There is increasing evidence that the activation of coagulation and inflammation are essential responses for host defense during critical illnesses such as sepsis, severe trauma, and in the current era of pandemic respiratory viruses. Venous thromboembolism (VTE), pulmonary microvascular thrombosis, and arterial thrombosis have been associated with influenza A virus and most recently with the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Similarly, there have been significant advances in transfusion medicine with the establishment of appropriate thresholds for blood product support in critically ill patients, enhanced understanding of transfusion-related complications, and use of blood alternatives. This chapter will discuss the pathophysiology of thrombosis during critical illness, and review the thrombotic complications and issues surrounding anticoagulation management particularly in patients with coronavirus disease-19 (COVID-19) and anticoagulant reversal agents. Indications for red blood cell, platelet, and plasma transfusion in critically ill and trauma patients will be reviewed as well as the indications for massive transfusion, complications of blood product support, and strategies to minimize blood loss and optimize hematopoiesis.
PATHOPHYSIOLOGY OF THROMBOSIS DURING CRITICAL ILLNESS
The coagulation system is a highly regulated cascade that ultimately leads to blood clot formation. The primary purpose of coagulation is hemostasis. In recent years, coagulation factors have been implicated in tissue repair and inflammatory responses in sepsis, major trauma, and other critical illnesses. During sepsis, activation of the coagulation cascade is important in the process of isolation of invading microorganisms. Coagulation abnormalities are present in virtually all patients with sepsis, and when exaggerated and dysregulated can lead to disseminated intravascular coagulation (DIC), associated with microvascular and macrovascular thrombosis, multi-organ dysfunction, and/or hemorrhage.1
Host-released proinﬂammatory molecules freed into the extracellular environment following tissue injury (histones, nucleosomes, cell-free chromosomal and mitochondrial DNA, high-mobility group box 1 protein [HMGB-1], and heat shock protein) are known as damage-associated molecular patterns (DAMPs) and play key roles in the immune system and tissue repair. DAMPs are released from dying cells or secreted from immune cells in response to infection or tissue injury. When DAMPs are recognized by monocytes, they deliver tissue factor (TF), a transmembrane glycoprotein, to the sites of pathogen exposure. The complex pathophysiology of sepsis-induced coagulopathy is mediated by pathogen-associated molecular patterns (PAMPs). PAMPs are exogenous substances associated with pathogens that are recognized by specific toll-like and complement receptors known as pattern recognition receptors (PRRs). This intracellular signaling results in the synthesis of proinflammatory cytokines, which are key mediators of inflammation and vascular dysfunction. Interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α) can induce the upregulation of TF on monocytes and macrophages with initiation of anticoagulation and fibrinolysis. TF can circulate in the blood in soluble form or associated with extracellular vesicles (EVs). EVs are submicron sized spherical particles that are enclosed by bilayer phospholipid membranes released from inflammatory cells into plasma that initiate coagulation with the expression of TF on their surfaces. Although platelet derived EVs were ...