There exist far more known causes of acquired hyperco-agulable disorders than inherited disorders. Additionally, several of the congenital hypercoagulable states may be seen as acquired states due to a change in the production or consumption of various factors. Many of the common causes of acquired hypercoagulable disorders will be discussed.
Heparin-induced Thrombocytopenia (HIT) and Heparin-induced Thrombocytopenia and Thrombosis Syndrome (HITTS)
Approximately 2 to 3% of patients who undergo heparin therapy will develop HIT or HITTS. Patients with HIT will have thrombocytopenia (characterized by a platelet count less than 100,000/mm3 or a decrease in the baseline count by more than 30%), will be resistant to anticoagulation with heparin, and may develop arterial or venous thromboses.
Two types of HIT exist. The first type is not associated with an immune mediated response and typically is seen in the first few days after initiation of heparin therapy. Typically, platelet levels do not fall below 100,000/mm3. Type II is immune-mediated with patients producing IgG antibodies against complexes of heparin and platelet factor 4. Antibody formation usually occurs between the fifth and tenth day after the first heparin exposure. The formation of these immune complexes creates a hypercoagulable state by activating platelets and the endothelium.8,20
Antibodies may develop against any form of heparin and the formation of antibodies is independent of the age or sex of the patient, the route of administration of heparin, or the amount of heparin administered. Clinically, a patient will have a declining platelet count, may have an increasing resistance to anticoagulation therapy with heparin, and may develop a new thrombosis. Laboratory testing may be performed, which includes testing for antibodies to heparin.1 Functional assays to detect platelet aggregation or activation in the presence of heparin-associated antibodies are well established. Enzyme-linked immunosorbent assays (ELISA) are readily available, but there is up to 40% discordance in the results of these antigenic assays, when compared with the functional platelet aggregation tests. The ELISA may detect IgM and IgA varieties, whereas platelet aggregation assays detect only the IgG antibodies.
The treatment of HIT includes the prompt discontinuation of heparin or low-molecular-weight heparin, and the administration of alternative anticoagulants such as recombinant hirudin or argatroban (both direct thrombin inhibitors). Danaparoid (a low-molecular-weight heparinoid) has been used in the past as an alternative anticoagulant in patients with HIT. However, danaparoid production was discontinued in 2002 due to a shortage in the drug substance. Fondaparinux (a pentasaccharide that inactivates factor Xa via an antithrombin-dependent mechanism) has had recent success as another alternative anticoagulant. As with hirudin and argatroban, there are no reliable agents that can reverse the anticoagulant effect of fondaparinux. Hirudin and fondaparinux are metabolized primarily via renal excretion, whereas argatroban is metabolized primarily by the liver.
Patients with heparin-induced thrombocytopenia are at high risk for the development of subsequent thromboses, and the discontinuation of heparin alone is usually not sufficient. Warfarin may be used for prolonged anticoagulation in patients with acute thromboses, but its initiation should be delayed until the platelet count has substantially recovered. In addition, warfarin therapy should overlap with the administration of a direct thrombin inhibitor until the platelet count normalizes.
Lupus Anticoagulant/Antiphospholipid Antibody Syndrome
The term antiphospholipid syndrome was developed to describe the clinical manifestations of a hypercoagulable state associated with antiphospholipid antibodies. The most commonly identified antiphospholipid antibodies are lupus anticoagulant, anti-cardiolipin antibody, and anti-P2-glycoprotein I antibodies.21
This syndrome is divided into primary and secondary syndromes. The primary syndrome occurs in patients without associated autoimmune disorders and the secondary syndromes occur in patients with systemic lupus erythematosus and/or other autoimmune disorders. The procoagulant effects of the antiphospholipid antibodies leading to thrombosis include inhibition of the activated protein C pathway, inhibition of antithrombin activity, inhibition of anticoagulant activity of P2-glycoprotein I, inhibition of fibrinolysis, potentiation of platelet activation, and enhanced platelet activation, among others.8,21
Antiphospholipid antibodies are found in 1 to 5% of the population and their prevalence increases with age. Among patients with SLE, the prevalence of antiphospholipid antibodies is much higher, with 12 to 30% having anticardio-lipin antibodies and 15 to 34% having lupus anticoagulant
TABLE 38.3 Criteria for the Classification of the Antiphospholipid Syndrome22
International consensus statement on preliminary criteria for the classification of the antiphospholipid syndrome
Vascular thrombosis: 1 or more clinical episodes of arterial, venous, or small vessel thrombosis, occurring within any tissue or organ.
