Coagulation Abnormalities in Sepsis

Objectives

This chapter will:

1.
Review the normal process of coagulation and describe the sepsis-induced coagulation abnormalities.
2.
Delineate the interaction between coagulation and inflammation during sepsis.
3.
Outline the pathogenesis of sepsis-associated coagulopathy and discuss relevant factors associated with its diagnosis, clinical presentation, associated outcomes, and management.

Sepsis now is defined as a life-threatening organ dysfunction resulting from a dysregulated host response to infection. The subsequent systemic inflammatory response is accompanied by the activation of the coagulation system, initiating the cross-talk between inflammation and coagulation, which plays a pivotal role in sepsis pathogenesis.

Virtually all patients with sepsis develop some coagulation abnormalities, with a wide range of severity. Sepsis-associated coagulopathy (SAC) is a frequent complication of sepsis, and around 35% of septic patients evolve to disseminated intravascular coagulation. The hemostatic pathways related to SAC are so intricate that a patient can have, simultaneously, an impaired ability to clot and a thrombotic state.

Normal Coagulation

The coagulation system works to reach two objectives: (1) the maintenance of the intravascular blood in a fluid state and free of clots and (2) in the presence of any kind of vascular injury, the induction of clot formation (thrombus) in a rapid, regulated, and localized manner. Regulatory mechanisms are crucial for the hemostatic process, because the initiation of the clotting cascade later must lead to thrombus elimination by fribrinolysis.

The major phases of the hemostasis are described below. These ubiquitously complex and dynamic phases are presented in a simplified review.

Platelet Plug Formation

After vascular injury, platelets are recruited promptly to the site of injury to “seal the break” of a closed, high-pressure circulatory system. The exposure of subendothelial elements (that normally are concealed) is the major signal for the initiation of platelet deposition. Platelet activation takes place at the site of injury, followed by adhesion, aggregation, granule secretion, and procoagulant activity. All of the following processes occur in a coordinated manner for the formation of the platelet plug :

Activation: Collagen, adenosine diphosphate (ADP), and thrombin are key players of this step. Collagen is one of the subendothelial factors exposed after any vascular injury, important for platelet activation and adhesion ; ADP is released by activated platelets at the site of injury and mediates platelet aggregation (paracrine and autocrine function) after binding to G-protein receptors P2Y1 and P2Y12 ; thrombin activates platelets by binding to protease-activated receptors-1 (PAR-1) and PAR-4 on the platelet surface, contributing to platelet aggregation.
Adhesion: Adhesive glycoproteins exposed in the subendothelium (mostly collagen and von Willebrand factor [vWF)]), bind to glycoprotein (GP) receptors on the surface of platelets: vWF binds to GP Ib/IX/V, whereas collagen binds to GP Ia/IIa (integrin α 2 β 1) and GP VI.
Aggregation: Mediated by the binding between fibrinogen (or vWF) and integrin α IIb β 3 (GPIIb/IIIa) present on two neighboring platelets. GPIIb/IIIa functions as a cross-linking receptor.
Granule secretion: Secretion of fibrinogen, vWF, thrombospondin, platelet-derived growth factor (PDGF), platelet factor 4, P-selectin (contained in the alpha granules), and adenosine diphosphate (ADP), adenosine triphosphate (ATP), ionized calcium, histamine, and serotonin (present in dense granules) enhances to synergize the activation, recruitment, adhesion, and aggregation of platelets.
Platelet procoagulant activity: Synthesis or activation of tissue factor (TF), formation of procoagulant microparticles rich in factor Va (FVa), and exposure of negatively charged phospholipids (mainly phosphatidylserine). Consequently, there is an increase in thrombin generation and further platelet activation.

Clotting Cascade and Clot Propagation

The clotting cascade function depends on the sequential reactions necessary for activation of zymogens into enzymes, and inactive procofactors into cofactors, with the objective of generating thrombin. Subsequently, fibrin is produced to consolidate the platelet plug. The amount of fibrin produced is controlled by feedback loops in the clotting cascade that prevent systemic and continuous fibrin production. The traditional model of the clotting cascade is based on intrinsic and extrinsic pathways, in which exposure of blood to a negatively charged surface triggers the intrinsic pathway, and TF, at the site of injury, initiates the extrinsic pathway. These two pathways activate factor X, leading to thrombin formation, followed by the conversion of fibrinogen to fibrin. Then activated factor XIII stabilizes fibrin and regulates the size of the clot (by controlling the volume of red cells trapped within a thrombus) ( Fig. 88.1A ). This model has been modified, but it is still a good tool for the interpretation of in vitro coagulation tests.

FIGURE 88.1, A, Simplified representation of the traditional model of coagulation cascade. B, Revised version of coagulation cascade with procoagulant effects of TF and thrombin. Black arrows indicate positive feedback loops, green arrows indicate negative feedback loops, dashed green arrows indicate inactivation of factors Va and VIIIa mediated by activated Protein C. APC, Activated protein C; EPCR, endothelial protein C receptor; TF, tissue factor; TM, thrombomodulin.

