Any disruption of vascular endothelium is a potent stimulus to clot formation. As a localized process, clotting acts to seal the break in vascular continuity, limit blood loss, and begin the process of wound healing. Prevention of an exuberant response that would result in pathologic thrombosis involves several counterbalancing mechanisms, including anticoagulant properties of intact endothelial cells, circulating inhibitors of activated coagulation factors, and localized fibrinolytic enzymes. Most abnormalities in hemostasis involve a defect in one or more of the integrated steps in this coagulation process. It is important, therefore, to understand the physiology of hemostasis.
Fifty years ago, two groups simultaneously described the “waterfall” or “cascade” model of soluble coagulation. The cascade model dovetailed well with the clotting assays that were developed at that time to guide warfarin and heparin dosing, and these tests came to be the gold standard for measuring soluble coagulation. Although this cascade model continues to be useful for interpretation of laboratory clotting tests, it does not accurately represent in vivo clotting.
In vivo coagulation follows exposure of the blood to a source of tissue factor (TF), typically on subendothelial cells following damage to a blood vessel. The intrinsic, or contact, pathway of coagulation has no role in these earliest clotting events. TF-initiated coagulation has two phases, one an initiation phase and a second, the propagation phase. The initiation phase begins as exposed TF binds to factor VIIa, picomolar amounts of which are present in the circulation. This VIIa-TF complex catalyzes the conversion of small amounts of factor X to Xa, which in turn generates similarly small amounts of thrombin.
The seemingly trivial amount of thrombin formed during the initiation phase triggers the propagation phase, which fosters explosive thrombin generation in abundance. Thrombin ramps up its own formation by activating platelets and factors (FV, FVIII), setting the stage for formation of the FVIIIa–IXa complex, a pivotal point in the propagation phase. Formation of this FVIIIa–IXa complex allows FXa generation to switch from a TF-VIIa complex–catalyzed reaction to one produced by the intrinsic Xase pathway. This switch is of enormous kinetic advantage, with the intrinsic Xase complex exhibiting 50-fold higher efficiency at Xa generation. The bleeding diathesis associated with hemophilia, with its intact initiation phase and absent propagation phase, is testament to the hemostatic importance of the propagation phase.
The commonly used laboratory tests of soluble coagulation only measure the kinetics of the initiation phase. The prothrombin time (PT) and activated partial thromboplastin time (aPTT) both have as endpoints the first appearance of fibrin gel, which occurs after completion of less than 5% of the total reaction. These tests are sensitive at detecting severe deficiencies in clotting factors, for example, hemophilia, and in guiding warfarin/heparin therapy; however, they do not model the sequence of events necessary for hemostasis and do not necessarily predict the risk of intraoperative bleeding.
In the venous circulation, the kinetic advantage of coagulation cascade assembly on the platelet surface is readily apparent; however, relatively small numbers of platelets are needed to fulfill this function. To increase the risk of venous bleeding, the platelet count must decrease to very low levels, that is, less than 10,000/μL. This contrasts sharply with the arterial circulation, in which the minimum platelet count needed to ensure hemostasis for operative procedures is at least five times that number (see “Arterial Coagulation” below).
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Hereditary deficiency of factor VII is a rare autosomal recessive disease with highly variable clinical severity. Only homozygous deficient patients have factor VII levels generally low enough (<15%) to have symptomatic bleeding. These patients are easily recognized from their unique laboratory pattern of a prolonged prothrombin time (PT) but normal partial thromboplastin time (PTT).
The treatment of a single-factor deficiency state depends on the severity of the deficiency. Most patients with mild to moderate factor VII deficiency can be treated with infusions of fresh frozen plasma (FFP). Patients with factor VII levels less than 1% generally require treatment with a more concentrated source of factor VII. The preferred product for prophylaxis of patients with factor VII deficiency is Proplex T (factor IX complex) because of its high level of factor VII. Treatment of factor VII deficiency with active bleeding is either Proplex T or the activated form, recombinant factor VIIa (NovoSeven), usually beginning with a dose of 20 to 30 μg/kg, with redosing according to prothrombin time results (see “Acquired Factor VIII or IX Inhibition” for comprehensive discussion of recombinant factor VIIa).
