1054 SECTION IX Pediatric Critical Care Hematology and Oncology Willebrand disease (vWD)—is associated with decreased platelet adhesion to areas of injury, with consequent increased bleeding This blee[.]
1054 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology kallikrein “Intrinsic” pathway “Extrinsic” pathway VII HMWK, PK XII XI HMWK, XIIa Ca2+ + + XIa VIIa + TF + IX IXa VIII VIIIa Trauma – Ca2+ PL X X Xa V Ca2+ PL Va IIa II FBGN Fibrin XIII TFPI “Common” pathway XIIIa Cross-linked clot • Fig 89.2 Classical coagulation cascade depicting the serial, stepwise activation of zymogen (inactive) serine proteases to active clotting factors that subsequently “activate” the next zymogen in the series In this depiction, factor XII (FXII) in the presence of high molecular weight kininogen (HMWK) and prekallikrein (PK) is converted to FXIIa Activated factor IX (FIXa) in complex with the nonserine protease FVIIIa, calcium (Ca21), and phospholipid (PL) (the “tenase” complex) catalyze the activation of FX to FXa Likewise, FXa in complex with the nonserine protease Va, calcium, and phospholipid (the “prothrombinase” complex) catalyzes the cleavage of prothrombin (FII) to thrombin (FIIa) The pathway commencing with FXII and ending with the generation of FXa is referred to as the “intrinsic” pathway while that spanning the activation of FVII in the presence of tissue factor (TF) resulting in FXa generation is referred to as the “extrinsic” pathway The cascade from FXa ending with the production of fibrin (from fibrinogen) is the “common” pathway Activated FXIII (FXIIIa) cross-links polymerized thrombin, rendering it relatively resistant to lysis by plasmin (the process of fibrinolysis) Several important areas of “positive” (blue lines) and “negative” (red lines) that crosstalk between the intrinsic and extrinsic clotting pathways are depicted Positive (1): FVIIa/ TF complex generates FVIIa from FVII FVIIa/TF complex activates FXI to FXia and FIX to FIXa FIIa with HMWK and Ca21 activates FXI to FXia FIIa produces FVa for FV and FVIIIa from FVIII FIIa generates FXIIIa from FXIII FXI enhances conversion of FV to FVa and FVIII to FVIIIa Negative (–): prolonged exposure of thrombin (FIIa) inactivates FVa and FVIIIa FBGN, Fibrinogen; TFPI, tissue factor pathway inhibitor Willebrand disease (vWD)—is associated with decreased platelet adhesion to areas of injury, with consequent increased bleeding This bleeding diathesis associated with vWD is further increased by a concomitant decrease in circulating FVIII that occurs in most individuals with vWD owing to an increased in vivo degradation of FVIII not complexed to vWF Role of Endothelial Cells in Hemostasis The endothelium plays a critical role in the regulation of blood coagulation and platelet activation It also modulates vascular tone and permeability,9 as detailed later (see also Chapter 25) ECs also synthesize and secrete components of the subendothelial extracellular matrix, including adhesive glycoproteins, collagen, fibronectin, and vWF ECs ordinarily present a nonthrombogenic surface to flowing blood but enhance clot formation when disrupted by trauma or injured by infection or inflammation This process involves multiple components of the protein C pathway (eFig 89.7).10 When this system is disrupted, the endothelium may become a prothrombotic rather than an antithrombotic organ, and localized thrombosis may occur When thrombin is generated as a consequence of bleeding, thrombomodulin expressed on the surface of ECs bind thrombin, which then facilitates the conversion of protein C bound to the EC protein C receptor (EPCR) to activated protein C (APC), which, in turn, degrades FVIIIa and FVa, thereby damping down further thrombin formation However, when ECs are stimulated (e.g., by inflammation), surface expressed TF facilitates the conversion of FVII to FVIIa with resultant generation of FXa, which can catalyze the cleavage of prothrombin (FII) to thrombin (FIIa) on cell (phospholipid) surfaces (e.g., platelets).11 The balance between the generation of thrombin and APC plays a central role CHAPTER 89 Coagulation and Coagulopathy Plasminogen PAI-1 tPA uPA α2AP α2M Plasmin Endothelial cells Xa/Va D-Dimer FDPs Fibrin Thrombin Prothrombin Fibrinogen Thrombomodulin TAFIa aPC Protein C TAFI • Fig 89.3 Various elements in promoting (blue arrows) and inhibiting (red arrows) fibrinolysis Positive: thrombin (FIIa) activates endothelial cells, producing urine plasminogen activator (uPA) and tissue plasminogen activator (tPA), which then cleaves plasminogen to form plasmin, which degrades fibrin Negative: Thrombin in the presence of thrombomodulin generates activate protein C (aPC), which inhibits thrombin formation by inactivating FVa to FVi and FVIII to FVIIIi Thrombomodulin also enables the conversion of thrombin activatable fibrinolysis inhibitor (TAFI) to its active form (TAFIa), which inhibits plasmin degradation of fibrin Both a-2-macroglobulin (a2M) and a-2-antiplasmin inhibitor (a2AP) also inhibit plasmin activity Upon injury to the endothelium, subendothelial matrix collagen and proteins are exposed, facilitating activation of circulating platelets Platelets then progress through a process