Hypercoagulability refers to an abnormally high tendency of the blood to clot, and is typically caused by alterations in coagulation factors. It contributes infrequently to arterial or intracardiac thrombosis but is an important underlying risk factor for venous thrombosis. The alterations of the coagulation pathways that predispose affected persons to thrombosis can be divided into primary (genetic) and secondary (acquired) disorders (
Table 4.2
Primary (inherited) hypercoagulability is most often caused by mutations in the factor V and prothrombin genes: • Approximately 2% to 15% of whites carry a specific factor V mutation (called the Leiden mutation, after the Dutch city where it was first described). Among those with recurrent deep venous thrombosis (DVT), the frequency of this mutation approaches 60%. The mutation alters an amino acid residue in factor V and renders it
Table 4.2 Hypercoagulable States
FactorVmutation(G1691Amutation;factorVLeiden)Prothrombinmutation(G20210Avariant)IncreasedlevelsoffactorVIII,IX,orXIorfibrinogen
ProlongedbedrestorimmobilizationMyocardialinfarctionAtrialfibrillationTissueinjury(surgery,fracture,burn)CancerProstheticcardiacvalvesDisseminatedintravascularcoagulationHeparin-inducedthrombocytopeniaAnti-phospholipidantibodysyndrome http://ebooksmedicine.net resistant to proteolysis by protein C. Thus, an important anti-thrombotic counterregulatory mechanism is lost. Heterozygotes carry a fivefold increased risk for venous thrombosis, with homozygotes having a 50-fold increased risk.
A single-nucleotide substitution (G to A) in the 3′-untranslated region of the prothrombin gene is a fairly common allele (found in 1%–2% of the general population). This variant results in increased prothrombin transcription and is associated with a nearly threefold increased risk for venous thromboses.
Elevated levels of homocysteine contribute to arterial and venous thrombosis, as well as to the development of atherosclerosis (Chapter 10). The prothrombotic effects of homocysteine may be due to thioester linkages formed between homocysteine metabolites and a variety of proteins, including fibrinogen. Marked elevations of homocysteine may be caused by an inherited deficiency of cystathione β-synthetase.
Less common primary hypercoagulable states include inherited deficiencies of anti-coagulants such as antithrombin III, protein C, or protein S; affected patients typically present with venous thrombosis and recurrent thromboembolism in adolescence or in early adult life.
Although the risk of thrombosis is only mildly increased in heterozygous carriers of factor V Leiden and the prothrombin gene variant, these genetic factors carry added significance for two reasons. First, both abnormal alleles are sufficiently frequent that homozygous and compound heterozygous persons are not uncommon, and these individuals are at much higher risk for thrombosis. More importantly, heterozygous individuals are at higher risk for venous thrombosis in the setting of other acquired risk factors, such as pregnancy, prolonged bed rest, and lengthy airplane flights. Consequently, inherited causes of hypercoagulability should be considered in young patients (<50 years of age), even when other acquired risk factors are present.
Secondary (acquired) hypercoagulability is seen in many settings (
Table 4.2 ). In some situations (e.g., cardiac failure or trauma), stasis or vascular injury may be the most important factor. The hypercoagulability associated with oral contraceptive use and the hyperestrogenic state of pregnancy may be related to increased hepatic synthesis of coagulation factors and reduced synthesis of anti-thrombin