Congenital deficiencies in factors X, V, and prothrombin are also inherited as autosomal recessive traits and severe deficiencies are quite rare, on the order of one in one million live births. Patients with severe deficiencies in any of these factors demonstrate prolongations of both the PT and PTT. Patients with congenital factor V deficiency may also have a prolonged bleeding time because of the relationship between factor V and platelet function in supporting clot formation.
Deficiencies in factors X, V, and prothrombin are can be corrected with FFP. The concentration of the vitamin K–dependent factors in FFP is approximately the same as that of normal plasma in vivo. Therefore, to obtain a significant increase in the level of any factor, a considerable volume of FFP must be infused. As a rule of thumb, at least four to six units of FFP are needed to attain a 20% to 30% increase in any missing factor level. This level represents a considerable volume of plasma (800–1200 mL) and may present a significant cardiovascular challenge to the patient. Moreover, the duration of effectiveness of this replacement therapy depends on the turnover time of each factor, which then dictates how often repeated infusions of FFP will be needed to maintain a factor level. Factor V is stored in platelet granules, and, particularly in a bleeding patient, platelet transfusion is an ideal alternative way to express deliver the missing factor V to the site of bleeding.
For a severe deficiency in a patient facing surgery with a significant risk of blood loss, several prothrombin complex concentrates (PCCs) are commercially available. The advantage of these products is that factor levels of 50% or higher can be achieved without the risk of volume overload. The disadvantages of PCCs are the risk induction of widespread thrombosis, thromboembolism, and disseminated intravascular coagulation (DIC). It is also important to recognize the variation in factor levels in the different products. Konyne-HT and Bebulin VH (factor IX complex) contain factors X and prothrombin in roughly equivalent amounts, while the prothrombin levels in Pronine-HT are more than twice the levels of factor X.
Defects in the propagation phase of coagulation convey a significant bleeding tendency. Some of these propagation phase defects are associated with an isolated prolongation of the activated partial thromboplastin time (aPTT). The X-linked recessive disorders hemophilia A and B are the principal examples of this type of abnormality. A marked reduction in either factor VIII or IX is associated with spontaneous and excessive hemorrhage, especially hemarthroses and muscle hematomas. A deficiency in factor XI, which is encoded by a gene on chromosome 4, also prolongs the aPTT but typically results in a less severe bleeding tendency. Not all deficiencies causing prolongation of the aPTT are associated with bleeding, however. The initial activation stimulus for this laboratory test is surface contact activation of factor XII (Hageman factor) to produce XIIa. This reaction is facilitated by the presence of high molecular weight kininogen and the conversion of prekallikrein to the active protease kallikrein, and deficiency in any of these three factors causes prolongation of the aPTT. However, as described in the Normal Hemostasis section these contact activation factors play no role in either the initiation phase or the propagation phase of clotting in vivo; thus, deficiencies of factor XII, high molecular weight kininogen, and prekallikrein are not associated with clinical bleeding. Patient with deficiencies in these particular factors require no special management except alteration of their coagulation testing to allow accurate measurement of physiologic factors critical to in vivo hemostasis.
The factor VIII gene is a very large, 186-kb gene on the X chromosome. The most severe hemophiliacs generally have an inversion or deletion of major portions of the X chromosome genome or a missense mutation, resulting in factor VIII activity of less than 1% of normal. Other mutations, including point mutations and minor deletions, generally result in milder disease with factor VIII levels greater than 1%. In some patients, a functionally abnormal protein is produced, which causes a discrepancy between the immunologic measurement of factor VIII antigen (protein) and the coagulation assay of factor VIII activity.
As a rule of thumb, clinical severity of hemophilia A is best correlated with the factor VIII activity level. Severe hemophiliacs have factor VIII activity levels less than 1% of normal (<0.01 U/mL) and are usually diagnosed during childhood because of frequent, spontaneous hemorrhages into joints, muscles, and vital organs. They require frequent treatment with factor VIII replacement and even then are at risk of developing a progressive, deforming arthropathy.
