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Section 9. Hematologic Disorders and Cancer
Chapter 70. Hypercoagulability and Anticoagulation
Topics:    Introduction | Hypercoagulable States | Prophylaxis of Venous and Arterial Thromboembolism

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Hypercoagulable States

The hypercoagulable (thrombophilic) states, which involve excess clotting factors and/or defective intrinsic regulatory (thromboresistance) mechanisms, can be inherited or acquired (see Table 70-1). Although inherited thrombophilias can manifest for the first time at an advanced age, most elderly people who experience a thrombotic event should be evaluated for an acquired thrombophilia.

Inherited Thrombophilias

With most inherited thrombophilias, venous thromboembolism is more common than arterial thromboembolism. However, MI and stroke have been reported (in some cases the result of paradoxical embolism or cerebral sinus thrombosis).

Activated Protein C Resistance

Nearly 30% of patients with spontaneous venous thrombosis have a defect in factor V that renders it resistant to activated protein C neutralization. The specific gene mutation, referred to as factor V Leiden defect, is present in nearly 5% of the general population, making activated protein C resistance by far the most common inherited thrombophilia. Activated protein C resistance increases the risk of venous thromboembolism approximately fivefold, with 30 to 40% of persons with this disorder experiencing a thrombotic event by age 60. Therefore, a relatively large proportion of affected persons either remain event-free or experience their first event later in life. Nearly 30% of men with their first venous thromboembolism after age 60 have the factor V Leiden mutation. The risk of recurrent idiopathic venous thromboembolism among these persons is increased fourfold to fivefold.

Activated protein C resistance is an important defect to be aware of when hormone therapy is being considered. Among women who experience venous thromboembolism during oral contraceptive use, 60% have the defect. The risk for women receiving postmenopausal estrogen replacement therapy has not been established. An association between protein C resistance and MI has been described in women who smoke.

Hyperhomocysteinemia

Several inherited defects in methionine metabolism can lead to either mild, moderate, or marked increases in plasma homocysteine levels. Acquired hyperhomocysteinemia is observed in persons with vitamin B6 (pyridoxine), B12 (cobalamin), and folate deficiency as well as in those with chronic renal failure and drug-induced abnormalities in folic acid (methotrexate, anticonvulsants), cobalamin (nitrous oxide), or pyridoxine (theophylline) metabolism.

Several epidemiologic studies have identified a relationship between hyperhomocysteinemia and venous thromboembolism. An association with arterial thrombosis (MI, stroke) has also been reported. If confirmed, hyperhomocysteinemia may represent one of the most common hypercoagulable states, given its worldwide prevalence and ability to manifest in both inherited and acquired forms.

Other Inherited Thrombophilias

Antithrombin deficiency, previously referred to as antithrombin III deficiency, may affect the elderly. Antithrombin is a glycoprotein that binds and inactivates thrombin and other coagulation proteins. The inhibitory effect of antithrombin is markedly accelerated by heparin administered exogenously (for therapeutic reasons) and by endogenous heparin sulfate found on the vascular endothelial surface.

Protein C deficiency (prevalence, about 1/100) occurs either because the quantity (type I protein C deficiency) of the protein is low or its quality (type II protein C deficiency) is abnormal. Up to 50% of persons with this disorder experience venous thromboembolism by age 50, and 75% experience it by age 60. Variable expression of disease and concomitant risk factors are responsible for first thromboembolism in later years.

Protein S deficiency usually produces a first venous thromboembolism by age 40. Protein S is a vitamin K-dependent glycoprotein synthesized in the liver that serves a pivotal supporting role for protein C activity.

There are no detailed data on the elderly. The prevalence of disease for inherited abnormalities would not change over time unless the events are fatal. Most people with deficiency of antithrombin, protein C, or protein S experience their first venous thromboembolism by age 40. However, in some cases, patients have not sought medical attention or been tested thoroughly for an inherited thrombophilia.

Acquired Thrombophilias

Antiphospholipid Antibody Syndrome

Antiphospholipid antibodies are a heterogeneous group of circulating polyclonal (IgG, IgM, IgA) or mixed immunoglobulins directed against negatively charged or neutral phospholipids. Within this group, the lupus anticoagulant and anticardiolipin antibodies are the most commonly acquired. They predispose to both arterial and venous thrombosis. Antiphospholipid antibodies occur in a variety of autoimmune disorders, malignancies, lymphoproliferative disorders, and systemic viral infections; however, most persons experiencing thromboembolism have no identifiable clinical condition. These persons are considered to have primary antiphospholipid antibody syndrome.

