Methods to Correct Drug-Induced Coagulopathy in Bleeding Emergencies

A Comparative Review

Shaughn Nalezinski, MS, MLS(ASCP)BB, MT(AMT)

Disclosures

Lab Med. 2022;53(4):336-343. 

In This Article

Abstract and Introduction

Abstract

Objective: Anticoagulant and antiplatelet therapy have become increasingly popular. The goal of therapy is to prevent venous thromboembolism and platelet aggregation, respectively. Traditional anticoagulant and antiplatelet drugs are quickly being replaced with novel medications with more predictable pharmacokinetics. Unfortunately, these drugs carry the risk of uncontrolled hemorrhage because of drug-induced coagulopathy. Uncontrolled hemorrhage continues to be a major cause of preventable death: hemorrhage accounts for approximately 30% of trauma-related deaths, second to brain injury. Controlling hemorrhage while dealing with comorbidities remains a challenge to clinicians. There are many gaps in care and knowledge that contribute to the struggle of treating this patient population.

Methods: This literature review is focused on the most effective ways to achieve hemostasis in a patient with drug-induced coagulopathy. The antiplatelet therapies aspirin, clopidogrel, ticlopidine, pasugrel, and ticagrelor are analyzed. Anticoagulant therapies are also reviewed, including warfarin, rivaroxaban, apixaban, edoxaban, and dabigatran. In addition, viscoelastic testing and platelet function assays are reviewed for their ability to monitor drug effectiveness and to accurately depict the patient's ability to clot. This review focuses on articles from the past 10 years. However, there are limitations to the 10-year restriction, including no new research posted within the 10-year timeline on particular subjects. The most recent article was then used where current literature did not exist (within 10 years).

Results: Traditional anticoagulants have unpredictable pharmacokinetics and can be difficult to correct in bleeding emergencies. Vitamin K has been proven to reliably and effectively reverse the effect of vitamin K antagonists (VKAs) while having a lower anaphylactoid risk than frozen plasma. Prothrombin complex concentrates should be used when there is risk of loss of life or limb. Frozen plasma is not recommended as a first-line treatment for the reversal of VKAs. Novel anticoagulants have specific reversal agents such as idarucizumab for dabigatran and andexxa alfa for factor Xa (FXa) inhibitors. Although reliable, these drugs carry a large price tag. As with traditional anticoagulants, cheaper alternative therapies are available such as prothrombin complex concentrates. Finally, static coagulation testing works well for routine therapeutic drug monitoring but may not be appropriate during bleeding emergencies. Viscoelastic testing such as thromboelastography and rotational thromboelastometry depict in vivo hemostatic properties more accurately than static coagulation assays. Adding viscoelastic testing into resuscitation protocols may guide blood product usage more efficiently.

Conclusion: This review is intended to be used as a guide. The topics covered in this review should be used as a reference for treating the conditions described. This review article also covers laboratory testing and is meant as a guide for physicians on best practices. These findings illustrate recommended testing and reversal techniques based off evidence-based medicine and literature.

Introduction

The aging populations (>65 years) of the United States and Europe present many challenges compared to younger patients because they have more comorbidities, disabilities, and fragility. Among these challenges are anticoagulation and antithrombotic agents. Direct oral anticoagulants have increased in use in this demographic along with traditional vitamin K antagonist (VKA) therapies. In addition, 40% to 66% of the aging population are taking at least 1 antithrombotic agent.[1]

This trend is cause for concern because 7.2 out of 100 patients taking anticoagulants require management for drug-induced coagulopathy or complications associated with antithrombotic prophylaxis or treatment.[1] Many of these bleeds are gastrointestinal, although intracranial hemorrhage is also of concern for those taking both VKAs and direct oral anticoagulants. The risk of fatal bleeding from anticoagulation is 1.31 people out of 100.[2,3]

Uncontrolled hemorrhage continues to be a major cause of preventable mortality in trauma patients, only second to brain injuries. In total, uncontrolled hemorrhage accounts for approximately 40% of deaths.[4] Managing hemorrhage during a bleeding emergency has difficulties of its own; adding anticoagulants and antiplatelet drugs further complicates treatment and resuscitation. In addition, novel direct oral anticoagulants are becoming increasingly popular and lack assays or assay availability to measure their degree of efficacy.

As a result, many providers have historically been uncomfortable with the thought of treating coagulopathy during a bleeding emergency, mainly because of the number of drugs and assays available and that there is no "one size fits all" treatment. Correcting coagulopathy and achieving hemostasis is vital in managing these patients. Improper treatment can lead to overtransfusion of blood products and, ultimately, death. Massive transfusion, although beneficial and lifesaving when indicated, still carries risks such as hypocalcemia, acidosis, shock, and multisystem failure.[5,6]

Traditional anticoagulants, direct oral anticoagulants, thrombin inhibitors, and antiplatelet drugs are explored in this article. Traditional anticoagulants include warfarin, which is a VKA that inhibits the activation of multiple coagulation factors such as II, VII, IX, and X along with proteins S, C, and Z.[7] In a cohort study by Yu and colleagues,[8] it was found that patients on warfarin therapy had a significant decrease in death resulting from stroke. However, there was a notable increased risk of hemorrhagic stroke (hazard ratio 1.01) and an association with subdural and gastrointestinal hemorrhage.[9]

Novel anticoagulants, such as rivaroxaban, apixaban, and edoxaban, are part of a drug group called direct oral anticoagulants. These drugs directly inhibit factor Xa (FXa). Direct oral anticoagulants act more reliably than traditional anticoagulants. Unfortunately, the U.S. Food & Drug Administration (FDA) and the European Medicines Agency (EMA) do not recommend them for patients with mechanical heart valves and severe mitral stenosis.[10]

Direct thrombin inhibitors (DTIs) inhibit free and clot-bound thrombin along with thrombin platelet aggregation. Dabigatran, lepirudin, desirudin, bivalirudin, and argatroban are also DTIs with similar mechanisms of action. Dabigatran is the only oral DTI in this group. Because it can be taken orally, more patients are on dabigatran than the other DTI drugs.

The antiplatelet agents aspirin and clopidogrel affect platelet aggregation and activation, respectively. Aspirin inhibits platelet aggregation via thromboxane-a2, and clopidogrel irreversibly blocks the P2Y12 receptor, inhibiting the adenosine diphosphate (ADP) pathway for platelet aggregation. Ticlopidine, ticagrelor, prasugrel, and cangrelor are antiplatelet drugs that belong to the same group as clopidogrel.

The purpose of this article is to highlight the challenges faced when thrombus formation is inhibited by drugs in the setting of coagulopathy associated with trauma (ie, dilutional and consumption coagulopathy). In addition, assays that are used to measure hemostasis/drug efficacy are explored. Finally, recommendations on how to treat these patients are identified using novel research. The drugs' mechanism of action is explored and considered with these recommendations.

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