Factor VIII levels as low as 1% to 5% of normal are enough to reduce the severity of the disease. These patients are at increased risk of hemorrhage with surgery or trauma but have much less difficulty with spontaneous hemarthroses or hematomas. Patients with factor levels between 6% and 30% are only mildly affected and may go undiagnosed well into adult life. They are at risk, however, for excessive bleeding with a major surgical procedure. Female carriers of hemophilia A can also be at risk with surgery. Lyonization of the X chromosome is not purely random, so that 10% of female carriers can have factor VIII activity less than 30%.
Severe hemophilia A patients have a significantly prolonged PTT, whereas with milder disease, the PTT may be only a few seconds longer than normal. Since the tissue factor VII–dependent (extrinsic) pathway of laboratory clotting is intact, the PT is normal.
Whenever major surgery is necessary in a patient with hemophilia A, the factor VIII level must be brought to near normal (100%) for the procedure. This requires an initial infusion of 50 to 60 U/kg (3500–4000 units in a 70-kg patient). Since the half-life of factor VIII is approximately 12 hours in adults, repeated infusions of 25 to 30 U/kg every 8 to 12 hours will be needed to keep the plasma factor VIII level above 50%. When lower doses (20–30 U/kg) are used, mean postinfusion plasma levels will peak at approximately 30% to 50% (for each unit per kilogram infused, the plasma VIII level will increase ∼2%). In children, the half-life of factor VIII may be as short as 6 hours, necessitating more frequent infusions and laboratory assays to confirm efficacy. Peak and trough factor VIII levels should be measured to confirm the appropriate dosing level and dosing interval. Therapy must be continued for up to 2 weeks to avoid postoperative bleeding that disrupts wound healing. Longer periods of therapy may be required in patients who undergo bone or joint surgery. In this situation, 4 to 6 weeks of replacement therapy may be needed.
Up to 30% of severe hemophilia A patients exposed to factor VIII concentrate or recombinant product will eventually develop inhibitor antibodies, some within 10 to 12 days of first exposure. Newer recombinant preparations have not resulted in a reduction in the incidence of inhibitor formation. (See “Acquired Factor VIII or IX Inhibitors” for a complete discussion of patients with this complication.)
Hemophilia B patients have a similar clinical spectrum of disease as is found with hemophilia A. Factor IX levels of less than 1% are associated with severe bleeding, whereas more moderate disease is seen in patients with levels of 1% to 5%. Patients with factor IX levels of between 5% and 40% generally have very mild disease. Milder hemophiliacs (>5% factor IX activity) may not be detected until surgery is performed or the patient has a dental extraction. Similar to the laboratory findings with hemophilia A, hemophilia B patients have a prolonged PTT and a normal PT.
General guidelines for managing hemophilia B patients do not differ significantly from those for hemophilia A patients. Recombinant/purified product or factor IX–PCC are used to treat mild bleeding episodes or as prophylaxis with minor procedures. However, a note of caution is needed when using factor IX–PCC preparations, which can contain activated clotting factors, at higher doses. When given in amounts sufficient to increase factor IX levels to 50% or greater, there is an increased risk of thromboembolic complications, especially in patients undergoing orthopedic procedures. Therefore, it is essential to use only recombinant IX in treating patients undergoing major orthopedic surgery and those with severe traumatic injuries or liver disease.
As for factor VIII replacement, purified factor IX concentrates or recombinant IX are used over several days to treat bleeding in hemophilia B. Because of absorption to collagen sites in the vasculature, recovery of factor IX is approximately half that of factor VIII, making dosing approximately double that for factor VIII concentrates. Therefore, in order to achieve a 100% plasma level in a severe hemophilia B patient, a dose of 100 U/kg (7000 units in a 70-kg patient) needs to be administered. At the same time, factor IX has a half-life of 18 to 24 hours, so repeated infusions at 50% of the original dose every 12 to 24 hours are usually sufficient to keep the factor IX plasma level above 50%. Like factor VIII recommendations, doses of 30 to 50 U/kg will generally give mean factor IX levels of 20% to 40%, which is adequate for less severe bleeds.
