chapter 62 - patient blood management: coagulationmiller8e:... · coagulation. thomas f. slaughter....

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C h a p t e r 6 2

Patient Blood Management: CoagulationTHOMAS F. SLAUGHTER

K e y P o i n t s

• Under normal physiologic conditions, clot formation requires participation of vascular endothelium, platelets, and plasma-mediated hemostasis.

• Tissue factor (extrinsic pathway) initiates plasma-mediated hemostasis, whereas factor XI (intrinsic pathway) amplifies the response.

• Thrombin generation proves the key regulatory enzymatic step in hemostasis. • Platelets participate in clot formation as (1) anchoring sites for coagulation factor

activation complexes, (2) delivery “vehicles” releasing hemostatically active proteins, and (3) major structural components of the clot.

• A carefully obtained history of bleeding remains the most effective means for identifying bleeding and thrombotic tendencies.

• Thrombosis is potentiated by stasis, vascular endothelial injury, and underlying hypercoagulable conditions.

• Heparin-induced thrombocytopenia comprises a heparin-mediated autoimmune response potentiating platelet activation and venous and arterial thromboses.

NORMAL HEMOSTASIS

Hemostasis comprises cellular and biochemical processes that limit blood loss resulting from injury, maintain intravascular blood fluidity, and promote revasculariza-tion of thrombosed vessels after injury. Normal physi-ologic hemostasis necessitates a delicate balance between procoagulant pathways responsible for generation of a stable localized hemostatic “plug” and counterregulatory mechanisms inhibiting thrombus formation beyond the injury site. Vascular endothelium, platelets, and plasma coagulation proteins play equally important roles in this process. Failure to maintain balance commonly leads to excessive bleeding or pathologic thrombus formation.

Vascular endothelial injury—mechanical or biochem-ical—leads to platelet deposition at the injury site, a pro-cess often referred to as primary hemostasis. Although primary hemostasis may prove adequate for a minor injury, control of more significant bleeding necessitates stable clot formation incorporating crosslinked fibrin—a process mediated by activation of plasma clotting factors and often referred to as secondary hemostasis. Although the terms primary and secondary hemostasis remain relevant for descriptive and diagnostic purposes, advances in understanding cellular and molecular pro-cesses underlying hemostasis suggest a far more complex

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interplay between vascular endothelium, platelets, and plasma-mediated hemostasis than is reflected in this model.

VASCULAR ENDOTHELIAL ROLE IN HEMOSTASIS

Under normal conditions, vascular endothelium provides a nonthrombogenic surface to promote blood fluidity. Healthy endothelial cells possess antiplatelet, anticoagu-lant, and profibrinolytic effects to inhibit clot formation.1 Negatively charged vascular endothelium repels platelets and produces prostacyclin and nitric oxide (NO), which are potent platelet inhibitors.2 Adenosine diphospha-tase synthesized by vascular endothelial cells degrades adenosine diphosphate (ADP), another potent platelet activator. Given these endogenous antiplatelet effects, nonactivated platelets do not adhere to healthy vascular endothelial cells. Vascular endothelium further expresses several inhibitors of plasma-mediated hemostasis, includ-ing thrombomodulin (an indirect thrombin inhibi-tor), heparin-like glycosaminoglycans, and tissue factor pathway inhibitor (TFPI).3 Finally, vascular endothelium synthesizes tissue plasminogen activator (t-PA), which is responsible for activating fibrinolysis—a primary coun-terregulatory mechanism limiting clot propagation.

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Chapter 62: Patient Blood Management: Coagulation 1869

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Despite these natural defense mechanisms to inhibit hrombus generation, a variety of mechanical and chemi-al stimuli may shift the balance such that the endo-helium promotes clot formation. Damage to vascular ndothelial cells exposes the underlying extracellular atrix (ECM), including collagen, von Willebrand factor

vWF), and other platelet-adhesive glycoproteins.4,5 Plate-ets bind to and are activated by exposure to ECM compo-ents. Exposure of tissue factor, constitutively expressed y fibroblasts in the ECM, activates plasma-mediated coag-lation pathways to generate thrombin and, ultimately, brin clot. Certain cytokines (i.e., interleukin-1, tumor ecrosis factor, and γ-interferon) and hormones (i.e., des-opressin acetate or endotoxin) induce prothrombotic

hanges in vascular endothelial cells, including synthe-is and expression of vWF, tissue factor, plasminogen ctivator inhibitor–1 (PAI-1, an inhibitor of fibrinolysis), nd down-regulate normal antithrombotic cellular and iochemical pathways.6,7 Thrombin, hypoxia, and high uid shear stress induce prothrombotic vascular endothe-

ial changes. Increased vascular endothelial synthesis of AI-1 and associated inhibition of fibrinolysis have been mplicated in the prothrombotic state and high incidence f venous thrombosis after surgery.8,9

LATELETS AND HEMOSTASIS

latelets contribute a critical role in hemostasis. Derived rom bone marrow megakaryocytes, nonactivated plate-ets circulate as discoid anuclear cells.10 The platelet

embrane is characterized by numerous receptors and surface-connected open canalicular system serving to ncrease platelet membrane surface area and provide rapid ommunication between the platelet interior and exter-al environment.11 Under normal circumstances, plate-

ets do not bind vascular endothelium; however, when njury exposes ECM, platelets undergo a series of bio-hemical and physical alterations characterized by three ajor phases: adhesion, activation, and aggregation.Exposure of subendothelial matrix proteins (i.e., col-

agen, vWF, fibronectin) allows for platelet adhesion to he vascular wall. vWF proves particularly important as bridging molecule between ECM and platelet glycopro-ein Ib/factor IX/factor V receptor complexes.12 Absence f either vWF (von Willebrand disease) or glycoprotein Ib/actor IX/factor V receptors (Bernard-Soulier syndrome) esults in a clinically significant bleeding disorder.

As platelets adhere along the ECM, a series of physi-al and biochemical changes occur termed platelet acti-ation. Platelets contain two specific types of storage ranules: α granules and dense bodies.11 Alpha granules ontain numerous proteins essential to hemostasis and ound repair, including fibrinogen, coagulation factors and VIII, vWF, platelet-derived growth factor, and oth-rs. Dense bodies contain the adenine nucleotides ADP nd adenosine triphosphate, as well as calcium, sero-onin, histamine, and epinephrine. During the activa-ion phase, platelets release granular contents, resulting n recruitment and activation of additional platelets and ropagation of plasma-mediated coagulation.13 Dur-

ng activation, platelets undergo structural changes to evelop pseudopod-like membrane extensions and to

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release physiologically active microparticles, with both mechanisms serving to increase dramatically platelet membrane surface area. Redistribution of platelet mem-brane phospholipids during activation exposes newly activated glycoprotein platelet surface receptors and phospholipid binding sites for calcium and coagulation factor activation complexes, which is critical to propaga-tion of plasma-mediated hemostasis.14

During the final phase of platelet aggregation, activa-tors released during the activation phase serve to recruit additional platelets to the site of injury. Newly active glycoprotein IIb/IIIa receptors on the platelet surface bind fibrinogen to provide for cross-linking with adja-cent platelets (platelet aggregation).15 The importance of these receptors is reflected by the bleeding disorder associated with their hereditary deficiency, Glanzmann thrombasthenia.

