Patient Blood Management: Coagulation

Key Points

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Normal hemostasis is a balance between generation of a localized hemostatic clot and uncontrolled thrombus formation.
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The extrinsic pathway of coagulation begins with exposure of blood plasma to tissue factor and represents the initiation phase of plasma-mediated hemostasis.
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The intrinsic pathway amplifies and propagates the hemostatic response to maximize thrombin generation.
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The common pathway generates thrombin, forms fibrin, and crosslinks fibrin strands to produce an insoluble fibrin clot.
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Routine preoperative coagulation testing of all surgical patients is costly and lacks predictive value for detection of hemostatic abnormalities. Testing should be based on the preoperative history and physical examination and the planned surgery.
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Antiplatelet agents and anticoagulants are used to reduce the formation of blood clots in the setting of coronary or cerebral atherosclerosis or after vascular thrombosis.
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Thrombolytic therapy is used to break up or dissolve blood clots.
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Procoagulant drugs (antifibrinolytics, factor replacements, prothrombin complex concentrate) help control blood loss during surgery.
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Perioperative management of patients who require chronic anticoagulation or antiplatelet therapy involves balancing the risk of surgical bleeding against the risk of developing postoperative thromboembolism.

Acknowledgment

The editors and publisher would like to thank Drs. Thomas F. Slaughter, Lawrence T. Goonough, and Terri G. Monk for their contributions in the prior edition of this work. Excerpts of their chapters were incorporated and serve as the foundation for the current chapter.

Introduction

Hemostasis is an ordered enzymatic process involving cellular and biochemical components that function to preserve the integrity of the circulatory system after injury. The ultimate goal of this process is to limit blood loss secondary to vascular injury, maintain intravascular blood flow, and promote revascularization after thrombosis. As such, normal physiologic hemostasis is a constant balance between procoagulant pathways responsible for generation of a stable localized hemostatic clot and counter-regulatory mechanisms inhibiting uncontrolled thrombus propagation or premature thrombus degradation. Vascular endothelium, platelets, and plasma coagulation proteins play equally important roles in this process. Derangements in this delicate system can lead to excessive bleeding or pathologic thrombus formation. This chapter will examine normal and abnormal hemostasis, mechanisms to monitor coagulation, medications to manipulate coagulation, and management options for the perioperative anticoagulated patient.

Normal Hemostasis

Vascular endothelial injury—mechanical or biochemical—leads to platelet deposition at the injury site, a process often referred to as primary hemostasis. Although this initial platelet plug 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 processes underlying hemostasis suggest a far more complex interplay between vascular endothelium, platelets, and plasma-mediated hemostasis than is reflected in this model.

Vascular Endothelial Role in Hemostasis

In order to maintain blood flow throughout the circulatory system, the vascular endothelium employs several strategies to inhibit unprovoked thrombus formation. Healthy endothelial cells possess antiplatelet, anticoagulant, and profibrinolytic effects to inhibit clot formation. The negatively charged vascular endothelium repels platelets, and endothelial cells produce potent platelet inhibitors such as prostacyclin (prostaglandin I ₂ ,) and nitric oxide (NO). An adenosine diphosphatase (CD39) expressed on the surface of vascular endothelial cells also serves to block platelet activation via degradation of adenosine diphosphate (ADP), a potent platelet activator. Given these endogenous antiplatelet effects, quiescent platelets normally do not adhere to healthy vascular endothelial cells.

The vascular endothelium also plays a pivotal anticoagulant role through expression of several inhibitors of plasma-mediated hemostasis. Endothelial cells increase activation of protein C, an anticoagulant, via surface glycoprotein thrombomodulin (TM), which acts as a cofactor for thrombin-mediated activation of protein C, making its activation 1000 times faster. Endothelial cells also increase endothelial cell protein C receptor, which further enhances protein C activation by an additional 20-fold. Endothelial-bound glycosaminoglycans, such as heparan sulfate, function to accelerate the protease activity of antithrombin (AT), which degrades factors IXa, Xa, and thrombin. Endothelial cells also produce tissue factor pathway inhibitor (TFPI), which inhibits the procoagulant activity of factor Xa as well as the TF-VIIa complex. Finally, the vascular endothelium synthesizes tissue plasminogen activator (t-PA), which is responsible for activating fibrinolysis, a primary counter-regulatory mechanism limiting clot propagation.