Hemophilia A patients are at significant risk of developing circulating inhibitors to factor VIII, with an incidence of 30% to 40% in patients severely deficient in factor VIII. Hemophilia B patients are less likely to develop an inhibitor to factor IX; only 3% to 5% of patients will become affected during their lifetime. A severe hemophilia-like syndrome can occur in genetically normal individuals secondary to the appearance of an acquired autoantibody to either factor VIII or, very rarely, to factor IX. These patients are usually middle-aged or older with no personal or family history of abnormal bleeding who present with the sudden onset of severe, spontaneous hemorrhage.
A test known as a mixing study is required to detect the presence of an inhibitor. This study is performed by mixing patient plasma and normal plasma in a 1:1 ratio to determine whether the prolonged PTT shortens. The mixing study of a classic hemophilia A patient with a deficiency in factor VIII activity but no circulating VIII inhibitor will usually show a shortening of the PTT to within 4 seconds or less of the normal PTT control. In contrast, a patient with a factor VIII inhibitor will not correct the PTT to that extent, if at all. It is also important to quantitate the factor VIII activity level and, using a modification of the PTT called the Bethesda assay method to measure the inhibitor titer (Bethesda units of inhibitor/milliliters of plasma). In general, factor VIII inhibitor patients fall into one of two groups according to the level of inhibitor. High responders (>10 U/mL) demonstrate a marked inhibitor response after any factor infusion, such that levels cannot be neutralized by high-dose replacement therapy. The response is typical of induction of an alloantibody, and the patient is constantly at risk of an anamnestic response when re-exposed to factor antigen. In contrast, low responders develop and maintain relatively low levels of inhibitor that are constant despite repeated exposure to factor VIII replacement.
Management of the hemophilia A patient with an inhibitor will vary according to whether the patient is a high or low responder. Low responders have titers less than 5 to 10 Bethesda U/mL and do not show anamnestic responses to factor VIII concentrates, whereas the high responders can have titers of several thousand Bethesda units and dramatic anamnestic responses to therapy. Patients in the low-responder category can usually be managed with factor VIII concentrates. Larger initial and maintenance doses of factor VIII are required and frequent assays of factor VIII levels are essential to guide therapy. When the titer of the factor VIII inhibitor exceeds 5 to 10 U/mL (high responder category), treatment with factor VIII concentrates is not feasible. Major life-threatening bleeds can be treated with bypass products such as activated PCCs (Autoplex T, FEIBA), or recombinant factor VIIa (NovoSeven). Treatment with activated PCCs runs the risk of initiating DIC or widespread thromboembolism, so recombinant factor VIIa is becoming the treatment of choice for acquired inhibitors. As discussed in the Normal Hemostasis section, although hemophiliacs can generate Xa via factor VIIa binding to tissue factor in the initiation phase, in the propagation phase, they are unable to generate Xa and the subsequent thrombin burst on the platelet surface in the absence of factor VIII or IX. Recombinant factor VIIa in high concentrations appears to essentially replace the VIIIa/IXa Xase complex requirement by binding to the platelet surface and increasing both Xa generation and the thrombin burst, unaffected by factor VIII or IX inhibitors. For active bleeding of patients with inhibitors, a dose of 90 to 120 μg/kg intravenously is recommended every 2 to 3 hours until hemostasis is achieved. Continuous infusions of factor VIIa have also been used to manage patients undergoing surgery. Laboratory monitoring will demonstrate a shortening of the PT, but this may not correlate with the clinical control of hemostasis. Although the thrombin formed via VIIa is not as strong as that seen with factor VIII therapy, recombinant VIIa therapy is successful in controlling bleeding in more than 80% of inhibitor patients. The risk of serious side effects, including widespread or local thrombosis, appears to be acceptable.
Severe hemophilia B patients are also at risk of developing a factor IX inhibitor, but the incidence is far less than in hemophilia A. A modified Bethesda assay is similarly used to quantitate the inhibitor level. Usually, factor IX inhibitor patients can be managed acutely using recombinant VIIa or the PCC products noted above.
