Hypercoagulable states

Abstract

Blood coagulation usually proceeds in an orderly fashion with the sequential activation of enzymes leading to the conversion of fibrinogen to fibrin by thrombin. Vessel patency is maintained or restored by the dissolution of fibrin by the fibrinolytic system. Most agree that in vivo thrombosis is likely to occur when the rate of blood flow is reduced, the vascular endothelial protective activity is reduced, the blood becomes hypercoagulable, and/or the fibrinolytic activity is impaired. Patients with hypercoagulable states are of a special concern to the vascular surgeon not only because they develop nonsurgical arterial and venous thromboses, which then require the attention of the surgeon, but also because the hypercoagulable states may adversely affect the results of surgical interventions. Hypercoagulable states are usually acquired, but they may be congenital. The acquired states occur in response to disease (e.g., increased blood viscosity from dehydration or polycythemia, and activation of coagulation by sepsis), in response to tissue injury (e.g., endothelial damage, and increases of fibrinogen, factor VIII, the platelet count, and alpha 1 antitrypsin), or in response to therapy (e.g., the heparin induced thrombocytopenia syndrome with platelet aggregation and thrombosis). The acquired hypercoagulable states are usually readily recognized and managed. The acquired condition of most concern to the vascular surgeon is the heparin-induced thrombocytopenia syndrome, which occurs in approximately 6% of patients receiving heparin. The syndrome is associated with arterial and venous thromboembolism and a morbidity of 23% to 61% and mortality of 12% to 23%.1Laster J Cirrit D Walker N Silver D The heparin induced thrombocytopenia syndrome: an update.Surgery. 1987; 102: 763-770PubMed Google Scholar Congenital hypercoagulable states are usually associated with reduced levels, or the presence of nonfunctional forms, of the regulatory proteins of coagulation or fibrinolysis. Antithrombin III (AT III) deficiency, with an incidence of one per 5000 of the population is the most prevalent inherited hypercoagulable state. Patients with low levels of AT III are predisposed primarily to venous thrombosis, but also have an increased risk for arterial thrombosis. The risk of thromboembolism is highest when the AT III falls below 60% of normal. Antithrombin III levels are reduced by intravascular thrombosis, hepatic insufficiency and sepsis. Protein C is a vitamin K dependent plasma protein that inhibits clot formation by inactivating activated factors V and VIII and enhances fibrinolysis by inhibiting tissue plasminogen activator inhibitor. Persons who are homozygous for protein C deficiency often develop thrombotic complications early in life. More than half of the persons who are heterozygous for protein C deficiency develop venous thromboembolism before the third decade.2Broekmans AW Veltkamp JJ Bertina RM Congenital protein deficiency and venous thromboembolism: a study of three dutch families.N Engl J Med. 1983; 309: 340-344Crossref PubMed Scopus (308) Google Scholar A type of deficiency has been described in which patients have immunologically normal, but functionally decreased protein C.3Bertina RM Brockmans AW Van ES Wijngaardan AV The use of a functional and immunologic assay for plasma protein C on the study of the heterogeneity of congenital protein C deficiency.Thromb Haemor. 1984; 51: 1-5PubMed Google Scholar Protein C may be reduced by hepatic insufficiency, vitamin K deficiency, and intravascular coagulation. Protein S is a vitamin K dependent plasma protein that functions as a cofactor for the anticoagulant effects of activated protein C. Protein C and protein S deficiencies have been found in 35% of patients less than 51 years of age with lower extremity vascular occlusive disease.4Jorgensen JE Flanigan DP Brace L Sawchuk AP et al.Hypercoagulable states and lower limb ischemia in young adults.J Vasc Surg. 1989; 9: 334-341PubMed Google Scholar The lupus anticoagulant, first described in patients with lupus erythematosus, but now found in patients without such systemic disorders, causes prolongation of the clotting tests (e.g., clotting time, prothrombin time, and the activated partial thromboplastin time). Most patients with the lupus anticoagulant do not bleed abnormally and usually tolerate major surgery without excessive bleeding. Paradoxically, patients with circulating lupus anticoagulants and the associated antiphospholipid antibodies have a high incidence of venous thromboembolism, myocardial infarction, abortions, and acute arterial occlusions. Patients with the anticoagulant are usually treated with long-term warfarin therapy. Increased thrombotic tendencies have also been found in patients with defects in plasminogen or the plasminogen activator system. These patients may suffer arterial and venous thromboses and are frequently treated with long-term warfarin therapy. It is accepted that hypercoagulable states adversely affect the efforts of vascular surgeons in restoring, pharmacologically or mechanically, vascular patency. Donaldson et al.5Donaldson MC Weinberg DS Belbin M Whittemore AD Mannick JA Screening for hypercoagulable states in vascular surgical practice: a preliminary study.J Vasc Surg. 1990; 11: 825-831PubMed Scopus (89) Google Scholar in this issue of the JOURNAL OF VASCULAR SURGERY have attempted to define the incidence and types of hypercoagulable states in the general vascular surgical population. They tested, before operation, 158 patients who subsequently had 137 “surgical reconstructions” for a variety of vascular disorders. One hundred fifty-seven patients had assays for AT III and proteins C and S; 150 patients were tested for heparin-associated antibodies; plasminogen was assayed in 141 patients; and lupus-like anticoagulant activity was assayed in 142 patients. Hypercoagulable states were detected in 14 of the 137 patients who subsequently had vascular reconstructions. The authors noted a much greater incidence of infrainguinal vein graft thrombosis in the “hypercoagulable” patients than in the patients with normal coagulation profiles. Flaws in the methodology of the authors included the following: (1) Some of the patients were taking warfarin or platelet function inhibitors at the time of their studies; (2) some of the patients may have been receiving heparin, which interferes with the aggregation assay for heparin associated antibodies; (3) it was not indicated how many of the patients had active thrombosis at the time of their assays. AT III and proteins C and S, and plasminogen are decreased during in vivo thrombosis; and (4) the patients were only studied once. To establish the presence of a congenital hypercoagulable state, the blood testing must also be “positive” at a time remote from the surgery or thrombotic event and after all drugs that affect the tests have been discontinued. Despite these problems with methodology, the report by Donaldson et al. support the growing body of data confirming that some patients are hypercoagulable and that these patients have an increased risk for thrombosis and vascular reconstructive failure. The suggestion by the authors concerning “routine preoperative screening” is valid. The best screen is a careful personal and family history concerning thrombotic events. Platelet count monitoring should be routine for all patients receiving heparin, with aggregation testing being done whenever the platelet count decreases and/or if new thromboembolism occurs. Any patient with an unexplained, prolonged prothrombin time and/or activated partial thromboplastin time should be tested for anticardiolipin antibodies to determine whether a lupus anticoagulant is present. It is difficult to recommend routine testing, at present, for the other factors in the panel selected by the authors. However, the vascular surgeon must be prepared, in addition to assaying for the presence of heparin-associated antibodies and the lupus anticoagulant, to obtain assays for AT III, proteins C and S, plasminogen and plasminogen inhibitors for any patient with a personal or family history of unexplained or recurrent thromboembolic events and for the patient with a nonmechanical, intraoperative or postoperative, intravascular thrombosis.