CHAPTER 115 CLASSIFICATION, CLINICAL MANIFESTATIONS AND EVALUATION OF DISORDERS OF HEMOSTASIS
CHAPTER 115 CLASSIFICATION, CLINICAL MANIFESTATIONS AND EVALUATION OF DISORDERS OF HEMOSTASIS
BARRY S. COLLER
Classification of Hemostatic Disorders
The Bleeding History
Evaluation Based on the Bleeding History and Initial Hemostatic Tests
Preoperative Assessment of Hemostasis
Specific Assays for Establishing the Diagnosis
Inhibitors to Coagulation Factors
Platelet Function Disorders
Evaluation of a hemostatic disorder is commonly initiated when: (1) A patient or a referring physician suspects a bleeding tendency; (2) a bleeding tendency is discovered in one or more family members; (3) an abnormal coagulation assay result is obtained in an individual as part of a routine examination; (4) an abnormal assay result is obtained in a patient during preparation for surgery; (5) a patient has unexplained diffuse bleeding during or after surgery or following trauma. The evaluation of a possible hemostatic disorder in each one of these scenarios is a stepwise process that requires knowledge of the various classes of hemostatic disorders commonly found under the particular circumstances. The history of the patient, the physical examination, and an initial set of hemostatic tests usually enable one to establish a tentative diagnosis. More specific tests, however, are commonly necessary to make a definitive diagnosis. In this chapter these steps will be reviewed.
Acronyms and abbreviations that appear in this chapter include: APTT, activated partial thromboplastin time; BT, bleeding time; DIC, disseminated intravascular coagulation; ELISA, enzyme-linked immunosorbent assay; PT, prothrombin time; RCF, ristocetin cofactor.
CLASSIFICATION OF HEMOSTATIC DISORDERS
Hemostatic disorders can conveniently be classified as either hereditary or acquired (Table 115-1). Alternatively, they can be classified according to the mechanism of the defect. Of the acquired disorders, the thrombocytopenias are by far the most frequent entities encountered. Thrombocytopenias can result from reduced production of platelets, excessive destruction caused by antibodies or disseminated intravascular coagulation, or pooling of platelets in the spleen as in hypersplenism (see Chap 117).
TABLE 115-1 CLASSIFICATION OF DISORDERS OF HEMOSTASIS
THE BLEEDING HISTORY
The bleeding history is a crucial element in the evaluation of a patient with a hemorrhagic disorder, helping to define both the subsequent diagnostic approach as well as the likelihood of future bleeding. Eliciting and interpreting all of the relevant information requires a systematic and methodical approach. The following points are worth considering.
Patients vary in their responses to hemorrhagic symptoms, with some ignoring significant symptoms and others being very sensitive to even minor symptoms. Thus, when asked in standardized questionnaires, many normal, healthy people indicate that they have excessive bleeding or bruising.1,2 Women are more likely to respond that they have excessive bleeding or bruising than men.
Patients with severe hemorrhagic disorders invariably have very abnormal bleeding histories.
The diagnostic value of any specific symptom varies in the different disorders, and so it is important to recognize typical patterns of bleeding (Table 115-2). Thus, unprovoked hemarthroses and muscle hemorrhages suggest one of the hemophilias, whereas mucocutaneous bleeding (epistaxis, gingival bleeding, and menorrhagia) are more characteristic of patients with qualitative platelet disorders, thrombocytopenia, or von Willebrand disease.
TABLE 115-2 CLINICAL MANIFESTATIONS TYPICALLY ASSOCIATED WITH SPECIFIC HEMOSTATIC DISORDERS
It is important to assess the extent of hemorrhage against the background of any trauma or provocation that may have elicited the hemorrhage. If a patient has never had a significant hemostatic challenge such as surgery, trauma, or childbirth, the lack of a significant bleeding history is much less valuable in excluding a mild hemorrhagic disorder. Thus, for example, a significant percentage of patients with mild von Willebrand disease or mild forms of hemophilia may have negative bleeding histories,1 even though they may be at considerable risk of excessive bleeding after surgery or other interventions. Thus, one needs to consider these diagnoses even in elderly patients if their first severe hemostatic challenge occurs at that age.