PLASMA-MEDIATED HEMOSTASIS

Plasma-mediated hemostasis, the coagulation cascade, might best be summarized as an amplification system to accelerate thrombin generation from an inactive precur-sor (i.e., prothrombin). Trace plasma proteins, activated by exposure to tissue factor or foreign surfaces, initiate a cascading series of reactions culminating in conversion of soluble fibrinogen to insoluble fibrin clot.16 Thrombin generation, the “thrombin burst,” represents the key regu-latory step in this hemostatic process. Thrombin not only generates fibrin but also activates platelets and mediates a host of additional processes affecting inflammation, mitogenesis, and even down-regulation of hemostasis.17

Traditionally, the coagulation cascade describing plasma-mediated hemostasis has been depicted as intrin-sic and extrinsic pathways, both of which culminate in a common pathway in which fibrin generation occurs.18 Although this cascade model has proved an oversimplifi-cation, it remains a useful descriptive tool for organizing discussions of plasma-mediated hemostasis (Fig. 62-1). Coagulation factors are, for the most part, synthesized hepatically and circulate as inactive proteins termed zymogens. The somewhat confusing nomenclature of the classic coagulation cascade derives from the fact that inactive zymogens were identified using Roman numerals assigned in order of discovery. As the zymogen is converted to an active enzyme, a lower-case letter “a” is added to the Roman numeral identifier. For example, inactive pro-thrombin is referred to as factor II and active thrombin is identified as factor IIa. Some numerals were subsequently withdrawn or renamed as our understanding of the bio-chemistry underlying hemostasis evolved.The coagula-tion cascade characterizes a series of enzymatic reactions in which inactive precursors—zymogens—undergo acti-vation to amplify the overall reaction. Each stage of the cascade requires assembly of membrane-bound activa-tion complexes, each composed of an enzyme (activated coagulation factor), substrate (inactive precursor zymo-gen), cofactor (accelerator or catalyst), and calcium.19 Assembly of these activation complexes occurs on phos-pholipid membranes (most often platelet or microparticle membranes) that localize and concentrate reactants. In the absence of phospholipid membrane anchoring sites,

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PART IV: Anesthesia Management1870

Figure 62-1. Depiction of the clas-sic coagulation cascade incorporat-ing extrinsic and intrinsic pathways of coagulation. (From Slaughter TF: The coagulation system and cardiac surgery. In Estafanous FG, Barasch PG, Reves JG, editors: Cardiac anesthesia: principles and clinical practice, ed 2, Philadel-phia, Lippincott Williams & Wilkins, 2001, p. 320, with permission.) Cross-linked fibrin

Intrinsic Pathway

XII

XIII

XIIIa

Fibrinogen Fibrin monomer

XIIaVascular endothelial

injury

Tissue factor/VIIa complex

“Prothrombinase complex”

XI XIa

IX IXaVIIIa

X Xa Va

II IIa

Va/VIIIa

Extrinsic Pathway

Figure 62-2. Clot formation at vascular injury site. Vascular injury exposes subendothelial tissue fac-tor (TF) initiating plasma-mediated hemostasis via the extrinsic path-way. The intrinsic pathway further amplifies thrombin and fibrin gen-eration. Platelets adhere to exposed collagen to undergo activation, resulting in recruitment and aggre-gation of additional platelets. (From Mackman N, Tilley RE, Key NS: Role of extrinsic pathway of blood coagu-lation in hemostasis and thrombosis, Arterioscleros Thromb Vasc Biol 27:1688, 2007, with permission.)

Thrombin

Binding of plateletsto collagen

TF-dependentinitiation of coagulation

Propagation Stabilization

Platelet-plateletinteraction

Fibrin deposition

Recruitment of plateletsto growing thrombus

Amplification ofcoagulation cascade

Blood

Microparticles

Platelets

TF TF TF TF TF TF TFTFEndothelium

Tissue

Fibrin

Initiation

activation of coagulation factors slows dramatically, fur-ther localizing clot generation to injury sites.

EXTRINSIC PATHWAY OF COAGULATION

The extrinsic pathway of coagulation, widely recognized as the initiating step in plasma-mediated hemostasis, begins with exposure of blood plasma to tissue factor.20 Tissue factor is prevalent in subendothelial tissues sur-rounding vasculature; however, under normal conditions the vascular endothelium minimizes contact between tis-sue factor and plasma coagulation factors. After vascular injury, small concentrations of factor VIIa circulating in plasma form phospholipid-bound activation complexes with tissue factor, factor X, and calcium to promote con-version of factor X to Xa.21 Recently, the tissue factor/factor VIIa complex has been demonstrated to activate factor IX of the intrinsic pathway, further demonstrating the key role of tissue factor in initiating hemostasis.22

INTRINSIC PATHWAY OF COAGULATION

Classically, the intrinsic or contact activation system was described as a parallel pathway for thrombin generation by way of factor XII. However, the rarity of bleeding disor-ders resulting from contact activation factor deficiencies led to our current understanding of the intrinsic pathway

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as an amplification system to propagate thrombin gen-eration initiated by the extrinsic pathway.22 Recent cell-based models of coagulation suggest that thrombin generation by way of the extrinsic pathway is limited by a natural inhibitor, TFPI.23 However, small quantities of thrombin generated before neutralization of the extrinsic pathway activate factor XI and the intrinsic pathway. The intrinsic pathway subsequently amplifies and propagates the hemostatic response to maximize thrombin genera-tion (Fig. 62-2). Although factor XII may be activated by foreign surfaces (i.e., cardiopulmonary bypass circuits or glass vials), the intrinsic pathway appears to play a minor role in initiation of hemostasis. Proteins of the intrinsic pathway may, however, contribute to inflammatory pro-cesses, complement activation, fibrinolysis, kinin genera-tion, and angiogenesis.22,24

Common Pathway of CoagulationThe final pathway, common to both extrinsic and intrin-sic coagulation cascades, depicts thrombin generation and subsequent fibrin formation. Signal amplification through both extrinsic and intrinsic pathways culminates in formation of prothrombinase complexes (phospholipid membrane–bound activation complexes) comprising fac-tor Xa, factor II (prothrombin), factor Va (cofactor), and calcium ions.25 Prothrombinase complexes mediate the thrombin burst—a surge in thrombin generation from the

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inactive precursor prothrombin. Thrombin proteolytically cleaves fibrinopeptides A and B from fibrinogen molecules to generate fibrin monomers, which polymerize into fibrin strands (i.e., fibrin clot).25 Finally, factor XIIIa, a transgluta-minase activated by thrombin, covalently crosslinks fibrin strands to produce an insoluble fibrin clot resistant to fibri-nolytic degradation. Both fibrinogen and factor XIII have been implicated in acquired bleeding disorders. Reduced concentrations of either protein may promote excess postoperative hemorrhage and transfusion requirements. Recent availability of plasma concentrates for both fibrino-gen and factor XIII suggest potential for randomized con-trolled trials to determine efficacy of these biologics in treatment of acquired coagulopathies.26 Regardless, throm-bin generation remains the key enzymatic step regulating hemostasis.27 Not only does thrombin activity mediate conversion of fibrinogen to fibrin, it also activates platelets and factor XIII, converts inactive cofactors V and VIII to active conformations, activates factor XI and the intrinsic pathway of coagulation, up-regulates cellular expression of tissue factor, and stimulates vascular endothelial expres-sion of PAI-1 to down-regulate fibrinolytic activity.17,27

Intrinsic Anticoagulant MechanismsOnce activated, regulation of hemostasis proves essential to limit clot propagation beyond the injury site. One simple, yet important, anticoagulant mechanism derives from flow-ing blood and hemodilution. The early platelet and fibrin clot proves highly susceptible to disruption by shear forces within flowing blood. Blood flow further limits localization and concentration of both platelets and coagulation factors such that a critical mass of hemostatic components may fail to coalesce.25,28 However, later in the clotting process more robust counterregulatory mechanisms are necessary to limit clot propagation. Four major counterregulatory pathways have been identified that appear particularly crucial for down-regulating hemostasis: fibrinolysis, TFPI, the protein C system, and serine protease inhibitors.

