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Home , Factor VII, Hemostasis

Pediatric Anesthesia 2010 doi:10.1111/j.1460-9592.2010.03410.x

Review Article Principles of hemostasis in children: models and maturation

NINA A. GUZZETTA MD AND BRUCE E. MILLER MD Department of Anesthesiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, Georgia

Section Editor: Jerrold Lerman

Summary Hemostasis is an active process regulating the formation and disso- lution of fibrin clot to preserve vascular integrity. The different phases of hemostasis are coordinated so that effective clotting occurs only at the site of vascular injury while maintaining flow in other parts of the circulation. Procoagulant processes culminate in generation and fibrin clot formation to protect the vasculature against uncontrolled after injury. Conversely, pro- cesses limit clot extension to unaffected portions of the vasculature. Lastly, fibrinolysis is responsible for clot dissolution once tissue repair and regeneration permit the return of normal blood flow. A precise and delicate interplay exists among these processes to ensure normal hemostasis. The hemostatic system is incompletely developed at birth and matures throughout infancy. Both full-term and preterm neonates are born with low levels of most procoagulant including all the contact activation factors and -dependent factors. Similarly, levels of the major anticoagulant proteins are low at birth. Although often characterized as ‘immature’, the neonatal hemostatic system is nevertheless functionally balanced with no tendency toward coagulopathy or . In this article, we will review the current models of hemostasis and the maturation of the hemostatic system. Our goal is to help clinicians gain a better understanding of the actions of procoagulant agents and of the disruptive effects of serious systemic illnesses on the precarious hemostatic balance of infants.

Keywords: hemostasis; ; children; maturation

Introduction anticoagulation to protect the vasculature from uncontrolled bleeding on the one hand and exces- Hemostasis is a complex physiological process that sive clotting on the other (1). In the past decade, our balances the opposing forces of coagulation and understanding of the mechanisms of hemostasis has been refined and new pharmacologic therapies have Correspondence to: Nina A. Guzzetta, MD, Department of Anes- been developed to help manage coagulation prob- thesiology, Children’s Healthcare of Atlanta at Egleston, 1405 Clifton Road, N.E., Atlanta 30322, Georgia (email: nina.guzzetta@ lems. In this review, we will describe the three emoryhealthcare.org). phases of hemostasis: primary hemostasis or forma-

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tion of a plug, secondary hemostasis or and the resultant high shear rate of coagulation, and tertiary hemostasis or fibrinolysis. blood flow appear to be required for platelet GPIb- We will discuss how, under normal physiologic vWF binding (3,4). During platelet adhesion, in conditions, these three phases act in a coordinated addition to binding vWF, bind manner so that effective clotting occurs only at the exposed in the subendothelial matrix by two high- site of injury while maintaining blood flow in other affinity binding receptors. Platelet-collagen binding parts of the vasculature. We will discuss why via these two receptors is essential to platelet recombinant activated factor VII (rFVIIa) and other adhesion and subsequent activation (2). coagulation factor concentrates are increasingly Once adherent to the injured vessel wall, platelets being used to promote coagulation in patients with become activated by strong agonists present at the uncontrolled bleeding from a variety of etiologies. site of injury, primarily collagen and thrombin. Finally, we will examine the maturation of the Upon activation, platelets undergo a change in hemostatic system. We will discover how the hemo- morphology and expose negatively charged phos- static system in neonates and young infants differs pholipids, previously unexpressed, on their surface from the definitive adult system and how this membrane (5). These negatively charged phospho- ‘immature’ system is capable of maintaining normal lipids play an important role in the adhesion of hemostasis. various coagulation factors to the activated platelet surface. Platelet activation also results in the release a Models of hemostasis of the contents of the platelet -granules and dense granules into the surrounding environment. These Primary hemostasis substances promote aggressive platelet aggregation and of the endothelial smooth Primary hemostasis begins with platelet adhesion muscle cells at the site of injury. (Figure 1). This process is initiated by the interaction Platelet aggregation, the final step in the formation of the platelet Ib (GPIb) receptor of a platelet plug, is mediated by the platelet surface complex with its primary ligand, von Willebrand receptor, the glycoprotein IIb ⁄ IIIa (GPIIb ⁄ IIIa) recep- Factor (vWF) (2). Although there is debate concern- tor, which is switched ‘on’ during platelet activation ing the precise event triggering this interaction, (6). is the primary adhesive molecule of disruption of the smooth endothelial lining of the the GPIIb ⁄ IIIa receptor. It cross-links platelets together by binding receptors on adjacent platelet surfaces. Platelet aggregation occurs in conjunction with the activation of coagulation factors on the platelet surface to support thrombin generation and the formation of a fibrin clot. Formation of a platelet plug is tightly controlled and limited only to areas of vascular injury. Indeed, intact endothelial cells themselves provide the main defense against the propagation of the platelet aggregate beyond the site of injury by producing powerful platelet aggregation inhibitors and vasodilators (3,5).