It is valuable to try to obtain objective confirmation of the subjective information conveyed in the bleeding history. Objective data include: (a) previous hospital or physician visits for bleeding symptoms, along with the results of previous laboratory evaluations, (b) previous transfusions of blood products, and (c) a history of anemia and/or previous treatment with iron.
Although self-administered questionnaires may provide useful background information, they are not a substitute for a dialogue between physician and patient. Thus, history taking in general, but most especially in the often subtle histories related to hemostatic disorders, is an intellectually active process involving data collection, hypothesis development, new question formulation, additional data gathering, and new hypothesis development.
A medication history is a crucial component of the bleeding history, with particular attention to nonprescription drugs, such as aspirin, that may affect bleeding symptoms. A medication history is especially important in patients with thrombocytopenia, since drug-induced thrombocytopenia is common (see Chap. 117 and Table 115-1). Medication may also affect hemostasis through effects on the liver or kidney (see Chap. 125). The increased use of herbal and alternative medicines poses particular problems since patients may not readily share information about what they are taking and the dose they are taking of any particular active ingredient may be very difficult to determine. Resources for assessing the effects and side effects of such therapies are limited, but books (e.g., PDR for herbal medicines), papers,3 and internet-based databases4 are now available.
A nutrition history should be obtained to assess the likelihood of: (a) vitamin K deficiency, especially if the patient is also taking broad spectrum antibiotics; (b) vitamin C deficiency, especially if the patient has skin bleeding consistent with scurvy; and (c) general malnutrition and/or malabsorption. In patients on oral anticoagulants, it is important to counsel the patient to try to maintain a consistent level of vitamin K intake. Thus, major alterations in diet should be discouraged unless accompanied by more frequent monitoring of the prothrombin time. Similarly, new vitamins and food supplements should be checked for their vitamin K content.
Several tissues have high local levels of fibrinolytic activity, including the urinary tract, endometrium, and mucous membranes of the nose and oral cavity. These sites are particularly likely to have prolonged oozing of blood after trauma in patients with hemostatic abnormalities, and excessive bleeding following tooth extraction is one of the most common manifestations (see below). Bleeding isolated to a single organ or system (e.g., hematuria, hematemesis, hemoptysis) is less likely to be due to a hemostatic abnormality than a local cause such as a neoplasm, an ulcer, or angiodysplasia, and thus one should perform a careful anatomic evaluation of the involved organ or system.
Bleeding or excessive hemorrhage may result from blood vessel disorders as well as disorders of platelets or coagulation proteins. Thus, it is important to consider hereditary hemorrhagic telangiectasias, Cushing’s disease, scurvy, Ehlers-Danlos syndrome, and vasculitis in the differential diagnosis. Many primary dermatologic disorders may also have a purpuric or hemorrhagic component, and these need to be considered as well (see Chap. 121).
A family history is particularly important when hereditary disorders are considered. Patients will not usually spontaneously offer a history of consanguinity, and so specific inquiry should be made about this possibility. A diagram of the patient’s genealogic tree, extending back at least one generation, should be included to document that genetic disorders were considered. A sex-linked pattern of inheritance is consistent with hemophilia A or B (see Chap. 123); an autosomal dominant pattern is characteristic of most forms of von Willebrand disease; and an autosomal recessive pattern is typical for all other coagulation factor deficiencies (see Chap. 122), inherited platelet disorders (see Chap. 119), and the rare severe, type 3 von Willebrand disease. Population genetic information may also be helpful, as for example, the higher prevalence of factor XI deficiency in Ashkenazi Jews (see Chap. 122).
The history should include information on diseases and organs that may also affect hemostasis, such as cirrhosis, renal insufficiency, essential thrombocythemia, acute leukemia, systemic lupus erythematosus, and Gaucher disease (Table 115-1).
Individual hemorrhagic symptoms often require detailed analysis before one can judge their significance with regard to the patient’s diagnosis or proper therapy. Some of the more common symptoms are discussed below.
Epistaxis is one of the most common symptoms of platelet disorders and von Willebrand disease; it also is the most common symptom of hereditary hemorrhagic telangiectasias. In the latter condition, epistaxis almost always becomes more severe with advancing age. Epistaxis is not uncommon in normal children, but it usually resolves before puberty. Dry air heating systems can provoke epistaxis even in otherwise normal individuals. If bleeding is confined to a single nostril, it is more likely due to a local vascular problem than a systemic coagulopathy.
