Heparin-Like Anticoagulant: First Case Described in a Metastatic Biliopancreatic Cancer

 

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The development of acquired heparin-like anticoagulants in vivo is an extremely rare condition that has been associated with hematological malignancies and other neoplastic processes such as bladder, breast, and hepatocellular carcinoma.[1] We report here the finding of a heparin-like anticoagulant in a young patient diagnosed with metastatic biliopancreatic adenocarcinoma.

A 45-year-old male with a previous history of alcoholism and smoking of 66 packs-years was admitted to hospital due to dyspnea on effort and inability to move his left arm. Patient referred weight loss of 30 kg and occasional nausea, vomiting, and night sweats that evolved over several months. Initial laboratory tests showed thrombocytopenia (platelet count 19 × 10⁹/L) and severe anemia (hemoglobin 5.2 g/dL), which required transfusion of 2 units of red blood cells. No bleeding was reported.

A chest computed tomography reported cervical lymphadenopathy, mediastinal and axillar masses generating functional impairment of the left arm. A lymphoproliferative syndrome was suspected. Flow cytometry and bone marrow smear showed no evidence of oncohematological disease. No bruising was reported as a result of the bone marrow examination. However, a massive infiltration of nonhematological malignant tumor cells in the bone marrow was observed. The patient also underwent a surgical procedure of a cervical lymph node biopsy without any hemostatic complications.

Initial laboratory assessment of hemostasis revealed a prolonged activated partial thromboplastin time (aPTT) of 67 seconds, a prothrombin time (PT) of 67%, an international normalized ratio of 1.31, and a normal fibrinogen level ([Table 1]). The aPTT did not correct with a 1:1 mix with normal pooled plasma (NPP). Thrombin time (TT) was extremely prolonged and reptilase time was normal. Anti-Xa activity was assessed and established the presence of heparin-like activity with a result of 0.30 IU/mL. As it was confirmed that the patient was not receiving heparin by any route of administration and preanalytical errors were excluded (including heparin contamination), the presence of a circulating heparin-like anticoagulant was suspected.

To exclude additional coagulopathies, plasma levels of factors II, V, VII, X, VIII, IX, XI, XII, and antithrombin activity were determined. All tests were performed in an automated coagulometer STA-Compact Max (Stago, France) and were within normal limits (data not shown). Testing for lupus anticoagulant was not performed given the heparin-like activity identified by anti-Xa assay.

Three days later, a new blood sample was drawn to confirm previous findings. An anti-Xa activity of 0.44 IU/mL was found. The prolonged TT was normalized after in vitro addition of protamine sulfate. A concentration of 4.5 antiheparin units/mL (AHU/mL) was required to completely correct the TT, while a protamine concentration of 0.45 AHU/mL corrected the TT of a NPP containing commercial unfractionated heparin at a level of 0.45 IU/mL anti-Xa activity ([Table 2]).

Addition of heparanase (Dade Hepzyme, Siemens) to 0.5 mL of patient plasma caused a shortening of both TT and aPTT and a complete neutralization of anti-Xa activity ([Table 3]).

Twelve days after admission, the patient developed hematomas on both arms and left flank. There was no evidence of an intra or retroperitoneal bleeding that could have explained a Grey-Turner's sign. No specific therapy was implemented, and palliative care was established due to a terminal prognosis. The patient died of cardiopulmonary arrest 3 days later. Autopsy revealed a poorly differentiated biliopancreatic ductal adenocarcinoma (PDAC) with multiple angiolymphatic embolism, ganglionar involvement, and bone marrow, pleural, gastric and pulmonary metastases.

Heparin-like anticoagulants have been previously described, typically associated with hematological malignancies, such as multiple myeloma, systemic mastocytosis, and chronic lymphoid leukemia, and other situations like asthma, systemic candidiasis, and pregnancy.[1] [3] Among solid tumors, they have been reported in breast carcinoma, transitional cell carcinoma, and bladder cancer.[1] [3] Most of these heparin-like compounds have been identified as glycosaminoglycans, biochemically and structurally similar to heparin, keratin, or chondroitin sulfate. These resemble the mechanism of action of heparin that inactivates coagulation proteases through antithrombin. Clinically, excessive production has been associated with bleeding, ranging from epistaxis to systemic hemorrhage and death.

Our patient showed initial laboratory testing with a PT result nearly within normal range and a prolonged aPTT without correction with NPP. The prolongation of TT and a measurable anti-Xa activity in the absence of exogenously administered heparin, and exclusion of heparin contamination, lead to the suspicion of a heparin-like event. The initial near-normal PT result might be attributed to the neutralization of heparin-like substances by polybrene in the commercial PT reagent.

The inhibitory effect was further characterized by two in vitro tests. First, TT was normalized after in vitro neutralization of the patient's plasma with protamine sulfate. The amount of protamine sulfate required was 10-fold higher than the amount needed to neutralize NPP spiked with the same amount of unfractionated heparin. The resistance of the anticoagulant to neutralization by protamine is a feature ascribed to heparan sulfate in contrast to unfractionated heparin or low-molecular-weight heparin.[2] Second, after in vitro heparanase digestion, a shortening of aPTT and TT was observed and no residual anti-Xa activity was found. The incomplete normalization of the aPTT and TT might be attributed to the heterogeneity of the polysaccharide. Unfortunately, insufficient material was available for additional biochemical characterization.

Some authors have described significant bleeding attributed to heparin-like anticoagulants released in vivo.[3] [4] [5] [6] In our case bleeding did eventually arise, but this was without hemodynamic compromise and therefore no specific treatment was implemented.

An extensive review of the literature revealed that the source of endogenous heparinoids in patients is not well understood. Some proposed theories are the direct production of glycosaminoglycans by tumor cells, as well as the release of a circulating enzyme that cleaves heparan chains from the endothelial glycocalyx. Syndecan-1 (CD138) is a heparan sulfate proteoglycan that plays a key role in the modulation of cancer cell proliferation and invasion, inflammation, and matrix remodeling. Overexpression of CD138 has been reported in PDAC tissue.[7] Moreover, serum CD138 was found at significantly higher levels in patients with PDAC compared with healthy controls.[8] Our laboratory findings could therefore be likely attributed to the circulating form of this proteoglycan.

In conclusion, we describe the first case of a patient with a heparin-like anticoagulant related to PDAC. Further research is necessary to investigate the source of heparin-like anticoagulants in this type of pathology.

Ethical Approval

The publication of this case was approved by our local ethics committee.

Publication History

Article published online:
24 July 2024

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