Despite these natural defense mechanisms to inhibit thrombus generation, a variety of mechanical and chemical stimuli may shift the balance such that the endothelium instead promotes clot formation. Damage to vascular endothelial cells exposes the underlying extracellular matrix (ECM), which contains collagen, von Willebrand factor (vWF), and other platelet-adhesive glycoproteins. Platelets bind to and are activated by exposure to ECM components. Exposure of tissue factor, constitutively expressed by fibroblasts in the ECM, activates plasma-mediated coagulation pathways to generate thrombin and fibrin clot. Certain cytokines (i.e., interleukin-1, tumor necrosis factor, and γ-interferon) and hormones (i.e., desmopressin acetate [DDAVP] or endotoxin) induce prothrombotic changes in vascular endothelial cells by increasing synthesis and expression of vWF, tissue factor, and plasminogen activator inhibitor-1 (PAI-1), and down-regulating normal antithrombotic cellular and biochemical pathways. Finally, thrombin, hypoxia, and high fluid shear stress can also induce prothrombotic vascular endothelial changes such as increased synthesis of PAI-1. This associated inhibition of fibrinolysis has been implicated in the prothrombotic state and high incidence of venous thrombosis after surgery.

Platelets and Hemostasis

Platelets contribute a critical role in hemostasis. Derived from bone marrow megakaryocytes, nonactivated platelets circulate as discoid anuclear cells with a lifespan of 8 to 12 days. Under normal conditions, approximately 10% of platelets are consumed to support vascular integrity with 1.2−1.5 × 10 ¹¹ new platelets formed daily. The platelet membrane is characterized by numerous receptors and a surface-connected open canalicular system serving to increase platelet membrane surface area and provide rapid communication between the platelet interior and exterior environment. Under normal circumstances, platelets do not bind the vascular endothelium. However, when injury occurs, platelets contribute to hemostasis by adhering to the damaged vasculature, aggregating with one another to form a platelet plug, and facilitating generation of fibrin crosslinks to stabilize and reinforce the plug. Initially, upon exposure of the ECM, platelets undergo a series of biochemical and physical alterations characterized by three major phases: adhesion, activation, and aggregation. Exposure of subendothelial matrix proteins (i.e., collagen, vWF, fibronectin) allows for platelet adhesion to the vascular wall. vWF proves particularly important as a bridging molecule between ECM collagen and platelet glycoprotein Ib/factor IX/factor V receptor complexes. Absence of either von Willebrand disease (vWF) or glycoprotein Ib/factor IX/factor V receptors (Bernard-Soulier syndrome) results in a clinically significant bleeding disorder.

In addition to promoting their adhesion to the vessel wall, the platelet interaction with collagen serves as a potent stimulus for the subsequent phase of thrombus formation, termed platelet activation. The generation of thrombin resulting from exposure of tissue factor, functions as a second pathway for platelet activation. Platelets contain two specific types of storage granules: α granules and dense bodies. α granules contain numerous proteins essential to hemostasis and wound repair, including fibrinogen, coagulation factors V and VIII, vWF, platelet-derived growth factor, and others. Dense bodies contain the adenine nucleotides ADP and adenosine triphosphate, as well as calcium, serotonin, histamine, and epinephrine. During the activation phase, platelets release granular contents, resulting in recruitment and activation of additional platelets and propagation of plasma-mediated coagulation. During activation, platelets undergo structural changes to develop pseudopod-like membrane extensions and to release physiologically active microparticles, which serve to dramatically increase platelet membrane surface area. Redistribution of platelet membrane 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 propagation of plasma-mediated hemostasis.

