Hereditary and Acquired Hypercoagulability Treatment & Management

Updated: Jul 12, 2021
  • Author: Manojna Konda, MD; Chief Editor: Srikanth Nagalla, MD, MS, FACP  more...
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Medical Care

The goal of this article is not to review the management of thrombotic episodes, which is described in Deep Venous Thrombosis and Pulmonary Embolism. Management of specific prothrombotic disorders is detailed in the following Medscape reviews:

However, indications for anticoagulation to prevent thromboembolism in patients at risk should be considered (ie, primary anticoagulation or prophylaxis). Indications for primary prophylaxis include the following:

  • Prolonged hospitalization
  • Postoperative status
  • Immobilization
  • Certain orthopedic disorders
  • Certain active cancers

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 first 6 weeks postpartum, when the risk of thrombosis is greatest. Anticoagulation should be strongly considered during pregnancy and in the postpartum period in patients with lupus anticoagulants. [39]

Conners provided guidance for the use of antepartum and postpartum prophylaxis with low molecular weight heparin (LMWH) in women with a known thrombophilia or prior venous thrombosis. Management of LMWH prophylaxis use around labor and delivery was also reviewed. [40]

A multicenter study of 2554 patients revealed that after a first unprovoked venous thromboembolism (VTE), men have a 2.2-fold higher risk of recurrent VTE than do women; this risk remained 1.8-fold higher in men after adjustment for previous hormone-associated VTE in women. [41] In patients with a first provoked VTE, risk of recurrence does not differ between men and women, with or without adjustment for hormone-associated VTE. This information might be useful when deciding on whether long-term anticoagulation is indicated.

Patients who have a venous thrombotic event or pulmonary embolus should be anticoagulated (secondary anticoagulation). Warfarin, [42] heparin, and LMWH have been used to manage venous thrombosis and pulmonary embolism. The direct oral anticoagulants (direct thrombin and direct factor Xa inhibitors) have become widely used for the treatment of VTE.

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.

Some organizations recommend that patients with lupus anticoagulants be treated more aggressively. For example, the American College of Chest Physicians recommends 12 months of anticoagulation and consideration of longer-term anticoagulation after a single thrombotic event in patients with antiphospholipid syndrome. [43]

Recommendations conflict on the optimal international normalized ratio (INR) level in patients with lupus anticoagulants who are on warfarin. In most cases, an INR of 2.0 to 3.0 is adequate. 

The risk of thrombosis should outweigh the risk of bleeding, especially in older patients, when deciding on anticoagulation.

Although strategies for assessment of thrombosis risk in adults are well established, similar guidelines for pediatric patients are lacking. Rühle and Stoll discuss risk prediction models for pediatric VTE that have the potential for improving thromboprophylaxis in children. [44]


Thrombin Inhibitors and Factor Xa Inhibitors

Direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) and direct thrombin inhibitors (dabigatran), especially oral agents, have been developed as alternatives to warfarin. They have been approved for use in VTE prophylaxis, VTE treatment, and stroke prevention in non-valvular atrial fibrillation. In patients with heparin-induced thrombocytopenia, fondaparinux, a long-acting anti-Xa agent, is thought to have advantages over the short-acting antithrombin agents argatroban and bivalirudin. [45]

Direct oral anticoagulants (DOACs) 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, continued evaluation of the value of direct oral anticoagulants in complex thrombotic syndromes (eg, antiphospholipid antibody syndrome) is important before these agents are widely used in these complex cases.

Low molecular weight heparin (LMWH) is commonly used to treat cancer-associated thrombosis. However, DOACs such as apixaban, [46]   rivaroxaban, [47]  and edoxaban [48]  may be also effective. Rivaroxaban and edoxaban should probably be avoided in patients with gastrointestinal malignancy due to higher risk of bleeding. Dabigatran has not been studied in patients with cancer. In patients with severe kidney insufficiency (creatinine clearance < 30 mL/minute), warfarin should be considered rather than LMWH or DOACs.

