Preoperative Assessment of Coagulation Disorders

Introduction This chapter provides an overview of the coagulation system with emphasis on the impact of specific disorders and tests during the preoperative period. The body's hemostatic system could be compared with a lever that is in constant balance on a fulcrum. At one end is the physiological need to maintain blood in the fluid state, allowing unimpeded circulation of oxygen and nutrients to the tissues. At the other end is the need to restrict the outflow of blood should damage to the vasculature occur. This delicate balance exists as the result of a complex interaction among the three major components of the hemostatic system: the vascular compartment, circulating blood platelets, and coagulation proteins. The system is fine-tuned by the constant action of numerous naturally occurring inhibitors that modulate the body's response to minor vessel injury and maintain normal blood flow. Overview of Coagulation The Vessel Wall The endothelium plays a major role in regulating membrane permeability, lipid transport, vasomotor tone, inflammation, vascular wall structure, and coagulation. The major components relevant to hemostasis are the intima lining, which is the point of contact between flowing blood and the vessel, and the muscular media, which is under the control of the autonomic nervous system. The intact vascular endothelium usually presents a thromboresistant surface. Several mechanisms are involved 1 : it dilates the vessel by producing several vasodilators, inhibits platelets and leukocyte activation, and has anticoagulant properties. Of the vasodilators known today, nitric oxide (NO) seems to have an increasingly important role in maintaining the patency of the blood flow. Since the discovery in 1980 of an endothelium-derived relaxing factor 2 and the further characterization of this compound as NO in 1987, 3 it has been shown that NO is produced not only by endothelial cells but also by most tissues in the body. The main mechanism of NO action is the activation of soluble guanylate cyclase and subsequent production of cyclic guanosine monophosphate (cGMP). 4,5 cGMP has direct effects on protein kinases and phosphodiesterases. These kinases mediate a cGMP-induced decrease in calcium in the vascular smooth muscle, leading to a decrease in vessel tone. NO also has an effect on platelet function mediated via cGMP 6 : it inhibits platelet aggregation, secretion, adhesion, and binding to fibrinogen via the GPIIb/IIIa receptor. Another substance released by the endothelium, prostacyclin (PGI2), has two main biological actions: to inhibit platelet aggregation and to serve as a powerful vasodilator. Both of these actions are mediated by cAMP. PGI2 secretion in humans is quite low, 7 making it unlikely that sufficient quantities are available for constant inhibition of platelet aggregation. Although NO and PGI2 are important relaxing factors, they cannot explain all endothelium-related relaxation. In 1984, Bolton and colleagues 8 demonstrated that a muscarinic agonist elicited endothelium-dependent hyperpolarization and relaxation of vascular smooth muscle. This phenomenon seems to be at least partially resistant to inhibitors of NO and cyclooxygenase; therefore, the existence of an endothelium-derived hyperpolarazing factor has been postulated, and this factor would induce relaxation by opening potassium channels on smooth muscle cells. Current candidates for this factor are carbon monoxide and hydrogen peroxide. 9,10 The endothelial cell also secretes ectozyme, an enzyme that catalyzes the transformation of adenosine diphosphate (ADP) to adenosine monophosphate, which is a potent platelet inhibitor. 11 Another system that the endothelium possesses to suppress the activation of coagulation at the microvascular level is the expression of a tissue factor (TF) pathway inhibitor (TFPI), which binds to activated factor X (Xa). TFPI directly inactivates factor Xa and produces feedback inhibition of the factor VIIa/TF catalytic complex. Animal studies established that TFPI functions as a natural anticoagulant that protects rabbits from intravascular coagulation, triggered by the exposure of blood to small amounts of TF. 12 As we have seen, the endothelium functions as an anticoagulant surface. It does, however, possess constricting factors that include endothelin, thromboxane A2, and angiotensin II. Platelets Under normal conditions, circulating cells such as leukocytes and platelets do not adhere to the endothelium because they circulate in the most central place of the vessel lumen and because adhesion molecules and their corresponding ligands are not expressed on the surface of platelets, leukocytes, and endothelial cells. Loss of the endothelial surface promotes platelet adhesion. Underneath the endothelium lies the intima, which is rich in connective tissue protein, capable of activating platelets to adhere to the vessel surface and subsequently aggregate. Two molecules are critical for this process: von Willebrand factor (VWF) and collagen. VWF acts as an intercellular glue that attaches platelets to the exposed subendothelium of the small vessels via the platelet receptor glycoprotein Ib. Consequently, platelets tumble over the subendothelium rather than flow by, but this is clearly incapable of acting as a barrier against the escape of blood under systemic pressure. A series of events now begin. 