Complications of Pregnancy:
1 or more unexplained deaths of morphologically normal fetuses at or after the 10th week of gestation; or
1 or more premature births of morphologically normal neonates at or before the 34th week of gestation; or
3 or more unexplained consecutive spontaneous abortions before the 10th week of gestation.
Anticardiolipin IgG or IgM antibodies present at moderate or high levels in the blood on 2 or more occasions at least 6 weeks apart.
Lupus anticoagulant antibodies
Lupus anticoagulant antibodies detected in the blood on two or more occasions at least six weeks apart.
antibodies. In patients with SLE and an antiphospholipid antibody, 50 to 70% may develop the antiphospholipid syndrome.1 In order for the diagnosis of antiphospholipid syndrome to be made, the patient must meet the criteria of the International Consensus Statement. A definitive diagnosis may be made if the patient has at least one of the clinical criteria and one of the laboratory criteria. The Consensus Statement is defined in Table 38.3.
Clinically, the most common manifestation of the antiphospholipid syndrome is deep venous thrombosis of the legs. Arterial thrombosis also may be seen but less often than venous thrombosis. Laboratory tests to detect the antiphos-pholipid antibodies include the activated partial thrombo-plastin time (aPTT), performed with and without exogenous normal plasma to detect the presence of an inhibitor. Other tests include the kaolin clotting time, and dilute Russell's viper venom time (dRVVT). ELISA tests are performed to detect anticardiolipin antibodies and anti-P2-glycoprotein I antibodies.21
Aspirin and hydroxychloroquine have been used in subsets of patients with the antiphospholipid syndrome for prophylaxis against thrombotic events. The treatment of established venous thromboembolism in these patients consists of acute heparinization and longer-term (possibly life long) vitamin K antagonists. The optimal intensity of warfarin anticoagulation (INR 2.0-2.9 versus 3.0-3.9) has not been determined.21
This disorder is the most severe nonhemorrhagic complication of oral anticoagulation. Although rare, it seems to show a predilection for perimenopausal obese women who are being anticoagulated. Venules and capillaries within the subcutaneous fat and overlying skin thrombose, leading to necrosis. This typically is seen in the subcutaneous fat of the breasts, thighs, buttocks, and legs. Clinically, the patient may initially have paresthesias, which are then followed by painful, erythematous lesions. When hemorrhagic bullae are present, this is indicative of full thickness skin necrosis.
The pathogenesis for this process is the depletion of protein C prior to the other vitamin K-dependent coagulation factors. As the half-life of protein C is only eight hours, its rapid depletion causes a transient hypercoagulable state until the rest of the vitamin K-dependent factors also are reduced to levels that produce anticoagulation.
The primary treatment is prevention with heparin or low-molecular-weight heparin anticoagulation for the first 48 to 72 hours of anticoagulation with warfarin. If skin necrosis develops, warfarin needs to be discontinued and anticoagulation may continue with heparin or a direct thrombin inhibitor.8
The risk of thrombosis is dependent on the type of surgery and the presence of additional risk factors. This risk may persist for up to several months after surgery. Patients who are at particularly high risk include those who undergo hip fracture surgery, hip or knee arthroplasty, neurosurgical procedures, and patients with major trauma. Injury to tissues and vessels during the procedure may enhance thrombogen-esis.8,23 Operative dissection, thermal injuries, and soft tissue trauma activate the coagulation cascade by inducing tissue factor release, thereby increasing the thrombogenic risk.
With a major traumatic injury, risk for venous thrombosis is highest in patients with spinal injuries, pelvic fractures, and lower extremity fractures. The risk of thrombosis also increases with greater injury severity. In part, this may be due to the accompanying systemic inflammatory response (another prothrombotic state, covered later).
