. Haemophilia 2019; 25 (03) e174-e179
  PubMedSearch in Google Scholar
• 124 Schmidt DE, Bruzelius M, Majeed A, Odeberg J, Holmström M, Ågren A. Whole blood ristocetin-activated platelet impedance aggregometry (Multiplate) for the rapid detection of Von Willebrand disease. Thromb Haemost 2017; 117 (08) 1528-1533
  PubMedSearch in Google Scholar
• 125 Awidi A, Maqablah A, Dweik M, Bsoul N, Abu-Khader A. Comparison of platelet aggregation using light transmission and multiple electrode aggregometry in Glanzmann thrombasthenia. Platelets 2009; 20 (05) 297-301
  PubMedSearch in Google Scholar
• 126 Castellino FJ, Liang Z, Davis PK. et al. Abnormal whole blood thrombi in humans with inherited platelet receptor defects. PLoS One 2012; 7 (12) e52878
  PubMedSearch in Google Scholar
• 127 Al Ghaithi R, Drake S, Watson SP, Morgan NV, Harrison P. Comparison of multiple electrode aggregometry with lumi-aggregometry for the diagnosis of patients with mild bleeding disorders. J Thromb Haemost 2017; 15 (10) 2045-2052
  PubMedSearch in Google Scholar
• 128 Lansdon LA, Chen D, Rush ET. et al. A novel likely pathogenic variant in a patient with Hermansky-Pudlak syndrome. Cold Spring Harb Mol Case Stud 2021; 7 (05) a006110
  PubMedSearch in Google Scholar
• 129 Akay OM, Mutlu F, Gulbas Z. Platelet dysfunction and other hemostatic disorders in women with menorrhagia: the utility of whole blood lumi-aggregometer. Intern Emerg Med 2008; 3 (02) 191-193
  PubMedSearch in Google Scholar
• 130 Mills HL, Abdel-Baki MS, Teruya J. et al. Platelet function defects in adolescents with heavy menstrual bleeding. Haemophilia 2014; 20 (02) 249-254
  PubMedSearch in Google Scholar
• 131 Takeyama M, Kasuda S, Sakurai Y. et al. Factor VIII-mediated global hemostasis in the absence of von Willebrand factor. Int J Hematol 2007; 85 (05) 397-402
  PubMedSearch in Google Scholar
• 132 Schmidt DE, Majeed A, Bruzelius M, Odeberg J, Holmström M, Ågren A. A prospective diagnostic accuracy study evaluating rotational thromboelastometry and thromboelastography in 100 patients with von Willebrand disease. Haemophilia 2017; 23 (02) 309-318
  PubMedSearch in Google Scholar
• 133 Regling K, Kakulavarapu S, Thomas R, Hollon W, Chitlur MB. Utility of thromboelastography for the diagnosis of von Willebrand disease. Pediatr Blood Cancer 2019; 66 (07) e27714
  PubMedSearch in Google Scholar
• 134 Szanto T, Nummi V, Jouppila A, Brinkman HJM, Lassila R. Platelets compensate for poor thrombin generation in type 3 von Willebrand disease. Platelets 2020; 31 (01) 103-111
  PubMedSearch in Google Scholar
• 135 Wieland Greguare-Sander A, Wuillemin WA, Nagler M. Thromboelastometry as a diagnostic tool in mild bleeding disorders: a prospective cohort study. Eur J Anaesthesiol 2019; 36 (06) 457-465
  PubMedSearch in Google Scholar
• 136 Tuman KJ, Spiess BD, Schoen RE, Ivankovich AD. Use of thromboelastography in the management of von Willebrand's disease during cardiopulmonary bypass. J Cardiothorac Anesth 1987; 1 (04) 321-324
  PubMedSearch in Google Scholar
• 137 Topal A, Kılıçaslan A, Erol A, Çankaya B, Otelcioğlu Ş. Anaesthetic management with thromboelastography in a patient with Glanzmann thrombasthenia. Turk J Anaesthesiol Reanim 2014; 42 (04) 227-229
  PubMedSearch in Google Scholar
• 138 Simha PP, Mohan Rao PS, Arakalgud D, Rajashekharappa R, Narasimhaih M. Perioperative management of a patient with Glanzmann's thrombasthenia for mitral valve repair under cardiopulmonary bypass. Ann Card Anaesth 2017; 20 (04) 468-471
  PubMedSearch in Google Scholar
• 139 Pivalizza EG. Heparinase and thromboelastography in liver transplantation for a patient with von Willebrand's disease. Anesthesiology 1996; 84 (05) 1236-1239
  PubMedSearch in Google Scholar
• 140 Pivalizza EG. Perioperative use of the thrombelastograph in patients with inherited bleeding disorders. J Clin Anesth 2003; 15 (05) 366-370
  PubMedSearch in Google Scholar
• 141 Al Midani A, Donohue C, Berry P, Jones G, Fernando B. Use of thromboelastography to guide platelet infusion in a patient with Wiskott-Aldrich syndrome undergoing renal transplant. Exp Clin Transplant 2020; 18 (05) 636-637
  PubMedSearch in Google Scholar
• 142 Favro M, Terrone C, Neira D. et al. Major surgery (radical cystectomy with urethrectomy) in a patient with von Willebrand's disease type I. Reliability and limits of hemocoagulative tests. Minerva Urol Nefrol 1998; 50 (04) 247-251
  PubMedSearch in Google Scholar
• 143 Grassetto A, Fullin G, Lazzari F. et al. Perioperative ROTEM and ROTEMplatelet monitoring in a case of Glanzmann's thrombasthenia. Blood Coagul Fibrinolysis 2017; 28 (01) 96-99
  PubMedSearch in Google Scholar
• 144 Guzman-Reyes S, Osborne C, Pivalizza EG. Thrombelastography for perioperative monitoring in patients with von Willebrand disease. J Clin Anesth 2012; 24 (02) 166-167
  PubMedSearch in Google Scholar
• 145 Boyd EZ, Riha K, Escobar MA, Pivalizza EG. Thrombelastograph platelet mapping in a patient with von Willebrand disease who was treated with Humate-P. J Clin Anesth 2011; 23 (07) 600
  PubMedSearch in Google Scholar
• 146 Campbell J, Yentis S. The use of thromboelastography for the peripartum management of a patient with platelet storage pool disorder. Int J Obstet Anesth 2011; 20 (04) 360 , author reply 361
  PubMedSearch in Google Scholar
• 147 Clements A, Jindal S, Morris C, Srivastava G, Ikomi A, Mulholland J. Expanding perfusion across disciplines: the use of thrombelastography technology to reduce risk in an obstetrics patient with gray platelet syndrome–a case study. Perfusion 2011; 26 (03) 181-184
  PubMedSearch in Google Scholar
• 148 Hale J, Galanti G, Langer A, Lassey S, Reiff E, Camann W. A case report of rotational thromboelastometry-assisted decision analysis for two pregnant patients with platelet storage pool disorder. A A Pract 2023; 17 (02) e01658
  PubMedSearch in Google Scholar
• 149 Monte S, Lyons G. Peripartum management of a patient with Glanzmann's thrombasthenia using thrombelastograph. Br J Anaesth 2002; 88 (05) 734-738
  PubMedSearch in Google Scholar
• 150 Palsson R, Vidarsson B, Gudmundsdottir BR. et al. Complementary effect of fibrinogen and rFVIIa on clotting ex vivo in Bernard-Soulier syndrome and combined use during three deliveries. Platelets 2014; 25 (05) 357-362
  PubMedSearch in Google Scholar
• 151 Rajpal G, Pomerantz JM, Ragni MV, Waters JH, Vallejo MC. The use of thromboelastography for the peripartum management of a patient with platelet storage pool disorder. Int J Obstet Anesth 2011; 20 (02) 173-177
  PubMedSearch in Google Scholar
• 152 Snow TA, Abdul-Kadir RA, Gomez K, England A. Platelet storage pool disorder in pregnancy: utilising thromboelastography to guide a risk-based delivery plan. Obstet Med 2022; 15 (02) 133-135
  PubMedSearch in Google Scholar
• 153 Zia AN, Chitlur M, Rajpurkar M. et al. Thromboelastography identifies children with rare bleeding disorders and predicts bleeding phenotype. Haemophilia 2015; 21 (01) 124-132
  PubMedSearch in Google Scholar
• 154 Shenkman B, Livnat T, Misgav M, Budnik I, Einav Y, Martinowitz U. The in vivo effect of fibrinogen and factor XIII on clot formation and fibrinolysis in Glanzmann's thrombasthenia. Platelets 2012; 23 (08) 604-610
  PubMedSearch in Google Scholar