Secondary hemostasis Figure 1 In 1964, investigators proposed the cascade model of Platelet adhesion mediated by (vWF) – platelet (GPIb) receptor binding. Subsequent coagulation, which described the overall structure of aggregation is mediated via fibrinogen – platelet glycoprotein coagulation as a series of proteolytic reactions (7). IIb ⁄ IIIa (GPIIb ⁄ IIIa) receptor binding. (Reproduced with permis- The intrinsic pathway begins with contact activation sion from Springer Science + Business Media, Canadian Journal of Anesthesia, Natural and Synthetic Antifibrinolytics in Cardiac by negatively charged substances such as kaolin or Surgery, Vol. 39, 1992, page 354, JF Hardy, J Desroches, Figure 1.) by the contact activation factors [factor XII (FXII),

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factor XI (FXI), high molecular weight propagation. It differs from the cascade model in that (HMWK), and (PK)] and ends with the it emphasizes a system regulated by cellular compo- activation of (FX). This pathway is assessed nents rather than one regulated by the kinetics of by the laboratory test called the activated partial coagulation factors. This model is now recognized as thromboplastin time (aPTT). The extrinsic pathway the prevailing model of the coagulation process begins with activation of factor VII in vivo. (FVII) and likewise ends with the activation of FX. It In the Cell-Based Model, the coagulation process is assessed by the laboratory test called the pro- begins with the initiation phase and the primary thrombin time (PT). Both the intrinsic and extrinsic initiator is tissue factor (TF) (10). When vascular pathways converge into a final common pathway integrity is lost, TF, an extra-vascular , is with the activation of FX. Activated FX (FXa), in exposed to the circulating blood. Zymogen FVII in complex with its activated FV (FVa), forms the circulation has an extremely high affinity for the ‘’ complex which is the main TF and, once bound to TF, is rapidly converted to its convertor of prothrombin into thrombin (8). At the activated form, activated FVII (FVIIa). The resultant time, the cascade model was extremely valuable to TF ⁄ FVIIa complex catalyzes two very important the understanding of coagulation; however, it was reactions (11,12). The first is the activation of FX to inadequate to explain several important clinical FXa. The second is the activation of FIX to activated observations. For example, if the activation of FX is FIX (FIXa). indeed part of a final common pathway, then why is In the first reaction, free FXa is rapidly broken the activation of FX through the extrinsic pathway down by natural inhibitors which are abundant in unable to compensate for the lack of factor VIII the environment of the TF-bearing cell. However, (FVIII) or factor IX (FIX) in the intrinsic pathway in FXa present on the surface of the TF-bearing cell is hemophiliacs (9)? relatively protected and can catalyze the conversion In 2000, Hoffman and Monroe (7) presented a of a small amount of prothrombin into thrombin second model of coagulation termed the cell-based (6,13). This small amount of thrombin, although model (Figure 2). This model consists of three insufficient to sustain the cleavage of fibrinogen into overlapping stages: initiation, amplification, and fibrin, is potent enough to fully activate platelets. In the second reaction, FIXa diffuses away from the TF- bearing cell and is attracted to the activated platelet surface. It is the negatively charged phospholipid membrane of the platelet surface, created during platelet activation, which is responsible for assem- bling coagulation factors on the platelet surface and supporting their reactions. As previously discussed, platelets release various substances from their a-granules during activation. Noteworthy is the release of (FV) onto the platelet surface and its conversion, by thrombin, to activated FV (FVa) (7,8). Thrombin also acts to dissociate vWF from circulating FVIII, thus releasing activated FVIII (FVIIIa) onto the activated platelet surface (7,8). Additionally, thrombin activates factor XIII (FXIIIa), which will eventually be responsible for the cross- Figure 2 linking of soluble fibrin monomers into an insoluble A model of tissue factor-initiated, cell-based hemostasis. TF, tissue factor; TFPI, tissue factor pathway inhibitor; vWF, von Willebrand fibrin matrix. Once activated coagulation factors are factor. (Reproduced with permission from DM Monroe et al., The assembled on the activated platelet surface, the stage Factor VII – Platelet Interplay: Effectiveness of Recombinant is set for a large-scale production of thrombin (7). Factor VIIa in the Treatment of Bleeding in Severe Thrombocy- topenia, Seminars in Thrombosis and Hemostasis, Vol. 26, No. 4, Activated platelets express high-affinity binding 2000, page 374.) sites for FIXa and FXa. When FIXa reaches and