Gingival hemorrhage is also very common in patients with both qualitative and quantitative platelet abnormalities and von Willebrand disease. Occasional gum bleeding occurs in normal individuals, especially with tooth brushing using a hard bristle tooth brush and dental hygiene procedures, and thus it may be difficult to establish whether the bleeding is excessive. Even frequent gingival hemorrhage can occur in individuals with normal hemostasis if they have gum disease.
Oral mucous membrane bleeding in the form of blood blisters is a common manifestation of severe thrombocytopenia. It usually has a predilection for sites where teeth may traumatize the inner surface of the cheek.
Skin hemorrhage in the form of petechiae, purpura, and ecchymoses are common manifestations of hemostatic disorders, but skin hemorrhage is also common among individuals without hemostatic disorders. Excessive bruising is more common in women than men; moreover, women frequently note that the severity of their bruising varies with the phase of their menstrual cycle, although the most severe phase of the cycle may differ in different women. When such bruising is an isolated finding and no systemic bleeding diathesis is present, the condition is called purpura simplex. Features that help establish the severity of the skin hemorrhage include the size of the bruises; their frequency; whether they occur spontaneously or only with trauma; and their appearance on regions of the body that usually are not traumatized, such as the trunk and back. The color of the bruise may also yield information, with red bruises on the extensor surfaces of the arms and hands indicative of loss of supporting tissues, as is found in Cushing syndrome, gluococorticoid therapy, senile purpura, and damage due to chronic sun exposure. Jet black bruises may be due to warfarin-induced skin necrosis and similar disorders.
Tooth extractions are common hemostatic challenges and so may be helpful in defining the risk of bleeding. Molar extractions are greater hemostatic challenges than extractions of other teeth. Objective data regarding excessive bleeding based on the need for blood products or the need to have the extraction site packed or sutured are very valuable.
Excessive bleeding in response to razor nicks is common in patients with platelet disorders or von Willebrand disease. If patients indicate that they use an electric razor or a depilatory, it may be valuable to ask if they ever used a blade razor, and if so, why they switched.
Hemoptysis is virtually never the presenting symptom of a bleeding disorder and is rare even in patients with serious bleeding disorders. Blood-tinged sputum in association with upper respiratory tract infections may, however, be more common in patients with hemostatic disorders.
Hematemesis, like hemoptysis, is virtually never the presenting symptom of a hemostatic disorder, but a hemostatic disorder may exacerbate hematemesis due to an anatomic abnormality. Some hemostatic disorders are more likely to result in hematemesis as a result of a combination of effects, such as liver disease with esophageal varices and aspirin ingestion with gastritis.
Hematuria also is rarely the presenting symptom of a hemostatic disorder, but hemostatic disorders can exacerbate hematuria caused by other disorders, including simple urinary tract infections.
Hematochezia in individuals with normal hemostasis is most often due to hemorrhoids, but von Willebrand disease and platelet disorders may contribute to repeated episodes of hematochezia when associated with any one of a number of different underlying causes, including diverticuli, hemorrhoids, and angiodyplasia. Not infrequently, it is difficult to identify the precise site of bleeding. Melena is also only rarely the presenting symptom of a hemorrhagic disorder, but repeated episodes of melena may occur in patients with hemorrhagic disorders. Objective data about gastrointestinal bleeding include the number of previous endoscopic evaluations and any previous need for blood products.
Menstrual bleeding is typically excessive in amount and duration in women with platelet disorders and von Willebrand disease, but it may be difficult to establish this by history. In general, menstrual bleeding can be considered excessive if the patient indicates that she has heavy flow for more than three days or total flow for more than six or seven days. Objective data regarding menstrual bleeding includes whether a previous physician prescribed birth control pills to suppress menses; treated the patient with blood products; told the patient she was anemic; prescribed iron; performed a dilatation and curettage; performed an emergency hysterectomy to secure hemostasis; or performed an elective hysterectomy or other procedure to prevent excessive bleeding.
Childbirth poses a considerable hemostatic challenge, and so it is important to obtain a detailed history of each pregnancy, including data on excessive bleeding and the need for transfusion, dilatation and curettage, hysterectomy, or iron therapy. Repeated spontaneous abortions raise the possibility that the patient has a quantitative or qualitative abnormality of fibrinogen (see Chap. 124), factor XIII deficiency or the antiphospholipid syndrome (see Chap. 128).