• 155 Budnik I, Shenkman B, Morozova O, Andreichyn J, Einav Y. Correction of coagulopathy in thrombocytopenia and Glanzmann thrombasthenia models by fibrinogen and factor XIII as assessed by thromboelastometry. Pathophysiology 2018; 25 (04) 347-351
  PubMedSearch in Google Scholar
• 156 Ahammad J, Kamath A, Shastry S, Chitlur M, Kurien A. Clinico-hematological and thromboelastographic profiles in Glanzmann's thrombasthenia. Blood Coagul Fibrinolysis 2020; 31 (01) 29-34
  PubMedSearch in Google Scholar
• 157 Barg AA, Hauschner H, Misgav M. et al. A novel approach using ancillary tests to guide treatment of Glanzmann thrombasthenia patients undergoing surgical procedures. Blood Cells Mol Dis 2018; 72: 44-48
  PubMedSearch in Google Scholar
• 158 Male C, Koren D, Eichelberger B, Kaufmann K, Panzer S. Monitoring survival and function of transfused platelets in Glanzmann thrombasthenia by flow cytometry and thrombelastography. Vox Sang 2006; 91 (02) 174-177
  PubMedSearch in Google Scholar
• 159 Lak M, Scharling B, Blemings A. et al. Evaluation of rFVIIa (NovoSeven) in Glanzmann patients with thromboelastogram. Haemophilia 2008; 14 (01) 103-110
  PubMedSearch in Google Scholar
• 160 Horne III MK, Williams SB, Gahl WA, Rick ME. Evaluation of the xylum clot signature analyzer in normal subjects and patients with the Hermansky-Pudlak syndrome. Thromb Res 2001; 104 (01) 57-63
  PubMedSearch in Google Scholar
• 161 Fricke W, Kouides P, Kessler C. et al. A multicenter clinical evaluation of the clot signature analyzer. J Thromb Haemost 2004; 2 (05) 763-768
  PubMedSearch in Google Scholar
• 162 Varon D, Lashevski I, Brenner B. et al. Cone and plate(let) analyzer: monitoring glycoprotein IIb/IIIa antagonists and von Willebrand disease replacement therapy by testing platelet deposition under flow conditions. Am Heart J 1998; 135 (5 Pt 2 Su): S187-S193
  PubMedSearch in Google Scholar
• 163 Shenkman B, Savion N, Dardik R, Tamarin I, Varon D. Testing of platelet deposition on polystyrene surface under flow conditions by the cone and plate(let) analyzer: role of platelet activation, fibrinogen and von Willebrand factor. Thromb Res 2000; 99 (04) 353-361
  PubMedSearch in Google Scholar
• 164 Revel-Vilk S, Varon D, Shai E. et al. Evaluation of children with a suspected bleeding disorder applying the Impact-R [Cone and Plate(let) analyzer]. J Thromb Haemost 2009; 7 (12) 1990-1996
  PubMedSearch in Google Scholar
• 165 Shenkman B, Einav Y, Salomon O, Varon D, Savion N. Testing agonist-induced platelet aggregation by the Impact-R [Cone and plate(let) analyzer (CPA)]. Platelets 2008; 19 (06) 440-446
  PubMedSearch in Google Scholar
• 166 Lehmann M, Ashworth K, Manco-Johnson M, Di Paola J, Neeves KB, Ng CJ. Evaluation of a microfluidic flow assay to screen for von Willebrand disease and low von Willebrand factor levels. J Thromb Haemost 2018; 16 (01) 104-115
  PubMedSearch in Google Scholar
• 167 Neeves KB, Onasoga AA, Hansen RR. et al. Sources of variability in platelet accumulation on type 1 fibrillar collagen in microfluidic flow assays. PLoS One 2013; 8 (01) e54680
  CrossrefPubMedSearch in Google Scholar
• 168 Grabowski EF, Curran MA, Van Cott EM. Assessment of a cohort of primarily pediatric patients with a presumptive diagnosis of type 1 von Willebrand disease with a novel high shear rate, non-citrated blood flow device. Thromb Res 2012; 129 (04) e18-e24
  PubMedSearch in Google Scholar
• 169 Grabowski EF, Van Cott EM, Bornikova L, Boyle DC, Silva RL. Differentiation of patients with symptomatic low von Willebrand factor from those with asymptomatic low von Willebrand factor. Thromb Haemost 2020; 120 (05) 793-804
  PubMedSearch in Google Scholar
• 170 Chen Z, Lu J, Zhang C. et al. Microclot array elastometry for integrated measurement of thrombus formation and clot biomechanics under fluid shear. Nat Commun 2019; 10 (01) 2051
  PubMedSearch in Google Scholar
• 171 Zwaginga JJ, Nash G, King MR. et al; Biorheology Subcommittee of the SSC of the ISTH. Flow-based assays for global assessment of hemostasis. Part 1: biorheologic considerations. J Thromb Haemost 2006; 4 (11) 2486-2487
  PubMedSearch in Google Scholar
• 172 Kazmi RS, Boyce S, Lwaleed BA. Homeostasis of hemostasis: the role of endothelium. Semin Thromb Hemost 2015; 41 (06) 549-555
  PubMedSearch in Google Scholar
• 173 Schneider SW, Nuschele S, Wixforth A. et al. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci U S A 2007; 104 (19) 7899-7903
  PubMedSearch in Google Scholar
• 174 Yakusheva AA, Butov KR, Bykov GA. et al. Traumatic vessel injuries initiating hemostasis generate high shear conditions. Blood Adv 2022; 6 (16) 4834-4846
  PubMedSearch in Google Scholar
• 175 Kalb ML, Potura L, Scharbert G, Kozek-Langenecker SA. The effect of ex vivo anticoagulants on whole blood platelet aggregation. Platelets 2009; 20 (01) 7-11
  PubMedSearch in Google Scholar
• 176 Truss NJ, Armstrong PC, Liverani E, Vojnovic I, Warner TD. Heparin but not citrate anticoagulation of blood preserves platelet function for prolonged periods. J Thromb Haemost 2009; 7 (11) 1897-1905
  PubMedSearch in Google Scholar
• 177 Germanovich K, Femia EA, Cheng CY, Dovlatova N, Cattaneo M. Effects of pH and concentration of sodium citrate anticoagulant on platelet aggregation measured by light transmission aggregometry induced by adenosine diphosphate. Platelets 2018; 29 (01) 21-26
  PubMedSearch in Google Scholar
• 178 Schneider DJ, Tracy PB, Mann KG, Sobel BE. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997; 96 (09) 2877-2883
  PubMedSearch in Google Scholar
• 179 Packham MA, Bryant NL, Guccione MA, Kinlough-Rathbone RL, Mustard JF. Effect of the concentration of Ca2+ in the suspending medium on the responses of human and rabbit platelets to aggregating agents. Thromb Haemost 1989; 62 (03) 968-976
  PubMedSearch in Google Scholar
• 180 Jones S, Evans RJ, Mahaut-Smith MP. Extracellular Ca(2+) modulates ADP-evoked aggregation through altered agonist degradation: implications for conditions used to study P2Y receptor activation. Br J Haematol 2011; 153 (01) 83-91
  PubMedSearch in Google Scholar
• 181 Mani H, Hellis M, Lindhoff-Last E. Platelet function testing in hirudin and BAPA anticoagulated blood. Clin Chem Lab Med 2011; 49 (03) 501-507
  PubMedSearch in Google Scholar
• 182 Chapman K, Favaloro EJ. Time dependent reduction in platelet aggregation using the multiplate analyser and hirudin blood due to platelet clumping. Platelets 2018; 29 (03) 305-308
  PubMedSearch in Google Scholar
• 183 Hellstern P, Stürzebecher U, Wuchold B. et al. Preservation of in vitro function of platelets stored in the presence of a synthetic dual inhibitor of factor Xa and thrombin. J Thromb Haemost 2007; 5 (10) 2119-2126
  PubMedSearch in Google Scholar
• 184 James PD, Connell NT, Ameer B. et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021; 5 (01) 280-300
  PubMedSearch in Google Scholar
• 185 Jigar Panchal H, Kent NJ, Knox AJS, Harris LF. Microfluidics in haemostasis: a review. Molecules 2020; 25 (04) 833
  PubMedSearch in Google Scholar
• 186 Mohammadi Aria M, Erten A, Yalcin O. Technology advancements in blood coagulation measurements for point-of-care diagnostic testing. Front Bioeng Biotechnol 2019; 7: 395
  PubMedSearch in Google Scholar
• 187 Kim CJ, Kim J, Sabaté Del Río J, Ki DY, Kim J, Cho YK. Fully automated light transmission aggregometry on a disc for platelet function tests. Lab Chip 2021; 21 (23) 4707-4715