The fibrinolytic system comprises a cascade of ampli-fying reactions culminating in plasmin generation and proteolytic degradation of fibrin and fibrinogen. As with the plasma-mediated coagulation cascade, inactive precur-sor proteins are converted to active enzymes, necessitat-ing a balanced system of regulatory controls to prevent excessive bleeding or thrombosis (Fig. 62-3). The principal enzymatic mediator of fibrinolysis, plasmin, is generated from an inactive precursor, plasminogen.29 In vivo, plas-min generation most often is initiated by release of t-PA or urokinase from vascular endothelium. Thrombin pro-vides a potent stimulus for t-PA synthesis.27 Factor XIIa and kallikrein of the intrinsic pathway activate fibrinolysis after exposure to foreign surfaces. The presence of fibrin accelerates plasmin generation.30 Rapid inhibition of free plasmin also limits spread of fibrinolytic activity. In addi-tion to enzymatic degradation of fibrin and fibrinogen, plasmin inhibits hemostasis by degrading essential cofac-tors V and VIII and reducing platelet glycoprotein surface receptors essential to adhesion and aggregation.31 Fibrin degradation products also possess mild anticoagulant properties.TFPI inhibits the tissue factor/factor VIIa com-plex and thereby the extrinsic coagulation pathway, which is responsible for initiation of hemostasis. TFPI and factor


Xa form phospholipid membrane–bound complexes that incorporate and inhibit tissue factor/factor VIIa com-plexes.3 Most TFPI is bound to vascular endothelium but may be released into circulation by heparin administra-tion. Heparin further catalyzes TFPI inhibitory activity.32 As TFPI rapidly extinguishes tissue factor/VIIa activity, the critical role of the intrinsic pathway to continued throm-bin and fibrin generation becomes apparent.22

The protein C system proves particularly impor-tant in down-regulating hemostasis because it inhib-its thrombin and the essential cofactors Va and VIIIa. Thrombin initiates this inhibitory pathway by binding a membrane-associated protein, thrombomodulin, to acti-vate protein C.33 Protein C, complexed with the cofac-tor protein S degrades both cofactors Va and VIIIa. Loss of these critical cofactors limits formation of tenase and prothrombinase activation complexes essential to for-mation of factor X and thrombin, respectively. Throm-bin, once bound to thrombomodulin, is inactivated and removed from circulation, providing another mecha-nism by which protein C down-regulates hemostasis.33

The most significant serine protease inhibitors regulat-ing hemostasis include antithrombin and heparin cofac-tor II. Antithrombin binds to and inhibits thrombin and factors IXa, Xa, XIa, and XIIa. Heparin cofactor II inhibits thrombin alone. Although the precise physiologic role for heparin cofactor II remains unclear, antithrombin plays a major role in down-regulating hemostasis.34 Heparin, a catalyst accelerator, binds antithrombin to promote inhibition of targeted enzymes.35 Heparin-like glycosami-noglycans, located on vascular endothelial cells, provide inhibitory sites for thrombin and factor Xa in vivo.

DISORDERS OF HEMOSTASIS

EVALUATION OF BLEEDING DISORDERS

Few would argue the importance of assessing bleeding risk preoperatively; however, appropriate methods for ascertaining this risk remain subject to debate. Although

Fibrin(ogen)Fibrin(ogen)degradation

products

Antifibrinolyticagents

t-PAUrokinase

�2-Antiplasmin

PAI-1

�

�

�

�

Plasminogen

Plasmin

Figure 62-3. Principal mediators of fibrinolysis. Dashed lines depict sites of action for promoters and inhibitors of fibrinolysis. PAI, Plas-minogen activator inhibitor; tPA, tissue plasminogen activator. (From Slaughter TF: The coagulation system and cardiac surgery. In: Estafanous FG, Barasch PG, Reves JG, editors: Cardiac anesthesia: principles and clinical practice, ed 2, Philadelphia, Lippincott Williams & Wilkins, 2001, p. 320, with permission.)



routine coagulation testing of all surgical patients pre-operatively intuitively may be appealing, this approach lacks predictive value for bleeding disorders and certainly lacks cost effectiveness.36 A carefully performed history of bleeding remains the single most effective predictor for perioperative bleeding.

A thorough history should focus on prior bleeding epi-sodes.37 Does the patient have a history of excessive bleed-ing in association with trauma or prior surgery? Were blood transfusions or reoperation required to control the bleeding? A history suggestive of a bleeding disorder might include frequent epistaxis of a severity necessitat-ing packing the nasal passage or surgical intervention. Oral surgery and dental extractions prove a particularly good test of hemostasis because of high concentrations of fibrinolytic activity in the oral cavity. Von Willebrand disease not infrequently manifests as menorrhagia, and postpartum hemorrhage commonly occurs in women with underlying disorders of hemostasis.38 A history of spontaneous hemorrhage (nontraumatic) proves par-ticularly concerning when associated with joints (hem-arthroses) or deep muscles. Identification of a bleeding disorder at an early age or in family members suggests an inherited, as opposed to acquired, condition.39 A care-ful medication history including direct questions relating to consumption of aspirin-containing nonprescription drugs, herbs, and fish oil may prove noteworthy. Finally, inquiries regarding coexisting diseases should be included (i.e., renal, hepatic, thyroid, and bone marrow disorders and malignancy).

For most patients, a thoughtfully conducted bleeding history will eliminate need for preoperative laboratory-based coagulation testing. Regardless, several valid rea-sons remain for preoperative coagulation testing. Should the preoperative history or physical examination reveal signs or symptoms suggestive of a bleeding disorder, fur-ther laboratory-based assessment of coagulation would be indicated. Preoperative screening tests of coagulation may be indicated, despite a negative history, in cases in which major surgery commonly associated with signifi-cant bleeding is planned (i.e., cardiopulmonary bypass). Finally, preoperative testing may prove justified in set-tings in which the patient is unable to provide a bleeding history preoperatively. Should evidence of a bleeding dis-order be detected preoperatively, underlying mechanisms must be ascertained if possible before proceeding with surgery.

INHERITED BLEEDING DISORDERS

Although inherited disorders of hemostasis may involve platelet function, plasma-mediated hemostasis, or fibri-nolytic pathways, von Willebrand disease characterized by quantitative or qualitative deficiencies of vWF proves the most common of inherited bleeding disorders.38 Vari-ants include types I and III with varying quantitative vWF deficiencies and type II comprising a collection of qualitative defects affecting vWF function. Under normal conditions, vWF plays a critical role in platelet adhesion to ECM. vWF further acts as a carrier molecule prevent-ing proteolytic degradation of factor VIII in free plasma.40 Classically, patients with von Willebrand disease describe


a history of easy bruising, recurrent epistaxis, and menor-rhagia, all characteristic of defects in primary (i.e., platelet mediated) hemostasis. In more severe cases (i.e., type III vWD), concomitant reductions in factor VIII may lead to serious spontaneous hemorrhage, including hemarthro-ses, which is common in hemophilia. Laboratory testing often demonstrates mild-to-moderate prolongation of the activated partial thromboplastin time (aPTT), prolonged bleeding time, decreased immunoreactive vWF concen-trations, and reduced platelet aggregation in response to ristocetin.38,41 Increasingly, the PFA-100 and similar ex-vivo platelet function tests have replaced bleeding times in assessing for vWD.42 Measurable reductions in factor VIII activity may occur in severe cases. Mild cases of vWD often respond to desmopressin acetate (DDAVP); however, given a significant bleeding history, specific replacement of vWF and factor VIII with select factor VIII concentrates (i.e., Humate-P (CSL Behring, King of Prus-sia, Pa.) may be indicated.43,44

Although relatively uncommon, the hemophilias merit consideration given their diverse clinical presentation. Hemophilia A, characterized by variable degrees of factor VIII deficiency, is an X-linked inherited bleeding disorder most frequently presenting in childhood as spontane-ous hemorrhage involving joints, deep muscles, or both. Hemophilia A occurs with an incidence of 1:5000 males; however, nearly one third of cases represent new muta-tions with no family history.45 In mild cases, patients with hemophilia may not be identified until later in life, often after unexplained bleeding with surgery or trauma. Classically, laboratory testing in patients with hemophilia reveals prolongation of the aPTT, whereas the prothrom-bin time (PT) and bleeding time remain within normal limits. Specific measurement of factor VIII:C is required to confirm the diagnosis and to clarify the severity of factor VIII deficiency. Mild cases of hemophilia A may be treated with desmopressin; however, in most cases, perioperative management of these patients necessitates consultation with a hematologist and administration of recombinant or purified factor VIII concentrates.43,46 An increasingly common complication of hemophilia, particularly in the case of hemophilia A, has been development of alloanti-bodies directed against the factor VIII protein. In cases of high-titer antibodies, administration of factor VIII con-centrates may fail to control bleeding. Several approaches have reduced bleeding in these patients, including substi-tution of porcine factor VIII, administration of activated or nonactivated prothrombin complex concentrates, or treatment with recombinant factor VIIa (NovoS-even, Novo Nordisk Inc., Bagsvaerd, Denmark) (see also Chapter 63).44,47 Also inherited as an X-linked disorder, hemophilia B (i.e., Christmas disease) occurs in approx-imately 1:40,000 and necessitates blood component replacement with factor IX concentrates.

