Disease States Associated With Hypercoagulability

Antiphospholipid antibodies, including lupus anticoagulants, anticardiolipin antibody, and anti–β ₂ -glycoprotein 1 antibody are associated with increased risk of thrombosis. Patients with lupus anticoagulants are actually hypercoagulable despite increased prothrombin times, and have increased risk for both arterial and venous thrombosis and miscarriage. Multiple mechanisms are responsible for increased thrombotic risk with antiphospholipid antibodies and are thought to be due to decreased thrombomodulin expression, increased tissue factor expression, and impairment of the protein C anticoagulant pathway. Patients with thrombosis (arterial or venous) or repeated pregnancy loss plus antiphospholipid antibody detected on at least two occasions at least 12 weeks apart meet diagnostic criteria for antiphospholipid syndrome. Patients with known antiphospholipid antibodies are at risk for recurrent thrombotic events and require ongoing anticoagulation, usually with warfarin.

Other important factors that contribute to hypercoagulability include renal and hepatic dysfunction, although these are commonly considered risks for bleeding. Severe hepatic dysfunction and cirrhosis lead to decreased synthetic capabilities and decreased levels of anticoagulant factors, including antithrombin, protein C, protein S, and plasminogen. Endothelial dysfunction, especially with renal failure and often pulmonary and portal vascular dysfunction, also occur. This, in turn, increases platelet activation and is an important cause of hypercoagulability. In nephrotic syndrome, fibrinogen levels are increased and antithrombin levels are low, increasing the potential for thrombosis.

Another important clinical setting is blood stasis, which commonly occurs with postoperative immobility or low cardiac output associated with heart failure—important risk factors for hypercoagulability. Although a low-flow state is a component of the Virchow triad, it alone does not create thrombosis. The importance of the other two Virchow factors— vessel wall abnormalities and dysfunctional blood constituents—is now becoming clear at the molecular level. Metabolic syndrome characterized by abdominal obesity, hypertension, elevated glucose, and increased cholesterol levels is associated with endothelial dysfunction and increased platelet aggregation. Cancer can have multiple causes for hypercoagulability, including cells that release microparticles to promote fibrin deposition. Advanced age is associated with procoagulant changes, including vascular dysfunction, increased fibrinogen levels, increased FVII, impaired fibrinolytic activity, and increased platelet aggregation. Many of these factors can be additive with complex interactions that are not well understood. Routine VTE prophylaxis is therefore an important part of perioperative management.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is an important antibody-mediated prothrombotic complication of heparin therapy that occurs in 0.5% to 5% of patients treated with heparin for at least 5 days (see Chapter 45 ). HIT is characterized by an otherwise unexplained drop in platelet count by 50% or more, often to less than 150,000/µL and frequently accompanied by thrombosis, plus the presence of HIT antibodies. When HIT is suspected, heparin, including low-molecular-weight heparin treatment, should be discontinued, and alternative anticoagulation therapy initiated even before laboratory confirmation.

HIT is mediated by antibodies to a complex of heparin and platelet factor 4 (PF4). Antibodies recognize antigenic sites newly exposed on PF4 when it is conformationally modified by binding to heparin. Platelets are activated by the Fc domain of the immunoglobulin G (IgG) in the heparin-PF4 immune complexes, and release microparticles that promote thrombin formation and thrombosis. Thrombocytopenia, excessive thrombin generation, and a prothrombotic state ensue. Antibody-mediated endothelial injury and tissue factor production further increase the prothrombotic state.

Up to 7% to 50% of heparin-treated patients generate heparin-PF4 antibodies, especially after cardiovascular surgery. HIT antibodies circulate with a median half-life of approximately 90 days. The presence and level of HIT antibodies, regardless of thrombocytopenia, are associated with increased morbidity or mortality in various clinical settings. Clinical HIT occurs in 1% to 5% of patients administered unfractionated heparin and less than 1% of patients administered low-molecular-weight heparin. Cardiac transplant and neurosurgery patients (11% and 15%, respectively), as well as orthopedic patients, are at increased risk of HIT.

HIT increases the risk of thrombosis, including deep VTE, pulmonary embolism, myocardial infarction, stroke, and limb artery occlusion requiring amputation. The overall risk for thrombosis in patients with HIT is 38% to 76%. Other risk factors for HIT-related thrombosis include female gender, malignancy, higher-titer heparin-PF4 antibodies, and more severe thrombocytopenia. Other complications include skin lesions at heparin injection sites, DIC, warfarin-associated venous limb ischemia, and acute systemic reactions after heparin bolus. Although counterintuitive, bleeding is rare even in the presence of severe thrombocytopenia.

HIT should be suspected whenever the platelet count drops by 50%, or new thrombosis occurs in a patient 5 to 14 days after the start of heparin therapy. Other causes of thrombocytopenia (e.g., sepsis, mechanical destruction with an intraaortic balloon pump or with extracorporeal circulation, or another drug-induced thrombocytopenia) should be excluded. In “rapid-onset” HIT, the platelet count begins to drop minutes to hours after heparin exposure, usually owing to heparin-PF4 antibodies from a previous heparin exposure within the prior 3 months. HIT should also be suspected if acute systemic reactions, such as hypotension, pulmonary hypertension, and/or tachycardia, occur 2 to 30 minutes after intravenous heparin bolus. This can be observed intraoperatively and can present as anaphylaxis, usually accompanied by acute thrombocytopenia. HIT can also occur days to weeks after stopping heparin (“delayed-onset HIT”), and should be considered if a recently hospitalized, heparin-treated patient presents with thrombosis. For suspected HIT, laboratory testing for heparin-PF4 antibody is recommended. Because of the high thrombotic risk early in HIT, treatment should not be withheld while awaiting laboratory results.

The recommended treatment for strongly suspected or confirmed HIT, with or without complicating thrombosis, is stopping heparin and initiating a nonheparin alternative anticoagulant. The mainstay agents include intravenous administration of a direct thrombin inhibitor, either argatroban or bivalirudin. Other heparin sources such as catheter flushes and heparin-coated devices should be eliminated. Different direct thrombin inhibitors are approved in the United States for use in HIT patients without initial thrombosis (argatroban), in HIT patients with thrombosis (argatroban), and in patients with or at risk of HIT undergoing percutaneous coronary intervention (argatroban, bivalirudin). Previously used agents that were derivatives of the leech protein hirudin are no longer available (desirudin, lepirudin). The more recently approved direct oral anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) provide potential alternatives for venous thromboembolic prophylaxis in patients but not as immediate therapies for HIT therapy. Recent evidence-based guidelines from the American College of Chest Physicians for the use of these alternative anticoagulants in patients with HIT in noninterventional and interventional settings have been reported. Alternative nonheparin anticoagulant strategies are required in HIT patients who need intraoperative anticoagulation. If heparin use is unavoidable or planned, the heparin exposure should be limited to the surgery itself, with alternative anticoagulation used preoperatively and postoperatively. If cardiac surgery is required, prospective studies have evaluated bivalirudin as the most investigated and useful alternative, although plasmapheresis has also been reported.