  PubMedSearch in Google Scholar
• 188 Sakurai Y, Hardy ET, Lam WA. Hemostasis-on-a-chip / incorporating the endothelium in microfluidic models of bleeding. Platelets 2023; 34 (01) 2185453
  PubMedSearch in Google Scholar
• 189 Liang HP, Morel-Kopp MC, Curtin J. et al. Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients. Thromb Haemost 2007; 98 (06) 1298-1308
  PubMedSearch in Google Scholar

Address for correspondence

Publication History

Article published online:
01 July 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

• References

• 1 Bowman M, Hopman WM, Rapson D, Lillicrap D, James P. The prevalence of symptomatic von Willebrand disease in primary care practice. J Thromb Haemost 2010; 8 (01) 213-216
  PubMedSearch in Google Scholar
• 2 Oved JH, Lambert MP, Kowalska MA, Poncz M, Karczewski KJ. Population based frequency of naturally occurring loss-of-function variants in genes associated with platelet disorders. J Thromb Haemost 2021; 19 (01) 248-254
  PubMedSearch in Google Scholar
• 3 Gresele P, Harrison P, Bury L. et al. Diagnosis of suspected inherited platelet function disorders: results of a worldwide survey. J Thromb Haemost 2014; 12 (09) 1562-1569
  PubMedSearch in Google Scholar
• 4 Pilsczek FH, Rifkin WD, Walerstein S. Overuse of prothrombin and partial thromboplastin coagulation tests in medical inpatients. Heart Lung 2005; 34 (06) 402-405
  PubMedSearch in Google Scholar
• 5 Noris P, Schlegel N, Klersy C. et al; European Hematology Association – Scientific Working Group on Thrombocytopenias and Platelet Function Disorders. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Haematologica 2014; 99 (08) 1387-1394
  PubMedSearch in Google Scholar
• 6 Hagembe J, Baumann A, Haffar A, Pierce GF, Toulon P. Development of a target product profile (TTP) for haemophilia point-of-care (POC) diagnostic devices for low-resource countries and remote settings. Haemophilia 2023; 29 (02) 671-673
  PubMedSearch in Google Scholar
• 7 Woźniak MJ, Abbasciano R, Monaghan A. et al. Systematic review and meta-analysis of diagnostic test accuracy studies evaluating point-of-care tests of coagulopathy in cardiac surgery. Transfus Med Rev 2021; 35 (01) 7-15
  PubMedSearch in Google Scholar
• 8 Collins P. Point-of-care coagulation testing for postpartum haemorrhage. Best Pract Res Clin Anaesthesiol 2022; 36 (3-4): 383-398
  PubMedSearch in Google Scholar
• 9 Caspers M, Holle JF, Limper U, Fröhlich M, Bouillon B. Global coagulation testing in acute care medicine: back to bedside?. Hamostaseologie 2022; 42 (06) 400-408
  Thieme ConnectPubMedSearch in Google Scholar
• 10 Barcellona D, Fenu L, Marongiu F. Point-of-care testing INR: an overview. Clin Chem Lab Med 2017; 55 (06) 800-805
  PubMedSearch in Google Scholar
• 11 Owen CA. A History of Blood Coagulation. Mayo Foundation for Medical;; 2001
  Search in Google Scholar
• 12 Rodgers RP, Levin J. A critical reappraisal of the bleeding time. Semin Thromb Hemost 1990; 16 (01) 1-20
  PubMedSearch in Google Scholar
• 13 Kadota RP, Bowie EJ, Emslander HC, Fass DN, Ilstrup DM. The capillary thrombometer revisited. Haemostasis 1987; 17 (1-2): 25-31
  PubMedSearch in Google Scholar
• 14 Kadota RP, Emslander HC, Sawada Y, Fass DN, Katzmann JA, Bowie EJ. The capillary thrombometer and von Willebrand factor. Thromb Res 1987; 45 (03) 235-248
  PubMedSearch in Google Scholar
• 15 Uchiyama S, Stropp JQ, Claypool DA, Didisheim P. Filter bleeding time: a new in vitro test of hemostasis. II. Application to the study of von Willebrand disease and platelet function inhibitors. Thromb Res 1983; 31 (01) 117-125
  PubMedSearch in Google Scholar
• 16 Boda Z, Tornai I, Rak K. Studies of the platelet filter test (shear dependent platelet aggregation) in patients with uncommon haemorrhagic disorders. Blood Coagul Fibrinolysis 1996; 7 (02) 162-164
  PubMedSearch in Google Scholar
• 17 Cariappa R, Wilhite TR, Parvin CA, Luchtman-Jones L. Comparison of PFA-100 and bleeding time testing in pediatric patients with suspected hemorrhagic problems. J Pediatr Hematol Oncol 2003; 25 (06) 474-479
  PubMedSearch in Google Scholar
• 18 Cattaneo M, Federici AB, Lecchi A. et al. Evaluation of the PFA-100 system in the diagnosis and therapeutic monitoring of patients with von Willebrand disease. Thromb Haemost 1999; 82 (01) 35-39
  PubMedSearch in Google Scholar
• 19 Chen YC, Yang L, Cheng SN, Hu SH, Chao TY. von Willebrand disease: a clinical and laboratory study of sixty-five patients. Ann Hematol 2011; 90 (10) 1183-1190
  PubMedSearch in Google Scholar
• 20 Dargaud Y, Bordet JC, Trzeciak MC, Mazet M, Dechavanne M, Negrier C. Inherited bleeding disorder due to familial type 2 platelet cyclo-oxygenase deficiency. Thromb Res 2005; 116 (06) 483-489
  PubMedSearch in Google Scholar
• 21 Dean JA, Blanchette VS, Carcao MD. et al. von Willebrand disease in a pediatric-based population–comparison of type 1 diagnostic criteria and use of the PFA-100 and a von Willebrand factor/collagen-binding assay. Thromb Haemost 2000; 84 (03) 401-409
  PubMedSearch in Google Scholar
• 22 Franchini M, Gandini G, Manzato F, Lippi G. Evaluation of the PFA-100 system for monitoring desmopressin therapy in patients with type 1 von Willebrand's disease. Haematologica 2002; 87 (06) 670
  PubMedSearch in Google Scholar
• 23 Fressinaud E, Veyradier A, Sigaud M, Boyer-Neumann C, Le Boterff C, Meyer D. Therapeutic monitoring of von Willebrand disease: interest and limits of a platelet function analyser at high shear rates. Br J Haematol 1999; 106 (03) 777-783
  PubMedSearch in Google Scholar
• 24 Fressinaud E, Veyradier A, Truchaud F. et al. Screening for von Willebrand disease with a new analyzer using high shear stress: a study of 60 cases. Blood 1998; 91 (04) 1325-1331
  CrossrefPubMedSearch in Google Scholar
• 25 Harrison C, Khair K, Baxter B, Russell-Eggitt I, Hann I, Liesner R. Hermansky-Pudlak syndrome: infrequent bleeding and first report of Turkish and Pakistani kindreds. Arch Dis Child 2002; 86 (04) 297-301
  PubMedSearch in Google Scholar
• 26 Kerényi A, Schlammadinger A, Ajzner E. et al. Comparison of PFA-100 closure time and template bleeding time of patients with inherited disorders causing defective platelet function. Thromb Res 1999; 96 (06) 487-492
  PubMedSearch in Google Scholar
• 27 Mammen EF, Comp PC, Gosselin R. et al. PFA-100 system: a new method for assessment of platelet dysfunction. Semin Thromb Hemost 1998; 24 (02) 195-202
  PubMedSearch in Google Scholar
• 28 Nitu-Whalley IC, Lee CA, Brown SA, Riddell A, Hermans C. The role of the platelet function analyser (PFA-100) in the characterization of patients with von Willebrand's disease and its relationships with von Willebrand factor and the ABO blood group. Haemophilia 2003; 9 (03) 298-302
  PubMedSearch in Google Scholar
• 29 Penas N, Pérez-Rodríguez A, Torea JH. et al. von Willebrand disease R1374C: type 2A or 2M? A challenge to the revised classification. High frequency in the northwest of Spain (Galicia). Am J Hematol 2005; 80 (03) 188-196
  PubMedSearch in Google Scholar
• 30 Philipp CS, Miller CH, Faiz A. et al. Screening women with menorrhagia for underlying bleeding disorders: the utility of the platelet function analyser and bleeding time. Haemophilia 2005; 11 (05) 497-503
  PubMedSearch in Google Scholar