ACQUIRED BLEEDING DISORDERS

A detailed account of acquired hemostatic disorders is beyond the scope of this discussion; however, given that a limited number of drugs and coexisting medical condi-tions account for the majority of acquired bleeding dis-orders, these conditions merit consideration. Heparin,



warfarin, and fibrinolytic drugs historically accounted for most serious drug-induced bleeding complications (Table 62-1).48,49 More recently, antiplatelet drug therapy fur-ther has complicated perioperative management (Table 62-2).49-52 Unfractionated heparin comprises a hetero-geneous mixture of membrane-associated glycosamino-glycans derived from either bovine or porcine mucosal tissues. Specificity and potency of unfractionated hepa-rin varies by molecular weight, which ranges between 5000 and 30,000 daltons.35 Heparin derives its antico-agulant effect by interacting with plasma antithrombin, which in turn inhibits serine proteases participating in plasma-mediated hemostasis.34 The half-life of heparin is 1 to 2 hours and varies directly with total dose. Heparin is cleared from the circulation both renally and hepati-cally. Most often, heparin’s anticoagulant effect is moni-tored using the aPTT with a target prolongation of 1.5 to 2 times control, commonly used for treatment of venous thrombosis.53 At heparin concentrations exceeding

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measurement limits of the aPTT, such as during cardio-pulmonary bypass or interventional cardiovascular pro-cedures, the activated clotting time (ACT) provides an alternative, albeit less sensitive, measure of heparin anti-coagulation.54 Heparin’s anticoagulant effect is rapidly reversible by protamine administration.55

More recently, low-molecular-weight heparins (LMWHs) have gained favor as a result of reduced dosing frequency and the lack of need for monitoring. Owing to shorter saccharide chain lengths, LMWHs exhibit reduced inhibi-tory activity toward thrombin while retaining factor Xa inhibitory activity.56 Theoretically, LMWHs may be associ-ated with reduced bleeding tendencies. Regardless, LMWHs have a more predictable pharmacokinetic response, fewer effects on platelet function, and a reduced risk for hepa-rin-induced thrombocytopenia (HIT). Although monitor-ing of LMWHs is not performed routinely, the PT and aPTT most often are unaffected, necessitating measure-ment of anti–factor Xa activity. Furthermore, should rapid

TABLE 62-1 ANTICOAGULANT AGENTS

Drug Site of Action Route Plasma Half-life Excretion AntidoteStop Before Procedure

Prolongation of PT/aPTT

Unfractionated heparin

IIa/Xa IV/subcutaneous 1.5 hr Hepatic Protamine 6 hr No/Yes

LMWH Xa Subcutaneous 4.5 hr Renal Protamine (partial reversal)

12-24 hr No/No

Streptokinase Plg IV 23 min Hepatic Antifibrinolytics 3 hr Yes/Yest-PA Plg IV <5 min Hepatic Antifibrinolytics 1 hr Yes/YesCoumarin Vitamin

K–dependent factors

Oral 2-4 days Hepatic Vitamin KrfVIIaPCCsPlasma

2-4 days Yes/No

Fondaparinux Xa SC 14-17 hr Renal None 3 days* No/NoBivalirudin IIa IV 25 min Hepatic None 3 hr Yes/YesArgatroban IIa IV 45 min Hepatic None 4-6 hr †Yes/YesLepirudin/

DesirudinIIa IV 1.5 hr Renal PMMA, dialysis 8-10 hr* †Yes/Yes

Rivaroxaban Xa Oral 9-13 hr Renal None 24-48 hr* Yes/YesApixaban Xa Oral 9-14 hr Hepatic None 26-30+ hr* Yes/YesDabigatran IIa Oral 14-17 hr Renal None ±5* days Yes/Yes

Data from Roberts HR, Monroe DM, Escobar MA: Current concepts of hemostasis: implications for therapy, Anesthesiology 100:722-730, 2004, with permission.HIT, Heparin-induced thrombocytopenia; IIa, thrombin; IV, intravenous; LMWH, low-molecular-weight heparin; PCCs, prothrombin complex concentrates;

Plg, plasminogen; PMMA, polymethyl methylacrylate; rFVlla, recombinant factor VIIa; t-PA, tissue plasminogen activator.*Limited data regarding safe interval (assumes prophylactic dosage regimen).†Argatroban and hirudins may increase the prothrombin time by several seconds.

TABLE 62-2 ANTIPLATELET AGENTS

Drug Site of Action Route Plasma Half-life Metabolism AntidoteStop Before Procedure

Prolongation of PT/aPTT

Aspirin COX 1-2 Oral 20 min Hepatic None 7 days No/NoDipyridamole Adenosine Oral 40 min Hepatic None 24 hr No/NoClopidogrel ADP Oral 7 hr Hepatic None 7 days No/NoPrasugrel ADP Oral 7 hr Serum/hepatic None 7-10 days No/NoTiclopidine ADP Oral 4 days Hepatic None 12-14 days No/NoAbciximab GPIIb-IIIa IV 30 min Renal None 48-72 hr No/NoEptifibatide GPIIb-IIIa IV 2.5 hr Renal None 24 hr No/NoTirofiban GPIIb-IIIa IV 2 hr Renal Hemodialysis 24 hr No/No

Data from Roberts HR, Monroe DM, Escobar MA: Current concepts of hemostasis: implications for therapy, Anesthesiology 100:722-730, 2004, with permission.ADP, Adenosine diphosphate; COX, cyclooxygenase diphosphate; IV, intravenous; GP, glycoprotein.

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reversal of LMWH prove necessary, protamine is only par-tially effective.57

Oral anticoagulant therapy in the form of coumarin derivatives, interferes with hepatic synthesis of vitamin K–dependent coagulation factors—factors II, VII, IX, X, protein C, and protein S.58 Specifically, coumarin inhib-its carboxylation of glutamic acid residues essential for anchoring coagulation factor activation complexes to phospholipid membranes. Coumarin therapy is moni-tored using the international normalized ratio (INR) sys-tem derived from the PT. Generally, an INR of 2 to 3 is considered reflective of adequate anticoagulation.53 In most cases, excessive coumarin anticoagulation is man-aged by withholding drug administration. However, given a half-life of 2 to 4 days, more rapid reversal in periop-erative settings may be needed. Vitamin K administered orally or parentally in doses of 1 to 2 mg reverses coumarin anticoagulation.58 More rapid reversal may be achieved by administration of plasma or prothrombin complex concentrates.59 Recombinant factor VIIa also has proved effective at reversing coumarin-associated bleeding.

