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Activated protein C resistance and myocardial infarction
  1. Department of Haematology,
  2. Imperial College School of Medicine,
  3. Hammersmith Hospital, Ducane Road,
  4. London W12 0NN, UK
  5. email:

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Our understanding of coagulation and thus the mechanisms causing thrombosis has grown enormously in recent years. A crucial part of this development has been an understanding of the anticoagulant systems that normally limit and regulate coagulation. Particular advances have been made in relation to the protein C-protein S system, which is one of the three natural anticoagulant systems. Together with antithrombin-heparin and tissue factor pathway inhibitor (TFPI), the protein C-protein S system acts to limit the extent and magnitude of thrombin generation and thus to prevent inappropriate thrombosis. A deficient response to this system, activated protein C resistance (APCR), is the subject of this review.

Regulation of coagulation

The physiological initiator of coagulation is tissue factor (TF), which is expressed ubiquitously in extravascular tissues and is an important constituent of atheromatous plaques. When plasma is exposed to TF, either as a result of injury or plaque rupture, factor VII is bound from plasma and activated to form a TF–VIIa complex. This then initiates coagulation by activating factor X and factor IX leading to generation of thrombin. A crucial step in generating sufficient thrombin to form a fibrin clot is the activation of factors V and VIII (to Va and VIIIa) by thrombin in a positive feedback effect. This is important because after initiating coagulation the TF–VIIa complex is neutralised by TFPI.

The regulatory or anticoagulant mechanisms limit the amount of thrombin generation and prevent propagation of thrombus as thrombin diffuses away from the site of injury. Free thrombin can be neutralised by plasma antithrombin to prevent propagation of thrombus but it may also bind to thrombomodulin, which is expressed on normal endothelium. When thrombin binds to thrombomodulin it becomes capable of converting protein C to its activated form, APC. APC has an important role in regulating coagulation because it inactivates factor VIIIa and …

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