• 31 Podda GM, Bucciarelli P, Lussana F, Lecchi A, Cattaneo M. Usefulness of PFA-100 testing in the diagnostic screening of patients with suspected abnormalities of hemostasis: comparison with the bleeding time. J Thromb Haemost 2007; 5 (12) 2393-2398
  PubMedSearch in Google Scholar
• 32 Posan E, McBane RD, Grill DE, Motsko CL, Nichols WL. Comparison of PFA-100 testing and bleeding time for detecting platelet hypofunction and von Willebrand disease in clinical practice. Thromb Haemost 2003; 90 (03) 483-490
  PubMedSearch in Google Scholar
• 33 Quiroga T, Goycoolea M, Muñoz B. et al. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study in 148 patients. J Thromb Haemost 2004; 2 (06) 892-898
  PubMedSearch in Google Scholar
• 34 Rand ML, Carcao MD, Blanchette VS. Use of the PFA-100 in the assessment of primary, platelet-related hemostasis in a pediatric setting. Semin Thromb Hemost 1998; 24 (06) 523-529
  PubMedSearch in Google Scholar
• 35 Schlammadinger A, Kerenyi A, Muszbek L, Boda Z. Comparison of the O'Brien filter test and the PFA-100 platelet analyzer in the laboratory diagnosis of von Willebrand's disease. Thromb Haemost 2000; 84 (01) 88-92
  PubMedSearch in Google Scholar
• 36 Wuillemin WA, Gasser Ka, Zeerleder SS, Lämmle B. Evaluation of a platelet function analyser (PFA-100) in patients with a bleeding tendency. Swiss Med Wkly 2002; 132 (31-32): 443-448
  PubMedSearch in Google Scholar
• 37 Srichumpuang C, Sosothikul D. Comparison between bleeding time and PFA-200 to evaluate platelet function disorder in children. J Pediatr Hematol Oncol 2021; 43 (05) e748-e749
  PubMedSearch in Google Scholar
• 38 Brazilek RJ, Tovar-Lopez FJ, Wong AKT. et al. Application of a strain rate gradient microfluidic device to von Willebrand's disease screening. Lab Chip 2017; 17 (15) 2595-2608
  PubMedSearch in Google Scholar
• 39 Cheeseman JE, Mills SP, Hardisty RM. Platelet aggregometry on whole blood: the use of the ELT 8/ds blood cell counter in the investigation of bleeding disorders. Clin Lab Haematol 1984; 6 (03) 265-272
  PubMedSearch in Google Scholar
• 40 Kundu SK, Heilmann EJ, Sio R, Garcia C, Davidson RM, Ostgaard RA. Description of an in vitro platelet function analyzer–PFA-100. Semin Thromb Hemost 1995; 21 (Suppl. 02) 106-112
  PubMedSearch in Google Scholar
• 41 Kratzer MA, Born GV. Simulation of primary haemostasis in vitro. Haemostasis 1985; 15 (06) 357-362
  PubMedSearch in Google Scholar
• 42 Favaloro EJ, Pasalic L, Lippi G. Towards 50 years of platelet function analyser (PFA) testing. Clin Chem Lab Med 2022; 61 (05) 851-860
  PubMedSearch in Google Scholar
• 43 Favaloro EJ. Utility of the platelet function analyser (PFA-100/200) for exclusion or detection of von Willebrand disease: a study 22 years in the making. Thromb Res 2020; 188: 17-24
  PubMedSearch in Google Scholar
• 44 Abstracts from the 10th Erfurt Conference on Platelets. June 20-23, 2004. Erfurt, Germany. Platelets 2004; 15 (08) 479-517
  PubMedSearch in Google Scholar
• 45 Cardinal DC, Flower RJ. The 'electronic platelet aggregometer' [proceedings]. Br J Pharmacol 1979; 66 (01) 138P
  PubMedSearch in Google Scholar
• 46 Hartert H. [Blood clotting studies with thrombus stressography; a new investigation procedure]. Klin Wochenschr 1948; 26 (37-38): 577-583
  PubMedSearch in Google Scholar
• 47 Connelly CR, Yonge JD, McCully SP. et al. Assessment of three point-of-care platelet function assays in adult trauma patients. J Surg Res 2017; 212: 260-269
  PubMedSearch in Google Scholar
• 48 Agarwal S, Johnson RI, Shaw M. Preoperative point-of-care platelet function testing in cardiac surgery. J Cardiothorac Vasc Anesth 2015; 29 (02) 333-341
  PubMedSearch in Google Scholar
• 49 Li CK, Hoffmann TJ, Hsieh PY, Malik S, Watson WC. The xylum clot signature analyzer: a dynamic flow system that simulates vascular injury. Thromb Res 1998; 92 (6, Suppl 2): S67-S77
  PubMedSearch in Google Scholar
• 50 Muga KM, Melton LG, Gabriel DA. A flow dynamic technique used to assess global haemostasis. Blood Coagul Fibrinolysis 1995; 6 (01) 73-78
  PubMedSearch in Google Scholar
• 51 Harrison P, Robinson MS, Mackie IJ. et al. Performance of the platelet function analyser PFA-100 in testing abnormalities of primary haemostasis. Blood Coagul Fibrinolysis 1999; 10 (01) 25-31
  PubMedSearch in Google Scholar
• 52 Ardillon L, Ternisien C, Fouassier M. et al. Platelet function analyser (PFA-100) results and von Willebrand factor deficiency: a 16-year 'real-world' experience. Haemophilia 2015; 21 (05) 646-652
  PubMedSearch in Google Scholar
• 53 Carcao MD, Blanchette VS, Dean JA. et al. The platelet function analyzer (PFA-100): a novel in-vitro system for evaluation of primary haemostasis in children. Br J Haematol 1998; 101 (01) 70-73
  PubMedSearch in Google Scholar
• 54 Kumar R, Bouskill V, Schneiderman JE. et al. Impact of aerobic exercise on haemostatic indices in paediatric patients with haemophilia. Thromb Haemost 2016; 115 (06) 1120-1128
  PubMedSearch in Google Scholar
• 55 Perez Botero J, Pruthi RK, Majerus JA. et al. Practice patterns in the diagnosis of inherited platelet disorders within a single institution. Blood Coagul Fibrinolysis 2017; 28 (04) 303-308
  PubMedSearch in Google Scholar
• 56 Favaloro EJ, Facey D, Henniker A. Use of a novel platelet function analyzer (PFA-100) with high sensitivity to disturbances in von Willebrand factor to screen for von Willebrand's disease and other disorders. Am J Hematol 1999; 62 (03) 165-174
  PubMedSearch in Google Scholar
• 57 Buyukasik Y, Karakus S, Goker H. et al. Rational use of the PFA-100 device for screening of platelet function disorders and von Willebrand disease. Blood Coagul Fibrinolysis 2002; 13 (04) 349-353
  PubMedSearch in Google Scholar
• 58 Casonato A, Galletta E, Daidone V. The elusive and heterogeneous pattern of type 2M von Willebrand disease: a diagnostic challenge. Eur J Haematol 2018
  PubMedSearch in Google Scholar
• 59 Naik S, Teruya J, Dietrich JE, Jariwala P, Soundar E, Venkateswaran L. Utility of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia. Pediatr Blood Cancer 2013; 60 (07) 1184-1187
  PubMedSearch in Google Scholar
• 60 Harrison P, Robinson M, Liesner R. et al. The PFA-100: a potential rapid screening tool for the assessment of platelet dysfunction. Clin Lab Haematol 2002; 24 (04) 225-232
  PubMedSearch in Google Scholar
• 61 Nitu-Whalley IC, Lee CA, Hermans C. Reassessment of the correlation between the von Willebrand factor activity, the PFA-100, and the bleeding time in patients with von Willebrand disease. Thromb Haemost 2001; 86 (02) 715-716
  PubMedSearch in Google Scholar
• 62 Veyradier A, Gervaise A, Boyer-Neumann C, Wolf M, Fernandez H. Screening for bleeding disorders in women with menorrhagia using a platelet function analyzer. J Thromb Haemost 2006; 4 (02) 483-485
  PubMedSearch in Google Scholar
• 63 Gursel T, Biri A, Kaya Z, Sivaslıoglu S, Albayrak M. The frequency of menorrhagia and bleeding disorders in university students. Pediatr Hematol Oncol 2014; 31 (05) 467-474
  PubMedSearch in Google Scholar
• 64 Nummi V, Lassila R, Joutsi-Korhonen L, Armstrong E, Szanto T. Comprehensive re-evaluation of historical von Willebrand disease diagnosis in association with whole blood platelet aggregation and function. Int J Lab Hematol 2018; 40 (03) 304-311