of tethering (the initial step of adhering to the endothelial cell) n adhesion n spreading n aggregation (platelet-to-platelet contact), resulting in the formation of a platelet thrombus FDPs, Fibrin degradation products Vascular injury Vasoconstriction Platelet activation vWF, fibrinogen Platelet plug Coagulation cascade Antithrombotic control Plasminogen Thrombin Fibrinogen Fibrin Blood clot Coagulation (secondary hemostasis) Primary hemostasis Plasmin Fibrinolysis • Fig 89.4 Three phases of hemostasis Hemostasis begins with formation of a platelet plug in the region of injury and involves primarily the adhesion of activated platelets to areas of damaged vascular endothelium Activation of the processes that result in the formation of a fibrin clot (coagulation) begins essentially simultaneously with platelet activation and adhesion Blood flow is reestablished by clot lysis (fibrinolysis) vWF, von Willebrand factor 1055 1056 S E C T I O N I X Pediatric Critical Care: Hematology and Oncology Favors clotting Favors bleeding Thrombin • Activation of coagulation cascade –Increase in FVIIIa and vWF • Cleavage of fibrinogen to fibrin • Platelet activation • Decrease natural anticoagulants Protein C, Protein S, ATIII • Inhibition of fibrinolysis –Increase in PAI-1 –Decrease in plasminogen –Increase in TAFIa • Decrease platelet count • Impair platelet function • Inactivate FVIIIa and FVa • Increase APC • Increase fibrinolysis –Increase tPA –Decrease α2-antiplasmin –Decrease TAFI activation by PF-4 –Increase PAI-1 DVT, PE, microvascular thrombosis with MODS Hemorrhage, DIC, hyperfibrinolysis • Fig 89.5 Hemostasis in critical illness Disruption of the normal balance in hemostasis that frequently occurs during critical illness may result in a phenotype of excess clot formation (thrombosis) or of insufficient clot formation (bleeding) APC, Activated protein C; ATIII, antithrombin-III; DIC, disseminated intravascular coagulation; DVT, deep venous thrombosis; MODS, multiple organ dysfunction syndrome; PAI-1, plasminogen activator inhibitor type-1; PE, pulmonary emboli; PF4, platelet factor 4; TAFI, thrombin activatable fibrinolysis inhibitor; tPA, tissue plasminogen activator; Subendothelial matrix Exposed collagen vWF GP VI GP Ib/IX/V Serotonin TxA2 Platelet activation Activation Granules GP IIb/IIIa Fibrinogen ADP • Fig 89.6 Platelets associate with cells and surfaces by adhesion (plate- let to nonplatelet cells and surfaces) and aggregation (platelet to platelet) These contact associations are mediated by specific platelet receptors The primary receptor for adhesion is the glycoprotein (GP) Ib/IX/V complex that binds von Willebrand factor (vWF) Binding of vWF to this receptor does not require that platelets become activated, although binding of sufficient vWF to platelets can result in platelet activation Aggregation involves the binding of fibrin (or fibrinogen) to the platelet GP IIb/IIIa (the a2b3 integrin receptor) Activation of platelets is required for binding to this receptor Other important adhesion receptors include those for collagen Upon activation, platelets secrete both platelet stimulatory and vasoactive molecules that include adenosine diphosphate (ADP), serotonin, and thromboxane A2 (TXA2), which enhance hemostasis in determining whether a clinical syndrome will be characterized by bleeding or by thrombosis An additional important property of APC is its modulation of fibrinolysis; APC is capable of neutralizing the fibrinolysis inhibitors plasminogen activator inhibitor type-1 (PAI-1) and thrombin activatable fibrinolysis inhibitor (TAFI).12 PAI-1 is a glycoprotein of the serine protease inhibitor family Its primary role in vivo is the inhibition of both tissue- and urokinase-type plasminogen activators PAI-1 is an acute-phase protein that increases during acute inflammation In patients with sepsis, increased levels of PAI-1 are associated with increased levels of various cytokines and acute-phase proteins, abnormal coagulation parameters, increased severity of disease, and poorer outcomes The regulation of the production of PAI-1 is multifactorial The 4G/5G insertion/ deletion promoter polymorphism of the PAI-1 gene has been shown to affect PAI-1 plasma levels; individuals with the 4G/4G genotype display the highest PAI-1 levels, whereas those with the 5G/5G genotype display the lowest (the 4G/5G genotype results in intermediate levels) Differences in PAI-1 levels have been demonstrated to affect the risk of developing severe complications and death from sepsis, higher PAI-1 levels generally being associated with increased mortality in animal models of sepsis and higher severity of illness and organ dysfunction scores in septic patients, including children with meningococcal sepsis.13 However, the regulation of PAI-1 levels is complex, involving more than promoters of synthesis APC can stimulate fibrinolysis by forming a tight 1:1 complex with PAI-1, leading to inactivation of this fibrinolysis inhibitor High levels of thrombin lead to increased levels of APC, which can complex to PAI-1 This complex is subsequently cleared from the circulation, resulting in PC depletion.14 Thrombin generation also increases the levels of