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.

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.

• Acute VTE: The usual treatment of acute VTE consists of unfractionated heparin or low-molecular-weight heparin followed by anticoagulation with warfarin (or other vitamin K antagonists). Warfarin can be started within the first 24 h. Heparin or low molecular-weight heparin (LMWH) is continued for at least 5 days or until the prothrombin time is in the therapeutic range, namely an International Normalized Ratio (INR) of 2.0–3.0.

• Antithrombin deficiency: Some patients with antithrombin deficiency are resistant to heparin and require large doses. This is in part due to the action of heparin to further lower antithrombin levels by approximately 30% over several days. Antithrombin concentrate has been used safely and effectively in patients with antithrombin deficiency and acute venous thrombosis. It is recommended in those patients who have unusually severe thrombosis, have difficulty achieving adequate anticoagulation or develop recurrent thrombosis despite adequate anticoagulation. It can also be used for antithrombotic prophylaxis in antithrombin-deficient patients in whom anticoagulation is contraindicated. The infusion of 50 units of plasma-derived antithrombin concentrate per kilogram of body weight will usually raise the plasma antithrombin level to approximately 120% in a congenitally deficient individual with a baseline value of 50%. One unit is defined as the amount in 1 mL of pooled normal human plasma. Plasma levels should be monitored to ensure that they remain above 80%; the administration of 60% of the initial dose at 24 h intervals is recommended to maintain antithrombin levels in the normal range. Recovery of plasma-derived antithrombin concentrate in vivo in patients with antithrombin deficiency is 1.4%�2.7% unit�1 kg�1. Recovery is lower in patients with acute thrombotic events and those receiving heparin therapy. The biologic half-life approximates 2.8–4.8 days.

• Protein C deficiency: Oral anticoagulation in a patient who is known or likely to be protein C deficient should be started under the cover of full heparinization. The dose of warfarin should be increased gradually, starting from a relatively low level (e.g. 2mg for the first 3 days and then in increasing amounts of 2–3mg day�1 until therapeutic anticoagulation is achieved). Patients with heterozygous protein C deficiency and a history of warfarin-induced skin necrosis have been successfully retreated with oral anticoagulants. Protein C administration, either in the form of fresh frozen plasma or protein C concentrate, can provide protection against recurrent skin necrosis until a stable level of anticoagulation is achieved.

• Pregnancy: In general, pregnant women with anticoagulant factor deficiencies and a personal or familial history of thrombosis should be considered for anticoagulant prophylaxis. Pregnant women with antithrombin deficiency appear to have an unusually high risk for thromboembolism, and should receive anticoagulant prophylaxis throughout pregnancy. Antithrombin concentrates are available but should be reserved for use during labor, delivery or obstetric complications where the risks of bleeding from anticoagulation are unacceptable. During pregnancy, adjusted-dose unfractionated heparin or low-molecular-weight heparin administered by the subcutaneous route has been the anticoagulant of choice because its efficacy and safety for the fetus are established. Heparin can produce bone loss but is not associated with the embryopathy that can result from the early administration of warfarin. LMWH is an attractive alternative to unfractionated heparin in this setting because of its better bioavailability, longer half-life, and ease of administration. Enoxaparin, for example, is rated by the US Food and Drug Administration (FDA) as pregnancy category B; while not FDA-approved for use in pregnancy, it appears to be safe and effective. The dose and duration of LMWH therapy in pregnancy however are uncertain since appropriately designed clinical trials have not yet been performed. The following approach is suggested.
  • Patients considered to be at high thrombotic risk should receive full-dose heparin or LMWH by subcutaneous injection every 12 h for the duration of pregnancy and approximately 6 weeks postpartum. For unfractionated heparin, the dose should be adjusted to maintain the 6 h postinjection activated partial thromboplastin time (aPTT) at 1.5 times the control value. For LMWH, firm guidelines regarding the need for monitoring have not been established. In view of the increase in total body plasma volume during pregnancy, intermittent monitoring of plasma heparin levels by anti- FXa assay should be performed, starting in the second trimester. The goal is a plasma heparin concentration of 0.5 1.0UmL�1 2–3 h after injection.
  • Women with a personal or family history of thrombosis and considered to be at intermediate risk can be treated with lower subcutaneous doses of heparin: 5000–10 000 units of unfractionated heparin subcutaneously every 12 h; or prophylactic doses of LMWH every 12 h. Therapy should be started during the second or third trimester and continued for approximately 6 weeks into the postpartum period.
  • Low-risk patients (e.g. asymptomatic carriers without a family history of recurrent thromboses) should be observed closely throughout the pregnancy.

