Definition of disease

• Major bleeds are those that result in death, are life threatening, cause chronic sequelae, or consume major health care resources.
  
• Criteria for major bleeding in non‐surgical patients are:
  
  
  
  • Fatal bleeding.
    
  • Symptomatic bleeding in a critical area or organ.
    
  • Bleeding causing a fall in hemoglobin level of 2.0 g/dL or more, or leading to transfusion of two or more units of whole blood or red cells.

Incidence/prevalence

• The risk of major bleeding with use of anticoagulation depends on several factors, including the agent used, indication for anticoagulation, intensity of anticoagulation effect, age, underlying comorbidities, concomitant medications, and duration of treatment (Table 55.1).
  
• Direct oral anticoagulants (DOACs) may be related to a higher risk of bleeding when used after hip surgery, acute coronary syndrome, or for thromboprophylaxis; but inversely cause less bleeding in patients with acute venous thromboembolism (VTE) or pulmonary embolism (PE).
  
• Collectively and individually the DOACs may cause equal or even less major bleeding when compared with vitamin K antagonists.

Etiology

• Anticoagulants, such as warfarin, heparin, direct thrombin inhibitors, factor Xa inhibitors, and antiplatelet agents are used for a variety of indications, including treatment and prophylaxis of VTE, stroke prevention in atrial fibrillation, ischemic cerebrovascular disease, and cardiovascular disease.
  
• Bleeding is a major complication of these agents in the setting of poor drug monitoring, advanced age, multiple patient comorbidities, drug–drug interactions, and trauma.
  
• Intracranial hemorrhage, gastrointestinal (GI) bleeding, and trauma‐related bleeding are some of the common consequences of bleeding secondary to anticoagulation.

Pathology/pathogenesis

• Coumarins/vitamin K antagonists (VKAs):
  
  
  
  • Vitamin K is a cofactor for the carboxylation of glutamate residues of vitamin K‐dependent coagulation factors (factors II, VII, IX, and X) that require carboxylation for their biologic activity.
    
  • By inhibiting vitamin K, coumarins cause hepatic production of partially carboxylated and decarboxylated coagulation factors with reduced procoagulant activity.
  
  
• Heparin:
  
  
  
  • Unfractionated heparin (UFH) binds to antithrombin III to irreversibly neutralize thrombin and factor Xa.
    
  • Low molecular weight heparin (LMWH) is produced from UFH by chemical or enzymatic depolymerization. It efficiently inactivates factor Xa and, to a lesser degree, thrombin.
  
  
• Factor Xa inhibitors:
  
  
  
  • Oral factor Xa inhibitors exert their anticoagulant effect by preventing factor Xa‐dependent conversion of prothrombin to thrombin.
    
  • Three oral factor Xa inhibitors are currently available for clinical use: rivaroxaban, apixaban, and edoxaban.
    
  • Oral factor Xa inhibitors directly bind to the active site of factor Xa, thereby inhibiting both free and clot‐associated factor Xa.
    
  • Indirect Xa inhibitors, such as fondaparinux, bind to antithrombin III to inhibit factor Xa without having any effect on factor IIa.
  
  
• Direct thrombin inhibitors (DTIs):
  
  
  
  • DTIs competitively and reversibly bind to the active site of free and clot‐bound thrombin, thereby blocking its pro‐coagulant activity.
    
  • Available DTIs include dabigatran (oral), bivalirudin (intravenous), desirudin (subcutaneous), argatroban (intravenous), and lepirudin (intravenous).
  
  
• Antiplatelet agents:
  
  
  
  • Several classes of FDA‐approved antiplatelet agents exist, including: aspirin, COX inhibitors, adenosine diphosphate receptor inhibitors, glycoprotein IIB/IIIA antagonists, and protease‐activated receptor‐1 antagonists.
    
  • The average lifespan of a platelet is 8–20 days. Thus, the effects of irreversible platelet inhibitors can be long lasting.

Predictive/risk factors

Drug monitoring

• VKA/heparin:
  
  
  
  • In the setting of VKA and heparin, the intensity of the treatment is strongly associated with the risk of bleeding. Therefore approaches to improve anticoagulation control by frequent point‐of‐care testing and minimizing INR/PTT fluctuations can improve the safety and effectiveness of these drugs.
  
  
• DOACs:
  
  
  
  • DTIs: thrombin time can be useful to determine the level of coagulopathy for DTIs.
    
  • Factor Xa inhibitors:
    
    
    
    • There are no specific laboratory parameters to monitor the anticoagulant impact of factor Xa inhibitors.
      
    • Antifactor Xa levels were originally designed and calibrated for LMWH; however, they can also be used to monitor or confirm overdose of factor Xa inhibitors. This test must be specifically calibrated for factor Xa inhibitors, as the results of the antifactor Xa level is assay specific.

Primary prevention

• It is important to educate patients on dietary restrictions and common OTC drug interactions.
  
• Use of an anticoagulant is associated with an increased risk of trauma‐associated bleeding. Patients who elect to participate in activities with a greater than average risk for blunt trauma should be aware of the risks of bleeding.