  PubMedSearch in Google Scholar
• 65 Haas T, Cushing MM, Varga S, Gilloz S, Schmugge M. Usefulness of multiple electrode aggregometry as a screening tool for bleeding disorders in a pediatric hospital. Platelets 2019; 30 (04) 498-505
  PubMedSearch in Google Scholar
• 66 Koessler J, Ehrenschwender M, Kobsar A, Brunner K. Evaluation of the new INNOVANCE® PFA P2Y cartridge in patients with impaired primary haemostasis. Platelets 2012; 23 (08) 571-578
  PubMedSearch in Google Scholar
• 67 Veyradier A, Fressinaud E, Boyer-Neumann C, Trossaert M, Meyer D. von Willebrand factor ristocetin cofactor activity correlates with platelet function in a high shear stress system. Thromb Haemost 2000; 84 (04) 727-728
  PubMedSearch in Google Scholar
• 68 Charpy J, Chaghouri PE, Benattar N. et al. Evaluation of the potential utility of the total thrombus-formation analysis system in comparison to the platelet function analyser in subjects with primary haemostatic defects. Br J Haematol 2020; 191 (01) e7-e10
  PubMedSearch in Google Scholar
• 69 Favaloro EJ. Template bleeding time and PFA-100 have low sensitivity to screen patients with hereditary mucocutaneous hemorrhages: comparative study of 148 patients–a rebuttal. J Thromb Haemost 2004; 2 (12) 2280-2282 , author reply 2283–2285
  PubMedSearch in Google Scholar
• 70 Favaloro EJ, Patterson D, Denholm A. et al. Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis. Br J Haematol 2007; 139 (04) 623-626
  PubMedSearch in Google Scholar
• 71 Favaloro EJ, Lloyd J, Rowell J. et al. Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (high purity)] in people with von Willebrand disorder. A randomised cross-over, multi-centre study. Thromb Haemost 2007; 97 (06) 922-930
  PubMedSearch in Google Scholar
• 72 Akin M, Karapinar DY, Balkan C, Ay Y, Kavakli K. Resemblance to vWD types and laboratory diagnosis of obligatory carriers of type 3 von Willebrand disease. Clin Appl Thromb Hemost 2011; 17 (06) E21-E24
  PubMedSearch in Google Scholar
• 73 Perel JM, Just S, Rowell J, Williams B, Kennedy GA. Utility of the PFA-100 analyser in the evaluation of primary haemostasis in a paediatric population. Int J Lab Hematol 2007; 29 (06) 480-481
  PubMedSearch in Google Scholar
• 74 Bakr S, Almutairi AA, Dawalibi A, Owaidah M, Almughiyri AA, Owaidah T. Screening hemostatic defects in Saudi University students with unexplained menorrhagia: a diagnosis, which could be missed. Blood Coagul Fibrinolysis 2021; 32 (04) 278-284
  PubMedSearch in Google Scholar
• 75 Cakı Kılıç S, Sarper N, Zengin E, Aylan Gelen S. Screening bleeding disorders in adolescents and young women with menorrhagia. Turk J Haematol 2013; 30 (02) 168-176
  PubMedSearch in Google Scholar
• 76 Valarche V, Desconclois C, Boutekedjiret T, Dreyfus M, Proulle V. Multiplate whole blood impedance aggregometry: a new tool for von Willebrand disease. J Thromb Haemost 2011; 9 (08) 1645-1647
  PubMedSearch in Google Scholar
• 77 Sap F, Kavaklı T, Kavaklı K, Dizdarer C. The prevalence of von Willebrand disease and significance of in vitro bleeding time (PFA-100) in von Willebrand disease screening in the İzmir region. Turk J Haematol 2013; 30 (01) 40-47
  PubMedSearch in Google Scholar
• 78 Geevar T, Dave RG, Mathews NS. et al. Laboratory characterization of obligate carriers of type 3 von Willebrand disease with a potential role for platelet function analyzer (PFA-200). Int J Lab Hematol 2022; 44 (03) 603-609
  PubMedSearch in Google Scholar
• 79 Favaloro EJ. Clinical utility of the PFA-100. Semin Thromb Hemost 2008; 34 (08) 709-733
  PubMedSearch in Google Scholar
• 80 Favaloro EJ, Kershaw G, Bukuya M, Hertzberg M, Koutts J. Laboratory diagnosis of von Willebrand disorder (vWD) and monitoring of DDAVP therapy: efficacy of the PFA-100 and vWF:CBA as combined diagnostic strategies. Haemophilia 2001; 7 (02) 180-189
  PubMedSearch in Google Scholar
• 81 Akin M, Karapinar DY, Balkan C, Ay Y, Kavakli K. An evaluation of the DDAVP infusion test with PFA-100 and vWF activity assays to distinguish vWD types in children. Clin Appl Thromb Hemost 2011; 17 (05) 441-448
  PubMedSearch in Google Scholar
• 82 Karger R, Donner-Banzhoff N, Müller HH, Kretschmer V, Hunink M. Diagnostic performance of the platelet function analyzer (PFA-100) for the detection of disorders of primary haemostasis in patients with a bleeding history-a systematic review and meta-analysis. Platelets 2007; 18 (04) 249-260
  PubMedSearch in Google Scholar
• 83 Callaghan MU, Chitlur MB, Fleming P, Rajpurkar M, Lusher JM. Thromboelastogram platelet mapping accurately predicts bleeding phenotype in Glanzmann thrombasthenia. Blood 2008; 112 (11) 4560-4560
  PubMedSearch in Google Scholar
• 84 Moenen FCJI, Vries MJA, Nelemans PJ. et al. Screening for platelet function disorders with multiplate and platelet function analyzer. Platelets 2019; 30 (01) 81-87
  PubMedSearch in Google Scholar
• 85 Al-Battat S, Rand ML, Bouskill V. et al. Glanzmann thrombasthenia platelets compete with transfused platelets, reducing the haemostatic impact of platelet transfusions. Br J Haematol 2018; 181 (03) 410-413
  PubMedSearch in Google Scholar
• 86 Albanyan A, Al-Musa A, AlNounou R. et al. Diagnosis of Glanzmann thrombasthenia by whole blood impedance analyzer (MEA) vs. light transmission aggregometry. Int J Lab Hematol 2015; 37 (04) 503-508
  PubMedSearch in Google Scholar
• 87 Bragadottir G, Birgisdottir ER, Gudmundsdottir BR. et al. Clinical phenotype in heterozygote and biallelic Bernard-Soulier syndrome–a case control study. Am J Hematol 2015; 90 (02) 149-155
  PubMedSearch in Google Scholar
• 88 Acharya S, Barraclough J, Ibrahim MS. et al. The usefulness of the platelet function analyser (PFA-100) in screening for underlying bleeding disorders in women with menorrhagia. J Obstet Gynaecol 2008; 28 (03) 310-314
  PubMedSearch in Google Scholar
• 89 Sladky JL, Klima J, Grooms L, Kerlin BA, O'Brien SH. The PFA-100 ® does not predict delta-granule platelet storage pool deficiencies. Haemophilia 2012; 18 (04) 626-629
  PubMedSearch in Google Scholar
• 90 Santos XM, Bercaw-Pratt JL, Yee DL, Dietrich JE. Recurrent menorrhagia in an adolescent with a platelet secretion defect. J Pediatr Adolesc Gynecol 2011; 24 (02) e35-e38
  PubMedSearch in Google Scholar
• 91 Rolf N, Knoefler R, Bugert P. et al. Clinical and laboratory phenotypes associated with the aspirin-like defect: a study in 17 unrelated families. Br J Haematol 2009; 144 (03) 416-424
  PubMedSearch in Google Scholar
• 92 Knöfler R, Lohse J, Stächele J. et al. Significance of platelet function diagnostics for clarification of suspected battered child syndrome. Hamostaseologie 2014; 34 (Suppl. 01) S53-S56
  PubMedSearch in Google Scholar
• 93 Lasne D, Baujat G, Mirault T. et al. Bleeding disorders in Lowe syndrome patients: evidence for a link between OCRL mutations and primary haemostasis disorders. Br J Haematol 2010; 150 (06) 685-688
  PubMedSearch in Google Scholar
• 94 Scavone M, Germanovich K, Femia EA, Cattaneo M. Usefulness of the INNOVANCE PFA P2Y test cartridge for the detection of patients with congenital defects of the platelet P2Y₁₂ receptor for adenosine diphosphate. Thromb Res 2014; 133 (02) 254-256
  PubMedSearch in Google Scholar
• 95 Kaufmann J, Adler M, Alberio L, Nagler M. Utility of the platelet function analyzer in patients with suspected platelet function disorders: diagnostic accuracy study. TH Open 2020; 4 (04) e427-e436