Patients who develop an autoantibody to factor VIII or IX without a history of hemophilia can present with life-threatening hemorrhage and may exhibit very high inhibitor levels in excess of several thousand Bethesda units. Treatment with recombinant factor VIIa or an activated prothrombin concentrate is required; factor VIII or IX alone will not be effective.
The only other defect causing an isolated prolongation of the PTT and a bleeding tendency is factor XI deficiency (Rosenthal's disease). It is inherited as an autosomal recessive trait and, therefore, affects males and females equally. It is much rarer than either hemophilia A or B, but it affects up to 5% of Jews of Ashkenazi descent from Eastern Europe. Generally, the bleeding tendency, if present at all, is quite mild and may only be apparent following a surgical procedure. Hematomas and hemarthroses are very unusual, even in those patients with factor XI levels of less than 5%. Patients homozygous for the type II mutation (Glu117Stop) have very low levels of factor XI and can develop a factor XI inhibitor when exposed to plasma therapy.
The treatment of factor XI deficiency depends on the severity of the deficiency and bleeding history. Most patients' factor XI deficiency can be treated with infusions of FFP. Treatment of factor XI deficiency with active bleeding is either PCCs or recombinant factor VIIa (NovoSeven), usually beginning with a dose of 20 to 30 μg/kg, with redosing according to prothrombin time results. Management of factor XI inhibitors is comparable to that of hemophilia A and B inhibitors and is discussed under “Acquired Factor VIII or IX Inhibitors.”
Congenital abnormalities in fibrinogen production will obviously interfere with the final step in the generation of a fibrin clot. Decreased levels of fibrinogen, either hypofibrinogenemia or afibrinogenemia, are relatively rare conditions inherited as autosomal recessive traits. Patients with afibrinogenemia have a severe bleeding diathesis with both spontaneous and posttraumatic bleeding. Since the bleeding can begin during the first few days of life, this condition may be initially confused with hemophilia. Hypofibrinogenemic patients usually do not have spontaneous bleeding but may have difficulty with surgery. Severe bleeding can be anticipated in patients with plasma fibrinogen levels below 50 to 100 mg/dL.
A more common defect is the production of an abnormal fibrinogen. Fibrinogen is synthesized in the liver under the control of three genes on chromosome 4. More than 300 different mutations producing dysfunctional and, at times, reduced amounts of fibrinogen have been reported, resulting in a dysfibrinogenemia. Many of these mutations are inherited as autosomal dominant traits. The clinical presentation of dysfibrinogenemia is highly variable. Patients who demonstrate both a reduced amount and a dysfunctional fibrinogen (hypodysfibrinogenemia) usually exhibit excessive bleeding. This is also true for a few families who are homozygous for dysfibrinogenemia. Most dysfibrinogenemic patients, however, appear to be heterozygous for the trait, and, although they have abnormal coagulation tests, most do not have a bleeding tendency. Overall, approximately 60% of dysfibrinogenemias are clinically silent, whereas the remainder can present with either a bleeding diathesis or a paradoxically thrombotic tendency, in equal measure. A small number of dysfibrinogenemias have been associated with spontaneous abortion and poor wound healing.
Laboratory evaluation of fibrinogen involves measurements of both fibrinogen concentration and function. The most accurate quantitative measurement of total fibrinogen protein is provided by immunoassay or a protein precipitation technique. Other screening tests for fibrinogen dysfunction include the thrombin time (TT) and clotting time using a venom enzyme such as reptilase. Both are sensitive to fibrinogen dysfunction. Definitive diagnosis and subclassification of dysfibrinogenemia require fibrinopeptide chain analysis by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and amino acid sequencing.
Most patients with dysfibrinogenemia have no clinical disease and, therefore, do not require therapy. For those who are symptomatic or are at risk of bleeding with surgery, cryoprecipitate therapy is warranted. To increase the fibrinogen level by at least 100 mg/dL in the average-size adult, 10 to 12 units of cryoprecipitate should be infused, followed by two to three units each day (fibrinogen is catabolized at a rate of 25% per day). By contrast, dysfibrinogenemia patients with a thrombotic tendency will require long-term anticoagulation.
