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Introduction Anticoagulant mechanisms Antithrombin deficiency Protein C Anticoagulant Pathway Protein C deficiency Protein S deficiency Discovery of APC resistance/FV Leiden
Introduction
Venous thromboembolism is a major medical problem, affecting 1 in 1000 individuals annually. Multifactorial disease; circumstantial and genetic mechanisms.
Virchow discussed 3 broad categories of factors contributing to venous thrombosis and pulmonary embolism.
Introduction
Genetic and circumstantial risk factors affecting one or more of the 3 categories of Virchows triad. Circumstantial factors;
Increasing
Introduction
Anticoagulant Mechanisms
Tissue factor pathway inhibitor (TFPI); binds and inhibits newly formed FXa that is associated with the TF-FVIIa complex.
The activated coagulation enzymes can all be inhibited by the circulating serine protease inhibitor (serpin) antithrombin (AT). Regulation of the 2 cofactors FVIIIa and FVa by the protein C (PC) anticoagulant system.
Antithrombin deficiency
Antithrombin deficiency
Antithrombin deficiency
AT is a multifunctional serpin, inhibiting essentially all the active enzymes of the coagulation pathway. AT is a slow inhibitor, but the heparan sulfate (HS) family of glycosaminoglycans present on intact endothelium stimulates its inhibitory activity. The AT-binding region in heparin has been localized to a pentasaccharide sequence.
Antithrombin deficiency
Protein C was isolated and identified as a vitamin Kdependent protein by Stenflo in 1976. Anticoagulant properties after its activation by thrombin. Thrombin itself is a poor activator of protein C.
Thrombomodulin (TM) as a cofactor for the reaction discovery by Owen and Esmon in 1981.
TM is present on the surface of endothelial cells. Thrombin binds with high affinity to TM.
Loss of the procoagulant activities of thrombin and gain of the ability to activate protein C. Concentration of TM in the microcirculation is crucial for local protein C activation. In recent years, an endothelial cell protein C receptor (EPCR) has been identified.
APC inhibits the coagulation pathway by specifically cleaving of peptide bonds in FVIIIa and FVa. APC is slowly inhibited by either the protein C inhibitor (PCI) or by 1antitrypsin.
Protein C deficiency
Protein C deficiency
In 1981, Griffin et al were the first to describe heterozygous protein C deficiency in a family with a history of recurring thrombosis. Homozygous protein C deficiency was found to be associated with severe neonatal purpura fulminans. Type I deficiency; decreased protein concentration. Type II deficiency; normal protein C concentration, low protein C activity.
Protein C deficiency
Protein C deficiency was found slightly more often than AT deficiency, but still in less than 5%.
Protein S deficiency
Protein S deficiency
In 1984, the first thrombosis patients with protein S deficiency were described.
Type I; free and total protein S levels were low. Type II; functional deficiency. Type III; only the free form was low.
Deficiencies of AT, protein C, and protein S were identified in lessthan 10%. Even though positive family histories were present in up to 40% of the cases.
1993 the discovery of APC resistance. APC resistance was found to be highly prevalent (20-60%) among thrombosis patients. 1994 The protein identity was coagulation factor V. Suggesting APC resistance to be caused by a mutation in the FV gene. The mutant FV is commonly referred to as FV Leiden.
Prothrombin mutation
The mutation is located in the 3 untranslated region of the prothrombin gene; does not change the structure of prothrombin.
Slightly increased plasma levels of prothrombin, a lifelong 3-to 4-fold increased risk of venous thrombosis.