Thrombophilia

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). 

Hypercoagulable state A disorder or state of excessive or frequent thrombus formation also known as thrombophilia. 

Tsuda H Iida H Nakahara M et al. Etiological analysis of thrombophilia. Jpn J Clin Pathol 1997 45,1025-30 (in Japanese). 

Thrifty genotype," 167 Thromboembolism, 176 Thrombophilias, 151 Tissues, gene expression profiles of, 89 Tissue susceptibility signatures, 147... 

Proper duration of therapy is unclear in first event with homozygous Factor V Leiden, homocystinemia, deficiency of protein C or S, or multiple thrombophilias and in recurrent events with reversible risk factors. 

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. 

In hormone replacement therapy, the risk of deep vein thrombosis is increased by a factor of 2-4 (35-37). The absolute increase in the treated population as a whole is low, with about one case of venous thromboembolism in 5000 women-years of use of hormone replacement therapy. However, in the subgroup with pre-existing risk factors, such as obesity, varicose veins, smoking, and a prior history of venous thromboembolism or superficial thrombophlebitis, the increase in risk from hormone replacement therapy can be substantial among these women are those with a genetic predisposition to thrombosis, generally due to some form of thrombophilia, such as deficiency of the coagulation inhibitors protein S, protein C, or anti thrombin III. In any of these subjects thrombosis can occur early in hormone replacement therapy. However, this tendency to early occurrence of deep vein thrombosis also seems to be present in all those who take hormone replacement therapy. 

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. 

Bloemenkamp KWM, Helmerhorst FM, Rosendaal FR, Vandenbroucke JP. Thrombophilias and gynaecology. Best Pract Res Clin Obstet Gynaecol 2003 17 509-28. 

Koopman, J., Haverkate, F., Lord, S. T., Grimbergen, J., and Mannucci, P. M. (1992). Molecular basis of fibrinogen Naples associated with defective thrombin binding and thrombophilia. Homozygous substitution of B beta 68 Ala —> Thr. J. Clin. Invest. 90, 238-244. 

Wu O, Robertson L, Langhorne P, et al. Oral contraceptives, hormone replacement therapy, thrombophilias and risk of venous thromboembolism a systematic review. The Thrombosis Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thromb Haemost. 2005 94 17-25. 

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. 

As low levels of protein C activation peptide are found in healthy individuals, it is suggested that protein C is constantly activated to a small degree (124). Protein C administration has been shown to inhibit both arterial and venous thrombosis in animal models (125). Heterozygous protein C deficiency or activated protein C resistance due to factor V mutation is thought to explain 60% to 70% of the cases of familial thrombophilia (I 16). 

The thrombotic disorders include atherothrombosis, endothelial dysfunction, hypercoagulable states, and the thrombophilias. Atherothrombosis or atherosclerosis is a systemic disease of the vessel wall occuring in the aorta, carotid, coronary, and peripheral arteries. The associated inflammatory response is mediated by macrophages and T-lymphocytes with continued smooth muscle cell proliferation, The levels of endothelin-l (ET-I), an extremely potent... 

Engesser L, Kluft C, Briet E, Brommer E. Familial elevation of plasma histidine-rich glycoprotein in a family with thrombophilia. BrJ Haematol 1987 67 355-358. 

Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993 90 1004-1008. 

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

Antithrombin. A serine protease inhibitor (serpin) that degrades the serine proteases of thrombin, factors IXa, Xa, XIa and Xlla. It is constantly active, but its adhesion to these factors is increased by the presence of heparin sulphate (a glycosaminoglycan) or the administration of heparins (different heparinoids increase affinity to factor Xa, thrombin, or both). Deficiency of antithrombin (inborn or acquired, e.g. in proteinuria) leads to thrombophilia. 

Various genetic blood disorders including sickle cell anemia and familial thrombophilias (Ch. 2) are associated with stroke. 

Thrombophilia e.g. antithrombin III deficiency, protein C deficiency, factor V Leiden mutation, protein S deficiency, plasminogen abnormality or deficiency Leukemia/lymphoma Polycythemia... 

Thrombophilias and other causes of hypercoagulability are rare causes of stroke (Matijevic and Wu 2006). Antithrombin III deficiency, protein C deficiency, activated protein C resistance owing to factor V Leiden mutation, protein S deficiency and plasminogen abnormality or deficiency can all cause peripheral and intracranial venous thrombosis. Thrombosis is usually recurrent and there is often a family history. Thrombophilia may cause arterial thrombosis, although the alternative diagnosis of paradoxical embolism should always be considered in patients with these disorders. It should be noted that deficiencies in any one of the factors associated with thrombophilia may be an incidental finding and cannot necessarily be assumed to be the cause of stroke. 

Thrombophilia personal or family history of thrombosis (usually venous, particularly in unusual sites such as hepatic vein) at unusually young age... 

Any underlying cause should be addressed for example, patients with a definite thrombophilia should probably take anticoagulation drugs for life oral contraceptives should never be used again, but a further pregnancy may be safe (Preter et al. 1996). 

---