During the final phase of platelet aggregation, activators released during the activation phase recruit additional platelets to the site of injury. Newly active glycoprotein IIb/IIIa receptors on the platelet surface bind fibrinogen, thereby promoting cross-linking and aggregation with adjacent platelets. The importance of these receptors is reflected by the bleeding disorder associated with their hereditary deficiency, Glanzmann thrombasthenia.

Plasma-Mediated Hemostasis

Plasma-mediated hemostasis was originally described as a cascade or waterfall sequence of steps involving the serial activation of enzymes and cofactors to accelerate and amplify fibrin generation by thrombin. Trace plasma proteins, activated by exposure to tissue factor or foreign surfaces, initiate this series of reactions culminating in conversion of soluble fibrinogen to insoluble fibrin clot. Thrombin generation, the “thrombin burst,” represents the key regulatory step in this 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.

Traditionally, the coagulation cascade describing plasma-mediated hemostasis has been depicted as extrinsic and intrinsic pathways, both of which culminate in a common pathway in which fibrin generation occurs. This cascade model has proven to be an oversimplification, as it does not fully reflect in vivo hemostasis. For instance, individuals with deficiencies in the intrinsic pathway (factor XII, prekallikrein, or high molecular weight kininogen) exhibit prolongations of the activated partial thromboplastin time (aPTT), but do not actually experience an increased bleeding risk. Nevertheless, the cascade model remains a useful descriptive tool for organizing discussions of plasma-mediated hemostasis ( Fig. 50.1 ). Coagulation factors are, for the most part, synthesized by the liver 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 prothrombin 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 coagulation pathway evolved.

Fig. 50.1, Depiction of the Classic Coagulation Cascade Incorporating Extrinsic and Intrinsic Pathways of Coagulation.

The cascade characterizes a series of enzymatic reactions in which inactive precursors—zymogens—undergo activation to amplify the overall reaction. Each stage of the cascade requires assembly of membrane-bound activation complexes, each composed of an enzyme (activated coagulation factor), substrate (inactive precursor zymogen), cofactor (accelerator or catalyst), and calcium. Assembly of these activation complexes occurs on platelet or microparticle phospholipid membranes that localize and concentrate reactants. Coagulation factor activation slows dramatically in the absence of these phospholipid membrane anchoring sites. This requirement functionally confines clot formation to sites of injury.

Extrinsic Pathway of Coagulation

The extrinsic pathway of coagulation is now understood to represent the initiation phase of plasma-mediated hemostasis and begins with exposure of blood plasma to tissue factor. Tissue factor is prevalent in subendothelial tissues surrounding the vasculature. Under normal conditions, the vascular endothelium minimizes contact between tissue 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 conversion of factor X to Xa. Additionally, the tissue factor/factor VIIa complex also activates factor IX of the intrinsic pathway, further demonstrating the key role of tissue factor in initiating hemostasis.

Intrinsic Pathway of Coagulation

Classically, the intrinsic or contact activation system was described as a parallel pathway for thrombin generation initiated by factor XII activation after contact with negatively charged surfaces such as glass, dextran sulfate, or kaolin. However, the rarity of bleeding disorders resulting from contact activation factor deficiencies led to our current understanding of the intrinsic pathway as an amplification system to propagate thrombin generation initiated by the extrinsic pathway. Recent cell-based models of coagulation suggest that thrombin generation by way of the extrinsic pathway is limited by a natural inhibitor, TFPI, but the small quantities of thrombin generated do activate factor XI and the intrinsic pathway. The intrinsic pathway then subsequently amplifies and propagates the hemostatic response to maximize thrombin generation ( Fig. 50.2 ). Although factor XII may be activated by foreign surfaces (i.e., cardiopulmonary bypass [CPB] circuits or glass vials), the intrinsic pathway plays a minor role in the initiation of hemostasis. Proteins of the intrinsic pathway may, however, contribute to inflammatory processes, complement activation, fibrinolysis, kinin generation, and angiogenesis.

Fig. 50.2, Clot Formation at Vascular Injury Site.