Hemarthroses are the hallmark abnormality in the hemophilias and are otherwise rare except in severe von Willebrand disease. Since discoloration of the skin overlying the joint is unusual with hemarthroses, patients may not recognize that their symptoms are due to bleeding into their joints; it is more valuable, therefore, to inquire about recurrent pain, swelling, and limitation of motion.
Excessive hemorrhage in response to surgical procedures provides vital prognostic information. Specific inquiry about tonsillectomy, which presents a significant hemostatic challenge, is important, since often patients forget having had this procedure. If possible, the hospital records should be obtained because they commonly contain information that the patient does not have. Delays in discharge from the hospital or the need for blood products are especially important facts to inquire about.
Excessive bleeding in response to circumcision is common in males with hemophilia A or B, and this is often the patient’s first symptom. Delayed bleeding after circumcision or from the umbilical stump may also be observed in patients with hemophilia A or B, but it is said to be particularly characteristic of bleeding due to factor XIII deficiency.
Patients with vascular disorders secondary to connective tissue abnormalities such as Ehlers-Danlos syndrome may give a history of easily distensible skin or extraordinary ligament laxness (“double-jointed”). Manifestations of Cushing syndrome include rounded facies, purple striae, truncal obesity, and fat deposition at the back of the neck. Old photographs may be very helpful in establishing a change in the patient’s appearance.
On physical examination one should look for signs of bleeding or their sequelae and for signs of a possible underlying disorder that can cause the hemostatic derangement (Table 115-1). Careful examination of the skin is essential for detection of petechiae and ecchymoses. These signs may be prominent on the legs, where the hydrostatic pressure is greatest.
Telangiectasias may range from pinpoint erythematous dots that blanch with pressure to classic cherry angiomata ranging in size up to several centimeters. Many normal individuals develop increasing numbers of telangiectasias with aging. Patients with hereditary hemorrhagic telangiectasias have more florid lesions that characteristically affect the vermilion border of the lips and the tongue (including the underside of the tongue), but not all patients have these classic features. Thus, a systematic search of the integument is necessary. Spider telangiectasias found in patients with liver disease have a more splotchy and serpigenous appearance than the telangiectasias associated with hereditary hemorrhagic telangiectasias; in addition, they tend to be concentrated on the shoulders, chest, and face.
The differential diagnosis of nonpalpable purpuras and palpable purpuras is detailed elsewhere (see Chap. 121). Hematomas, ecchymoses, and protacted oozing should be looked for at sites of venipunctures, injections, and arterial and venous catheter insertion sites. Joint deformities and limited joint mobility are suggestive of severe deficiency of factor VII, VIII, IX, or X, or severe von Willebrand disease (Chap. 122, Chap. 123, and Chap. 135). Hyperelasticity of the skin and hyperextensibility of joints are typical of Ehlers-Danlos syndrome, and hyperextensibility only of the thumb probably represents one of its variants.5
EVALUATION BASED ON THE BLEEDING HISTORY AND INITIAL HEMOSTATIC TESTS
The patient’s history and physical examination provide important information on the likelihood of the patient having a hemostatic defect, and the possible cause of the defect if one is present. It is, however, important to also perform an initial set of tests, including a prothrombin time (PT), an activated partial thromboplastin time (APTT), and platelet count, to broadly assess the major components of the hemostatic system, because: (1) the patient’s history is sometimes unreliable, (2) the patient may have a mild hemostatic abnormality that has not previously manifested itself for lack of hemostatic challenge, (3) the patient may have developed an acquired hemostatic defect that has remained asymptomatic, and (4) the tests may reveal more than one abnormality.6 Figure 115-1 shows a series of algorithms that integrate the patient’s bleeding history and the results of the initial hemostatic tests. A prolonged APTT as a sole abnormality can be caused by a deficiency of factors VIII, IX, XI, or XII, or by an inhibitor, which can either be factor-specific (e.g., an antibody against factor VIII), or factor nonspecific (e.g., heparin or a lupus-type anticoagulant) Fig. 115-1A. A prolonged PT as the sole finding can be indicative of a deficiency of factor VII or the presence of an inhibitor Fig. 115-1B. When both the PT and APTT are abnormal, there may be an abnormality in fibrinogen, prothrombin, factor V, or factor X, an inhibitor to one of these components, or a combined deficiency of coagulation factors Fig. 115-1C.