• Management of a first acute thrombotic episode: The initial management of deep vein thrombosis or pulmonary embolism in patients with heritable thrombophilia is, in general, no different from the management of venous thrombosis in any other patient. (Grade B recommendation). For the majority, initial anticoagulation with unfractionated or low-molecular-weight heparin for a minimum of 5 d is followed in the non-pregnant by oral anticoagulation for 6 months at a target International Normalized Ratio (INR) of 2´5 (range 2´0±3´0).

• Duration of anticoagulant therapy:
  • After a first venous thromboembolism, anticoagulant therapy is generally administered for 6 months. A shorter period of treatment may be acceptable when the thrombus is confined to distal veins (calf veins) and if there is evidence of a temporary risk factor that is no longer present. It is recommended that when there is a persisting thrombotic risk factor such as cancer or already identified high-risk thrombophilic defects (e.g. type I or type II reactive site antithrombin deficiency or combined defects), consideration should be given to extending the usual period of anticoagulation on an individual patient basis (Grade B recommendation).
  • Identification of the most prevalent forms of heritable thrombophilia, heterozygosity for factor V Leiden or prothrombin G20210A, should not influence decisions about the duration of anticoagulant therapy (Grade B recommendation).

• Management of recurrent venous thrombosis:
  • When recurrent events have occurred while the patient was no longer anticoagulated, it is sufficient to reintroduce coumarin at a target INR of 2´5 after initial treatment with heparin, but when a recurrent event has occurred while the patient was on anticoagulants and their INR was within the target range of 2´0±3´0, an increase in the intensity of anticoagulation to a target INR of 3´5 (range 3´0±4´0) is indicated (Grade C recommendation).
  • In general, patients who have had two or more apparently spontaneous venous thrombotic events require consideration for indefinite anticoagulant thromboprophylaxis (Grade C recommendation).
  • However, patients who have had recurrent thrombotic events in association with identifiable prothrombotic triggers (for example pregnancy, surgery, oestrogen use) and in whom those prothrombotic triggers are no longer present may not require indefinite anticoagulant thromboprophylaxis but do require prophylaxis during high-risk situations.

• • Chronic venous ulceration: Chronic venous reflux and venous hypertension promote inflammation and skin changes of the lower extremity that predispose the skin to ulceration. Lymphatic destruction, excessive colloid filtration resulting in regional edema, fibrin deposition, a diffusion barrier to oxygen, and infiltration of lymphocytes and neutrophils have all been shown to occur in the setting of elevated lower extremity venous pressure. Compression therapy is the mainstay of treatment for CVUs with up to 96% of ulcers healing. The current CHEST guidelines based on randomized control trials show a significant benefit to the use of 30 mmhg-40 mmhg compression stockings for at least 2 years in decreasing progression of venous disease after an episode of DVT. Surgical correction of venous reflux does not seem to aid in ulcer healing of primary CVUs; however, it does seem to reduce ulcer recurrence rates. Other treatments, identified by the CHEST guidelines, showing some benefit in the healing of venous ulcers are pentoxifylline and rutosides. There is currently no evidence for modifying these recommendations in patients with thrombophilia.