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Thrombosis in VWF and Hemophilia

From Crystal Wilson: Hello George, I am writing to ask if you could help me to understand how, on rare occasions, patients suffering from bleeding disorders such as von Willebrand disease or hemophilia have suffered from hypercoagulable episodes such as pulmonary emboli or deep vein thrombosis. Thanks.

Hello, Crystal, I sent your question to several colleagues for advice. I received this comprehensive message from Bob Gosselin on 8-5-21: Hey CW + GF, looking at US/FDA approved [as opposed to EMA approved which may be different] drug prescribing information, the newer factor VIII replacement products Advate, Adynovate, Eloctate, Esperoct, Jivi, Novoeight or porcine factor VIII (Obizur) do not indicate thrombotic risk, whereas the factor IX products Alprolix, Idelvion, Rebinyn and the VWF treatment Humate-P all suggest thrombotic risk after administration. Afstyla factor VIII clinical trials excluded patients with recent history of thrombosis, but indicated catheter thrombosis may occur. Refacto had a thrombosed catheter adverse event listed, whereas in the UK prescribing information they indicate thrombophlebitis being a rare event. Fibrinogen [Fibryga, RiaSTAP] and factor XIII replacement Tretten also suggest thrombotic risk, whereas the factor X replacement Coagadex does not. All of the activated prothrombin complex concentrates such as FEIBA or unactivated PCCs such as Kcentra or Profilnine suggest thrombotic risk.  The bypassing agent, HemLibra has black box warning about thrombosis.
I am not sure whether any gene Rx patients have developed any thrombosis to date considering some have gain-in-function characteristics.
Drug prescribing information gets updated if there are changes to dosing, indications, or adverse events, so case reports may be observational and cause-effect conclusions seem premature unless they are known adverse events, but theoretically it would seem plausible. If the hemophilia patients are the older variety and have secondary liver disease due to earlier treatments, the liver disease can be associated with thrombotic risk due to hemostatic imbalance. BG.

Also, on 8-4-21 my colleague Dan Kaczor provided two references:

Girolami A, Scandellari R, Zanon E, Sartori R, Girolami B. Non-catheter associated venous thrombosis in hemophilia A and B. A critical review of all reported cases.
J Thromb Thrombolysis 2006; 21: 279–84.

Bicer M, Yanar M, Tuydes O. Spontaneous deep vein thrombosis in hemophilia A: a case report. Cases Journal 2009, 2:6390 doi: 10.4076/1757-1626-2-6390.

Crystal, come back to this entry from time to time as we gather additional information, and meanwhile thank you for your thought-provoking question.

Comments (1)
Bleeding Disorders
Aug 6, 2021 9:26pm

Such a simple question has a
From Dr. Favaloro: Such a simple question has a complex answer. First, patients with congenital von Willebrand disease (VWD) or hemophilia A or B (HA, HB; representing deficiency of factors VIII and IX respectively) would be expected to be at low risk of congenitally triggered thrombosis. Moreover, they would be expected to be at lower risk of thrombosis caused by acquired ‘triggers’, of which there are many, for example ‘immobility’, advancing age, obesity, malignancy. However, they would still be at risk for thrombosis due to such acquired conditions. Also, von Willebrand factor (VWF) and factor VIII (FVIII), and perhaps to a lesser extent IX, are risk factors for thrombosis when present in excess. However, why would VWD and HA be at risk for thrombosis where VWF and FVIII are deficient? One potential trigger for thrombosis is treatment of VWD and HA, which respectively is undertaken using (preferably recombinant) VWF and FVIII ‘concentrates’. However, recombinant concentrates are not available or used everywhere. Thus, in some patients with VWD or HA, clinicians may use a combined FVIII/VWF concentrate. The problem here is that both FVIII and VWF is given for conditions in which (in general) only one factor is deficient, and thus there is a risk that the other factor reaches high, potentially prothrombotic, levels. Thus, treatment of VWD with a combined FVIII/VWF concentrate can lead to an excess of plasma FVIII, and treatment of HA with a combined FVIII/VWF concentrate can lead to an excess of plasma VWF, with levels on occasion exceeding 200U/dL. Finally, even patients with VWD or HA/HB treated specifically with specific recombinant VWF or FVIII or FIX are not immune to thrombosis, if such therapy also leads to excess levels of these factors.

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