FIGURE 115-1 Measures to establish a tentative diagnosis of a hemostatic disorder by using initial tests of hemostasis and the patient’s history of bleeding. APTT, activated partial thromboplastin time; BT, bleeding time; DIC, disseminated intravascular coagulation; HK, high-molecular-weight kininogen; N, normal; PK, prekallikrein; PLT-platelets; PT, prothrombin time; vWd, von Willebrand disease.
To distinguish between a deficiency state and the presence of an inhibitor it is useful to repeat the PT and APTT using a 1:1 mixture of patient’s plasma and normal plasma. When such a mixture normalizes or nearly normalizes the prolonged PT or APTT, a deficiency state is likely. When, however, the mixture still yields a significantly prolonged PT or APTT, an inhibitor is probably present. Some inhibitors, such as antibodies to factor VIII, require a period of time to inhibit the assay, whereas other inhibitors, such as lupus-type anticoagulants and heparin, do not. It is desirable, therefore, to incubate the mixture for a period of time, commonly 2 h at 37°C (98.6°F), before performing the coagulation assay.
When none of the initial tests (PT, APTT, and platelet count) is abnormal and the patient exhibits bleeding manifestations, the bleeding time (BT), ristocetin cofactor (RCF) activity, and examination of the blood film can be helpful in distinguishing between various candidate hemostatic abnormalities. An algorithm that includes these secondary tests is shown in Fig. 115-2. It should be noted that not infrequently patients with type 1 and type 2 von Willebrand disease will have normal results in the initial laboratory tests, since the factor VIII levels may be sufficiently high (>30 U/dl) to have a normal APTT (see Chap. 135). Examination of the blood film is helpful in distinguishing between Bernard-Soulier syndrome and von Willebrand disease since giant platelets are characteristic of the former (see Chap. 119). To distinguish type 2B and platelet-type von Willebrand disease from the other types of von Willebrand disease, the ristocetin-induced platelet aggregation test is useful. In type 2B and platelet-type von Willebrand disease, there is an enhanced response to low concentrations of ristocetin, whereas in the other types of von Willebrand disease, a decreased response is found. Total absence of platelet aggregates in a blood film prepared from nonanticoagulated blood, and absent clot retraction, are characteristic of Glanzmann thrombasthenia (see Chap. 119).
FIGURE 115-2 The tentative diagnoses in patients with bleeding manifestations and normal primary hemostatic tests, by using secondary tests: Bleeding time (BT), ristocetin cofactor activity (RCF), and clot retraction (CR). vWd, von Willebrand disease.
Another simple test that may be useful for distinguishing among hemostatic disorders is the thrombin time (i.e., the time for plasma to clot after adding thrombin). The thrombin time is prolonged in: (1) afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemias (Chap. 124), (2) the presence of heparin, (3) disseminated intravascular coagulation (DIC) due to increased levels of fibrin(ogen) degradation products inhibiting fibrin monomer polymerization (Fig. 115-1D) (Chap. 126), and (4) patients with amyloidosis and an immunoglobulin inhibitor of thrombin.7
PREOPERATIVE ASSESSMENT OF HEMOSTASIS
Surgical procedures constitute a great challenge to the hemostatic system, and therefore it is important to carefully assess the risk of bleeding in every patient. The assessment is based on the history of bleeding, the underlying disorder if any, the initial hemostatic tests (PT, APTT, and platelet count), and the type of surgery that is planned. Table 115-3 lists low- and high-risk conditions. For the high-risk conditions a critical analysis of each potential cause of bleeding should be undertaken.
TABLE 115-3 EVALUATION OF THE RISK OF BLEEDING DURING SURGERY
In addition to the extent of the surgical trauma, the magnitude of the fibrinolytic activity at the site of surgery has to be considered; prostatectomy, for example, carries considerable risk of prolonged bleeding because of the presence of high fibrinolytic activity in urine. Some surgical procedures can be anticipated to cause hemostatic abnormalities, such as operations in which extracorporeal circulation is employed (since the extracorporeal circuits and/or the anticoagulation cause platelet dysfunction) and operations on patients with extensive malignancies or brain injury (which can give rise to disseminated intravascular coagulation). Finally, the ability to institute local hemostatic measures should be considered. Thus, liver and kidney biopsies, though considered minor procedures, have a significant risk of bleeding because it is not possible to use local measures, such as direct pressure, to control bleeding.