  PubMedSearch in Google Scholar
• 96 Guay J, Faraoni D, Bonhomme F, Borel Derlon A, Lasne D. Ability of hemostatic assessment to detect bleeding disorders and to predict abnormal surgical blood loss in children: a systematic review and meta-analysis. Paediatr Anaesth 2015; 25 (12) 1216-1226
  PubMedSearch in Google Scholar
• 97 Roschitz B, Thaller S, Koestenberger M. et al. PFA-100 closure times in preoperative screening in 500 pediatric patients. Thromb Haemost 2007; 98 (01) 243-247
  PubMedSearch in Google Scholar
• 98 Koscielny J, von Tempelhoff GF, Ziemer S. et al. A practical concept for preoperative management of patients with impaired primary hemostasis. Clin Appl Thromb Hemost 2004; 10 (02) 155-166
  PubMedSearch in Google Scholar
• 99 van Vliet HH, Kappers-Klunne MC, Leebeek FW, Michiels JJ. PFA-100 monitoring of von Willebrand factor (VWF) responses to desmopressin (DDAVP) and factor VIII/VWF concentrate substitution in von Willebrand disease type 1 and 2. Thromb Haemost 2008; 100 (03) 462-468
  PubMedSearch in Google Scholar
• 100 Hanebutt FL, Rolf N, Loesel A, Kuhlisch E, Siegert G, Knoefler R. Evaluation of desmopressin effects on haemostasis in children with congenital bleeding disorders. Haemophilia 2008; 14 (03) 524-530
  PubMedSearch in Google Scholar
• 101 Akin M. Response to low-dose desmopressin by a subcutaneous route in children with type 1 von Willebrand disease. Hematology 2013; 18 (02) 115-118
  PubMedSearch in Google Scholar
• 102 Favaloro EJ, Thom J, Patterson D. et al. Potential supplementary utility of combined PFA-100 and functional von Willebrand factor testing for the laboratory assessment of desmopressin and factor concentrate therapy in von Willebrand disease. Blood Coagul Fibrinolysis 2009; 20 (06) 475-483
  PubMedSearch in Google Scholar
• 103 Meskal A, Vertessen F, Van der Planken M, Berneman ZN. The platelet function analyzer (PFA-100) may not be suitable for monitoring the therapeutic efficiency of von Willebrand concentrate in type III von Willebrand disease. Ann Hematol 1999; 78 (09) 426-430
  PubMedSearch in Google Scholar
• 104 Pekrul I, Kragh T, Turecek PL, Novack AR, Ott HW, Spannagl M. Sensitive and specific assessment of recombinant von Willebrand factor in platelet function analyzer. Platelets 2019; 30 (02) 264-270
  PubMedSearch in Google Scholar
• 105 Trossaërt M, Flaujac C, Jeanpierre E. et al. Assessment of primary haemostasis with a new recombinant von Willebrand factor in patients with von Willebrand disease. Haemophilia 2020; 26 (02) e44-e48
  PubMedSearch in Google Scholar
• 106 Castaman G, Tosetto A, Goodeve A. et al. The impact of bleeding history, von Willebrand factor and PFA-100(®) on the diagnosis of type 1 von Willebrand disease: results from the European study MCMDM-1VWD. Br J Haematol 2010; 151 (03) 245-251
  PubMedSearch in Google Scholar
• 107 Ortel TL, James AH, Thames EH, Moore KD, Greenberg CS. Assessment of primary hemostasis by PFA-100 analysis in a tertiary care center. Thromb Haemost 2000; 84 (01) 93-97
  PubMedSearch in Google Scholar
• 108 Favaloro EJ, Zafer M, Nair SC, Hertzberg M, North K. Evaluation of primary haemostasis in people with neurofibromatosis type 1. Clin Lab Haematol 2004; 26 (05) 341-345
  PubMedSearch in Google Scholar
• 109 Tanous O, Steinberg Shemer O, Yacobovich J. et al. Evaluating platelet function disorders in children with bleeding tendency - a single center study. Platelets 2017; 28 (07) 676-681
  PubMedSearch in Google Scholar
• 110 Weston H, Just S, Williams B, Rowell J, Kennedy GA. PFA-100 testing for pretherapeutic assessment of response to DDAVP in patients with von Willebrand's disease. Haemophilia 2009; 15 (01) 372-373
  PubMedSearch in Google Scholar
• 111 Heubel-Moenen FCJI, Brouns SLN, Herfs L. et al. Multiparameter platelet function analysis of bleeding patients with a prolonged platelet function analyser closure time. Br J Haematol 2022; 196 (06) 1388-1400
  PubMedSearch in Google Scholar
• 112 Hayward CP, Harrison P, Cattaneo M, Ortel TL, Rao AK. Platelet Physiology Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Platelet function analyzer (PFA)-100 closure time in the evaluation of platelet disorders and platelet function. J Thromb Haemost 2006; 4 (02) 312-319
  PubMedSearch in Google Scholar
• 113 Favaloro EJ. Clinical utility of closure times using the platelet function analyzer-100/200. Am J Hematol 2017; 92 (04) 398-404
  PubMedSearch in Google Scholar
• 114 Ogiwara K, Nogami K, Hosokawa K, Ohnishi T, Matsumoto T, Shima M. Comprehensive evaluation of haemostatic function in von Willebrand disease patients using a microchip-based flow chamber system. Haemophilia 2015; 21 (01) 71-80
  PubMedSearch in Google Scholar
• 115 Daidone V, Barbon G, Cattini MG. et al. Usefulness of the total thrombus-formation analysis system (T-TAS) in the diagnosis and characterization of von Willebrand disease. Haemophilia 2016; 22 (06) 949-956
  PubMedSearch in Google Scholar
• 116 Nakajima Y, Yada K, Ogiwara K. et al. A microchip flow-chamber assay screens congenital primary hemostasis disorders. Pediatr Int 2021; 63 (02) 160-167
  PubMedSearch in Google Scholar
• 117 Nogami K, Ogiwara K, Yada K. et al. Assessing the clinical severity of type 1 von Willebrand disease patients with a microchip flow-chamber system. J Thromb Haemost 2016; 14 (04) 667-674
  PubMedSearch in Google Scholar
• 118 Nakajima Y, Nogami K, Yada K. et al. Evaluation of clinical severity in patients with type 2N von Willebrand disease using microchip-based flow-chamber system. Int J Hematol 2020; 111 (03) 369-377
  PubMedSearch in Google Scholar
• 119 Ågren A, Holmström M, Schmidt DE, Hosokawa K, Blombäck M, Hjemdahl P. Monitoring of coagulation factor therapy in patients with von Willebrand disease type 3 using a microchip flow chamber system. Thromb Haemost 2017; 117 (01) 75-85
  PubMedSearch in Google Scholar
• 120 Minami H, Nogami K, Ogiwara K, Furukawa S, Hosokawa K, Shima M. Use of a microchip flow-chamber system as a screening test for platelet storage pool disease. Int J Hematol 2015; 102 (02) 157-162
  PubMedSearch in Google Scholar
• 121 Lecchi A, La Marca S, Padovan L, Boscarino M, Peyvandi F, Tripodi A. Flow-chamber device (T-TAS) to diagnose patients suspected of platelet function defects. Blood Transfus 2023
  PubMedSearch in Google Scholar
• 122 Al Ghaithi R, Mori J, Nagy Z. et al. Evaluation of the total thrombus-formation system (T-TAS): application to human and mouse blood analysis. Platelets 2019; 30 (07) 893-900
  PubMedSearch in Google Scholar
• 123 Nakajima Y, Nogami K, Yada K. et al. Whole blood ristocetin-induced platelet impedance aggregometry does not reflect clinical severity in patients with type 1 von Willebrand disease. Haemophilia 2019; 25 (03) e174-e179
  PubMedSearch in Google Scholar
• 124 Schmidt DE, Bruzelius M, Majeed A, Odeberg J, Holmström M, Ågren A. Whole blood ristocetin-activated platelet impedance aggregometry (Multiplate) for the rapid detection of Von Willebrand disease. Thromb Haemost 2017; 117 (08) 1528-1533
  PubMedSearch in Google Scholar
• 125 Awidi A, Maqablah A, Dweik M, Bsoul N, Abu-Khader A. Comparison of platelet aggregation using light transmission and multiple electrode aggregometry in Glanzmann thrombasthenia. Platelets 2009; 20 (05) 297-301