Dysfibrinogenemia
A more common defect is the production of an abnormal fibrinogen. Fibrinogen is synthesized in the liver under the control of three genes on chromosome 4. More than 300 different mutations producing dysfunctional and, at times, reduced amounts of fibrinogen have been reported, resulting in a dysfibrinogenemia. Many of these mutations are inherited as autosomal dominant traits. The clinical presentation of dysfibrinogenemia is highly variable. Patients who demonstrate both a reduced amount and a dysfunctional fibrinogen (hypodysfibrinogenemia) usually exhibit excessive bleeding. This is also true for a few families who are homozygous for dysfibrinogenemia. Most dysfibrinogenemic patients, however, appear to be heterozygous for the trait, and, although they have abnormal coagulation tests, most do not have a bleeding tendency. Overall, approximately 60% of dysfibrinogenemias are clinically silent, whereas the remainder can present with either a bleeding diathesis or a paradoxically thrombotic tendency, in equal measure. A small number of dysfibrinogenemias have been associated with spontaneous abortion and poor wound healing.
Laboratory evaluation of fibrinogen involves measurements of both fibrinogen concentration and function. The most accurate quantitative measurement of total fibrinogen protein is provided by immunoassay or a protein precipitation technique. Other screening tests for fibrinogen dysfunction include the thrombin time (TT) and clotting time using a venom enzyme such as reptilase. Both are sensitive to fibrinogen dysfunction. Definitive diagnosis and subclassification of dysfibrinogenemia require fibrinopeptide chain analysis by sodium dodecyl sulfate–polyacrylamide gel electrophoresis and amino acid sequencing.
Anesthetic Considerations
Most patients with dysfibrinogenemia have no clinical disease and, therefore, do not require therapy. For those who are symptomatic or are at risk of bleeding with surgery, cryoprecipitate therapy is warranted. To increase the fibrinogen level by at least 100 mg/dL in the average-size adult, 10 to 12 units of cryoprecipitate should be infused, followed by two to three units each day (fibrinogen is catabolized at a rate of 25% per day). By contrast, dysfibrinogenemia patients with a thrombotic tendency will require long-term anticoagulation.
Stability of the fibrin clot is hemostatically important. Factor XIII (fibrin-stabilizing factor) deficiency is a rare autosomal recessive disorder with an estimated prevalence of one in five million. Patients present at birth with persistent umbilical or circumcision bleeding. Adult patients demonstrate a severe bleeding diathesis, characterized by recurrent soft-tissue bleeding, poor wound healing, and a high incidence of intracranial hemorrhage. Typically, the bleeding is somewhat delayed based on the role of factor XIII in stabilizing the fibrin clot. Blood clots form but are weak and unable to maintain hemostasis. Fetal loss in women with factor XIII deficiency can approach 100%, suggesting a critical role for this factor in maintaining pregnancy.
Factor XIII deficiency should be considered in a patient with a severe bleeding diathesis who has otherwise normal coagulation screening tests, including PT, PTT, fibrinogen level, platelet count, and bleeding time. Clot dissolution in 5M urea can be used as a screen. Definitive diagnosis after an abnormal screen can be accomplished by enzyme-linked immunosorbent assay. Patients at risk of severe hemorrhage have factor XIII levels of 1% of normal. Heterozygotes (factor XIII levels of approximately 50%) usually exhibit no bleeding tendency.
Factor XIII–deficient patients can be treated with FFP, cryoprecipitate, or a plasma-derived factor XIII concentrate, Fibrogammin P. Preoperative prophylaxis is possible using intravenous injections of 10 to 20 U/kg at 4- to 6-week intervals depending on the patient's preinfusion plasma factor XIII level. Acute hemorrhage should be treated with an infusion of 50 to 75 U/kg body weight. Factor XIII has a long circulating half-life of 7 to 12 days, and adequate hemostasis is
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