The initial hemostatic tests may also give other important information in managing patients undergoing surgery, providing: (1) baseline values for future comparison if bleeding occurs, and (2) information about deficiencies of factor XII, prekallikrein, or high-molecular-weight kininogen, for which no treatment is necessary, or the lupus anticoagulant, for which anticoagulant prophylaxis may be indicated.
SPECIFIC ASSAYS FOR ESTABLISHING THE DIAGNOSIS
By following the stepwise process of evaluation outlined in Fig. 115-1 and Fig. 115-2, a tentative diagnosis can be made. Further testing is usually required, however, to establish a definitive diagnosis.
When the laboratory reports an abnormally low platelet count, it is essential to look at the blood film to exclude pseudothrombocytopenia.8 Examination of the blood film can also reveal the presence of: giant platelets, as in some inherited thrombocytopenias; giant platelets and Döhle bodies in leukocytes, as in May-Hegglin anomaly; moderately enlarged platelets, as occurs in immune thrombocytopenia or other conditions associated with shortened platelet survival; small platelets, as found in Wiskott-Aldrich syndrome; schistocytes and burr cells, as in the hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura, and occasionally in disseminated intravascular coagulation; rouleaux formation, as in monoclonal gammopathies; macrocytosis and/or hypersegmentation, as in vitamin B12 or folic acid deficiency; and abnormal white blood cells as in leukemias and myeloproliferative disorders. Further discussion of the evaluation and differential diagnosis of the thrombocytopenias is presented in Chap. 117 and Chap. 119.
Coagulation factors are usually assayed by measuring their clotting acitvity. The most common assays analyze the ability of dilutions of the patient’s plasma to correct the clotting time of a plasma known to be deficient in the factor to be measured (substrate plasma). The results are then compared to the ability of dilutions of a normal reference plasma to correct the abnormality in the substrate plasma. The activities of factors II, V, VII, and X are usually determined in PT-based assays, whereas the activities of factors VIII, IX, XI, XII, prekallikrein, and high-molecular-weight kininogen are measured in APTT-based assays. The plasma level of fibrinogen is most commonly measured by assessing the time it takes for thrombin to clot the patient’s diluted plasma (Clauss method).9 For measurement of factor XIII activity, several assays of transglutaminase activity are available,10 but a simple qualitative test that is based on dissolving a fibrin clot in 5 M urea is usually sufficient (see Chap. 122). The ristocetin cofactor function of von Willebrand factor can be measured by the ability of the patient’s plasma to support the agglutination of a suspension of formaldehyde-fixed normal platelets by ristocetin.11 This activity is defined as ristocetin cofactor activity. As with the coagulation factor assays, the results using patient plasma are compared to those obtained with a normal reference plasma.
To determine whether a coagulation factor activity deficiency is due to a quantitative decrease in protein or a qualitative abnormality in the protein, immunological assays can be employed using specific polyclonal or monoclonal antibodies to assess the presence of the protein, independent of its function. Electroimmunoassays, enzyme-linked immunosorbent assays (ELISAs), and immunoradiometric assays have all been employed successfully. Crossed immunoelectrophoresis measures both the immunologic reactivity and the mobility of the protein in an electric field, and thus it can detect protein abnormalities that affect electrophoretic migration. These can include the presence of antibody-antigen complexes, which migrate differently from the protein itself (e.g., antiprothrombin-prothrombin complexes in patients with systemic lupus erythematosus or antiphospholipid syndrome) or changes in the multimeric structure of the protein that affect migration (e.g., lack of large von Willebrand factor multimers). The diagnosis of the specific type of von Willebrand disease requires additional tests of the multimeric structure of plasma and, perhaps, platelet von Willebrand factor.
