Factor V Leiden

Individuals with heterozygous protein C deficiency are seven times more likely to be afflicted with venous thrombosis than normal individuals. A combination of protein C deficiency with a mutation in the factor V gene (factor V Leiden) carries a much greater risk for venous thrombosis than the presence of only one of these conditions (89). 

Thrombogenic mutations (e.g., factor V Leiden, protein C or S deficiency, antithrombin III... 

Thromboembolism increased with factor V Leiden, factor II (prothrombin), or high factor VII variants... 

Middeldorp, S., et al., "A Prospective Study of Asymptomatic Carriers of the Factor V Leiden Mutation to Determine the Incidence of Venous Thromboembolism," Ann. Intern. Med., 135, 322-327 (2001). 

Sarasin, F.P. and H. Bounameaux, "Decision Analysis Model of Prolonged Oral Anticoagulant Treatment in Factor V Leiden Carriers with First Episode of Deep Vein Thrombosis," BMJ, 316, 95-99 (1998). 

Spannagl, M., et al., "Are Factor V Leiden Carriers Who Use Oral Contraceptives at Extreme Risk for Venous Thromboembolism " Eur. ]. Contracept. Reprod. Hlth. Care, 5, 105-112 (2000). 

Chapman, J., Wang, N., Treves, T.A., Korczyn, A.D., Borstein, N.M. (1998) ACE, MTHFR, factor V Leiden, and APOE polymorphisms in patients with vascular and Alzheimer s dementia. Stroke, 29, 1401-1404. 

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. 

K6. Kowalski, A., Radu, O., and Gold, B., Colorimetric microwell plate detection of the factor V Leiden mutation, Clinical Chemistry 8, 1195—1198 (2000). 

Controls were a sample of 723 postmenopausal women without MI who were matched to cases by age, calendar year, and hypertension status. The main outcome measure was risk of hrst nonfatal MI based on current use of HRT and the presence or absence of coagulation factor V Leiden and prothrombin 20210 G A variants among cases and controls, stratihed by hypertension. 

In the study populations, 108 MI cases and 387 controls had hypertension. Among women with hypertension, the prothrombin variant was a risk factor for MI (odds ratio 4.32). Compared with nonusers of HRT with wild-type genotype, women who were current users and who had the prothrombin variant had a nearly 11-fold increase in risk of a nonfatal MI. The interaction was absent among normo-tensive women. No interaction was found for factor V Leiden in either hypertensive or normotensive women. 

Defects in natural anticoagulants result in an increased risk of venous thrombosis. The most common defect in the natural anticoagulant system is a mutation in factor V (factor V Leiden), which results in resistance to inactivation by the protein C, protein S mechanism. 

For example, women who have the factor V Leiden mutation and take oral contraceptives have a synergistic increase in risk. 

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. 

Machin SJ, Mackie IJ, Guillebaud J. Factor V Leiden mutation, venous thromboembolism and combined oral contraceptive usage. Br J Fam Planning 1995 21 13-4. 

Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet 1995 346(8990) 1593-6. 

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. 

Rees DC, Liu YT, Cox MJ, Elliott P, Wainscoat JS. Factor V Leiden and thermolabile methylenetetrahydrofolate reductase in extreme old age. Thromb Haemost 1997 78 1357-1359. 

The inherited (primary) hypercoagulable states include activated protein C resistance due to the factor V Leiden mutation, prothrombin gene mutation, antithrombin deficiency, protein C or protein S deficiency, and dysfibrino-genemia. The most important cause of activated Protein C resistance is the defect in factor V involving the mutation of Arg506 to Gln506 (191). 

Hepatic venous thrombosis, also known as Budd-Chiari syndrome, is caused by hypercoagulable disorders precipitated by pregnancy, infection, and birth control medication. An acute painful abdomen, sudden enlargement of the liver, and the presence of ascites make up a triad of clinical symptoms that are important in the diagnosis of this syndrome. Myeloproliferative disorders such as polycythemia vera and paroxysmal nocturnal dyspnea were previously thought to be responsible. Factor V Leiden and prothrombin 20210 mutations are also known to be responsible, Other intraabdominal thromboses include portal vein thrombosis, mesenteric vein thrombosis and renal vein thrombosis. 

Epidemiological studies indicate that elevated plasma tHcy increases the risk of venous thromboembolism (43,44), In homocystinuria, the presence of the factor V Leiden mutation further increases the risk of thromboembolism (45). It has been proposed that hyperhomocysteinemia might interfere with the inhibition of activated factor V by activated protein C, possibly via similar effects as those caused by the factor V Leiden mutation (46,47), However, one in vitro study (48) and one large clinical study failed to demonstrate an association between hyperhomocysteinemia and activated protein C resistance (49). 

Hey has been shown to reduce binding of tPA to its endothelial cell receptor, annexin II, in cell cultures (50). Animal studies have indicated that elevated plasma tHcy could cause acquired dysfibrinogenemia, leading to the formation of clots that are abnormally resistant to fibrinolysis (51), Elevated plasminogen activator inhibitor and tHcy in patients with acute coronary syndrome have been shown to be associated with increased risk for major adverse cardiac events (MACE) after successful percutaneous coronary intervention (PCI) and stenting (52), whereas factor V Leiden mutation and lipoprotein (a) were not. 

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