TAFI, also known as carboxypeptidase R TAFI is an important negative regulator of the fibrinolytic system and has been shown to inactivate inflammatory peptides that play a role in the contact activation of coagulation, such as complement factors C3a and C5a The full role of TAFI in the hemostatic and innate immune response to sepsis is still under active investigation Studies suggest that its role as a regulator of fibrinolysis appears to be of prognostic significance similar to that of PAI-1 (i.e., elevated levels resulting in decreased fibrinolysis appear to be associated with a poorer outcome in sepsis).15 Crosstalk Between Coagulation and Inflammation Evidence exists that the coagulation system developed during evolution as an intrinsic component of the human host defense to infection Consequently, inflammation, whether induced by infection or noninfectious causes, has the potential to result in activation of coagulation leading to dysregulation of hemostasis During sepsis, TF expression is upregulated in activated monocytes and ECs as a response to endotoxin and other pathogen-associated/ pathogen-initiated events, with both increased secretion of proinflammatory cytokines and activation of coagulation leading to increased thrombin generation This increase in thrombin generation results in upregulation of coagulation and inflammation through platelet activation and induction of both procoagulant and anticoagulant proteins, and the induction of proinflammatory and antiinflammatory cytokines and mitogenic responses (eFig 89.8).16,17 Concurrent with coagulation activation, two other crucial mechanisms occur during sepsis One is the depression of natural anticoagulant systems, involving antithrombin and protein C (PC, APC), and the second is the inhibition of fibrinolysis through the production of PAI-1 and TAFI 1056.e1 Hemostasis Platelet IIa High Va IIa Low dation Degra VIIIa and of Va II VIIIa Xa X Xa APC VII/VIIa TM PC APC IIa IIa EPCR TM IXa TF VIIa TF X VIIa TF X VIIa Xa TF EPCR Quiescent endothelial cell Extravascular cell, stimulated endothelial cell or monocyte • eFig 89.7 Platelet-endothelial cell–mediated hemostasis Protein C (PC) bound to the endothelial pro- tein C receptor (EPCR) in the presence of thrombin (IIa) bound thrombomodulin (TM) is converted to activated PC (APC), which then inactivates activated factor V (Va) and factor VIII (VIIIa) to inactive species, thereby downregulating factor Xa formation via the “tenase” complex (IXa/VIIIa/Ca/phospholipid) and IIa (thrombin) formation via the “prothrombinase” complex (Xa/Va/Ca/phospholipid) Monocytes activated by circulating factors (such as lipopolysaccharide, zymosan, or peptidoglycan) or by tissue factor (TF) generated by injured endothelial cells activate coagulation via FVIIa/TF–mediated factor Xa generation II, Prothrombin; V, factor V; Va, activated factor V; VII, factor VII; VIIa, activated factor VII; VIIIa, activated factor VIII; IXa, activated factor IX; X, factor X; Xa, activated factor X NOD1 Treg induction TLR9 TLR7,8 TLR5 TLR3 TLR4 TLR4 TLR5 TLR2 TLR2 TLR1 1056.e2 CD4+ NOD2 Leukocyte recruitment Innate immunity: EC TLR and NOD activation Adaptive immunity: EC-leukocyte interaction Microvascular endothelium EC-platelet-leukocyte interaction VCAM-1 and ICAM-1 upregulation Immune-/inflammationdriven angiogenesis Coagulation and inflammation CD4+CD25+ PC EPCR Plateletplatelet aggregation Plateletleukocyte aggregation TM-EPCR complex TM APC Antiinflammatory effect Resting endothelium PC sEPCR sTM Decreased antiinflammatory effect Angiogenic factors Activated endothelium • eFig 89.8 Coagulation, endothelial cells, complement, and inflammation Inflammation, coagulation, and immune response are interconnected at various points Endothelial cell (EC) interactions with leukocytes are important in adaptive immune responses and in modulating the innate immune response via various toll-like receptor (TLR) receptors In conjunction with ECs and leukocytes, platelets play an important role in host pathogen responses by formation of neutrophil extracellular traps (NETs) and induction of NETosis Coagulation and inflammation intersect via activation of the complement system, and ECs, leukocytes, and platelets all play roles in wound healing and angiogenesis APC, activated protein C; EPCR, endothelial cell protein C receptor; ICAM-1, intercellular adhesion molecule 1; NOD, nucleotide-binding oligomerization domain-like receptor; PC, protein C; sTM, soluble thrombomodulin; TM, thrombomodulin; sEPCR, soluble endothelial cell protein C receptor; VCAM1, vascular cell adhesion protein ... with PAI-1, leading to inactivation of this fibrinolysis inhibitor High levels of thrombin lead to increased levels of APC, which can complex to PAI-1 This complex is subsequently cleared from... platelet GP IIb/IIIa (the a2b3 integrin receptor) Activation of platelets is required for binding to this receptor Other important adhesion receptors include those for collagen Upon activation, platelets... the glycoprotein (GP) Ib/IX/V complex that binds von Willebrand factor (vWF) Binding of vWF to this receptor does not require that platelets become activated, although binding of sufficient vWF