Thrombophilia medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2]

Overview

The treatment for thrombophilia depends on the underlying hypercoagulable state and the clinical presentation. The mainstay of therapy for thrombophilia is anticoagulation with either warfarin, low molecular weight heparin, direct Xa inhibitors, or direct thrombin inhibitors. Treatment should be tailored to the individual patient. The risks and benefits, required monitoring, and costs associated with each form of anticoagulation should be discussed with the patient prior to initiation of therapy. All patients on anticoagulation should be monitored for bleeding.

• Regardless of whether an underlying inherited thrombophilia is identified, patients with history of recurrent VTE are often candidates for long-term anticoagulation. Testing for inherited thrombophilia in patients with prior VTE events will therefore not influence decisions regarding clinical management. Additionally, such testing may be confounded by ongoing disease or treatment. For example, protein C, protein S antigen, and ATIII levels are low in the setting of acute VTE. Likewise, protein C and S (vitamin K–dependent proteins) will be low in the setting of anticoagulation with warfarin. Moreover, ATIII activity and antigen levels are low in the setting of heparin use. Lack of provider awareness regarding these interactions may have important negative consequences, including a spurious diagnosis of thrombophilia, unnecessary hematology consultation, and psychological distress to patients in the form of ongoing unwarranted testing or apprehension regarding recurrence.
• Pregnant women with a family history or personal history of VTE may also benefit from inherited thrombophilia testing, as this may influence antepartum or postpartum management. The National Institute for Health and Clinical Excellence (NICE) guidelines recommend consideration of testing for hereditary thrombophilia in patients with unprovoked VTE and a first-degree relative with VTE, if stopping anticoagulation treatment is planned; however, these recommendations are based solely on Guideline Development Group’s experience and opinion. Regardless, testing for inherited thrombophilia has significant potential consequences. Patients at risk should meet with an outpatient hematologist and/or a genetic counselor, if available, to determine the risks and benefits of testing.

Medical Therapy

• The 2016 guidelines from the American College of Chest Physicians (ACCP) recommend that patients with provoked venous thrombosis from reversible risk factors should receive 3-6 months of anticoagulation
  • • Response to anticoagulation can be monitored clinically, with repeat ultrasongraphy for deep vein thrombosis or measuring D-dimer levels after treatment
• The 2016 guidelines from the ACCP recommend that direct oral anticoagulants (DOACs), including direct Xa inhibitors and direct thrombin inhibitors, be used for long term treatment of most patients

• Important exceptions include:
  • Pregnancy
  • Renal insufficiency
  • Malignancy

• Low molecular weight heparin (LMWH) is recommended for anticoagulation for the following acquired thrombophilias:
  • Post-surgery prophylaxis
    • The duration of anticoagulation after surgery is variable. Most clinical trials have evaluated anticoagulation for 10-35 days
    • General recommendations for thrombophrophylaxis is 7-10 days for standard risk patients and 10-35 days for higher risk patients as described in the algorithims below and for patients undergoing abdominal and pelvic surgeries for gynecologic malginancies
    • DOACs may be considered as agents for extended thromboprophylaxis after total hip replacement and total knee replacement.
  • Pregnancy and postpartum
    • Patients who develop acute thrombosis during pregnancy should be anticoagulated for the remainder of the their pregnancy and 6 weeks postpartum for a minimum of 3 months
    • A similar duration of anticoagulation is recommended for patients with high risk thrombophilias as described in the algorithims below
  • Malignancy
• Alternative agents include Warfarin and Fondaparinux
  • Warfarin is the agent of choice for prophylactic anticoagulation in patients with nephrotic syndrome, as there are no studies evaluating DOACs and LMWH for this clinical indication. Refer to the treatment algorithim below. It is important to note that the recommendations for prophylactic anticoagulation in patients with nephrotic syndrome are not based on expert consensus guidelines.
    • Lee et al created an online tool to assist in evaluating the benefits and risks of prophylactic anticoagulation in patients with membranous nephropathy.

Treatment algorithims for both acquired and inherited thrombophilias are presented below:

• Thromboprophylaxis or indefinate anticoagulation may be required for certain inherited thrombophilias

Management of acute thrombosis in patients with inherited thrombophilias

Management of asymptomatic patients with inherited thrombophilias

Management of patients with acquired thrombophilias

• • Bleeding risk is assessable through the HAS-BLED, RIETE, OBRI, KUIJER, ACCP, HEMORR2HAGES, and ORBIT scores. The HAS-BLED score performed best to predict bleeding risk in patients with atrial fibrillation and is recommended in guidelines. Treatment duration following VTE divides into three phases: acute (a few days following the event), intermediate (short-term anticoagulation for three months) and chronic (long-term anticoagulation for more than 3 months). Factors such as male gender, age, proximal compared to distal deep vein thrombosis which has a higher thrombotic burden, increased d-dimer, and unprovoked VTE implicate a higher recurrence rate and can trigger extended coagulation. Risk stratification tools for the estimation of VTE recurrence in cancer include the COMPASS-CAT, Ottawa (Louzada) and Khorana scores.

• • Different anticoagulants and antiplatelets are available to prevent recurrent VTE. They include vitamin K antagonist (VKA), aspirin (as assessed in the WARFASA and ASPIRE trials), rivaroxaban (EINSTEIN trial), dabigatran (RE-MEDY and RE-SONATE trials), and apixaban (AMPLIFY trial). Additional considerations are prudent regarding special populations. The CLOT trial assessed low molecular weight heparin against warfarin in cancer patients. Heparin did not show teratogenicity and is FDA-approved during pregnancy and the postpartum period. Prevention of thrombotic events includes compression stockings and mobility. Rosuvastatin prevents the occurrence of VTE.