Common Pathway of Coagulation

The final pathway, common to both extrinsic and intrinsic coagulation cascades, depicts thrombin generation and subsequent fibrin formation. Signal amplification results from activation of factor X by both intrinsic (FIXa, FVIIIa, Ca ²⁺ ) and extrinsic (tissue factor, FVIIa, Ca ²⁺ ) tenase complexes. The tenase complexes in turn facilitate formation of the prothrombinase complex (FXa, FII [prothrombin], FVa [cofactor], and Ca ²⁺ ), which mediates a surge in thrombin generation from prothrombin. Thrombin proteolytically cleaves fibrinopeptides A and B from fibrinogen molecules to generate fibrin monomers, which polymerize into fibrin strands to form clot. Finally, factor XIIIa, a transglutaminase activated by thrombin, covalently crosslinks fibrin strands to produce an insoluble fibrin clot resistant to fibrinolytic 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 fibrinogen and factor XIII suggest the potential for randomized controlled trials to determine efficacy of these biologics in treatment of acquired coagulopathies.

Thrombin generation remains the key enzymatic step regulating hemostasis. Not only does thrombin activity mediate conversion of fibrinogen to fibrin, but it also has a host of other actions. It activates platelets and factor XIII, converts inactive cofactors V and VIII to active conformations, activates factor XI and the intrinsic pathway, up-regulates expression of tissue factor, stimulates vascular endothelial expression of PAI-1 to down-regulate fibrinolytic activity, and suppresses uncontrolled thrombosis through activation of protein C.

Intrinsic Anticoagulant Mechanisms

Once activated, regulation of hemostasis proves essential to limit clot propagation beyond the injury site. One simple, yet important, anticoagulant mechanism derives from flowing blood and hemodilution. The early platelet and fibrin clot proves highly susceptible to disruption by shear forces from 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. However, later in the clotting process, more robust counter-regulatory mechanisms are necessary to limit clot propagation. Four major counter-regulatory pathways have been identified that appear particularly crucial for down-regulating hemostasis: fibrinolysis, TFPI, the protein C system, and serine protease inhibitors (SERPINs).

The fibrinolytic system comprises a cascade of amplifying reactions culminating in plasmin generation and proteolytic degradation of fibrin and fibrinogen. As with the plasma-mediated coagulation cascade, inactive precursor proteins are converted to active enzymes, necessitating a balanced system of regulatory controls to prevent excessive bleeding or thrombosis ( Fig. 50.3 ). The principal enzymatic mediator of fibrinolysis is the serine protease, plasmin, which is generated from plasminogen. In vivo, plasmin generation is most often accomplished by release of t-PA or urokinase from the vascular endothelium. Activity of t-PA and urokinase is accelerated in the presence of fibrin, which limits fibrinolysis to areas of clot formation. Factor XIIa and kallikrein of the intrinsic pathway also contribute to fibrinolysis through activation of plasminogen after exposure to foreign surfaces. Fortunately, fibrinolytic activity is limited by the rapid inhibition of free plasmin. In addition to enzymatic degradation of fibrin and fibrinogen, plasmin inhibits hemostasis by degrading essential cofactors V and VIII and reducing platelet glycoprotein surface receptors essential to adhesion and aggregation. Fibrin degradation products also possess mild anticoagulant properties.

Fig. 50.3, Principal Mediators of Fibrinolysis.

TFPI and factor Xa form phospholipid membrane-bound complexes that incorporate and inhibit tissue factor/factor VIIa complexes. This inhibition leads to downregulation of the extrinsic coagulation pathway. As TFPI rapidly extinguishes tissue factor/VIIa activity, the critical role of the intrinsic pathway to continued thrombin and fibrin generation becomes apparent.

The protein C system proves particularly important in down-regulating coagulation through inhibition of thrombin and the essential cofactors Va and VIIIa. After binding to TM, thrombin’s procoagulant function decreases and instead its ability to activate protein C is augmented. Protein C, complexed with the cofactor protein S, degrades both cofactors Va and VIIIa. Loss of these critical cofactors limits formation of tenase and prothrombinase activation complexes essential to formation of factor Xa and thrombin, respectively. Additionally, once bound to TM, thrombin is rapidly inactivated and removed from circulation, providing another mechanism by which the protein C pathway down-regulates hemostasis.

