Inherited thrombophilias

In about 30-40% of patients with suspected inherited thrombophilia the PC-pathway is disturbed by a mutation ofFV (FV-Leiden). TheFV-Leiden mutation affects one of the APC cleavage sites within the FV molecule. As a consequence, mutated FVa becomes resistant to rapid APC inactivation (APC resistance). About 4-7% of the middle European population cany this polymorphism of FV. Inborn deficiencies of Protein-S or Protein-C are much less frequent (< < 1% and 0.2-0.4%, respectively). 

Manucci PM. The molecular basis of inherited thrombophilia. Vox Sang Suppl 2000 2 39-45. 

Dahlback B. Inherited thrombophilia resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 1995 85 607-14. 

De Stefano V, Rossi E, Paciaroni K, Leone G. Screening for inherited thrombophilia indications and therapeutic implications. Haematologica 2002 87 1095-1108. 

Several hematologic disorders and hemostatic defects increase risk of ischemic stroke. Inherited thrombophilias (such as factor V Leiden protein S, protein C, or antithrombin III deficiency or the prothrombin G20210A mutation) rarely contribute to stroke in adults, but may play a larger role in pediatric stroke. Antiphospholipid antibody syndrome consists of venous and arterial occlusive disease in multiple organs, miscarriages, and livedo reticularis [7]. The association between antiphospholipid antibodies and stroke in the absence of antiphospholipid antibody syndrome is strongest for young adults. In the Antiphospholipid Antibodies in Stroke substudy of WARSS (WARSS/ APASS), antiphospholipid antibodies were detected in 40.7% of stroke patients, but they had no effect on the risk of stroke recurrence (see Table 2.5) [88]. Thrombotic thrombocytopenic purpura (TTP) has... 

Third, there is a need to determine the underlying cause since this may be on an inherited basis described as thrombophilia where all family members need to be investigated. Experience and access to a superior haemostasis laboratory is needed. Defects may extend from hyperhomocysteinaemia through sticky platelet syndrome to mutations of factors V and II or reduced levels of the naturally occurring anticoagulants. Treatments differ and more than one abnormality in what is known as genetic coexpression may co-exist. Correspondence acquired lesions may reflect environmental influences. 

Data from the Leiden Thrombophilia Study have been used to construct a case-control study, based on contraceptive users who had experienced a first episode of objectively proven deep vein thrombosis (100). Patients and controls were considered thrombophilic when they had protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden mutation, or a prothrombin 20210 A mutation. Among healthy women, the risk of developing deep vein thrombosis was trebled in the first 6 months and doubled in the first year of contraceptive use. Among women with thrombophilia, the risk of deep vein thrombosis was increased 19-fold during the first 6 months and 11-fold (95% Cl = 2.1, 57) in the first year of use. Venous thrombosis during the first period of oral contraceptive use might actually point to the presence of an inherited clotting defect. 

The inherited disorders characterized by an tendency to form thrombi (thrombophilia) derive from either quantitative or qualitative abnormalities of the natural anticoagulant system. Deficiencies in the natural anticoagulants antithrombin, protein C, and protein S account for approximately 15% of selected patients with juvenile or recurrent thrombosis and 5-10% of unselected cases of acute venous thrombosis. Additional causes of thrombophilia include the factor V Leiden mutation, hyperhomocystinemia, and the prothrombin 20210 mutation that together account for the greater number of hypercoagulable patients. 

Inherited together, G1691A (factor V) and G20210A (factor II, prothrombin) convey at least a twentyfold increased risk for a venous thromboembolic event (VTE). They are commonly seen together in thrombophilia patients thus supporting the additive genetic effect associated with complex diseases. ... 

Lilli crap D. Molecular diagnosis of inherited bleeding disorders and thrombophilia. Semin Hematol 1999 36 340-351. 

THROMBATE III (Bayer) is a plasma-derived product that is used to treat AT-III deficiency, the first inherited trait discovered which was identified in 1965. The condition is associated with thrombophilia caused by low levels of AT-III or the presence of altered AT-III activity. Both conditions can result in excessive blood clotting. Acquired AT-III deficiency is another condition that occurs in situations with high risk of thrombosis such as trauma, burns, and sepsis. GTG Biotherapeutics conducted chnical trials with ATryn in high-risk situations such as surgery or child de-Hvery to prevent deep-vein thrombosis in hereditary AT-III-deficient patients and heparin-resistant patients with acquired AT-III deficiency undergoing coronary bypass. A pharmacokinetic study in patients with hereditary AT-III deficiency indicated that the administration of the recombinant product resulted in an increase in blood... 

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