  PubMedSearch in Google Scholar
• 126 Castellino FJ, Liang Z, Davis PK. et al. Abnormal whole blood thrombi in humans with inherited platelet receptor defects. PLoS One 2012; 7 (12) e52878
  PubMedSearch in Google Scholar
• 127 Al Ghaithi R, Drake S, Watson SP, Morgan NV, Harrison P. Comparison of multiple electrode aggregometry with lumi-aggregometry for the diagnosis of patients with mild bleeding disorders. J Thromb Haemost 2017; 15 (10) 2045-2052
  PubMedSearch in Google Scholar
• 128 Lansdon LA, Chen D, Rush ET. et al. A novel likely pathogenic variant in a patient with Hermansky-Pudlak syndrome. Cold Spring Harb Mol Case Stud 2021; 7 (05) a006110
  PubMedSearch in Google Scholar
• 129 Akay OM, Mutlu F, Gulbas Z. Platelet dysfunction and other hemostatic disorders in women with menorrhagia: the utility of whole blood lumi-aggregometer. Intern Emerg Med 2008; 3 (02) 191-193
  PubMedSearch in Google Scholar
• 130 Mills HL, Abdel-Baki MS, Teruya J. et al. Platelet function defects in adolescents with heavy menstrual bleeding. Haemophilia 2014; 20 (02) 249-254
  PubMedSearch in Google Scholar
• 131 Takeyama M, Kasuda S, Sakurai Y. et al. Factor VIII-mediated global hemostasis in the absence of von Willebrand factor. Int J Hematol 2007; 85 (05) 397-402
  PubMedSearch in Google Scholar
• 132 Schmidt DE, Majeed A, Bruzelius M, Odeberg J, Holmström M, Ågren A. A prospective diagnostic accuracy study evaluating rotational thromboelastometry and thromboelastography in 100 patients with von Willebrand disease. Haemophilia 2017; 23 (02) 309-318
  PubMedSearch in Google Scholar
• 133 Regling K, Kakulavarapu S, Thomas R, Hollon W, Chitlur MB. Utility of thromboelastography for the diagnosis of von Willebrand disease. Pediatr Blood Cancer 2019; 66 (07) e27714
  PubMedSearch in Google Scholar
• 134 Szanto T, Nummi V, Jouppila A, Brinkman HJM, Lassila R. Platelets compensate for poor thrombin generation in type 3 von Willebrand disease. Platelets 2020; 31 (01) 103-111
  PubMedSearch in Google Scholar
• 135 Wieland Greguare-Sander A, Wuillemin WA, Nagler M. Thromboelastometry as a diagnostic tool in mild bleeding disorders: a prospective cohort study. Eur J Anaesthesiol 2019; 36 (06) 457-465
  PubMedSearch in Google Scholar
• 136 Tuman KJ, Spiess BD, Schoen RE, Ivankovich AD. Use of thromboelastography in the management of von Willebrand's disease during cardiopulmonary bypass. J Cardiothorac Anesth 1987; 1 (04) 321-324
  PubMedSearch in Google Scholar
• 137 Topal A, Kılıçaslan A, Erol A, Çankaya B, Otelcioğlu Ş. Anaesthetic management with thromboelastography in a patient with Glanzmann thrombasthenia. Turk J Anaesthesiol Reanim 2014; 42 (04) 227-229
  PubMedSearch in Google Scholar
• 138 Simha PP, Mohan Rao PS, Arakalgud D, Rajashekharappa R, Narasimhaih M. Perioperative management of a patient with Glanzmann's thrombasthenia for mitral valve repair under cardiopulmonary bypass. Ann Card Anaesth 2017; 20 (04) 468-471
  PubMedSearch in Google Scholar
• 139 Pivalizza EG. Heparinase and thromboelastography in liver transplantation for a patient with von Willebrand's disease. Anesthesiology 1996; 84 (05) 1236-1239
  PubMedSearch in Google Scholar
• 140 Pivalizza EG. Perioperative use of the thrombelastograph in patients with inherited bleeding disorders. J Clin Anesth 2003; 15 (05) 366-370
  PubMedSearch in Google Scholar
• 141 Al Midani A, Donohue C, Berry P, Jones G, Fernando B. Use of thromboelastography to guide platelet infusion in a patient with Wiskott-Aldrich syndrome undergoing renal transplant. Exp Clin Transplant 2020; 18 (05) 636-637
  PubMedSearch in Google Scholar
• 142 Favro M, Terrone C, Neira D. et al. Major surgery (radical cystectomy with urethrectomy) in a patient with von Willebrand's disease type I. Reliability and limits of hemocoagulative tests. Minerva Urol Nefrol 1998; 50 (04) 247-251
  PubMedSearch in Google Scholar
• 143 Grassetto A, Fullin G, Lazzari F. et al. Perioperative ROTEM and ROTEMplatelet monitoring in a case of Glanzmann's thrombasthenia. Blood Coagul Fibrinolysis 2017; 28 (01) 96-99
  PubMedSearch in Google Scholar
• 144 Guzman-Reyes S, Osborne C, Pivalizza EG. Thrombelastography for perioperative monitoring in patients with von Willebrand disease. J Clin Anesth 2012; 24 (02) 166-167
  PubMedSearch in Google Scholar
• 145 Boyd EZ, Riha K, Escobar MA, Pivalizza EG. Thrombelastograph platelet mapping in a patient with von Willebrand disease who was treated with Humate-P. J Clin Anesth 2011; 23 (07) 600
  PubMedSearch in Google Scholar
• 146 Campbell J, Yentis S. The use of thromboelastography for the peripartum management of a patient with platelet storage pool disorder. Int J Obstet Anesth 2011; 20 (04) 360 , author reply 361
  PubMedSearch in Google Scholar
• 147 Clements A, Jindal S, Morris C, Srivastava G, Ikomi A, Mulholland J. Expanding perfusion across disciplines: the use of thrombelastography technology to reduce risk in an obstetrics patient with gray platelet syndrome–a case study. Perfusion 2011; 26 (03) 181-184
  PubMedSearch in Google Scholar
• 148 Hale J, Galanti G, Langer A, Lassey S, Reiff E, Camann W. A case report of rotational thromboelastometry-assisted decision analysis for two pregnant patients with platelet storage pool disorder. A A Pract 2023; 17 (02) e01658
  PubMedSearch in Google Scholar
• 149 Monte S, Lyons G. Peripartum management of a patient with Glanzmann's thrombasthenia using thrombelastograph. Br J Anaesth 2002; 88 (05) 734-738
  PubMedSearch in Google Scholar
• 150 Palsson R, Vidarsson B, Gudmundsdottir BR. et al. Complementary effect of fibrinogen and rFVIIa on clotting ex vivo in Bernard-Soulier syndrome and combined use during three deliveries. Platelets 2014; 25 (05) 357-362
  PubMedSearch in Google Scholar
• 151 Rajpal G, Pomerantz JM, Ragni MV, Waters JH, Vallejo MC. The use of thromboelastography for the peripartum management of a patient with platelet storage pool disorder. Int J Obstet Anesth 2011; 20 (02) 173-177
  PubMedSearch in Google Scholar
• 152 Snow TA, Abdul-Kadir RA, Gomez K, England A. Platelet storage pool disorder in pregnancy: utilising thromboelastography to guide a risk-based delivery plan. Obstet Med 2022; 15 (02) 133-135
  PubMedSearch in Google Scholar
• 153 Zia AN, Chitlur M, Rajpurkar M. et al. Thromboelastography identifies children with rare bleeding disorders and predicts bleeding phenotype. Haemophilia 2015; 21 (01) 124-132
  PubMedSearch in Google Scholar
• 154 Shenkman B, Livnat T, Misgav M, Budnik I, Einav Y, Martinowitz U. The in vivo effect of fibrinogen and factor XIII on clot formation and fibrinolysis in Glanzmann's thrombasthenia. Platelets 2012; 23 (08) 604-610
  PubMedSearch in Google Scholar
• 155 Budnik I, Shenkman B, Morozova O, Andreichyn J, Einav Y. Correction of coagulopathy in thrombocytopenia and Glanzmann thrombasthenia models by fibrinogen and factor XIII as assessed by thromboelastometry. Pathophysiology 2018; 25 (04) 347-351
  PubMedSearch in Google Scholar
• 156 Ahammad J, Kamath A, Shastry S, Chitlur M, Kurien A. Clinico-hematological and thromboelastographic profiles in Glanzmann's thrombasthenia. Blood Coagul Fibrinolysis 2020; 31 (01) 29-34
  PubMedSearch in Google Scholar
