Hypercoagulability - Hereditary Thrombophilia and Lupus Anticoagulants Associated With Venous Thrombosis and Emboli Treatment & Management

The goal of this article is not to review the management of venous thrombosis and pulmonary embolism; therapy for these conditions is reviewed in other articles.(See Antiphospholipid Syndrome, Protein C Deficiency, Protein S Deficiency, Antithrombin III Deficiency, and Antiphospholipid Antibody Syndrome and Pregnancy for greater detail.)

However, indications for anticoagulation to prevent thromboembolism in patients at risk should be considered (primary anticoagulation or prophylaxis). Primary prophylaxis would be indicated during prolonged hospitalization, postoperatively, immobilization, certain orthopedic disorders, and in patients with active cancer.

Primary prophylaxis in patients with thrombophilia during pregnancy is controversial. Patients with thrombophilia, a history of thrombosis, and other risk factors could be considered for prophylactic anticoagulation, especially during the 6-week postpartum period in which there is the greatest risk of thrombosis. Anticoagulation should be strongly considered during pregnancy and in the postpartum period in patients with lupus anticoagulants.^[19]

A multicenter study of 2554 patients revealed that after a first unprovoked venous thromboembolism, men have a 2.2-fold higher risk of recurrent venous thromboembolism than do women; this risk remained 1.8-fold higher in men after adjustment for previous hormone-associated venous thromboembolism in women.^[20] Among patients with a first provoked venous thromboembolism, risk of recurrence does not differ between men and women with or without hormone-associated venous thromboembolism. This information might be useful when deciding on the indications of long-term anticoagulation.

Patients who have a venous thrombotic event or pulmonary embolus should be anticoagulated (secondary anticoagulation). Warfarin,^[21] heparin, and LMWH have been used to manage venous thrombosis and pulmonary embolism. Antithrombin agents may become another option for managing venous thrombosis and pulmonary embolism.

The decision to institute long-term or extended anticoagulation is complex, and it should be based on evidence of recurrent thrombosis and the assessment of all risk factors. The benefits of anticoagulation must outweigh the risk of bleeding, especially in elderly patients.

Direct thrombin inhibitors and Xa inhibitors

Anti-Xa and direct antithrombin agents, especially oral agents, have been developed as alternatives to warfarin. Apixaban and enoxaparin have been compared for their ability to prevent thrombosis after hip replacement.^[22] Oral rivaroxaban has been evaluated in patients with venous thromboembolism.^[23] Oral dabigatran, a long-acting, direct antithrombin agent has been used in patients with atrial fibrillation^[24] and with venous thrombotic events.^[25] Dabigatran has recently been approved by the US Food and Drug Administration (FDA) for strokes and thrombosis in patients with strokes. Rivaroxaban (Xarelto), an oral factor Xa inhibitor, is currently being evaluated by the FDA.

Fondaparinux, a long-acting anti-Xa agent, is thought to have several advantages over argatroban and bivalirudin, short-acting antithrombin agents, in patients with heparin-induced thrombocytopenia.^[26]

Anti-Xa and antithrombin agents have several possible advantages over warfarin, including the following:

• No or limited interaction with other drugs and diet
• Metabolic half-lives that allow for once or twice daily dosing
• No need to monitor due to predictable pharmacokinetics
• Possibly less bleeding complications

However, continuing to evaluate the value of anti-Xa and antithrombin agents for their antithrombotic actions, as well as for their safety, is important. Scrutiny has revealed that the oral direct thrombin inhibitor ximelagatran can significantly affect hepatic function; therefore, it has been not been approved by the US Food and Drug Administration.^[27] .

Table 2. Several Commonly Used Antithrombotic Agents (Open Table in a new window)

Monitoring of anticoagulation and management of bleeding

Unfractionated heparin is monitored by an aPTT and warfarin is monitored by a PT (INR).

In general, LMWHs are administered without routine laboratory monitoring because the dosage effects are fairly consistent. The most common method for monitoring LMWH is a chromogenic assay for anti–factor Xa activity. This assay does not accurately estimate risk for bleeding or whether anticoagulation is sufficient to prevent thrombosis.

