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Contempo 1999 |

Anticoagulant-Induced Thrombosis

J. O. Ballard, MD
JAMA. 1999;282(4):310-312. doi:10.1001/jama.282.4.310.
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Each year thromboembolism affects millions of individuals worldwide. As a result, anticoagulants are among the most commonly prescribed drugs in clinical practice. Heparin sodium and warfarin sodium are used alone or sequentially for primary and secondary prophylaxis in the management of a variety of thrombotic diseases. Bleeding complications associated with these agents are well-known; however, the risks and causes of paradoxical venous or arterial thrombosis occurring during anticoagulant therapy have only recently been elucidated. This article reviews the current understanding of serious acquired-prothrombotic states that can occasionally develop during treatment with anticoagulants. As background, a brief description of each drug's mechanism of action is first presented.

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Figure. Proposed Pathogenetic Mechanism for the Prothrombotic State Associated With Heparin-Induced Thrombocytopenia and the Adverse Effect of Warfarin Treatment
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Platelet factor 4 (PF4), released from platelets on activation, forms an antigen complex with heparin or native endothelial cell–derived heparan sulfate stimulating the formation of anti-heparin/PF4 IgG antibody (heparin-induced thrombocytopenia [HIT]-IgG). The immune complex of HIT-IgG and its antigen binds to the platelet Fc receptor and initiates coagulation by triggering further platelet activation, aggregation, and platelet microparticle release. Experimental evidence suggests HIT-IgG also binds to heparan sulfate/PF4 complexes on endothelium enhancing the expression of tissue factor. The sum of these 2 processes is intense thrombin generation. One of the naturally occurring inhibitors of coagulation, protein C (PC), is activated (+) by thrombin bound to thrombomodulin (TM) on endothelium. Activated protein C (aPC) and its cofactor protein S (PS) down-regulate (−) thrombin generation by inhibiting activated clotting factors V and VIII. This dampening effect on thrombin generation is diminished during treatment with warfarin, which impairs the synthesis of functional proteins C and S.



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