Considerable efforts have recently been made to evaluate the role of oral and parenteral thrombin inhibitors and factor Xa inhibitors in preventing and managing thrombosis. The value of combining these agents with traditional warfarin and heparin therapy has been assessed. Disparate clinical settings such as advanced age, pregnancy, coronary artery disease, and surgery were studied. Although these studies have provided new information, many of them concluded that more information was needed to safely use new and standard anticoagulation therapy to provide optimal thrombosis prevention and management. [49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59]

Hospital formularies will be challenged to appropriately use and manage these new medications. [52]  The introduction of new-generation factor Xa and direct thrombin inhibitors in patients receiving antiplatelet therapy was associated with a dramatic increase in major bleeding events. [53]



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 be carried out in laboratories with extensive experience with these tests.


Monitoring of Anticoagulation and Management of Bleeding

Unfractionated heparin therapy is monitored by measuring activated partial thromboplastin time (aPTT). Warfarin therapy is monitored by measuring prothrombin time (PT) and international normalized ratio (INR). The therapeutic ranges for heparin and warfarin are well established. However, the therapeutic ranges of direct thrombin and direct Xa inhibitors are not known. [60]

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. [61] 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 among these preparations. Thus, the physician must understand the characteristics of the LMWH being prescribed. [62]

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 drawn 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. [63]

Moreover, standardization of the chromogenic assay for anti–factor Xa activity from different providers and in different laboratories is not yet ideal. [43] Although high doses of LMWH are considered to pose a greater risk of bleeding, no correlation has been shown 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 have been issued by the American College of Chest Physicians [64] and the British Committee for Standards in Haematology. [65] Both organizations indicate that routine monitoring is unnecessary for most patients. However, monitoring to be certain that no excess heparin accumulates in the blood should be conducted in patient subgroups such as the following:

  • Overweight and underweight patients
  • Children
  • Patients with reduced creatinine clearance
  • Patients undergoing prolonged therapy (eg, for cancer)
  • Pregnant women (especially in the third trimester)

Monitoring thrombin inhibitors

The Ecarin clotting time (ECT), [66] activated clotting time, [67] and activated factor X tests have been used to monitor antithrombin agent therapy. 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. [66] Unfortunately, the Ecarin clotting time is not available at most medical centers.

Monitoring Factor Xa inhibitors

For determining the anticoagulant effect of DOACs, several quantitative tests maybe useful by measuring the plasma drug concentration. Various laboratory monitoring assays using liquid chromatography–mass spectrometry/mass spectrometry (LCMS/MS) can be used but are not readily available. Anti–factor Xa assay calibrated to DOAC can be used for factor Xa inhibitors; if that is not available, an anti–factor Xa assay calibrated for another anticoagulant such a LMWH can be used but is not ideal.

Reversal of anticoagulation

A major consideration in the administration of anticoagulants is the reversal of anticoagulation in cases of bleeding. 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 fresh frozen plasma, 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 [68]  and cationic concatemeric peptides [69] are under investigation but have not yet entered clinical use.

There has been progress in developing antidotes to direct thrombin and factor Xa inhibitors. Idarucizumab, a humanized monoclonal antibody that binds to and inactivates dabigatran, has received expedited approval from the US Food and Drug Administration (FDA). [70]

Andexanet alfa is a genetically engineered factor Xa molecule that has no procoagulant activity but can bind with and sequester factor Xa inhibitors. [71]  It has received FDA approval for reversal of anticoagulation by rivaroxaban and apixaban in patients with life-threatening bleeding.

No antidotes are available for lepirudin, bivalirudin, and argatroban at present.

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. [72] This recommendation is in part due to the lack of reliability or availability of the tests for monitoring LMWH and thrombin inhibitors. For example, anti–factor Xa assay 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 thrombin inhibitors have a long half-life. [73] The reversal of bleeding due to LMWH and thrombin inhibitors, especially if the agent has a long half-life, has proved difficult.