In practice, monitoring of LMWH is complicated by several factors.^[30] The formulations available for clinical use vary in their composition and relative amounts of anti–factor IIa and anti–factor Xa activity. The optimal anti–factor Xa levels vary amongst these preparations. Thus, the physician must understand the characteristics of the LMWH being prescribed.^[31] The peak plasma concentrations are achieved at periods of about 4 hours following subcutaneous administration, and this is the time at which blood is usually obtained for monitoring. However, because of different dosage regimens (once or twice daily) and the possibility of different clearance rates, there is no perfect method for the optimum timing of monitoring or determination of desired target levels.^[32]

Moreover, standardization of the chromogenic assay for anti–factor Xa activity from different providers and in different laboratories is not yet ideal.^[17] Although high doses of LMWH are considered to present a greater risk of bleeding, there has not been a correlation between anti–factor Xa activity levels and actual incidence of bleeding in patients. Likewise, the assay has limited predictive value for predicting antithrombotic efficiency.

Guidelines for monitoring of LMWH were issued by the College of American Pathologists in 1998 and by the Control of Anticoagulation Subcommittee of the International Society for Thrombosis and Hemostasis. Both organizations indicate that routine monitoring is unnecessary for most patients. However, patient subgroups such as overweight and underweight individuals, children, those with reduced creatinine clearance, and persons undergoing prolonged therapy (eg, cancer patients and pregnant women (especially in the third trimester) should be monitored to be ascertain that no excess heparin accumulates in the blood.

Monitoring antithrombin agents

The Ecarin clotting time (ECT),^[33] activated clotting time,^[34] and activated factor X tests have been used to monitor antithrombin agents. The Ecarin clotting time is thought to be the most reliable test, but further clinical experience with this assay would be important to establish a more complete track record.^[33] Unfortunately, the Ecarin clotting time is not available at most medical centers.

Reversal of anticoagulation

A major consideration in the administration of anticoagulants is the reversal of anticoagulation in patients who bleed. All currently available anticoagulants carry similar risks of serious bleeding episodes. Unfractionated heparin is readily reversible with protamine, but protamine carries some risk of hypotensive and anaphylactic reactions. Warfarin can be reversed in a short time by the administration of FFP, but reversal with vitamin K can take several hours.

Protamine has limited ability to reverse bleeding due to LMWH. Reversal agents such as low molecular weight protamines^[35] and cationic concatemericpeptides^[36] are under investigation but are not yet in clinical use.

Fondaparinux (Arixtra, Sanofi-Aventis Corp) is the pentasaccharide that binds to antithrombin III. There is no known antidote for this drug. The long half-lives of LMWH and fondaparinux and the possibility of continued release into the circulation from the site of subcutaneous injection further complicates the reversal process.

Likewise, no antidotes are available for lepirudin, bivalirudin, and argatroban, or for the oral direct thrombin inhibitors that are currently in clinical trials.

Recombinant factor VIIa has been proposed as a reversal agent for patients who bleed while undergoing anticoagulation. However, as yet there have been no controlled studies to determine its efficacy. Thrombosis may be a significant risk of recombinant factor VIIa therapy.

In summary, it has been proposed that monitoring LMWH and direct thrombin inhibitors is not necessary since their effects are predictable.^[37] This recommendation is in part due to the lack of reliability or unavailability of the tests for monitoring LMWH and antithrombin agents. For example, Factor Xa levels are not reliable for determining whether the level of anticoagulation is sufficient to prevent thrombosis, as well as not reliable for predicting the risk for bleeding.

The inadequacy of monitoring tests and the fact that antidotes are not available places patients who bleed at considerable risk, especially because some of the LMWH and antithrombin agents have a long half-life.^[38] The reversal of bleeding due to LMWH and antithrombin agents, especially if the agent has a long half-life, has been difficult.

A hematologist experienced in the diagnosis and management of thrombophilias and hypercoagulable disorders should be consulted. Equally important is that the laboratory evaluations for thrombophilia are carried out in laboratories with extensive experience with these tests.