During pregnancy, there is an associated hypercoagulable state due to the increase in factors I, VII, VIII, IX, X, XI, and XII. Additionally, platelet counts increase and concentrations of protein S and antithrombin decrease. The fibrino-lytic system also may be inhibited secondary to the increased production of plasminogen-activated inhibitors 1 and 2 by the placenta. Compounding this risk is the degree of stasis that occurs as a result of compression of the lower extremity veins by the gravid uterus. In the postpartum period, the risk for thrombosis is up to five times greater than during pregnancy. Approximately two months after delivery, the coagulation and fibrinolytic systems will return to normal.1
The risk of thrombosis is increased further in pregnant women who have a genetic risk for thrombosis. Depending on the inherited thrombophilia, a woman with a thrombo-philia who becomes pregnant may have a risk of venous thrombosis up to eight times higher than those without a thrombophilia.4 In addition, women with a genetic risk for thrombosis are also at an increased risk for fetal loss and pre-eclampsia. Many women with a history of thrombo-philia or thromboembolism are treated with heparin, low-molecular-weight heparin, and/or aspirin while pregnant.24
Oral contraceptives are one of the most frequently used drugs by women. The use of oral contraceptives initially was associated with a three-fold increased risk of venous thrombosis. With the decrease in the amount of estrogen placed in the pill, a subsequent decrease in the incidence of venous thrombosis was seen. With lower levels of estrogen, the risk of thrombosis is 1.5 to 2 times that over control patients. Additionally, newer oral contraceptives using newer progesterones have shown an increased risk of thromboembolism.25
The risk for venous thrombosis is highest during the first year of use of the oral contraceptive and the risk is not cumulative with prolonged use. Once the pill is discontinued, the risk returns to baseline for that patient.25,26
Oral contraceptives influence the plasma levels of nearly every protein involved in coagulation. Factors VII, VIII, IX, X, and XI increase, and the natural anticoagulants anti-thrombin and protein S decrease. However, oral contraceptive administration is associated with elevated protein C, ^-antitrypsin, and fibrinolytic proteins, producing an anti-thrombotic effect. Additionally, the pill has been associated with an acquired activated protein C resistance occurring within three days of initiation of the pill and reversing with discontinuation. This resistance has been shown to have a more pronounced increase in those women using third-generation oral contraceptives. The combination of activated protein C resistance, increased prothrombin levels, and decreased protein S levels produces a net pro-thrombotic affect and confers the prothrombotic risk of oral contraceptives.27,28
In women with inherited thrombophilias who also take oral contraceptives, the risk for thrombosis increases 30- to 50-fold. For example, women who take oral contraceptives and are heterozygous for the Factor V Leiden mutation have been shown to have an increased risk of venous thrombosis by a factor of approximately 35. This increased relative risk for venous thrombosis is in the same order of magnitude as patients who are homozygous for the Factor V Leiden mutation (almost 50-fold increased risk). The women who have other inherited thrombophilias also appear to have a remarkably increased risk.4,25
Historically, hormone replacement therapy (HRT) has been used to reduce the progression of osteoporosis, relieve the symptoms of menopause, and reduce the cardiovascular risk profile. Several studies including the Heart Estrogen/ Progestin Replacement Study (HERS) and the Women's Health Initiative (WHI) have shown an increased risk of venous thromboembolism with the use of HRT. A two- to four-fold increased risk, compared to nonusers, has been shown.26,29
Similar to oral contraceptives, the risk of venous throm-boembolism is highest during the first year of HRT. Once HRT is discontinued, the risk of thrombosis returns to baseline. Additionally, increasing age has been associated with an increased risk of venous thrombosis. Several studies also have shown an increased risk in patients using HRT who had lower extremity fractures, recent surgery, previous venous thromboembolism, cancer, and obesity.29 Also similar to oral contraceptive pills, patients on HRT with thrombophilias have a significantly increased risk of venous thromboembo-lism.4 The coagulation factor changes, which occurs as a result of hormone replacement therapy, and is similar to those changes that occur with oral contraceptive pills, but to a lesser degree.
Systemic Inflammatory Response (SIR) and Sepsis
With the systemic inflammatory response, cytokines and other inflammatory mediators are released causing a pro-thrombotic state. Specifically, tumor necrosis factor a and interleukin-1a are increased. These factors activate the coagulation cascade, cause an increase in tissue factor expression, and decrease levels of protein C and S. Fibrino-gen synthesis also will increase as part of the inflammatory response. Additionally, the inflammatory response is enhanced by thrombin, which augments leukocyte adhesion and activates platelets. Platelet activation in turn, further promotes tissue factor expression and increases cytokine release. All these factors contribute to the hypercoagulable state seen with SIRS and sepsis and predispose the patient to thrombosis.30
Venous thromboembolism (VTE) is a common complication of cancer. In 10% of patients who present with an idiopathic VTE, malignancy will be discovered. The majority of thrombotic episodes occur spontaneously, although patients with cancer often have other concurrent risk factors (inherited thrombophilias, immobilization, major surgical proce dures, chemotherapy, and central venous catheters) that place them at high risk for venous thromboembolism.