The revised version of the clotting cascade includes the procoagulant activities (positive feedback loops) of TF and thrombin. TF activates factor IXa (FIXa), whereas thrombin activates factors V, VIII XI, and platelets, amplifying the cascade's self-generation (via the traditional intrinsic pathway). Negative feedback loops are also present in this revised version, which comprises activated protein C (APC), thrombin-thrombomodulin complex, protein S, and lipid cofactors (discussed later in this chapter) ( Fig. 88.1B ).

Termination of Thrombosis

AT, tissue factor pathway inhibitor (TFPI), and the protein C pathway are the major factors involved in termination of thrombosis. Antithrombin complexes irreversibly to several coagulation factors (mostly thrombin, and factors Xa, IXa, XIIa, and IXa), leading to their neutralization. This process can be enhanced 1000- to 4000-fold when heparins (endogenous or exogenous) bind to an antithrombin heparin-binding site. TFPI, also named lipoprotein-associated coagulation inhibitor or extrinsic pathway inhibitor, is present at very low concentrations compared with AT and circulates mostly in association with lipoproteins. TFPI is synthesized by endothelial cells, megakaryocytes, and smooth muscle cells. TFPI's inhibitory effect is mediated by a quaternary protein complex formed by two binary complexes, TF/FVIIa and TFPI/FXa, which leads to neutralization of FXa and FVIIa. The protein C pathway is one of the most relevant participants of the negative feedback reactions of the clotting cascade. The activation of protein C is mediated by its binding to surface endothelial protein C receptor (EPCR) and by proteolysis of the thrombin-thrombomodulin complex. APC triggers anticoagulant activity by proteolytic inactivation of factors Va and VIIIa, with contribution of proteins and lipid cofactors, including protein S, phospholipids on platelet surfaces, lipoproteins (HDL), and microparticles from endothelial cells.

Thrombus Elimination and Fibrinolysis

After thrombus formation, the thrombus must be removed from the vessels to restore vessel patency. The activation of plasminogen by plasmin is critical for thrombus removal. Plasminogen is activated by tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) to form plasmin, which cleaves fibrin at multiple sites and releases fibrin degradation products (FDPs), mostly D-dimer. Plasmin also can minimize the cross-linking of fibrin by induction of cleavage of FXIIIa. Fibrinolysis (lysis of fibrin) is regulated by plasminogen activator inhibitor 1 (PAI-1), α2-antiplasmin, and thrombin-activatable fibrinolysis inhibitor (TAFI): PAI-1 decreases plasmin formation through tPA inhibition; α2-antiplasmin inhibits fibrinolysis by direct inhibition of plasmin; and TAFI lowers the rate of fibrinolysis by decreasing the incorporation and activation of plasminogen into the clot.

Coagulation in Sepsis

SAC refers to changes in the coagulation system induced by sepsis, manifested as hyper- and/or hypocoagulability. Several pathologic derangements of coagulation occur in patients with sepsis (e.g., decreased production of coagulation factors, increased coagulation factor destruction, and increased platelet destruction), which may induce bleeding and/or thrombotic complications because of the prothrombotic state induced by sepsis. SAC includes asymptomatic patients with slight changes in coagulation parameters; patients with nonovert disseminated intravascular coagulation (DIC); and patients with overt DIC.

Decreased Coagulation Factor Production and Increased Coagulation Factor Destruction in Sepsis

Sepsis-induced hepatic dysfunction, deficiency of vitamin K (because of inadequate dietary intake, use of antibiotics that alter the gut flora), use of vitamin K antagonists, and SAC are factors associated with decreased production or increased destruction of coagulation factors in sepsis. Sepsis-induced hepatic dysfunction and/or vitamin K deficiency decreases synthesis of coagulation factors, whereas DIC is the major cause of increased consumption of coagulation factors and the leading cause of bleeding in septic patients. The coagulation system is activated in sepsis even in the absence of overt DIC, also contributing to greater consumption of coagulation factors. The consequent thrombin generation promotes fibrinolysis and production of fibrin degradation product (FDP), such as D-dimer, although sepsis is associated with impaired fibrinolysis.

Thrombocytopenia in Sepsis

Sepsis-induced thrombocytopenia is extremely common in sepsis and is caused by impaired platelet production, increased consumption or destruction, and/or sequestration of platelets in the spleen. Although the most important cause of platelet consumption during sepsis is SAC, the continuous generation of thrombin in sepsis (even in the absence of DIC) also activates and enhances platelets consumption, contributing to thrombocytopenia. Other factors associated with thrombocytopenia in sepsis are heparin-induced thrombocytopenia (HIT), hemophagocytosis (phagocytosis of megakaryocytes), and neutrophil extracellular traps (NETs). HIT is caused by a heparin-induced antibody that binds to the heparin-platelet factor-4 complex on the platelet surface, leading to massive platelet activation and consumption and arterial and venous thrombosis. Hemophagocytosis may be attributed to increased levels of macrophage colony stimulation factor in sepsis. NET formation involves the participation of activated platelets and also may decrease platelet count because of increased platelet consumption.

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