13 Platelets are “activated,” which means that they lose their discoid shape and start forming pseudopods, exposing procoagulant receptors (Table 1) and releasing the content of their granules. Alpha granules contain proteins such as platelet factor IV, fibrinogen, factor V, and VWF. The dense or δ granules contain adenosine triphosphate (ATP) ADP, calcium, and serotonin. The importance of these granules is manifested in the severe bleeding seen in congenital dense granules deficiencies, such as Hermansky-Pudlak syndrome. 14 Finally, all these events lead to a more stable platelet matrix, recruitment of more platelets, vasoconstriction, increased fibrin formation, and decreased fibrinolysis.Table 1: Platelet Receptors and Their FunctionThe Coagulation Cascade While this platelet response takes place, the intima simultaneously initiates activity involving the plasma proteins of the coagulation cascade. Most of the coagulation proteins are synthesized in the liver and are thus dependent on intact hepatic activity for normal synthesis and function. In addition, factor VIII (antihemophilic factor) is manufactured in extrahepatic sites (Table 2). Classically, fibrin formation has been understood to be the result of two separate pathways of activation. For conceptual and in vitro laboratory purposes, we have been taught that there is an intrinsic pathway and an extrinsic pathway, ending in a final common pathway leading to fibrin formation. There is a lot of interaction between both processes; and, in general, what is called a coagulation cascade is a series of protein or zymogen conversions to active proteins or enzymes. Factor activation proceeds in a sequential fashion, with each factor acting as a substrate in an enzymatic reaction catalyzed by the previous factor in the sequence. Enzymatic cleavage of a protein fragment activates the enzymes, which are called “serine proteases” because the active site for its protease activity is a serine aminoacid residue (Figure 1).Table 2: Coagulation FactorsFigure 1.: Coagulation cascade. HMW = high-molecular-weight; Ca ++ = calcium.The principal initiating pathway of blood coagulation in vivo is the extrinsic system, which uses components from both blood and vascular elements. This pathway begins with the release from damaged endothelium cells of a complex protein called tissue factor (TF). TF is not normally in contact with any plasma-clotting factor. After endothelial injury, TF activates coagulation factor VII. Once this factor is activated, it combines with calcium, resulting in the activation of factor X and, ultimately, in the generation of fibrin. The intrinsic system runs in close interaction with the extrinsic system and can be considered as coagulation initiated exclusively by components within the vascular system. It involves more protein-protein interactions and proceeds at a slower rate than the extrinsic pathway. The intrinsic pathway begins with the exposure of plasma to the subendothelial intima, which causes structural rearrangement of factor XII. Factor XII then causes, in a sequential and amplifying manner, the conversion of many of the coagulation proteins from an inactive zymogen form to the active catalytic state. The end result here is also fibrin formation. The description of two distinct systems for the activation of factor X is oversimplified, and there is evidence of a definite interaction between the intrinsic and extrinsic systems of coagulation. It has been demonstrated that factor VIIa of the extrinsic system can also activate factor IX of the intrinsic system, 15 and it is probable that the amount of TF generated regulates the amounts of factor X or factor IX activated by factor VIIa. 16 The combined or independent activities of the extrinsic and intrinsic pathways result in formation of factor Xa, which converts prothrombin to thrombin (IIa). In this reaction, the prothrombinase complex is formed by factors Xa, V, phospholipids, and calcium. At this point is useful to remember that platelets are actively secreting the content of α granules, which are rich in factor V and markedly increases the rate of thrombin activation. Thrombin now catalyzes the conversion of fibrinogen into fibrin, and this is