Anticoagulation in the intensive care unit

Introduction

Patients in an intensive care unit (ICU) often have received or require anticoagulation for multiple reasons that include acute thrombotic issues, mechanical valves, venous thromboembolic prophylaxis, atrial fibrillation, ischemic cardiovascular disease, and/or extracorporeal life support. The types of anticoagulation and need for therapy vary depending on whether patients have arterial or venous thromboembolic issues. These issues are important in critically ill patients and have critical perspectives for management. The concept of anticoagulation and the various therapeutic approaches have rapidly changed over recent years, with the advent of many oral anticoagulation agents that will be considered. In addition, there are important links between coagulation and other critical physiologic responses including inflammation, that are beyond the scope of this review.

ICU patients are anticoagulated for both thrombosis treatment and thromboprophylaxis. As initially mentioned, this includes a broad spectrum of potential indications. Although multiple therapeutic agents prevent or treat thrombosis in pathologic states, it is crucial to consider that all anticoagulation agents can cause bleeding. Thus causes of bleeding in an ICU setting often are the result of an acquired hemostatic defect caused by alterations in the physiologic equilibrium of procoagulant and anticoagulation balances. Under normal physiologic states in healthy patients, anticoagulation is favored because of a multitude of mediators and vascular endothelial cells. After vascular injury resulting from metabolic causes, surgery, or trauma, patients also develop procoagulant changes that alter this complex balance. As a result, hemostasis and coagulation are far more complex than the simplified coagulation cascades that most clinicians have learned or considered because of the complex equilibrium among blood cells, platelets, coagulation factors, natural inhibitors of coagulation, and the fibrinolytic system.

In ICU settings, patients may receive anticoagulants for multiple indications that include venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) for either prevention or therapy. Patients may also have additional problems that include acute coronary syndromes, percutaneous coronary interventions (PCIs), or with an acute ischemic stroke that are arterial issues. Arterial thrombi are mediated by platelet responses, and important interactions exist in hemostasis and thrombus formation. With an arterial injury, injury or rupture of an atherosclerotic arterial plaque serves as a procoagulant focus for clot formation caused by platelet adhesion, activation, and aggregation, with the clinical end result of myocardial infarction (MI) or stroke. Platelets normally circulate in an inactivated state, but after activation as described, they express glycoprotein IIb/IIIa receptors that allow fibrinogen to bind, cross-link platelets, aggregate, and form a thrombus. Vascular injury causes thrombin formation but also platelet activation and the formation of the platelet-fibrinogen plug. Because platelets have a pivotal role in the pathogenesis of thrombosis after plaque rupture, antiplatelet agents, including aspirin, thienopyridines (clopidogrel, prasugrel, ticagrelor, cangrelor), and the glycoprotein IIb/IIIa inhibitors, reduce adverse events that are associated with arterial thrombotic events, including plaque rupture.

Patients therefore commonly present in the ICU with underlying hemostatic disorders because of preexisting preoperative anticoagulation or antiplatelet therapy. All therapies that prevent clots from forming in pathologic states also interfere with normal hemostasis, an important mechanism to protect patients from exsanguination. Multiple anticoagulation agents are also administered in the ICU setting that include low-molecular-weight heparins (LMWHs), oral anticoagulants (vitamin K antagonists [VKAs]/warfarin and the new direct non–vitamin K oral agents apixaban, dabigatran, edoxaban, or rivaroxaban), platelet inhibitors (the thienopyridines clopidogrel, prasugrel, or ticagrelor), or parenteral direct thrombin inhibitors (bivalirudin, argatroban). ^, This chapter focuses on current pharmacologic anticoagulation therapies ICU patients may receive and the therapeutic perioperative and prohemostatic pharmacologic approaches that are used to treat or prevent bleeding in this setting.

Anticoagulation

The basis of anticoagulation is modulating clot formation by inhibiting both thrombin activation and platelet activation. Thrombin is a critical component of hemostasis (stopping bleeding) and a critical procoagulant in coagulation. Thrombin catalyzes the formation of fibrin from soluble fibrinogen but also activates factors V and VIII and platelets. Activated platelets adhere to injured vascular endothelium through a von Willebrand factor bridge between the vasculature and the platelets. Platelets also, when activated, express IIb/IIIa receptors where fibrinogen binds, causing aggregation, but also facilitate the further generation of thrombin. There are also complex humoral amplification pathways that link both inflammatory and coagulation responses to generate thrombin and prothrombotic effects. Thus anticoagulation is based on inhibiting thrombin activation, platelet activation, and/or both. Current anticoagulants used to prevent clot formation will be considered. An overview of the specific targets of the different anticoagulants is shown in Fig. 128.1 .

Heparin

Heparin, the most commonly used anticoagulant, especially in an ICU setting, is isolated from porcine intestine, where it is stored in the mast cell granules. Unfractionated heparin (UFH) is a combination of 3000- to 30,000-dalton (Da) fragments. Heparin binds to antithrombin III (also called antithrombin [AT]), increasing the rate of thrombin-AT complex formation, but also inhibits other steps in coagulation. Heparin anticoagulation has major advantages in an ICU setting, as it can be rapidly reversed with protamine, has a short half-life of ~1 hour, and is one of the few anticoagulants that can be readily administered in patients with renal dysfunction that may otherwise prolong the half-lives of most agents. One of the major side effects of UFH is heparin-induced thrombocytopenia (HIT) that can occur in ~1%–5% of ICU patients, especially postoperatively and after cardiac surgery with cardiopulmonary bypass.

Synthetic Xa inhibitors