The most significant SERPINs regulating hemostasis include AT and heparin cofactor II. AT inhibits thrombin, as well as factors IXa, Xa, XIa, and XIIa. Heparin binds AT causing a conformational change that accelerates AT-mediated inhibition of targeted enzymes. Heparin cofactor II is a more recently discovered SERPIN that inhibits thrombin alone. Although the precise physiologic role for heparin cofactor II remains unclear, when bound by heparin, its inhibitory activity is dramatically increased.

Disorders of Hemostasis

Evaluation of Bleeding Disorders

The perioperative period presents significant challenges to the hemostatic system; therefore, identification and correction of hemostatic disorders can be of vital importance. Unfortunately, assessment of bleeding risk continues to be a challenge and the optimal methods for preoperative evaluation remain controversial. Although routine preoperative coagulation testing of all surgical patients may seem prudent, such an approach is costly and lacks predictive value for detection of hemostatic abnormalities. Standard coagulation tests such as the prothrombin time (PT) and aPTT were designed as diagnostic tests to be used when a bleeding disorder is suspected based on clinical evaluation. As a result, when used as screening tests, these in vitro assays are limited in their ability to reflect the in vivo hemostatic response. For example, because of the nature of establishing normal value ranges for these tests, 2.5% of healthy individuals will have abnormal PT or aPTT values. Meanwhile, those with mild hemophilia A, vWD, and factor XIII deficiency may experience clinically significant bleeding despite having normal values on standard testing. Consequently, a carefully performed bleeding history remains the single most effective predictor of perioperative bleeding.

A thorough history should focus on prior bleeding episodes. In particular, patients should be asked whether they have experienced excessive bleeding after hemostatic challenges such as dental extractions, surgery, trauma, or childbirth and whether blood transfusions or reoperation were required to control the bleeding. Common presentations suggestive of a bleeding disorder may include frequent epistaxis necessitating nasal packing or surgical intervention. Oral surgery and dental extractions prove particularly good tests of hemostasis because of increased fibrinolytic activity on the mucous membranes of the oral cavity. Women with platelet disorders or vWD may experience menorrhagia, and postpartum hemorrhage commonly occurs in those with underlying disorders of hemostasis. A history of spontaneous nontraumatic hemorrhage proves particularly concerning when associated with hemarthroses or deep muscle bleeding. Identification of a bleeding disorder at an early age or in family members suggests an inherited condition. A careful medication history including direct questions relating to consumption of aspirin and nonsteroidal antiinflammatory drugs (NSAIDs), as well as supplements such as ginkgo and vitamin E. 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 the need for preoperative laboratory-based coagulation testing. Should the preoperative history or physical examination reveal signs or symptoms suggestive of a bleeding disorder, further laboratory testing is indicated. Preoperative coagulation screening tests may be indicated, despite a negative history, in cases in which the planned surgery is commonly associated with significant bleeding (i.e., CPB). Finally, preoperative testing may prove justified in settings in which the patient is unable to provide an adequate preoperative bleeding history. Should evidence of a bleeding disorder be detected, underlying etiologies should be clarified if possible before proceeding with surgery.

Inherited Bleeding Disorders

Von Willebrand Disease

Inherited disorders of hemostasis include those involving platelet quantity and function, coagulation factor deficiencies, or disorders of fibrinolytic pathways. Among these inherited bleeding disorders, vWD is the most common and is characterized by quantitative or qualitative deficiencies of vWF resulting in defective platelet adhesion and aggregation. Affecting up to 1% of the population, vWD is categorized into three main types (types 1, 2, and 3). with most cases demonstrating an autosomal dominant inheritance pattern. Types 1 and 3 lead to varying quantitative vWF deficiencies, while type 2 encompasses four subtypes expressing qualitative defects that affect vWF function. Under normal conditions, vWF plays a critical role in platelet adhesion to the ECM and prevents degradation of factor VIII by serving as a carrier molecule. Classically, patients with vWD describe a history of easy bruising, recurrent epistaxis, and menorrhagia, which are characteristic of defects in platelet-mediated hemostasis. In more severe cases (i.e., type 3 vWD), concomitant reductions in factor VIII may lead to serious spontaneous hemorrhage, including hemarthroses.