Despite relatively short half-lives and increasing fibrin specificity, fibrinolytic drug administration continues to be associated with significant bleeding potential. Bleed-ing after fibrinolytic drugs proves multifactorial resulting from proteolytic degradation of fibrin and fibrinogen, proteolysis of cofactors V and VIII, and digestion of plate-let glycoprotein surface receptors.29 In addition, both fibrin and fibrinogen degradation fragments impair plate-let function and inhibit assembly of fibrin monomers into strands. Once the fibrinolytic agent is cleared from plasma, antifibrinolytic drugs prove of limited benefit. Therapy must rely on selective repletion of platelet and plasma protein constituents. In many cases, cryoprecipi-tate or fibrinogen concentrate will be administered to replace fibrinogen and platelet infusions will be needed to compensate for qualitative platelet dysfunction. Plasma infusions may be required to replete plasma coagulation factors, particularly cofactors V and VIII.

Liver DiseaseHemostatic defects associated with hepatic failure prove complex and multifactorial. Severe liver disease impairs synthesis of coagulation factors, impedes clearance of activated clotting and fibrinolytic proteins, and produces quantitative and qualitative platelet dysfunction. Labo-ratory findings commonly associated with liver disease include a prolonged PT, possible prolongation of the aPTT, and thrombocytopenia.60 Prolongation of bleeding time reflects qualitative defects in platelet adhesion and aggregation. Treatment of bleeding in the setting of liver disease most often is based on laboratory abnormalities. Plasma and platelets frequently are administered for acute bleeding. Low fibrinogen concentrations may necessitate administration of cryoprecipitate or fibrinogen concen-trate. In addition, low-grade fibrinolysis may benefit from antifibrinolytic drug administration in select settings.

Renal DiseasePlatelet dysfunction commonly occurs in association with chronic renal failure, as reflected by a prolonged bleeding time and propensity for bleeding associated with surgery

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or trauma. Underlying mechanisms appear multifacto-rial and may include accumulation of guanidinosuccinic acid and NO in uremic plasma.61 In addition, red blood cell (RBC) concentration has been speculated to play a role as correction of anemia results in shortened bleeding times, presumably related to the role of RBCs in causing platelet margination along the vessel wall under laminar flow conditions.28 Both dialysis and correction of anemia have been reported to shorten bleeding times in patients with chronic renal failure. Traditionally, cryoprecipitate administration occurs in this setting; however, desmo-pressin 0.3 μg/kg and conjugated estrogens similarly may shorten bleeding times.43 Risks associated with these therapies, and the predictive value of bleeding time for subsequent hemorrhage, remain unclear.

Disseminated Intravascular CoagulationDisseminated intravascular coagulation (DIC) comprises a pathophysiologic hemostatic response to tissue fac-tor/factor VIIa complex exposure and activation of the extrinsic pathway of coagulation. Numerous underlying disorders may precipitate DIC, including trauma, amni-otic fluid embolus, malignancy, sepsis, or incompatible blood transfusions.62 Most often, DIC presents clinically as a diffuse bleeding disorder associated with consump-tion of coagulation factors and platelets during wide-spread microvascular thrombotic activity. Underlying fibrinolysis, providing a counterregulatory mechanism to maintain vascular integrity, proves common as well. Laboratory findings typical of DIC include reductions in platelet count; prolongation of the PT, aPTT, and throm-bin time (TT); and elevated concentrations of soluble fibrin and fibrin(ogen) degradation products. Chronic DIC states have been identified with relatively normal screening tests of coagulation accompanied by elevated concentrations of soluble fibrin and fibrin(ogen) degrada-tion products.63 Management of DIC requires alleviating the underlying condition precipitating hemostatic activa-tion. Otherwise, treatment includes selective blood com-ponent transfusions to replete coagulation factors and platelets consumed in the process. Antifibrinolytic ther-apy generally is contraindicated in DIC owing to poten-tial for catastrophic thrombotic complications.

PROTHROMBOTIC STATES

Thrombophilia, a propensity for thrombotic events, most often manifests clinically in the form of venous throm-bosis (frequently deep venous thrombosis of the lower extremity).64 As with bleeding disorders, thrombophilia may result from inherited or acquired conditions (Box 62-1). In the majority of cases, a precipitating event may be identified.65 For example, thrombotic complica-tions often occur after surgery, during pregnancy, and in association with obesity or underlying malignancy.66 Random screening of asymptomatic patients for throm-botic risk has not proved cost effective or clinically effi-cacious.67,68 As with bleeding disorders, a careful history focusing on prior thrombotic events, family history of thrombosis, and concurrent drug therapy offers greater predictive value than random screening.

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Common Inherited Thrombotic DisordersAlthough understanding of thrombotic disorders from a biochemical and molecular level remains limited at pres-ent, careful testing may identify an underlying heritable thrombotic predisposition in as many as 50% of patients with venous thromboembolism.69 Relatively common inherited conditions underlying prothrombotic ten-dencies include single point mutations in genes for fac-tor V (factor V Leiden) or prothrombin (prothrombin G20210A). In the case of the factor V Leiden mutation, the essential cofactor Va acquires resistance to degrada-tion by protein C.70 This simple alteration in balance between hemostasis and the protein C counterregula-tory system induces a prothrombotic tendency present in approximately 5% of the population. In the case of the prothrombin gene mutation, increased prothrombin concentrations in plasma again generate a hypercoagu-lable state. Less common inherited forms of thrombo-philia include deficiencies of antithrombin, protein C, and protein S.34 Inherited forms of thrombophilia are characterized by highly variable penetrance affected by blood type, sex, and other confounding variables. In the absence of coexisting precipitating conditions, absolute thrombotic risk secondary to a heritable thrombophilia proves limited.71 In the presence of a family history or test abnormality suggesting thrombophilia with no his-tory of thrombosis, risks associated with long-term pre-ventive anticoagulation may outweigh potential benefits. After a thrombotic complication, however, these patients most often are managed with life-long anticoagulation.

COMMON ACQUIRED THROMBOTIC DISORDERS

Antiphospholipid SyndromeAntiphospholipid syndrome describes an acquired auto-immune disorder characterized by venous or arterial thromboses, or both, and recurrent pregnancy loss. This syndrome may occur secondarily to autoimmune disor-ders such as systemic lupus erythematosus or rheumatoid arthritis, or it may occur in isolation. Characteristically,

HigH Risk

Heparin-induced thrombocytopeniaAntithrombin deficiencyProtein C deficiencyProtein S deficiencyAntiphospholipid antibody syndrome

ModeRate Risk

Factor V Leiden genetic polymorphismProthrombin G20210A genetic polymorphismHyperhomocysteinemiaDysfibrinogenemiaPostoperative prothrombotic stateMalignancyImmobilization

BOX 62-1 Hypercoagulable States and Risk for Perioperative Thrombosis


antiphospholipid syndrome results in mild prolongation of the aPTT and positive testing for lupus anticoagulant or anticardiolipin antibodies.72 Despite the prolonged aPTT, antiphospholipid syndrome poses no increased bleeding risk but rather increases the potential for throm-bosis. Antibodies associated with antiphospholipid syn-drome interfere with phospholipids common to many laboratory-based tests of coagulation. Isolated prolonga-tion of an aPTT in a preoperative patient merits consid-eration of the diagnosis of antiphospholipid syndrome. Patients with this syndrome who have experienced a thrombotic complication are at increased risk for recur-rent thrombosis and most often are managed by life-long anticoagulation.73

Heparin-Induced ThrombocytopeniaHeparin-induced thrombocytopenia describes an auto-immune-mediated drug reaction occurring in as many as 5% of patients receiving heparin therapy. As opposed to other drug-induced thrombocytopenias, HIT results in platelet activation and potential for venous and arterial thromboses.74,75 Evidence suggests that HIT is mediated by immune complexes (composed of immunoglobulin G [IgG] antibody, platelet factor 4 [PF4], and heparin) that bind platelet Fcγ receptors to activate platelets. Anti-PF4/heparin antibodies may “activate” vascular endothelium, monocytes, and macrophages by up-regulating tissue fac-tor expression (Fig. 62-4). Patients developing HIT dur-ing heparin therapy experience substantially increased risk for thrombosis (odds ratio 20:40, absolute risk 30% to 75%).74,75