accomplished in three steps. Initially, fibrin is formed in monomers and then polymers held together by weak electrostatic bonds. Finally, stabilization of the clot occurs by the action of factor XIII, which catalyzes a transamidation reaction between adjacent fibrin monomers to form the covalent bonds necessary for mechanical stability. Regulatory Mechanisms Now the vessel is sealed. When there is no longer a need for thrombus formation, there has to be a system that prevents the coagulation process from spreading to other sites where it is not needed. This is accomplished by an active enzymatic process occurring at the site of injury at the same time as the coagulation process. Thrombin is the most important coagulation modulator: it activates factors V, VIII, I, and XIII and stimulates platelet recruitment. It also prevents clot spread by inducing the release of tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator from endothelial cells. Thrombin also interacts with thrombomodulin and activates protein C. Generation of low levels of thrombin can, therefore, stimulate the formation of the inhibitory protein C/protein S complex and, in concert with antithrombin III (AT-III), block the complete activation of the coagulation cascade. AT-III is the major physiological inhibitor of blood coagulation. Small amounts of thrombin or other activated coagulation factors are rapidly inactivated by AT-III, preventing undesired generalized coagulation. AT-III blocks the action of thrombin (IIa) by covalently binding to its active site. AT-III also blocks the action of other coagulation factors (XIIa, XIa, IXa, and Xa), kallikrein, and plasmin. When there is localized major injury to the vasculature, however, the amounts of thrombin and other factors generated are large enough to override the inhibitory effect of AT-III, and hemostasis takes place. AT-III potency is increased several thousandfold by heparin. The process called fibrinolysis is responsible for degrading fibrin. The most important reaction in this process is the conversion of plasminogen into plasmin, which breaks down fibrin into small, soluble components. Plasminogen is synthesized in the liver and is present in the blood, saliva, and tears. The major source of plasminogen activator in physiological thrombolysis is the vascular endothelium. 17 In this process, t-PA, plasminogen, and plasmin bind to fibrin of the forming clot, and fibrinolysis occurs in a three-step fashion, resulting in the production of fragments D and E. The plasmin degradation products of cross-linked fibrin can be distinguished from those of fibrinogen by the presence of the D dimer, which is derived from the cross-linked gamma-gamma chains of fibrin. The final breakdown products also inhibit platelet adhesion and aggregation. Laboratory Tests of Hemostasis Anesthesiologists have to make decisions about coagulation tests in their patients on a daily basis. Some questions they are faced with are which tests should be ordered, when to order them, and what to do with an abnormal result, even if the test was ordered by another care provider. To clarify these questions, the most common coagulation tests used in clinical practice are briefly reviewed. Platelet Count The evaluation of platelet function is still mostly restricted to quantitative rather than qualitative assays. These tests are most often performed by electronic particle counters. The accuracy and precision of these determinations are linear in most instruments for counts ranging from 103 and 106 platelets/mm3. Quantitative manual confirmation usually is not necessary, but qualitative morphological assessment is desirable, especially when certain conditions, such as pseudothrombocytopenia caused by ethyenediaminetetraacetic acid-induced clumping of platelets, can fool an electronic counter. The clinical significance of different degrees of thrombocytopenia varies. In general, spontaneous bleeding rarely occurs with a platelet count >20,000/ mm3. A patient with a platelet count between 20,000 and 100,000 will not have spontaneous bleeding but may have bleeding associated with surgery and trauma. A platelet count >100,000/mm3, assuming that function is normal, is adequate for any challenge of hemostasis. It is important to remember that young and rapidly turning-over platelets are hemostatically very effective, so disorders causing peripheral platelet destruction with a normal bone marrow may cause less bleeding than the thrombocytopenia of inadequate bone marrow production. The lack of any tests to assess platelet function led to the development of the platelet-activating clotting factor test (PACT) (Coulter Electronics Hialeah, FL) and the PFA100 (Dade International, Miami, FL). Several studies evaluated these devices with and with and bleeding in and however, to be less than