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binds to the activated platelet surface, it joins FVIIIa cleavage of a mature fibrin clot into its degradation to form the ‘’ complex (FVIIIa ⁄ FIXa). This products, the smallest of which are known as complex activates large amounts of FXa, which may D-dimers (9). is activated from its zymogen then join with its co-factor, FVa, to form the form, plasminogen, by at least three different acti- ‘prothrombinase’ complex (FXa ⁄ FVa). This ‘pro- vating systems (1). The most important is tissue thrombinase’ complex is responsible for the large- (t-PA), which binds to fibrin scale conversion of prothrombin to the thrombin via lysine binding sites and enzymatically converts necessary for the formation of a stable fibrin cross- plasminogen into plasmin. t-PA only activates plas- linked clot (7). minogen that is bound to fibrin thus limiting Uncontrolled blood coagulation is extremely dan- fibrinolysis to the site of clot formation. gerous thus regulation is exerted at multiple levels of the process. Tissue factor pathway inhibitor Recombinant activated factor VII (TFPI) regulates the initiation phase of blood coag- ulation by inhibiting the actions of the TF ⁄ FVIIa A thorough understanding of the cell-based model complex (14). There are no known deficiency states of coagulation allows clinicians to appreciate the of TFPI in humans perhaps indicating that lack of mechanisms by which high-dose rFVIIa (Novo- TFPI is incompatible with life. Indeed, when mice Seven RT; Novo Nordisk, Bagsvaerd, Denmark) are genetically altered to lack TFPI, they die in utero promotes coagulation and ameliorates bleeding. from uncontrolled coagulation (15). The anticoagu- rFVIIa is a synthetic coagulation factor nearly iden- lant protein, (AT), is a powerful tical to the human plasma coagulation factor VIIa, inhibitor of both FXa and thrombin and is designed but cloned and expressed in hamster kidney cells. to limit the coagulation process to the site of vascular Originally, rFVIIa was developed for the treatment injury (1). (PC), another important anti- of bleeding complications in hemophiliac patients coagulant protein, is activated by thrombin once it who had developed alloantibodies, also termed has bound to the membrane protein, thrombomod- inhibitors, against exogenously administered FVIII ulin, on the surface of intact endothelial cells. When or FIX (16). Recently, increasingly high-dose rFVIIa activated, it inhibits coagulation through the break- has been used to promote coagulation in pediatric down of FVa and FVIIIa (7). patients with nonhemophiliac bleeding from a vari- ety of etiologies (16–18). Although no randomized Tertiary hemostasis controlled clinical trial in children has found rFVIIa to be more effective than placebo in reducing The final phase of hemostasis, termed ‘fibrinolysis’, surgical bleeding, numerous observational studies involves the removal of clot once it is no longer have found a strong temporal relationship between needed (Figure 3). Plasmin is the principle rFVIIa therapy and reduced blood loss or blood of the fibrinolytic system and is responsible for the product transfusion (19–21). rFVIIa works via two probable mechanisms: one is clot TF-dependent, the other TF-independent (22). In the t-PA former, rFVIIa works synergistically with the pa- tient’s zymogen factor VII to complex all exposed TF. Consequently, more active FVIIa ⁄ TF complexes are formed and result in an increase in local Plasminogen Plasmin thrombin generation. In the TF-independent mech- anism, rFVIIa, at sufficiently high doses, binds to negatively charged phospholipids on the surface of activated platelets and activates factor X directly. PAI FDP This provides a platelet surface source of FXa that can catalyze the large burst of thrombin required to Figure 3 t-PA, tissue plasminogen activator; PAI, plasminogen activator support fibrin formation. Recent studies have shown inhibitor; FDP, fibrin degradation products. that, while both mechanisms probably work in