In most cases, HIT manifests clinically as thrombocy-topenia occurring 5 to 14 days after initiating heparin therapy. However, with prior heparin exposure, thrombo-cytopenia or thrombosis may occur within 1 day. In some reported cases, thrombosis occurred simultaneously with thrombocytopenia, providing no warning. Although HIT remains a clinical diagnosis, laboratory testing provides confirmatory evidence. Both functional (i.e., serotonin platelet release assays or heparin-induced platelet aggre-gation) and quantitative (i.e., solid-phase enzyme-linked immunosorbent assays [ELISA]) tests for PF4/heparin immune complexes prove beneficial.75 Recent evidence suggests that PF4/heparin antibodies alone, in the absence of thrombocytopenia or thrombosis, may predict adverse outcomes.76,77

A diagnosis of HIT should be entertained for any patient experiencing thrombosis or thrombocytopenia (absolute or relative [≥50% reduction in platelet count]) during or after heparin administration. In cases in which HIT is suspected, heparin must be discontinued immediately (i.e., including unfractionated heparin, heparin-bonded catheters, heparin flushes, LMWH). Alternative nonhepa-rin anticoagulation must be administered concurrently. In most cases, a direct thrombin inhibitor (i.e., bivaliru-din, lepirudin, argatroban) is substituted for heparin until adequate prolongation of the INR can be achieved with warfarin.78,79 Typically, PF4/heparin immune complexes clear from the circulation within 3 months. If possible, patients experiencing HIT should avoid future expo-sure to unfractionated heparin; however, several reports describe subsequent limited perioperative reexposure to



Figure 62-4. Mechanisms under-lying thrombosis in heparin-induced thrombocytopenia (HIT). Immune complexes composed of heparin, platelet factor 4 (PF4), and antibodies bind to platelet surface Fcγ receptors to activate platelets. PF4/heparin immune complexes further activate vascular endo-thelium, monocytes, and macro-phages to increase tissue factor expression. IgG, Immunoglobulin G. (From Slaughter TF, Greenberg CS: Heparin-associated thrombo-cytopenia and thrombosis: Implica-tions for perioperative management, Anesthesiology 87:669, 1997, with permission.)

Activatedplatelet

Procoagulantmicroparticles

Heparan sulfateVascularendothelium Clot

Heparin IgG

IgG

PF4

PF4

PF4

PF4

PF4

PF4

unfractionated heparin after laboratory testing to ensure absence of PF4/heparin immune complexes.

MONITORING COAGULATION

Traditionally, perioperative coagulation monitoring has focused on (1) preoperative testing to identify patients at increased risk for perioperative bleeding and (2) intra-operative monitoring of heparin therapy during cardiac and vascular surgery. As discussed previously, routine preoperative coagulation testing lacks either predictive value or cost efficacy.80 However, in patients with a his-tory suggestive of a bleeding disorder or whose surgery may be associated with a high incidence of bleeding or coagulopathy, baseline preoperative coagulation testing may be advisable.

Given the widely acknowledged pharmacokinetic and pharmacodynamic response to heparin, monitoring anti-coagulation during cardiac and vascular surgery remains necessary. Patient-specific factors affecting response to heparin include age, weight, intravascular volume, and plasma and membrane concentrations of antithrombin, heparin cofactor II, PF4, and other heparin-binding pro-teins. Therefore, patients experience widely divergent anticoagulant responses to identical weight-based doses of heparin. Regardless, monitoring of heparin anticoagu-lation must be performed if only to prevent the rare, but potentially lethal, complication resulting from inadver-tent failure to administer heparin before cardiopulmo-nary bypass or vascular surgery.

The ideal test of perioperative coagulation would prove simple to perform, accurate, reproducible, diag-nostically specific, and cost effective. No current coag-ulation monitor meets these expectations; however, integrating results from multiple forms of monitoring may provide valuable diagnostic insight into periopera-tive coagulopathies.

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COMMON LABORATORY-BASED MEASURES OF COAGULATION

Activated Partial Thromboplastin TimeThe aPTT assesses integrity of the intrinsic and common pathways of plasma-mediated hemostasis. It measures the time required in seconds for clot formation to occur after mixing a sample of patient plasma with phospho-lipid, calcium, and an activator of the intrinsic path-way of coagulation (i.e., celite, kaolin, silica, or ellagic acid). In most cases, coagulation factor deficiencies are detectable at factor concentrations below 30% to 40% of normal; however, aPTT reagents vary in sensitivity to factor concentrations, necessitating institutional specific determination of “normal” ranges.81 Prolongation of the aPTT is evaluated further with mixing studies to deter-mine whether delayed clot formation is attributable to a coagulation factor deficiency or an inhibitor (i.e., hepa-rin, antiphospholipid antibody, fibrin split products). The mixing study is performed by mixing the patient’s plasma sample with “normal” donor plasma. In the case of a coagulation factor deficiency, time to clot formation will correct and sequential assays for specific coagula-tion factor concentrations allow for identification of the deficiency. A common means of confirming heparin pro-longation of the aPTT is to perform a thrombin clotting time (TCT) test. In this test, the patient’s citrate-contain-ing plasma sample is mixed with thrombin and time to clot formation is measured in seconds.39 The most com-mon mechanism underlying prolongation of the TCT is presence of heparin or a direct thrombin inhibitor anti-coagulant; however, dysfibrinogenemia or fibrin(ogen) degradation products also may impair clot formation in this setting.

Prothrombin TimeThe PT assesses integrity of the extrinsic and common pathways of plasma-mediated hemostasis. It measures

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time required in seconds for clot formation to occur after mixing a sample of patient plasma with tissue factor (thromboplastin) and calcium. As with the aPTT, throm-boplastin test reagents vary in sensitivity, limiting the ability to compare results between laboratories. Given the importance of monitoring PT results for patients on long-term warfarin therapy, the INR was introduced as a means of normalizing PT results among different labo-ratories.81 Thromboplastin reagents are tested against an international recombinant standard and assigned an international sensitivity index (ISI) based on results. The INR subsequently is calculated as INR = (patient PT/stan-dard PT)ISI, in which the standard PT represents the geo-metric mean of multiple normal samples from the testing laboratory. Institution of the INR substantially reduced interlaboratory variations in the PT. As with the aPTT, prolongation of the PT is assessed further with mixing studies.

Platelet Count and Bleeding TimeThe platelet count remains a standard component in screening for coagulation abnormalities. Automated platelet counts are performed in bulk using either optical-based or impedance-based measurements. Recommenda-tions regarding optimal platelet counts prove somewhat arbitrary; however, platelet counts exceeding 100,000/μL commonly are associated with normal hemostasis. Abnormally low platelet counts merit further assessment, including a visual platelet count using a blood smear. Sample hemodilution and platelet clumping are com-mon causes for false low platelet counts. Ethylenediami-netetraacetic acid (EDTA)-induced platelet clumping, a common artifact underlying thrombocytopenia, may be identified by manually counting platelets or by substitut-ing a citrate anticoagulant (as opposed to EDTA).

With growth in point-of-care platelet function moni-tors the bleeding time has declined in popularity; how-ever, under controlled conditions the bleeding time may provide useful information regarding primary hemostasis. Employing a commercial template cutting device and a sphygmomanometer adjusted to 40 mm Hg venous pressure, bleeding times of 2 to 10 minutes on the anterior forearm are considered normal. Limitations of the bleeding time include poor reproducibility, time needed to perform the test, and potential for scarring. Furthermore, the bleeding time is affected by numerous confounding variables, including skin temperature, skin thickness, age, ethnicity, anatomic test location, and a host of other factors.82 In general, the bleeding time has not proved predictive of bleeding and for that reason its use as a preoperative screening test to assess bleeding risk is not recommended.