Malignancy

A strong association exists between malignancy and venous thromboembolism. The overall incidence of venous thromboembolism among cancer patients ranges from 1 to 15% in clinical series and up to 30% in autopsy-based reports. Malignancies with the highest rates of thromboembolism include mucin-producing adenocarcinomas of the gastrointestinal tract followed by tumors of the lung, breast, and ovary. Myeloproliferative disorders and leukemias are also associated with an increased incidence of thromboembolism.

In elderly patients, it is not uncommon for DVT or pulmonary embolism to be the initial manifestation of malignancy. Therefore, careful screening should be carried out in all patients > 60 who experience idiopathic (spontaneous) venous thromboembolism.

Disseminated Intravascular Coagulation

Abnormal generation of fibrin in the circulating blood.

Disseminated intravascular coagulation (DIC) can accompany a wide variety of conditions, including sepsis, metabolic acidosis, acute and chronic leukemias, malignancy, and hemolytic transfusion reactions. The initial event is often mediated by tissue factor that is released by vascular endothelial cells, monocytes, or amnionic cells. The trigger itself varies from endotoxins to amnionic fluid and procoagulant factors released by tumor cells.

DIC begins with a stimulus for intravascular thrombosis followed by a consumption of coagulation factors and stimulation of fibrinolysis. The clinical expression of DIC is a combination of thrombosis, characteristically affecting the microcirculation, and hemorrhage. Acute DIC is a fulminant process that causes both tissue necrosis and life-threatening hemorrhage. When chronic DIC accompanies malignant conditions, thrombosis often predominates.

Diagnosis

The prothrombin time (PT), activated partial thromboplastin time (aPTT), and thrombin time are typically prolonged, and the fibrinogen level and platelet count are decreased. Schistocytes (evidence of intravascular hemolysis) are present in about 50% of patients, a finding shared by other conditions that cause microangiopathic hemolytic anemia. Fibrinogen (fibrin) degradation products (FDP) are elevated in 85 to 100% of patients with DIC; however, they too are nonspecific even when quantitated using a latex agglutination assay. Nonetheless, because enhanced fibrinolysis is a feature of DIC, many clinicians still use the FDP as an initial screening test.

In contrast to FDP, d-dimers are specific for factor X activation and fibrin formation. Although d-dimers may also be elevated in patients with DVT and pulmonary embolism (without DIC), the assay is considered the most reliable method for diagnosing DIC. Results are elevated in nearly 95% of cases.

Antithrombin levels and quantitative thrombin-antithrombin complexes represent important means for diagnosing and monitoring DIC. Antithrombin is consumed in DIC as antithrombin-thrombin complexes are generated. Determination of fibrinogen levels does not add additional diagnostic information, but levels should be measured in patients with uncontrolled hemorrhage, because patients with low fibrinogen levels and DIC accompanied by life-threatening hemorrhage may benefit from cryoprecipitate transfusion.

Once the diagnosis of DIC is confirmed by finding high d-dimer and FDP titers (in combination with low antithrombin levels), subsequent monitoring (and assessment of DIC status) can be carried out as needed with serial d-dimer assays.

Treatment

The keys to managing DIC center on the diagnosis and treatment of the underlying disorder. The specific treatment of DIC is limited but can be broken down into three categories: (1) restoration of hemostasis, (2) prevention of thrombosis, and (3) removal of thrombus. Transfusion of packed RBCs and fresh frozen plasma may be required to restore intravascular volume and to replace consumed coagulation factors. Cryoprecipitate and platelet transfusions can be used in patients with severe bleeding, although there is a theoretical risk that this will worsen clotting. Low-dose heparin (300 to 400 U/hour) can prevent microthrombosis in patients in whom the risk of bleeding is relatively minor compared with the probability of thrombosis. Low-dose heparin is most useful in patients with septic shock and DIC. It also should be considered when a thrombotic event (eg, pulmonary embolism) is the precipitating cause of DIC. In this case, standard heparin doses may be used if bleeding is not evident. When bleeding occurs, thrombectomy (surgical, extraction catheter) and filter placement should be considered.

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