How do anticoagulants (blood thinners) cause hemorrhage (excessive bleeding)?

From the Guidelines

Anticoagulants cause hemorrhage by interfering with the body's normal blood clotting mechanisms, and the risk of bleeding is higher in patients with advanced age, previous bleeding, active cancer, and chronic renal or hepatic disease, as reported in the 2020 European Heart Journal study 1.

Mechanism of Hemorrhage

Anticoagulants work by targeting different parts of the coagulation cascade, which is the series of reactions that form blood clots. For example, warfarin (Coumadin) inhibits vitamin K-dependent clotting factors, while heparin and low molecular weight heparins like enoxaparin (Lovenox) enhance the activity of antithrombin III to inhibit thrombin and factor Xa. Direct oral anticoagulants (DOACs) such as apixaban (Eliquis), rivaroxaban (Xarelto), and dabigatran (Pradaxa) directly inhibit specific clotting factors. When these medications excessively thin the blood, normal hemostasis becomes impaired, meaning even minor injuries that would typically stop bleeding quickly continue to bleed.

Risk Factors for Hemorrhage

The risk of anticoagulant-related bleeding is influenced by several factors, including:

• Advanced age (particularly >75 years) 1
• Previous bleeding (if not associated with a reversible or treatable cause) or anaemia 1
• Active cancer 1
• Previous stroke, either haemorrhagic or ischaemic 1
• Chronic renal or hepatic disease 1
• Concomitant antiplatelet therapy or non-steroidal anti-inflammatory drugs (to be avoided, if possible) 1
• Other serious acute or chronic illness 1
• Poor anticoagulation control 1

Assessment and Management of Bleeding Risk

The patient’s bleeding risk should be assessed, either by implicit judgement after evaluating individual risk factors or by the use of a bleeding risk score, at the time of initiation of anticoagulant treatment, and reassessed periodically 1. Bleeding risk assessment should be used to identify and treat modifiable bleeding risk factors, and it may influence decision-making on the duration and regimen/dose of anticoagulant treatment after acute PE. The 2020 European Heart Journal study recommends that the risk of major bleeding is higher in the first month of anticoagulant treatment, and then declines and remains stable over time 1.

From the FDA Drug Label

Fatal or nonfatal hemorrhage from any tissue or organ. This is a consequence of the anticoagulant effect. Bleeding during anticoagulant therapy does not always correlate with PT/INR Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID use increases the risk of bleeding

Anticoagulants like apixaban and warfarin increase the risk of bleeding by preventing the formation of blood clots.

• The anticoagulant effect can lead to fatal or nonfatal hemorrhage from any tissue or organ.
• Bleeding can occur even when the PT/INR is within the therapeutic range.
• Concomitant use of other medications like antiplatelet agents, fibrinolytics, heparin, aspirin, and chronic NSAID can further increase the risk of bleeding 2, 3.

From the Research

Anticoagulant-Associated Hemorrhage

• Anticoagulant medications are commonly used for the prevention and treatment of thromboembolism, but they are also associated with significant bleeding risks 4.
• Numerous individual clinical factors have been linked to an increased risk of hemorrhage, including older age, anemia, and renal disease 4.
• The direct oral anticoagulants (DOACs) are associated with similar or lower risk of bleeding compared with warfarin, but the need for reversal of their anticoagulant effect may occur in patients with life-threatening bleeding or those requiring urgent surgery 5.

Mechanisms of Hemorrhage

• Anticoagulants work by inhibiting the coagulation cascade, which can lead to an increased risk of bleeding 6.
• The risk of hemorrhage is higher in patients with certain underlying conditions, such as renal disease or anemia 4.
• The use of anticoagulants can also lead to drug-induced coagulopathy, which can increase the risk of uncontrolled hemorrhage 7.

Reversal of Anticoagulation

• Specific reversal agents, such as idarucizumab for dabigatran and andexanet alfa for factor Xa inhibitors, are available to reverse the anticoagulant effect of DOACs 5, 6.
• Prothrombin complex concentrates can also be used to reverse the anticoagulant effect of DOACs, especially in patients with life-threatening bleeding 5, 6.
• Vitamin K can be used to reverse the anticoagulant effect of warfarin, but it is not effective for reversing the anticoagulant effect of DOACs 8.

Management of Bleeding

• The management of bleeding in patients on anticoagulant therapy requires a multidisciplinary approach, including the use of reversal agents, supportive measures, and careful monitoring of the patient's condition 6, 7.
• Viscoelastic testing, such as thromboelastography and rotational thromboelastometry, can be used to guide blood product usage and monitor the patient's response to treatment 7.
• The decision to resume anticoagulation after a bleeding event should be made on a case-by-case basis, taking into account the patient's underlying risk of thromboembolism and the risk of further bleeding 6.