COMMON POINT-OF-CARE MEASURES OF COAGULATION

Although laboratory-based measures of coagulation remain the mainstay of preoperative coagulation testing, increasing availability of sensitive and specific point-of-care coagulation monitoring may soon offer opportunities to direct blood component and hemostatic drug therapy more specifically without delays inherent to standard

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laboratory testing. Commercially available point-of-care monitors applicable in the perioperative setting may be considered in four broad categories: (1) functional mea-sures of coagulation or assays that measure the intrinsic ability of blood to generate clot, (2) heparin concentra-tion monitors, (3) viscoelastic measures of coagulation, and (4) platelet function monitors.

Functional Measures of CoagulationThe ACT, described by Hattersley in 1966 as a variation of the Lee-White whole blood clotting time, employs a con-tact activation initiator, typically celite (diatomaceous earth) or kaolin, to accelerate clot formation and reduce time for assay completion. Kaolin is recommended for use in patients receiving the antifibrinolytic drug aprotinin because celite ACTs in this setting are subject to artifactual prolongation.83 Failure to appreciate this drug-mediated effect may result in inadequate heparin administration if using celite ACT measurements with aprotinin. Whether high plasma concentrations of aprotinin affect the kaolin ACT remains unclear.

Current commercial ACT monitors automate clot detection. One of the more widely available ACT mon-itors uses a glass test tube containing a small magnet (Hemochron Response Whole Blood Coagulation Sys-tem, ITC, Edison, NJ). After adding sample blood, the tube is placed into the analyzer and the tube is rotated slowly at 37° C, allowing the magnet to maintain contact with a proximity detection switch. As fibrin clot forms, the magnet becomes entrapped and dislodged from the detection switch, thereby triggering an alarm to sig-nal completion of the ACT. Another ACT device uses a “plumb bob” flag assembly that is raised and released repeatedly to settle in the sample vial containing blood and contact activator (Hepcon HMS Plus, Medtronic, Minneapolis, Minn.). With clot formation, the descent rate of the flag through the blood sample slows, trig-gers an optical detector, and sets off an alarm to signal completion of the ACT.

The ACT in normal individuals is 107 ± 13 seconds (mean ± SD). However, the time at which a patient’s base-line ACT is measured influences the result.83 After surgi-cal incision, baseline ACT may decrease. Because the ACT measures clot formation by way of intrinsic and common pathways, heparin and other anticoagulants prolong time to clot formation. The ACT proves somewhat resis-tant to platelet dysfunction and thrombocytopenia.

ACT testing remains a popular perioperative coagula-tion monitor because of its simplicity, low cost, and lin-ear operating response at high heparin concentrations. Limitations of ACT monitoring include lack of sensitiv-ity at low heparin concentrations and poor reproduc-ibility.83 ACT testing performed with and without added heparinase improves sensitivity for detecting low heparin concentrations. Further limitations of the ACT include artifactual prolongation of results with hemodilution or hypothermia and the fact that ACT values beyond 600 seconds exceed the linear response range for the assay. Duplicate measurements improve results; however, newer electrochemically based ACT analyzers (i-STAT, Abbott, Princeton, NJ) improve reproducibility such that single ACT determinations may prove adequate.

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The high-dose thrombin time (HiTT) (ITC) provides an alternative functional measure of heparin anticoagu-lation. Primarily employed in cardiac surgical settings, the HiTT assay contains high thrombin concentrations to cleave fibrinogen directly and generate fibrin clot.84 Given excess thrombin concentrations, clot formation occurs independently of plasma coagulation factors other than fibrinogen. As a result, HiTT is prolonged by heparin (or other thrombin inhibitors), extreme degrees of hypofibrinogenemia or dysfibrinogenemia, and high concentrations of fibrin split products (as occur with fibri-nolysis). During most surgical procedures requiring hepa-rin administration, HiTT prolongation will correlate with heparin anticoagulant effect.

Heparin Concentration MeasurementProtamine titration remains the most popular point-of-care method for determining heparin concentration in perioperative settings. Protamine, a strongly basic poly-cationic protein, directly inhibits heparin in a stoichio-metric manner. In other words, 1 mg of protamine will inhibit 1 mg (∼100 units) of heparin, thereby forming the basis for protamine titration as a measure of heparin con-centration. As increasing concentrations of protamine are added to a sample of heparin-containing blood, time to clot formation decreases until the point at which the protamine concentration exceeds heparin concentration to delay clot formation. If a series of blood samples with incremental doses of protamine are analyzed, the sample in which the protamine and heparin concentrations are most closely matched will clot first. In this manner, prot-amine titration methodology allows for heparin concen-tration estimation. Assuming that the heparin-protamine titration curve for an individual patient remains constant throughout the operative period, protamine titration methods may estimate heparin doses required to achieve a desired plasma heparin concentration or the protamine dose needed to reverse a given heparin concentration in blood.54 Current point-of-care heparin concentration monitoring employs automated measurement techniques (Hepcon HMS Plus, Medtronic). Advantages of heparin concentration measurement include sensitivity for low heparin concentrations as well as relative insensitivity to hemodilution and hypothermia. In addition, heparin concentration measures are unaffected by aprotinin.

A major limitation of heparin concentration monitor-ing is failure to assess directly for an anticoagulant effect. To use an extreme example, consider a patient with a homozygous deficiency of antithrombin; in this setting, heparin concentration determination alone would fail to identify the lack of anticoagulant effect after heparin administration.

Viscoelastic Measures of CoagulationInitially developed in the 1940s, viscoelastic measures of coagulation have undergone a resurgence in popularity. The unique aspect of viscoelastic monitors lies in their ability to measure in whole blood the entire spectrum of clot formation from early fibrin strand generation through clot retraction and eventual fibrinolysis. The early throm-boelastograph (TEG) developed by Hartert in 1948 has evolved into two independent viscoelastic monitors: the

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modern TEG, or TEG 5000 Thromboelastograph Hemosta-sis Analyzer System (Haemoscope, Braintree, Mass.) and rotational thromboelastometry (ROTEM) (TEM Systems, Durham, NC). In the case of the thromboelastograph (TEG 5000), a small (0.35-mL) sample of whole blood is placed into a disposable cuvette within the instrument. The cuvette is maintained at a temperature of 37° C and continuously rotates around an axis of approximately 5 degrees. A sensor “piston” attached by a torsion wire to an electronic recorder is lowered into the blood within the cuvette. Addition of an activator, most often kaolin or celite, initiates clot formation. As the fibrin-platelet plug evolves, the piston becomes enmeshed within the clot, transferring rotation of the cuvette to the piston, torsion wire, and electronic recorder.85

Although variables derived from the TEG tracing do not coincide directly with laboratory-based tests of coag-ulation, the TEG depicts characteristic abnormalities in clot formation and fibrinolysis. Various parameters describing clot formation and lysis are identified and measured by the TEG. For example, the R value (reaction time) measures time to initial clot formation (normal, 7.5 to 15 minutes). Comparable to the whole blood clotting time, addition of a contact activator (i.e., celite or kaolin) to the sample cuvette reduces time to results. The R value may be prolonged by a deficiency of one or more plasma coagulation factors or inhibitors such as heparin. Maxi-mum amplitude (MA) provides a measure of clot strength and may be decreased by either qualitative or quantita-tive platelet dysfunction or decreased fibrinogen concen-tration. Normal MA is 50 to 60 mm. The α angle and K (BiKoatugulierung or coagulation) values measure rate of clot formation and may be prolonged by any variable slowing clot generation such as a plasma coagulation fac-tor deficiency or heparin anticoagulation. Modification of clotting activators may be incorporated to assess plate-let or fibrin contributions to clot strength.86 In a some-what analogous manner, ROTEM measures viscoelastic changes in a sample of whole blood subjected to activa-tion of coagulation. Specific activators differ from that of the TEG 5000 with resulting quantitative measures termed (1) coagulation time (CT; seconds), (2) α angle (clot formation time; seconds), (3) maximal clot firmness (MCF; millimeter), and (4) lysis time (LT; second).