Routine coagulation studies are generally not helpful in the diagnosis of vWD, as the platelet count and PT will be normal in most patients and the aPTT may demonstrate mild-to-moderate prolongation depending on the level of factor VIII reduction. Instead, initial screening tests involve measurement of vWF levels (vWF antigen) and vWF platelet binding activity in the presence of the ristocetin cofactor, which leads to platelet agglutination. Measurable reductions in factor VIII activity may occur in severe cases. Increasingly, platelet function tests have replaced bleeding times in assessing for vWD. Mild cases of vWD often respond to DDAVP, which results in the release of vWF from endothelial cell. Use of vWF:factor VIII concentrates (Humate-P, CSL Behring, King of Prussia, PA) may be indicated in the perioperative period if there is a significant bleeding history.

Hemophilias

Although less common than vWD, the hemophilias merit consideration given their diverse clinical presentation. Hemophilia A, factor VIII deficiency, and hemophilia B, factor IX deficiency, are both X-linked inherited bleeding disorders most frequently presenting in childhood as spontaneous hemorrhage involving joints, deep muscles, or both. Hemophilia A occurs with an incidence of 1:5000 males and hemophilia B in 1:30,000 males. While most cases are inherited, nearly one third of cases represent new mutations with no family history. The severity of the disease depends on an individual’s baseline factor activity level. 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 PT, bleeding time, and platelet count remain within normal limits. However, a normal aPTT may also be seen in mild forms of hemophilia; therefore, specific factor analyses need to be performed to confirm the diagnosis and determine the severity of the factor deficiency. In most cases, perioperative management of patients with hemophilia A or B necessitates consultation with a hematologist and administration of recombinant or purified factor VIII or factor IX concentrates, respectively. Mild cases of hemophilia A may be treated with desmopressin. An increasingly common complication of hemophilia, particularly in the case of hemophilia A, has been the development of alloantibodies directed against the factor VIII protein. Administration of factor VIII concentrates will fail to control bleeding in patients with high-titer antibodies. Several approaches to reduce bleeding in these patients include: substitution of porcine factor VIII, administration of activated (FEIBA, Shire Inc., Lexington, MA) or non-activated prothrombin complex concentrates (PCCs), or treatment with recombinant factor VIIa (NovoSeven, Novo Nordisk Inc., Bagsvaerd, Denmark).

Acquired Bleeding Disorders

Drug Induced

Medications represent the most significant cause of acquired coagulopathy in perioperative patients. In addition to anticoagulants such as heparin and warfarin, the increasing number of direct oral anticoagulants(DOACs) and antiplatelet drugs have further complicated perioperative management. An understanding of the effect of these agents and strategies for reversal can be critical to reduce bleeding complications during urgent and emergent procedures. Additionally, there are several classes of medications that may unintentionally increase bleeding risk due to side effects, primarily via platelet inhibition. β-Lactam antibiotics impair platelet aggregation that can result in clinically significant bleeding in patients with higher baseline risk. Nitroprusside, nitroglycerin, and NO also result in decreased platelet aggregation and secretion. Similarly, selective-serotonin reuptake inhibitors, such as paroxetine, decrease platelet serotonin storage, which inhibits platelet aggregation and may have clinical consequences in individuals with preexisting coagulopathies. These medications should be considered in patients with an otherwise unexplained coagulopathy.

