What causes an increased risk of bleeding?

From the Guidelines

Bleeding risk is primarily caused by factors that impair normal blood clotting mechanisms or damage blood vessel integrity, with the most significant risk factors including advanced age, history of previous bleeding, uncontrolled hypertension, and the presence of multiple comorbid conditions such as liver disease, kidney disease, and certain cancers, as noted in the 2020 guidelines for management of venous thromboembolism 1. The causes of increased bleeding risk can be multifaceted, involving:

• Medications like anticoagulants (warfarin, heparin, direct oral anticoagulants like apixaban and rivaroxaban), antiplatelet drugs (aspirin, clopidogrel), and NSAIDs (ibuprofen, naproxen) 1
• Medical conditions such as liver disease, kidney disease, certain cancers, vitamin K deficiency, hemophilia, von Willebrand disease, and thrombocytopenia (low platelet count) 1
• Advanced age, history of previous bleeding, uncontrolled hypertension, and alcohol abuse, which also contribute to higher bleeding risk 1
• Surgical procedures and trauma, which naturally increase bleeding risk due to tissue damage 1 When multiple risk factors are present simultaneously, the bleeding risk compounds significantly, emphasizing the need for careful assessment and management, particularly in patients on anticoagulants, where medication adherence and regular monitoring of INR levels for warfarin users are crucial 1.

From the FDA Drug Label

Apixaban tablets increases the risk of bleeding and can cause serious, potentially fatal, bleeding [see Dosage and Administration (2. 1) and Adverse Reactions (6.1)]. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions (7. 3)].

Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12. 3)]. Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions (5.2)].

The increased risk of bleeding is caused by:

• Concomitant use of drugs affecting hemostasis, including:
  • Aspirin and other antiplatelet agents
  • Other anticoagulants
  • Heparin
  • Thrombolytic agents
  • Selective serotonin reuptake inhibitors
  • Serotonin norepinephrine reuptake inhibitors
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Coadministration of certain medications, including:
  • Enoxaparin
  • Warfarin
  • Aspirin
  • Clopidogrel
  • Chronic NSAID use
• Combined P-gp and strong CYP3A inhibitors, which can increase exposure to rivaroxaban and may increase the risk of bleeding 2.

It is essential to carefully evaluate the benefits and risks of anticoagulant therapy and to monitor patients for signs and symptoms of bleeding when using these medications, especially in combination with other drugs that affect hemostasis 3.

From the Research

Causes of Increased Risk of Bleeding

• Anticoagulant therapy is a major cause of increased bleeding risk, as all anticoagulant drugs can cause hemorrhages, which can sometimes be life-threatening 4
• The use of direct oral anticoagulants (DOACs) with aspirin can increase the risk of bleeding, with some studies showing a higher risk of bleeding with DOACs + ASA compared to warfarin + ASA 5
• Certain medications, such as clopidogrel, corticosteroids, and nonsteroidal anti-inflammatory drugs (NSAIDs), can increase the risk of bleeding when used with anticoagulants like warfarin 6, 7
• The combination of warfarin and NSAIDs or COX-2 inhibitors can significantly increase the risk of gastrointestinal bleeding and general bleeding 7
• Warfarin use can also increase the risk of bleeding, with a trend towards an increase in major bleeding risk compared to aspirin, particularly for intracranial hemorrhage 8

Risk Factors for Bleeding

• Demographics, medical conditions, and concomitant medications can affect the risk of bleeding in patients on direct oral anticoagulants (DOACs) 6
• Previous gastrointestinal bleeding episodes and exposure to certain medications, such as clopidogrel and corticosteroids, can increase the risk of bleeding 6
• The use of aspirin with warfarin or DOACs can also increase the risk of bleeding, particularly for nonmajor bleeding 5