The Sonoclot Analyzer (Sienco, Arvada, Colo.) pro-vides an alternative viscoelastic measure of coagulation. In contrast to thromboelastography and ROTEM, the Sonoclot Analyzer immerses a rapidly vibrating probe into a 0.4-mL sample of blood. As clot formation pro-ceeds, impedance to probe movement through the blood increases to generate an electrical signal and characteris-tic clot signature. The analyzer signature may be used to derive the ACT and to provide information regarding clot strength and presence of fibrinolysis.

Viscoelastic monitors generate characteristic diagrams by translating mechanical resistance to sensor move-ment within a sample of whole blood to an electronic waveform subject to quantitative analysis. One of the more common applications for viscoelastic monitoring has been real-time detection of excess fibrinolysis during liver transplantation or cardiac surgery. Evidence sug-gests that viscoelastic monitoring may prove beneficial in

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differentiating surgically related bleeding from that due to a coagulopathy. When used as one component of a diag-nostic algorithm, both thromboelastography and ROTEM have been demonstrated to reduce blood administration. More widespread application of viscoelastic monitoring has been hindered by lack of specificity associated with abnormal findings and qualitative assay interpretation.86 Digital automation of these instruments has simplified interpretation and improved reproducibility.

PLATELET FUNCTION MONITORS

Assessment of platelet function has proved challenging for several reasons. Historically, tests of platelet function have proved costly, time consuming, and technically demand-ing. Platelet dysfunction may occur as a result of diverse inherited or acquired disorders affecting surface receptors involved in adhesion or aggregation, storage granules, internal activation pathways, phospholipid membranes, or other mechanisms.51 Lack of standardized quality con-trols necessitates use of local donor blood to establish nor-mal control ranges. Furthermore, even established tests such as platelet aggregation lack performance standardiza-tion, resulting in widely varying results across laboratories. Complicating assessment further is the fact that platelets are highly susceptible to activation or desensitization dur-ing sample collection, transport, storage, and processing.

Although viscoelastic measures of coagulation (i.e., TEG 5000 or ROTEM) may detect platelet dysfunction, sensitivity and specificity prove limited. Incorporation of a platelet mapping assay into thromboelastography provides a method for viscoelastic measurement of drug-induced platelet inhibition with reasonable correlation to optical aggregometry.85 The standard laboratory-based method for identifying qualitative platelet dysfunction remains optical aggregometry performed using specific platelet agonists and samples of platelet-rich plasma. Flow cytometry employing fluorescent-labeled antibod-ies provides another sensitive method for quantitating platelet activation, responsiveness, and surface recep-tor availability.87 Despite representing standards of care, these measures remain technically challenging, costly, and time-consuming laboratory-based assays.

Fortunately, an increasing array of platelet function assays specifically designed as point-of-care instruments are available.88,89 As a measure of primary hemostasis, the PFA-100 (Platelet Function Analyzer, Siemens, Tarrytown, NY) increasingly has replaced the bleeding time in assess-ment of primary hemostasis. Unique among both labora-tory-based and point-of-care platelet function monitors, the PFA-100 incorporates high-shear conditions to simu-late small vessel injury in the presence of either ADP or epinephrine, both potent platelet activators.90 Time to clot–mediated aperture occlusion is reported as closure time. The PFA-100 has proved effective in detecting von Willebrand disease and aspirin-mediated platelet dysfunc-tion. This instrument, as a component of a standardized screening protocol, reduces time to identify and classify platelet dysfunction. Limitations of the PFA-100 include interference by thrombocytopenia and hemodilution.

The HemoSTATUS (Medtronic) platelet function test exploits the ability of platelet activating factor (PAF) to


accelerate clot formation of the kaolin-activated ACT. HemoSTATUS testing is performed on the Medtronic HMS Plus coagulation analyzer employing a six-channel kaolin ACT cartridge preloaded with serially increas-ing concentrations of PAF. A clot ratio is determined for each individual patient assay based on the ratio of the PAF-accelerated ACT to the standard ACT. An indi-vidual patient’s clot ratio is compared with a maximal clot ratio derived from normal volunteers to provide a relative measure of platelet function. In the presence of platelet dysfunction, higher concentrations of PAF are required to achieve a comparable PAF-activated ACT. In cardiac surgery, investigators demonstrated a relationship between platelet dysfunction and postoperative bleed-ing.83 Furthermore, the maximal clot ratio as determined by HemoSTATUS improved after desmopressin or platelet administration. Other investigators, however, failed to identify a relationship between platelet dysfunction as measured by HemoSTATUS and postoperative bleeding.

The VerifyNow System (formerly known as the Ultegra Rapid Platelet Function Analyzer, Accumetrics, San Diego, Calif.) is an automated turbidimetric whole blood platelet function assay that assesses ability of activated platelets to bind fibrinogen-coated polystyrene beads. On addition of the whole blood test sample, thrombin receptor activat-ing peptide directly activates platelets within the sample to stimulate glycoprotein IIb/IIIa platelet surface recep-tor expression. As activated platelets bind and aggregate fibrinogen-coated beads, light transmission through the sample increases to generate a signal. Although the Veri-fyNow System is simple to operate and provides a rapid bedside measure of platelet function, a baseline reference measurement is suggested for each patient to calculate the extent of subsequent changes in platelet function.88 Potential applications for this methodology in the peri-operative setting remain unclear.

Plateletworks (Helena Laboratories, Beaumont, Tex.) employs a hemocytometer to perform automated platelet counts on whole blood samples collected in the presence and absence of platelet-stimulating agonists such as col-lagen or ADP. The difference in platelet counts before and after agonist addition provides a direct measure of platelet aggregation (i.e., platelet responsiveness) and is reported as “% aggregation.” Preliminary investigations demon-strated reasonable correlations between platelet counts attained with the Plateletworks monitor and laboratory-based instruments.88 In addition, the Plateletworks assay proved effective in identifying platelet dysfunction in the setting of glycoprotein IIb/IIIa antagonists and appeared to correlate relatively well with laboratory-based mea-sures of platelet aggregation.

Employing a sample of whole blood, the Hemostasis Analysis System (Hemodyne, Bethesda, Md.) measures platelet contractile force, the force produced by platelets during clot retraction, and clot elastic modulus, a mea-sure of clot rigidity. In preliminary investigations, plate-let contractile force was reduced after cardiopulmonary bypass and modestly correlated with perioperative blood loss.

Advances in our understanding of hemostasis and thrombosis at the molecular level have contrib-uted directly to recent biotechnologic innovations in



point-of-care testing. Further advances in point-of-care coagulation monitoring offer the opportunity for cli-nicians to make informed decisions about transfusion therapy and hemostatic drug administration to mini-mize perioperative bleeding. In considering any point-of-care coagulation testing, it must be recognized that results will not necessarily mirror those reported from laboratory-based testing. Reagent sensitivities vary across manufacturers and even one lot of reagent to another. In addition, point-of-care testing typically relies on whole blood samples for testing as opposed to laboratory-based testing using plasma or processed platelets. A final consid-eration for which point-of-care platelet function testing provides a particularly relevant example is that monitors from different manufacturers measure differing aspects of platelet-mediated or plasma-mediated hemostasis. In the case of platelet function monitors, a dozen instruments purport to measure platelet function. However, using dif-ferent instruments results may vary from “severe” plate-let dysfunction to “no platelet dysfunction” in a single sample of blood. Before adopting any point-of-care moni-toring, an understanding of the quality assurance require-ments, test methodology, and concomitant strengths and weaknesses will prove essential to inform patient care.

Complete references available online at expertconsult.com.

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