• Protein C deficiency: Protein C deficiency is treatable by replacement with protein C concentrate. Neonatal PF is controllable with protein C replacement from fresh frozen plasma (FFP) or human plasma-derived, viral inactivated protein C concentrate. Anticoagulation treatments, such as high-intensity warfarin or low-molecular-weight heparin are also options. Protein C replacement can be costly, leading to the use of anticoagulation therapies in specific settings such as VTEs occurring in children.
• Management of acute deep vein thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients typically includes anticoagulation with IV unfractionated heparin (UFH) or low molecular weight heparin with an eventual transition to oral anticoagulation as below. Anticoagulation promptly with heparin or LMWH provides a quick therapeutic range to avoid the progression of thrombosis and reduce associated mortality.[14] After initiating these intravenous anticoagulants, vitamin K antagonists (e.g., warfarin) can then be added for chronic and extended management once patients achieve a therapeutic INR. For an initial, provoked thrombosis (especially simple distal DVT), the recommended duration is typically 3 months. For the first episode of provoked thrombosis with extensive clot burden, massive pulmonary embolism associated with hemodynamic compromise, or in patients with multiple persistent provoking risk factors, one should consider at least 3-6 months duration (or longer in select cases). Discontinuing therapy, before established guidelines on duration, can increase the risk of recurrent thrombosis. Medication compliance/adherence is very important to decrease the risk of recurrence. In patients with recurrent DVT or PE, the duration of therapy becomes more complex, and the determination of strong provoking or transient risk factors is important for guiding treatment. Patients with active malignancy as a provoking risk factor for thrombosis should typically continue anticoagulation therapy for 6 months or longer. Historically, LMWH has been preferred in those with thrombosis and malignancy. However, exceptions exist, and newer guidelines are now incorporating the use of certain direct oral anticoagulants (e.g., edoxaban) for management in patients with malignancy. Anticoagulation with thrombosis in pregnancy, perioperatively in those with thrombosis (especially orthopedic surgery), thrombosis in those with hereditary or acquired thrombophilia, and management of patients with recurrent or "breakthrough" thrombosis (despite therapeutic anticoagulation) becomes significantly more complicated. These cases are best managed under the guidance of a hematologist consultant.
• In those with true unprovoked thrombosis, the duration of therapy is typically longterm and can be lifelong. With the advent of newer direct oral anticoagulants (DOACs), many of which are non-inferior to older agents such as warfarin (with certain clinical exceptions, notably antiphospholipid syndrome or valvular A. Fib), the options for anticoagulation in acute thrombosis continues to expand. As of this writing, DOAC agents include dabigatran, edoxaban, rivaroxaban, and apixaban. Dabigatran is a direct thrombin inhibitor, while the other three are direct factor Xa inhibitors. The American Society of Hematology (ASH) has recommended in 2018 that the direct oral anticoagulants (DOACs) can be used in certain circumstances for the management of acute VTE while taking into consideration the risk of bleeding, renal impairment, and comorbidities that may reduce their efficacy (e.g., morbid obesity).[15] When using unfractionated heparin, the partial thromboplastin time requires close monitoring, and the dose should be adjusted each time based on the value. LMWH does not require monitoring, though occasionally for patients who are morbidly obese can be monitored by checking anti-Factor Xa levels. For vitamin K antagonists (i.e., warfarin), the PT/INR should be monitored and maintained in therapeutic range (INR typically between 2 and 3). With the DOACs, no routine blood monitoring is necessary; however, medication compliance/adherence remains paramount to assuring the efficacy of these medications. As of this writing, for patients with confirmed acute heparin-induced thrombocytopenia & thrombosis (HITT), a non-heparin anticoagulant such as argatroban should be utilized, and expert consultation with hematology is the recommendation. In patients with confirmed antiphospholipid syndrome and acute thrombosis, vitamin k antagonism with warfarin is preferred, and consultation with hematology may be helpful. The use of DOACs in these settings is still under investigation.
• For patients who are admitted to the hospital, the American Society of Hematology (ASH), consistent with other subspecialty society guidelines have recommended that prophylactic-dose unfractionated heparin (UFH) or low molecular heparin (LMWH) should be used (with adjustment for renal impairment as indicated). If there is any contraindication to anticoagulation or high bleeding risk, mechanical prophylaxis of lower extremities should be employed. Mechanical methods of prophylaxis include intermittent compression devices and graduated elastic compression stockings. With certain exceptions, it is not generally recommended to extend pharmacologic prophylaxis following hospitalization. Prophylaxis should be strongly considered in acutely and critically ill patients who are hospitalized.
• Apart from pharmacological management, endovascular treatment is also used in some facilities to manage thrombosis. It is reported to be more successful if the thrombus is truly acute (i.e., formation two weeks before the presentation). Different endovascular methods include catheter-directed thrombolysis, percutaneous aspiration thrombectomy, venous balloon dilatation, pharmacomechanical catheter-directed thrombolysis. The use of inferior vena cava (IVC) filters remains controversial in the acute setting and should only be considered in select cases. IVC filters carry their own risk of potential complications, and they can serve as a nidus for thrombus formation. In general, for acute venous thrombosis, the use of IVC filters should be avoided unless there is an absolute contraindication to anticoagulation or severe active bleeding. When used, a retrievable type of IVC filter is preferred, and anticoagulation should be offered as soon as safely feasible.