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concert, TF-dependent thrombin generation acti- FX) as well as trace amounts of FVIII, FVIIa, and vated by rFVIIa is much more efficient than TF- FIXa are present in most PCC preparations although independent thrombin generation (23,24). the specific composition and amount of each clotting Thromboembolic complications are infrequent in factor in the concentrate varies depending on the hemophiliacs receiving rFVIIa, but occur more fre- manufacturer. Once again, the major adverse effect quently in patients receiving rFVIIa for off-label uses is thrombosis. Concentrates with high prothrombin (25). In hemophilia, thrombin generation is reduced (FII) and high FVII activity tend to be associated because of an isolated factor deficiency (either FVIII with a greater thromboembolic risk (27). Some or FIX). However, these patients have normal levels manufacturers have added and AT or PC, of anticoagulant factors. Conversely, in patients or both, in an attempt to reduce the thrombogenicity bleeding after trauma or surgery, the reduction in of the concentrate; however, the effectiveness of this thrombin generation is accompanied not only by a practice has not been clearly demonstrated. decrease in procoagulant factor levels but also by a decrease in anticoagulant factor levels. Reduced AT Maturation of hemostasis levels with normal or even increased levels of FVIII or FIX may render rFVIIa therapy potentially pro- Although all the key components of the hemostatic thrombotic (26). Thus, monitoring AT levels during system are present at birth, important quantitative rFVIIa therapy may assist in reducing the thrombotic and qualitative differences exist between neonates complications occasionally seen in patients receiving and adults (Table 1). For procoagulant factors, these rFVIIa for nonhemophiliac bleeding conditions. differences are primarily quantitative. Levels of the four contact activation factors (FXII, FXI, HMWK, Coagulation factor concentrates and PK) are low at birth and remain so until approximately 6 months of age (33). This paucity Other plasma-derived coagulation factor concen- of contact activation factors contributes to the pro- trates are available, among them prothrombin com- longed aPTT seen in neonates and young infants. plex concentrates (PCCs), fibrinogen concentrates, The vitamin K-dependent factors [prothrombin or and FXIII concentrates. Most commonly, these con- factor II (FII), FVII, FIX, and FX] are also low at birth centrates are administered for replacement therapy and, similarly, do not reach adult ranges until in patients with congenital or acquired coagulation approximately 6 months of age (33). Levels of FV factor deficiencies. PCCs are also indicated to and FXIII are initially low but increase rapidly to reverse the anticoagulant effects of vitamin K antag- those of an adult by day five of life (33,34). onists (27). As with rFVIIa, coagulation factor con- Interestingly, FVIII and vWF are the only two centrates are being used more frequently for the procoagulant proteins that exhibit markedly treatment of acquired bleeding disorders. In animal models of uncontrolled hemorrhage and dilutional Table 1 coagulopathy, the administration of PCC and fibrin- Neonatal vs adult hemostasis ogen concentrate was able to restore clot formation, Component Neonatal vs adult level reduce blood loss and improve mortality (28,29). Primary hemostasis M platelet count Although human data, particularly from pediatric ›vWF patients, are lacking, PCCs, fibrinogen concentrates, Coagulation factors fl FII, FVII, FIX, FX and FXIII concentrates have all been reported to be fl FXI, FXII fl to M FV, FXIII efficacious in controlling massive intraoperative and M fibrinogen postoperative bleeding (30–32). ›FVIII, vWF Coagulation factor concentrates enhance coagula- Anticoagulant factors fl TFPI, AT, PC, PS ›a2M tion simply by increasing the in vivo content of fl plasminogen coagulation factor(s) present in the concentrate. M to › PAI PCCs contain all the coagulation factors required to vWF, von Willebrand factor; F, factor; TFPI, tissue factor pathway promote thrombin generation. The four vitamin K- inhibitor; AT, antithrombin; PC, protein C; PS, ; a2M, dependent coagulation factors (FII, FVII, FIX, and alpha-2-macroglobulin; PAI, plasminogen activator inhibitor.