Liver Disease

Hemostatic defects associated with hepatic failure prove complex and multifactorial. Severe liver disease impairs synthesis of coagulation factors, produces quantitative and qualitative platelet dysfunction, and impedes clearance of activated clotting and fibrinolytic proteins. The liver is the primary site for the production of procoagulant factors including fibrinogen, prothrombin (factor II), factors V, VII, IX, X, XI, XII, as well as the anticoagulants protein C and S, and AT. Laboratory findings commonly associated with liver disease include a prolonged PT and possible prolongation of the aPTT, suggesting that these individuals are at increased risk of bleeding. However, the abnormal values only reflect the decrease in procoagulant factors and do not account for the concomitant decrease in anticoagulant factors. As a result, patients with chronic liver disease are thought to have a rebalanced hemostasis and actually generate amounts of thrombin equivalent to healthy individuals.

Similarly, thrombocytopenia from splenic sequestration is often observed in patients with liver disease and portal hypertension and is accompanied by platelet dysfunction due to increased production of endothelial NO and prostacyclin resulting in platelet inhibition. Despite these alterations, increases in vWF commonly observed in these patients may serve to restore platelet function. Also, levels of the plasma metalloprotease ADAMTS13, responsible for cleaving vWF multimers, are decreased in chronic liver disease and result in high circulating levels of large vWF multimers that promote platelet aggregation. This increase in vWF may in part correct for thrombocytopenia and platelet dysfunction but also can result in a prothrombotic state and increased clotting risk.

Fibrinolysis of formed clot is also aberrant in patients with liver disease. Normally, fibrin clot is degraded by plasmin, which is converted to its active form by t-PA and urokinase plasminogen activator (u-PA). Excessive fibrinolysis is prevented by thrombin-activatable fibrinolysis inhibitor (TAFI), which blocks activation of plasmin from plasminogen. TAFI is synthesized by the liver and as levels are decreased in patients with chronic liver disease, it was believed that such individuals are at increased bleeding risk due to hyperfibrinolysis. However, levels of PAI-1, a SERPIN of t-PA and u-PA, are also increased in liver disease, which may in actuality normalize fibrinolysis.

In summary, procoagulant and anticoagulant hemostatic mechanisms are rebalanced in patients with chronic liver disease, but this balance is easily disrupted and these patients are at risk for both bleeding and inappropriate clotting. Traditional coagulation testing does not correlate with bleeding risk in these patients, which has led to studies looking at the use of viscoelastic coagulation testing using thromboelastography (TEG) or rotational thromboelastometry (ROTEM) as a means of assessing functional coagulation and guiding perioperative blood product transfusion and administration of antifibrinolytic agents.

Renal Disease

Platelet dysfunction commonly occurs in association with chronic renal failure and uremia, as reflected by a prolonged bleeding time and propensity for bleeding associated with surgery or trauma. The underlying mechanisms are multifactorial but have mostly been attributed to decreased platelet aggregation and adhesion to injured vessel walls. Impaired adhesion is likely due to defects of the glycoprotein IIb/IIIa, which facilitates platelet binding of fibrinogen and vWF. Additionally, accumulation of guanidinosuccinic acid and the resulting increase in endothelial NO synthesis further decreases platelet responsiveness. Red blood cell (RBC) concentration has also been speculated to contribute to platelet dysfunction, 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. Both dialysis and correction of anemia have been reported to shorten bleeding times in patients with chronic renal failure. Treatment of platelet dysfunction related to chronic renal disease includes transfusion of cryoprecipitate (rich in vWF) or administration of desmopressin (0.3 μg/kg), which stimulates release of vWF from endothelial cells. Additionally, conjugated estrogens (0.6 mg/kg intravenously for 5 days) have been demonstrated to shorten bleeding times, perhaps via decreased generation of NO.

Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is a pathologic hemostatic response to tissue factor/factor VIIa complex that leads to excessive activation of the extrinsic pathway, which overwhelms natural anticoagulant mechanisms and generates intravascular thrombin. Numerous underlying disorders may precipitate DIC, including trauma, amniotic fluid embolus, malignancy, sepsis, or incompatible blood transfusions. Most often, DIC presents clinically as a diffuse bleeding disorder associated with consumption of coagulation factors and platelets during widespread microvascular thrombotic activity, which results in multiorgan dysfunction. Laboratory findings typical of DIC include reductions in platelet count; prolongation of the PT, aPTT, and thrombin time (TT); and elevated concentrations of soluble fibrin and fibrin degradation products. However, DIC is both a clinical and laboratory diagnosis; hence, laboratory data alone do not provide sufficient sensitivity or specificity to confirm a diagnosis. For example, chronic DIC states have been identified with relatively normal screening coagulation tests accompanied by elevated concentrations of soluble fibrin and fibrin degradation products. Management of DIC requires management of the underlying condition precipitating hemostatic activation. Otherwise, treatment is mostly supportive and includes selective blood component transfusions to replete coagulation factors and platelets consumed in the process. The use of anticoagulants such as heparin remains controversial with recommendations that its use be limited to conditions with the highest thrombotic risk. Antifibrinolytic therapy generally is contraindicated in DIC, owing to the potential for catastrophic thrombotic complications.

Cardiopulmonary Bypass-Associated Coagulopathy

Institution of CPB by directing blood flow through an extracorporeal circuit causes significant perturbations to the hemostatic system. Initial priming of the bypass circuit results in hemodilution and thrombocytopenia. Adhesion of platelets to the synthetic surfaces of the bypass circuit further decreases platelet counts and contributes to platelet dysfunction. During CPB, expression of platelet surface receptors important for adhesion and aggregation (GPIb, GPIIb/IIIa) are downregulated and the number of vWF-containing α granules are decreased, thereby impairing platelet function. Furthermore, induced hypothermia during CPB results in reduced platelet aggregation and plasma-mediated coagulation by decreasing clotting factor production and enzymatic activity. Hyperfibrinolysis may also occur as a result of CPB, supporting the use of antifibrinolytic drugs to decrease intraoperative blood loss.

Trauma-Induced Coagulopathy

Uncontrolled hemorrhage is a frequent cause of trauma-related deaths. Coagulopathy in this setting may be due to acidosis, hypothermia, and hemodilution from resuscitation; however, an independent acute coagulopathy is also experienced by these individuals. Termed trauma-induced coagulopathy (TIC) or acute traumatic coagulopathy, this process involves disordered hemostasis and increased fibrinolysis observed early after injury. The anticoagulant effect of activated protein C (APC) is thought to play a primary role in TIC by decreasing thrombin generation via inhibition of factor Va and VIIIa and promoting fibrinolysis through inhibition of PAI-1. The relevance of APC in the development of TIC is supported by the association of hypoperfusion and increasing injury severity with increased levels of APC activity. Hypoperfusion is thought to be the stimulus for APC activation. Additionally, degradation of the endothelial glycocalyx (EG), a gel-like matrix lining the vascular endothelium, is linked to factors associated with trauma, including tissue damage, hypoperfusion, elevated catecholamines, and inflammation. The EG has anticoagulant properties and contains proteoglycans such as syndecan-1, hyaluronic acid, heparan sulfate, and chondroitin sulfate which are shed during endothelial injury. Shedding of proteoglycans results in an “autoheparinization” phenomenon that contributes to TIC. Markers of EG degradation have been found to be associated with inflammation, coagulopathy, and increased mortality in trauma patients.

Although platelet counts appear to be normal, platelet dysfunction contributes to increased bleeding in TIC. Significant platelet hypofunction in response to various agonists, including ADP, arachidonic acid, and collagen, has been observed acutely in trauma patients prior to resuscitation. It is hypothesized that trauma patients experience “platelet exhaustion” as a result of activation from widespread release of ADP from injured tissues. This diffuse activation renders platelets unresponsive to subsequent stimulation. Platelet insensitivity to ADP is also associated with increased susceptibility of clots to tPA-mediated fibrinolysis. The importance of early treatment to reduce hyperfibrinolysis in trauma is supported by the findings of the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2 (CRASH-2) trial, which demonstrated a mortality benefit from early administration of tranexamic acid (TXA).

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