• 157 Barg AA, Hauschner H, Misgav M. et al. A novel approach using ancillary tests to guide treatment of Glanzmann thrombasthenia patients undergoing surgical procedures. Blood Cells Mol Dis 2018; 72: 44-48
  PubMedSearch in Google Scholar
• 158 Male C, Koren D, Eichelberger B, Kaufmann K, Panzer S. Monitoring survival and function of transfused platelets in Glanzmann thrombasthenia by flow cytometry and thrombelastography. Vox Sang 2006; 91 (02) 174-177
  PubMedSearch in Google Scholar
• 159 Lak M, Scharling B, Blemings A. et al. Evaluation of rFVIIa (NovoSeven) in Glanzmann patients with thromboelastogram. Haemophilia 2008; 14 (01) 103-110
  PubMedSearch in Google Scholar
• 160 Horne III MK, Williams SB, Gahl WA, Rick ME. Evaluation of the xylum clot signature analyzer in normal subjects and patients with the Hermansky-Pudlak syndrome. Thromb Res 2001; 104 (01) 57-63
  PubMedSearch in Google Scholar
• 161 Fricke W, Kouides P, Kessler C. et al. A multicenter clinical evaluation of the clot signature analyzer. J Thromb Haemost 2004; 2 (05) 763-768
  PubMedSearch in Google Scholar
• 162 Varon D, Lashevski I, Brenner B. et al. Cone and plate(let) analyzer: monitoring glycoprotein IIb/IIIa antagonists and von Willebrand disease replacement therapy by testing platelet deposition under flow conditions. Am Heart J 1998; 135 (5 Pt 2 Su): S187-S193
  PubMedSearch in Google Scholar
• 163 Shenkman B, Savion N, Dardik R, Tamarin I, Varon D. Testing of platelet deposition on polystyrene surface under flow conditions by the cone and plate(let) analyzer: role of platelet activation, fibrinogen and von Willebrand factor. Thromb Res 2000; 99 (04) 353-361
  PubMedSearch in Google Scholar
• 164 Revel-Vilk S, Varon D, Shai E. et al. Evaluation of children with a suspected bleeding disorder applying the Impact-R [Cone and Plate(let) analyzer]. J Thromb Haemost 2009; 7 (12) 1990-1996
  PubMedSearch in Google Scholar
• 165 Shenkman B, Einav Y, Salomon O, Varon D, Savion N. Testing agonist-induced platelet aggregation by the Impact-R [Cone and plate(let) analyzer (CPA)]. Platelets 2008; 19 (06) 440-446
  PubMedSearch in Google Scholar
• 166 Lehmann M, Ashworth K, Manco-Johnson M, Di Paola J, Neeves KB, Ng CJ. Evaluation of a microfluidic flow assay to screen for von Willebrand disease and low von Willebrand factor levels. J Thromb Haemost 2018; 16 (01) 104-115
  PubMedSearch in Google Scholar
• 167 Neeves KB, Onasoga AA, Hansen RR. et al. Sources of variability in platelet accumulation on type 1 fibrillar collagen in microfluidic flow assays. PLoS One 2013; 8 (01) e54680
  CrossrefPubMedSearch in Google Scholar
• 168 Grabowski EF, Curran MA, Van Cott EM. Assessment of a cohort of primarily pediatric patients with a presumptive diagnosis of type 1 von Willebrand disease with a novel high shear rate, non-citrated blood flow device. Thromb Res 2012; 129 (04) e18-e24
  PubMedSearch in Google Scholar
• 169 Grabowski EF, Van Cott EM, Bornikova L, Boyle DC, Silva RL. Differentiation of patients with symptomatic low von Willebrand factor from those with asymptomatic low von Willebrand factor. Thromb Haemost 2020; 120 (05) 793-804
  PubMedSearch in Google Scholar
• 170 Chen Z, Lu J, Zhang C. et al. Microclot array elastometry for integrated measurement of thrombus formation and clot biomechanics under fluid shear. Nat Commun 2019; 10 (01) 2051
  PubMedSearch in Google Scholar
• 171 Zwaginga JJ, Nash G, King MR. et al; Biorheology Subcommittee of the SSC of the ISTH. Flow-based assays for global assessment of hemostasis. Part 1: biorheologic considerations. J Thromb Haemost 2006; 4 (11) 2486-2487
  PubMedSearch in Google Scholar
• 172 Kazmi RS, Boyce S, Lwaleed BA. Homeostasis of hemostasis: the role of endothelium. Semin Thromb Hemost 2015; 41 (06) 549-555
  PubMedSearch in Google Scholar
• 173 Schneider SW, Nuschele S, Wixforth A. et al. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci U S A 2007; 104 (19) 7899-7903
  PubMedSearch in Google Scholar
• 174 Yakusheva AA, Butov KR, Bykov GA. et al. Traumatic vessel injuries initiating hemostasis generate high shear conditions. Blood Adv 2022; 6 (16) 4834-4846
  PubMedSearch in Google Scholar
• 175 Kalb ML, Potura L, Scharbert G, Kozek-Langenecker SA. The effect of ex vivo anticoagulants on whole blood platelet aggregation. Platelets 2009; 20 (01) 7-11
  PubMedSearch in Google Scholar
• 176 Truss NJ, Armstrong PC, Liverani E, Vojnovic I, Warner TD. Heparin but not citrate anticoagulation of blood preserves platelet function for prolonged periods. J Thromb Haemost 2009; 7 (11) 1897-1905
  PubMedSearch in Google Scholar
• 177 Germanovich K, Femia EA, Cheng CY, Dovlatova N, Cattaneo M. Effects of pH and concentration of sodium citrate anticoagulant on platelet aggregation measured by light transmission aggregometry induced by adenosine diphosphate. Platelets 2018; 29 (01) 21-26
  PubMedSearch in Google Scholar
• 178 Schneider DJ, Tracy PB, Mann KG, Sobel BE. Differential effects of anticoagulants on the activation of platelets ex vivo. Circulation 1997; 96 (09) 2877-2883
  PubMedSearch in Google Scholar
• 179 Packham MA, Bryant NL, Guccione MA, Kinlough-Rathbone RL, Mustard JF. Effect of the concentration of Ca2+ in the suspending medium on the responses of human and rabbit platelets to aggregating agents. Thromb Haemost 1989; 62 (03) 968-976
  PubMedSearch in Google Scholar
• 180 Jones S, Evans RJ, Mahaut-Smith MP. Extracellular Ca(2+) modulates ADP-evoked aggregation through altered agonist degradation: implications for conditions used to study P2Y receptor activation. Br J Haematol 2011; 153 (01) 83-91
  PubMedSearch in Google Scholar
• 181 Mani H, Hellis M, Lindhoff-Last E. Platelet function testing in hirudin and BAPA anticoagulated blood. Clin Chem Lab Med 2011; 49 (03) 501-507
  PubMedSearch in Google Scholar
• 182 Chapman K, Favaloro EJ. Time dependent reduction in platelet aggregation using the multiplate analyser and hirudin blood due to platelet clumping. Platelets 2018; 29 (03) 305-308
  PubMedSearch in Google Scholar
• 183 Hellstern P, Stürzebecher U, Wuchold B. et al. Preservation of in vitro function of platelets stored in the presence of a synthetic dual inhibitor of factor Xa and thrombin. J Thromb Haemost 2007; 5 (10) 2119-2126
  PubMedSearch in Google Scholar
• 184 James PD, Connell NT, Ameer B. et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv 2021; 5 (01) 280-300
  PubMedSearch in Google Scholar
• 185 Jigar Panchal H, Kent NJ, Knox AJS, Harris LF. Microfluidics in haemostasis: a review. Molecules 2020; 25 (04) 833
  PubMedSearch in Google Scholar
• 186 Mohammadi Aria M, Erten A, Yalcin O. Technology advancements in blood coagulation measurements for point-of-care diagnostic testing. Front Bioeng Biotechnol 2019; 7: 395
  PubMedSearch in Google Scholar
• 187 Kim CJ, Kim J, Sabaté Del Río J, Ki DY, Kim J, Cho YK. Fully automated light transmission aggregometry on a disc for platelet function tests. Lab Chip 2021; 21 (23) 4707-4715
  PubMedSearch in Google Scholar
• 188 Sakurai Y, Hardy ET, Lam WA. Hemostasis-on-a-chip / incorporating the endothelium in microfluidic models of bleeding. Platelets 2023; 34 (01) 2185453
  PubMedSearch in Google Scholar
• 189 Liang HP, Morel-Kopp MC, Curtin J. et al. Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients. Thromb Haemost 2007; 98 (06) 1298-1308
  PubMedSearch in Google Scholar

• Supplementary Material