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elevated levels at birth when compared to adult 100; Dade Behring, Miami, FL, USA) and throm- values (33,34). belastometry coagulation times (ROTEM; Penta- Levels of the major anticoagulant factors (TFPI, pharm GmbH, Munich, Germany) are all shorter in AT, and PC) are low at birth in both full-term and neonates than adults suggesting that under physio- preterm neonates (33,35). By approximately logic conditions neonatal platelets are as efficient as 3 months of age, mean levels of AT increase to adult platelets in achieving primary hemostasis those of adults whereas PC remains low until (44,45). This inconsistency may be explained by the 6 months of age (33,35). TFPI levels remain low prominent role that vWF plays in neonatal hemo- throughout most of childhood (36). Conversely, stasis (44). As previously discussed, vWF is a large alpha-2-macroglobulin (a2M), a thrombin inhibitor multimeric glycoprotein that assists in the adherence of secondary importance in adults, is markedly of platelets to areas of vascular injury. Compared elevated in neonates and often reaches levels twice with adults, neonates have not only a higher con- those measured in adults (37). Some investigators centration of circulating vWF, but also a greater have suggested that the increased levels of a2M in percentage of the large vWF multimers, the mole- neonatal plasma may compensate to some extent for cules most effective in promoting platelet-vessel the decreased levels of other (37,38). wall adhesiveness. Indeed, studies comparing the relative importance Mean fibrinogen values are comparable between of a2M and AT on the inhibition of radio-labeled neonates and adults. However, evidence suggests thrombin confirmed that a2M contributed more to that neonatal fibrinogen is qualitatively dysfunc- the inhibition of thrombin in neonatal and infant tional and exists in a fetal form until approximately plasma than in adult plasma (39). These findings led 1 year of age (37). The original idea that a fetal form investigators to conclude that in neonates a2M is at of fibrinogen might exist was based upon obser- least as important a thrombin inhibitor as AT. vations that the polymerization of fibrin from cord Further studies comparing plasma levels of the fibrinogen was slower than that of fibrin from adult thrombin inhibitors between healthy and critically fibrinogen (46). Additionally, biochemical studies ill neonates found that the latter are often deficient have proven that neonatal fibrinogen has a different not only in AT but in a2M as well thus significantly electrical charge and higher phosphorus content impairing normal thrombin inhibition (40,41). The than adult fibrinogen (43,47). More recent studies cumulative deficiencies of these thrombin inhibitor utilizing thrombelastography (TEG; Hemoscope proteins may explain the thrombotic occlusion of Corp., Niles, IL, USA) measurements have con- major vessels often seen in many sick neonates who firmed the functional differences between fetal and undergo physiologically challenging surgeries and adult fibrinogen (48). In adults, fibrinogen values long postoperative recovery times. show excellent correlation with TEG maximum Neonatal platelet counts and mean neonatal amplitude (MA) after modification with a glycopro- platelet volumes do not differ from normal adult tein IIb ⁄ IIIa receptor blocker that uncouples platelet- ranges (34). However, neonatal platelets do show a fibrinogen interactions. This correlation is lost in notable decrease in function for the first 2–4 weeks children <1 year of age indicating that a dysfunc- after birth. When examined in vitro, platelets from tional state of fibrinogen exists in these children. both full-term and preterm newborns show de- Plasminogen is the only coagulation protein in creased responses to a variety of standard agonists neonates that exhibits both quantitative and quali- including epinephrine, ADP, collagen, and thrombin tative differences when compared to adult plasmin- (42). This decreased responsiveness is manifest as a ogen. Normal newborn plasma contains decrease in platelet granule secretion, a decrease in approximately 50% of the plasminogen found in the expression of fibrinogen binding sites on the adult plasma. Neonatal levels of plasminogen do not platelet surface, and a decrease in platelet aggrega- reach those of an adult until approximately tion as reflected in conventional laboratory assays 6 months of age (37). Neonatal plasminogen itself (43). However, most in vivo assays of platelet is qualitatively impaired with slow activation kinet- function do not show platelet dysfunction. Bleeding ics by its major activator protein, t-PA. One inves- times, platelet function analyzer closure times (PFA- tigation found that five times the amount of t-PA

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was required in the newborn to achieve similar References activation of plasminogen to plasmin as seen in 1 Brummel-Ziedins K, Orfeo T, Jenny NS et al. Blood coagulation adults (49). Conversely, plasminogen activator and fibrinolysis. In: Greer JP, Foerster J, Rodgers GM, Par- inhibitor (PAI), a primary inhibitor of fibrinolysis, askevas F, Glader B, Arber DA, Means RT Jr, eds. Wintrobe’s Clinical Hematology, 12th edn. Philadelphia: Lippincott exhibits normal to elevated values at birth (37). Williams and Wilkins, 2009: 528–529. 580–7. When combined, these differences lead to an overall 2 Denis CV, Wagner DD. Platelet adhesion receptors and their decrease in plasmin generation and fibrinolytic ligands in mouse models of thrombosis. Arterioscler Thromb activity in neonates (50). These findings suggest that Vasc Biol 2007; 27: 728–739. 3 Calverley DC, Thienelt CD. Platelet structure and function in fibrinolytic therapy in the neonate may require a hemostasis and thrombosis. 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