in patients For a it was that this test the of the hemostatic platelets and endothelium. the however, numerous studies clearly that bleeding time is not an of bleeding during in patients with a bleeding to the of bleeding time so many that it cannot be The test is also by in and and it has also been shown that the bleeding time from an in the not bleeding in the body. Consequently, the bleeding time has no role in the preoperative evaluation of a patient with a and bleeding even in those patients time by in the final common pathway of coagulation as as the presence of factor the extrinsic pathway. The when levels of factor V, and X of normal and when prothrombin levels are less than of The is used to The is also by of fibrinogen and very levels of heparin. of the is an of an extrinsic or common pathway It may be to a of a factor in congenital or a of factors, as is the in most of the disorders of coagulation. The clinical significance of this test is time the of the intrinsic pathway of coagulation and thus is to of all of the factors other than and The activity level of the factors has to be less than of normal to the This test is in the presence of certain and is often used to This test is in preoperative is an and its level may be normal in response to or There are patients have of fibrinogen, but the of this is Coagulation and Their Tests When the of both the and are normal, it is unlikely that there are in any of the coagulation causes for in the or include intravascular coagulation liver a congenital factor factor VIII to von a or specific coagulation factor of these is now as as the of their by and in preoperative patients with a bleeding There are a of factors to and of these should be therefore, in coagulation tests are unlikely to be the of The of liver with is the time liver is severe enough to cause there are enough clinical and of liver function tests such as and The of or is it is that these or this from their care usually the and, if very also the a patient has not a the of by means of and is a a of a normal is however, then preoperative is not to be for the of this When there is of factors VIII, or the most common of which are of factors and the will be and the Factor is most common in of and is not associated with clinical of have abnormal even when with and they do not need plasma any In the even the can the of abnormal bleeding not on the result of the test but on the presence or not of a or of Factor XII is very common among of As factor XII the even when there is complete of this there is not an associated increased of Factor VIII and factor IX are responsible for A and It is to these because these patients are to even with minor very in factor VIII may also in patients with von the bleeding is for only or this may be The may be useful in the of von in factor the but not the in factor V, and X both of these are so that it would of to the with these during preoperative anticoagulant will the with this or an have an increased of and there is not a bleeding these cause thrombocytopenia or low thrombin levels and, a will have a only if the is also For this the is more than the in this A resulting from anticoagulant may cause a surgery to be or with The final to in the of a and is a coagulation factor inhibitor. to factors VIII and IX can and will the At only are with spontaneous factor VIII inhibitor to surgery during the same period. to other factors are several less In for patients with a bleeding the principal of the is to factor and XII deficiencies, the presence of or factor VIII associated with von causes of a with a normal are which to the of this test in the preoperative to the The most important to remember about the patient is that no test can for a and a The should include the there any or of a bleeding the patient surgery or there any of or there any of or vascular is the patient or has the patient on any A should any or should be by of or any other of liver of the and surface is In a of preoperative and colleagues that the platelet count was low in less than of and further rarely any The and abnormal in and of and a large of patients and that the no to the or of in a but it was a of in the Their preoperative coagulation to patients with active known or bleeding disorders of liver or other associated with and to patients may with normal coagulation. series in the that preoperative coagulation in an any or the or When an challenge to the hemostatic system is all patients a platelet and if for no other than to The of coagulation tests by different and it is dependent on the level of a or At a of common and clinical practice has led to the development of the shown in for preoperative coagulation = prothrombin = = von Willebrand factor. with of is as the of one blood within a period. 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