Management of bleeding complications in cancer patients on DOACs

Major bleeding can be life or limb threatening and incurs substantial health care costs, whereas clinically relevant non-major bleeds are mainly very disturbing for the patients and may reduce their quality of life. Bleeding in patients with anticoagulation for venous thromboembolism (VTE) the incidence is front-loaded. Patients with a major bleeding are usually not given extended anticoagulant treatment.

In pooled analysis of the phase III trials with direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKA) for treatment of VTE the rate of major bleeding was at least double in patients with compared to without cancer; on DOACs 2.9% vs. 1.0% and on VKA 3.7% vs. 1.6% (Van Es N et al. Blood 2014;124:168-75).

Patients on chemotherapy may be thrombocytopenic. Anticoagulation should be avoided in patients with platelet count <50 and definitely if <30. Anticoagulant related bleeding in severe thrombocytopenia requires platelet transfusions. Except for this, the management of bleeding on DOACs is similar to that in patients without cancer.

Certain data have to be obtained at first sight: What DOAC is the patient taking and when was the last dose? Is there renal known renal impairment? Is the patient also taking any antiaggregant drug? Blood is drawn for complete blood count, prothrombin time, activated partial thromboplastin time and creatinine. In case of availability of specialized tests and if the patient took dabigatran a dilute thrombin time (Hemoclot) should be obtained and if the patient took an oral factor Xa inhibitor a factor Xa level, calibrated specifically for the actual drug should be obtained. Further treatment in case of major bleeding should start before the results of these tests have been obtained.

The management of the bleeding should always include supportive measures: fluid replacement, oxygen, pain control, local hemostasis if feasible, and tranexamic acid for trauma-related bleeding or mucosal bleeds – except in case of hematuria when it is contraindicated. Lipophilic drugs that were ingested within the past 1-3 hours can be neutralized by active charcoal lavage, as has been shown in model experiments with dabigatran and apixaban. Dialysis is only applicable for drugs with low binding to plasma proteins, which for the DOACs only applies to dabigatran. After 4-6 h of dialysis a clinically important amount of dabigatran will be eliminated.

A specific antidote only exists and has been approved for dabigatran and the standard dose of idarucizumab (PraxBind®) is 5 g as an intravenous bolus dose. If the patient continues to bleed or re-bleeds within 24 h hematology should be consulted before giving a new bolus dose since there may be other reasons that require different management. It is at this point that the baseline measurement of dabigatran level (dilute thrombin time) will be informative.

In countries where idarucizumab has not been approved, there is an alternative option with activated prothrombin complex concentrate (FEIBA) at a dose of 50 units/kg. This factor concentrate is usually available where there is a Hemophilia Treatment Center.

For factor Xa inhibitors and class specific antidote, andexanet alfa, is in phase III clinical trial. It is given as a bolus dose followed by infusion over 2 h and the dose depends on the Xa inhibitor that is reversed. At hospitals not participating in the clinical trial andexanet alfa is not available. Emerging clinical data demonstrate that 4-factor prothrombin complex concentrate appears to be effective to reverse oral factor Xa inhibitor-associated bleeding. The most frequently tested dose was 2000 units.

With any reversal method for DOACs there have been observations of thromboembolic events with an incidence of up to 12%. This is at least partly due to the fact that the patients have a prothrombotic background, which is the reason why they were on an anticoagulant. When the protection from the latter is interrupted the patients run an inevitable risk of thromboembolism. In addition, the bleeding and the triggering trauma, as well as any resulting invasive procedures can activate the coagulation cascade. It is therefore crucial to initiate thromboprophylaxis as soon as possible and to resume therapeutic anticoagulation as soon as it is safe. For non-major bleeds and also for some of the major bleeds it is not necessary to reverse the anticoagulation completely but rather to use the supportive measures discussed above.

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