Tissue factor and cancer procoagulant are produced by tumor cells. The cancer procoagulant directly activates factor X independently of factor VII. Additionally, tumor cells produce proteins that may regulate the fibrinolytic system. These proteins impair fibrinolytic activity leading to a prothrombotic state.31 Tumor cells also produce various cytokines and affect the coagulation cascade and induce a thrombogenic state in a similar manner as SIRS. TNF-a and interleukin ip are released by cancer cells and induce tissue factor expression and down-regulate thrombomodulin. Furthermore, tumor cells activate other cytokines and several different types of leukocytes, which also increase tissue factor expression and activate platelets. The interaction of all these processes lead to a prothombotic condition.31
We perform testing for inherited thrombophilic conditions in the following clinical circumstances: idiopathic DVT, recurrent DVT, DVT with young age at onset, and venous thromboses in unusual locations (mesenteric or portal venous thrombosis, cerebral vein thrombosis). Many hospitals provide testing with a "hypercoagulable panel." However, the clinician should ascertain that the following tests are being performed: antithrombin activity, protein C activity, protein S activity, testing for either activated protein C resistance or factor V Leiden, prothrombin gene mutation, homocysteine levels, anticardiolipin antibody and lupus anticoagulant testing, factor VIII activity. Antithrombin, protein C, and protein S levels may be depressed by the presence of acute thrombosis. Protein C and S may be similarly affected by warfarin administration. Therefore, an abnormal test result drawn during these time periods does not necessarily signify the presence of an inherited throm-bophilic condition. Repeat testing is required.
Other Acquired Hypercoagulable Conditions and Treatment Stratification
Patients are predisposed to thrombosis via many other clinical conditions. These conditions may affect the coagulation cascade, the fibrinolytic system, and/or platelet function, thereby increasing the risk of thrombosis. With two or more conditions that predispose to thrombosis, the patient is at a higher risk for suffering a thrombosis.
The objectives for treating acute venous thromboembolism include the prevention of death from pulmonary embolism, reduction of lower extremity symptoms, prevention of the post-phlebitic syndrome, and prevention of recurrent venous thromboembolism. By limiting the propagation of
TABLE 38.4 American College of Chest Physicians Recommendations for Duration of Anticoagulation for Venous Thromboembolism32
First episode DVT/transient risk
First episode DVT/concurrent cancer
First episode DVT/thrombophilia antithrombin deficiency protein C and S deficiency factor V leiden prothrombin 20210 homocysteinemia factor VIII elevation (>90th %)
First episode DVT/thrombophilia Antiphospholipid antibodies 2 or more thrombophilias
UH/LMWH followed by 3 mos
VKA 3-6 mos LMWH Indefinite anticoagulation until cancer resolves UH/LMWH followed by 6-12 mos
VKA (suggest indefinite) UH or LMWH followed by 6-12 mos VKA (suggest indefinite if idiopathic)
UH or LMWH followed by 12 mos VKA (suggest indefinite)
UH or LMWH followed by indefinite VKA
UH = unfractionated heparin, LMWH = low-molecular-weight heparin, VKA = vitamin K antagonist.
thrombus, anticoagulation potentially has a role in achieving all of these objectives. Initial anticoagulation with unfrac-tionated heparin or low-molecular-weight heparin, followed by six weeks to six months of oral vitamin K antagonists has been the mainstay of therapy. More recently, the American College of Chest Physicians Consensus Statement has stratified the type and duration of anticoagulation, based in part on the whether the patient has a concurrent thrombo-philic condition (see Table 38.4).32 In general, the overall trend is to extend the duration of anticoagulation, especially in patients with recurrent DVT, antiphospholipid syndrome, and patients with multiple thrombophilic conditions. In patients with malignancy and venous thromboembolism, the recommended duration of low-molecular-weight heparin therapy has been extended to three to six months, followed by long-term vitamin K antagonists.
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