INHIBITORS TO COAGULATION FACTORS
If an inhibitor is suspected as a result of a prolonged PT or PTT performed on a l:l mixture of patient’s plasma and normal plasma, further studies can help define the nature of the inhibitor. Among inhibitors that do not require incubation (i.e., immediate-type), perhaps the most common cause is the presence of heparin in the sample. This can be verified by finding a prolonged thrombin time test on the patient’s plasma that corrects with toluidine blue or other agents that neutralize heparin. The lupus-type anticoagulant also does not require incubation. Several methods are available for specific detection of lupus-type anticoagulants (see Chap. 128). It should be noted, however, that with lupus-type anticoagulants, the PT is usually less prolonged than is the APTT and that APTT reagents differ markedly in their sensitivity to lupus-type anticoagulants.
Immunoglobin inhibitors to specific coagulation factors may develop either after factor replacement therapy in patients with inherited deficiencies of coagulation factors or spontaneously in patients without factor deficiencies (see Chap. 122 and Chap. 123). Antibodies that neutralize factor activity can frequently be detected by incubating the patient’s plasma with normal plasma, usually for 2 h at 37°C (98.6°F), and then assaying the specific factor. The Bethesda assay was originally designed to quantify factor VIII inhibitors but can be modified to detect other inhibitors12 (see Chap. 123). Some inhibitors do not directly neutralize clotting activity but rather reduce factor levels by forming complexes with coagulation factors, which are then rapidly cleared from the circulation. Such plasmas will not produce prolonged clotting times when mixed 1:1 with normal plasma and thus may be confused with inherited deficiency states. More elaborate assays are required to identify this type of inhibitor, which may, for example, produce severe deficiencies of prothrombin in some patients with the antiphospholipid syndrome (see Chap. 128) and von Willebrand factor in some acquired forms of von Willebrand disease (see Chap. 135).13
PLATELET FUNCTION DISORDERS
A prolonged bleeding time is suggestive of a platelet function disorder (inherited or acquired) or von Willebrand disease; the use of the ristocetin cofactor activity assay, platelet aggregation, and/or clot retraction are useful for the initial assessment of whether the patient has von Willebrand disease or a platelet function disorder (Fig. 115-2). Chapter 119 contains a flow diagram of the steps required to diagnose the different qualitative disorders of platelet function. Additional platelet function assays and glycoprotein analysis may be required to establish the diagnosis.
Miller CH, Graham JB, Goldin LR, Elston RC: Genetics of classic von Willebrand’s disease. II. Optimal assignment of the heterozygous genotype (diagnosis) by discriminant analysis. Blood 54:137, 1979.
Wahlberg T, Blomback M, Hall P, Axelsson G: Application of indicators, predictors and diagnostic indices in coagulation disorders. I. Evaluation of a self-administered questionnaire with binary questions. Methods Inf Med 19:194, 1980.
Miller LG: Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med 158:2200, 1998.
Horton RM: Alternative medicine resources on the internet. Curr Pract Med 1:71, 1998.
Kaplinsky C, Kenet G, Seligsohn U, Rechavi G: Association between hyperflexibility of the thumb and an unexplained bleeding tendency: is it a rule of thumb? Br J Haematol 101:260, 1998.
Rapaport SI: Preoperative hemostatic evaluation: which tests, if any? Blood 61:229, 1983.
Gastineau DA, Gertz MA, Daniels TM, Kyle RA, Bowie EJ: Inhibitor of the thrombin time in systemic amyloidosis: a common coagulation abnormality. Blood 77:2637, 1991.
Payne BA, Pierre RV. Pseudothrombocytopenia: A laboratory artifact with potentially serious consequences. Mayo Clin Proc 59:123, 1984.
Clauss A: Gerinnungsphysiologische schnell methodes zur des fibrinogens. Acta Haematol 17:327, 1957.
Fickenscher K, Aab A, Stuber W: A photometric assay for blood coagulation factor XIII. Thromb Haemost 65:535, 1991.
McFarlane DE, Stibbe J, Kirby EP, et al: A method for assaying von Willebrand factor (ristocetin cofactor). Thromb Diath Haemorrh 34:306, 1975.
Kasper CK, Aledort L, Aronson D, et al: Proceedings: a more uniform measurement of factor VIII inhibitors. Thromb Diath Haemorrh 34:612, 1975.
Inbal A, Bank I, Zivelin A, et al: Acquired von Willebrand disease in a patient with angiodysplasia resulting from immune-mediated clearance of von Willebrand factor. Br J Haematol 96:179, 1997.
Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn