Chapter 116: Classification, Clinical Manifestations, and Evaluation of Disorders of Hemostasis

Hemostatic disorders can conveniently be classified as either hereditary or acquired (Table 116–1). Alternatively, hemostatic disorders can be classified according to the mechanism of the defect. Of the acquired disorders, the thrombocytopenias are the most frequently encountered entities. Thrombocytopenias can result from reduced production of platelets, excessive destruction caused by antibodies or other consumptive processes, or pooling of platelets in the spleen, as in hypersplenism (Chap. 119); however, if hypersplenism is the sole cause of a hemostatic disorder, it is rarely severe enough to cause pathologic bleeding.

The bleeding history is a crucial element in the evaluation of a patient with a hemorrhagic disorder. The bleeding history helps define the subsequent diagnostic approach and 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:

1. Patients vary in their responses to hemorrhagic symptoms. Some patients ignore significant symptoms, whereas other patients are highly sensitive to even minor symptoms. When asked in standardized questionnaires, many normal, healthy people indicate they have excessive bleeding or bruising.^1,2 Therefore, some experts believe the question “Do you bruise easily?” is virtually worthless. Women are more likely to respond that they have excessive bleeding or bruising than are men.

2. Patients with severe hemorrhagic disorders invariably have very abnormal bleeding histories, for example, severe hemophilia A or hemophilia B, type 3 (homozygous) von Willebrand disease, and Glanzmann thrombasthenia. Importantly, these patients may experience spontaneous bleeding episodes.

3. The diagnostic value of any specific symptom varies in the different disorders. Therefore, recognizing typical patterns of bleeding is important (Table 116–2). Unprovoked hemarthroses and muscle hemorrhages suggest one of the hemophilias, whereas mucocutaneous bleeding (epistaxis, gingival bleeding, menorrhagia) are more characteristic of patients with qualitative platelet disorders, thrombocytopenia, or von Willebrand disease.

4. Assessing the extent of hemorrhage against the background of any trauma or provocation that may have elicited the hemorrhage is important. If a patient has never had a significant hemostatic challenge, such as tooth extraction, surgery, trauma, or childbirth, the lack of a significant bleeding history is much less valuable in excluding a mild hemorrhagic disorder. 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 for excessive bleeding after surgery or other interventions. Thus, these diagnoses must be considered even in elderly patients if their first severe hemostatic challenge occurs at that age.

5. Obtaining objective confirmation of the subjective information conveyed in the bleeding history is valuable. Objective data include (1) previous hospital or physician visits for bleeding symptoms, (2) results of previous laboratory evaluations, (3) previous transfusions of blood products for bleeding episodes, and (4) a history of anemia and/or previous treatment with iron.

6. Although self-administered questionnaires may provide useful background information, they cannot substitute for a dialogue between the physician and the patient. Thus, history taking in general, but 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. However, this iterative procedure has its limitations even when it is carefully pursued.^3,4

7. A medication history is a crucial component of the bleeding history, with particular attention to nonprescription drugs, such as aspirin and nonsteroidal antiinflammatory agents, which may affect bleeding symptoms. A medication history is especially important in patients with thrombocytopenia, because drug-induced thrombocytopenia is common (Chap. 120 and see Table 116–1). Medication also may affect hemostasis through deleterious effects on the liver or kidney functions. The increased use of herbal and alternative medicines poses particular problems, because patients may not readily share information about what they are taking, and the dose they are taking of any particular active ingredient may be difficult to determine. Ginkgo biloba and ginseng are the most commonly used herbals that can cause platelet dysfunction and induce bleeding.⁵ Other dietary supplements can display similar effects.^5,6

8. A nutrition history should be obtained to assess the likelihood of (1) vitamin K deficiency, especially if the patient also is taking broad-spectrum antibiotics, (2) vitamin C deficiency, especially if the patient has skin bleeding consistent with scurvy (perifollicular purpura), and (3) general malnutrition and/or malabsorption.

9. Several tissues have an increased local fibrinolytic activity. Such tissues include 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. Excessive bleeding following tooth extraction is one of the most common manifestations. Bleeding resulting from defects in fibrin crosslinking (factor XIII deficiency) or fibrinolytic defects may often manifest as delayed bleeding after trauma.

10. Bleeding isolated to a single organ or system (e.g., hematuria, hematemesis, melena, hemoptysis, or recurrent nosebleeds) is less likely to result from a hemostatic abnormality than from a local cause such as neoplasm, ulcer, or angiodysplasia. Thus, careful anatomic evaluation of the involved organ or system should be performed.

11. Bleeding may result from blood vessel disorders such as hereditary hemorrhagic telangiectasias, Cushing disease, scurvy, or Ehlers-Danlos syndrome. Many primary dermatologic disorders also have a purpuric or hemorrhagic component and must also be considered in the differential diagnosis (Chap. 122).

12. A family history is particularly important when hereditary disorders are considered. Patients usually will not spontaneously offer a history of consanguinity, so specific inquiry should be made about this possibility. A diagram of the patient’s genealogic tree, extending back at least two generations, should be included to document consideration of genetic disorders. A sex-linked pattern of inheritance is consistent with hemophilia A or B (Chap. 123). An autosomal dominant pattern is characteristic of most forms of von Willebrand disease (Chap. 126). An autosomal recessive pattern is typical for all other coagulation factor deficiencies (Chap. 124), inherited platelet disorders (Chap. 120), and the rare, severe (homozygous), type3 von Willebrand disease. Population genetic information may be helpful; for example, the higher prevalence of factor XI deficiency in Ashkenazi Jews (Chap. 124).

13. The history should include information on diseases and organs that may affect hemostasis, such as cirrhosis, renal insufficiency, myeloproliferative neoplasms (e.g., essential thrombocythemia), acute leukemia, myelodysplasia, systemic lupus erythematosus, and Gaucher disease.

Individual hemorrhagic symptoms often require detailed analysis before the significance of the symptoms and the resulting diagnosis or therapy can be determined. Some of the more common symptoms are discussed below, and Table 116–2 summarizes clinical manifestations that are typical for specific hemostatic disorders.

1. Epistaxis is one of the most common signs of platelet disorders and von Willebrand disease. It also is the most common symptom of hereditary hemorrhagic telangiectasia. 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. Bleeding confined to a single nostril more likely results from a local vascular problem than a systemic coagulopathy.

2. Gingival hemorrhage is very common in patients with both qualitative and quantitative platelet abnormalities and von Willebrand disease. Occasional gum bleeding occurs in normal individuals, especially if they use a hard bristle tooth brush and dental hygiene procedures. Thus, establishing whether the bleeding is excessive may be difficult. Frequent gingival hemorrhage can occur in individuals with normal hemostasis if they have gingivitis.

3. Oral mucous membrane bleeding in the form of blood blisters is a common manifestation of severe thrombocytopenia. Such bleeding usually has a predilection for sites where teeth can traumatize the inner surface of the cheek.

4. Skin hemorrhage in the form of petechiae and ecchymoses are common manifestations of hemostatic disorders. However, skin hemorrhage also is 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. Features that help establish the severity of skin hemorrhage include the size of the bruises, the frequency of bruising, whether the bruises occur spontaneously or only with trauma, and the appearance of bruises on regions of the body that usually are not traumatized, such as the trunk and back. The color of the bruise may yield information. Red bruises on the extensor surfaces of the arms and hands indicate loss of supporting tissues, as occurs in Cushing syndrome, glucocorticoid therapy, senile purpura, and damage from chronic sun exposure. Jet-black bruises may be caused by warfarin-induced skin necrosis and similar disorders. Easy bruising can also occur in patients with Ehlers-Danlos syndrome manifested by distensible skin or extraordinary ligament laxness, and in patients with hyperflexibility of the thumb.⁸

5. Tooth extractions are common hemostatic challenges and 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 pack or suture the extraction site are valuable.

6. Excessive bleeding in response to razor nicks is common in patients with platelet disorders or von Willebrand disease.

7. Hemoptysis almost never is the presenting symptom of a bleeding disorder and is rare even in patients with serious bleeding disorders. However, blood-tinged sputum in association with upper respiratory tract infections may be more common in patients with hemostatic disorders.

8. Hematemesis, like hemoptysis, almost never is the presenting symptom of a hemostatic disorder. However, a hemostatic disorder may lead to hematemesis because of an anatomic abnormality in the upper gastrointestinal tract and bleeding may be more severe than expected. Some hemostatic disorders more likely result in hematemesis because of a combination of effects, such as liver disease with deficient synthesis of coagulation proteins and with esophageal varices and aspirin ingestion with gastritis.

9. Hematuria is rarely the presenting symptom of a hemostatic disorder except for the hemophilias. However, hemostatic disorders can exacerbate hematuria caused by other disorders, including simple urinary tract infections.

10. Rectal bleeding in individuals with normal hemostasis most often results from hemorrhoids. However, von Willebrand disease and platelet disorders may contribute to repeated episodes of rectal bleeding when associated with a number of different underlying causes, including diverticula, hemorrhoids, or angiodysplasia. Melena is also only rarely the presenting symptom of a hemorrhagic disorder. However, repeated episodes of melena may occur in patients with hemorrhagic disorders.

11. Menorrhagia is common in women with platelet disorders and von Willebrand disease. In general, menstrual bleeding is considered excessive if the patient indicates she has heavy flow for more than 3 days or total flow for more than 7 days. However, an objective distinction between menorrhagia (loss of more than 80 mL blood per period) and normal blood loss can only be made by a visual assessment technique using pictorial charts of towels or tampons.⁷

12. Postpartum hemorrhage. Childbirth poses a considerable hemostatic challenge. Consequently, patients with bleeding disorders commonly manifest excessive bleeding during or after labor necessitating blood transfusion. An exception may be mild and moderate von Willebrand disease due to the vast increase in von Willebrand factor during pregnancy.

13. Habitual spontaneous abortions raise the possibility that the patient has a quantitative or qualitative abnormality of fibrinogen (Chap. 125), factor XIII deficiency (Chap. 124), or the antiphospholipid syndrome (Chap. 131). There is also an association between infertility and spontaneous abortion in patients with inherited thrombophilia (Chap. 130).

14. Hemarthroses are the hallmark abnormality in the hemophiliac; they are rare in other disorders except in severe factor VII deficiency and type 3 von Willebrand disease (Chaps. 124 and 126). Because discoloration of the skin overlying the joint with hemarthroses does not occur, patients may not recognize that their symptoms (pain, swelling, and limitation of motion) are caused by bleeding into their joints.

15. Excessive hemorrhage associated with surgical procedures is common in patients with hemorrhagic disorders. Procedures involving tissues with increased local fibrinolytic activity like urinary tract, nose, tonsils and oral cavity are particularly prone to bleed.

16. Excessive bleeding following circumcision is common in males with severe hemostatic disorders such as hemophilia A, hemophilia B, or Glanzmann thromboasthenia, and often is the patient’s first symptom.

17. Bleeding from the umbilical stump is characteristic of factor XIII deficiency (Chap. 124) and afibrinogenemia (Chap. 125).

Physical examination is essential for identifying signs of bleeding or their sequelae and for signs of a possible underlying disorder that can cause the hemostatic derangement (see Table 116–1). Careful examination of the skin is essential for detecting petechiae and ecchymoses. These signs may be prominent on the legs, where the hydrostatic pressure is greatest, or around the hair follicles in vitamin C deficiency.

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 telangiectasia 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 chronic liver disease have a more splotchy and serpiginous appearance than the telangiectasias associated with hereditary hemorrhagic telangiectasia. In addition, the telangiectasias tend to be concentrated on the shoulders, chest, and face.

Chapter 122 details the differential diagnosis of nonpalpable purpuras and palpable purpuras. Hematomas, ecchymoses, and protracted oozing should be sought at venipuncture sites, injection sites, and arterial and venous catheter insertion sites. Joint deformities and limited joint mobility are suggestive of severe hemophilia A or B, severe deficiency of factor VII, or type 3 von Willebrand disease (Chaps. 123, 124, and 126). Hyperelasticity of the skin and hyperextensibility of joints are typical of Ehlers-Danlos syndrome, and hyperextensibility of only the thumb probably is a variant.⁸

The patient’s history and results of 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. However, performing an initial set of widely available and inexpensive tests, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet count, is important for the following reasons: (1) The patient’s history sometimes is unreliable; (2) the patient may have a mild hemostatic abnormality that has not 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.⁹

Figure 116–1 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 factor VIII, IX, XI, or XII; presence of heparin; or by an inhibitor, which can be either factor specific, such as an antibody against factor VIII, or factor nonspecific, such as the presence of heparin or a lupus anticoagulant (Fig. 116–1A). A prolonged PT as the sole finding can indicate a factor VII deficiency, a mild vitamin K deficiency, or the presence of an inhibitor (Fig. 116–1B). Abnormalities of both PT and aPTT may indicate a deficiency of fibrinogen, prothrombin, factor V or factor X, an inhibitor to one of these factors, or a combined deficiency of coagulation factors (Fig. 116–1C).

To distinguish between a deficiency state and the presence of an inhibitor, repeating the abnormal test, the PT and/or aPTT, using a 1:1 mixture of the patient’s plasma and normal plasma is useful. If the mixture normalizes the prolonged PT or aPTT, a deficiency state is likely, as most coagulation tests are calibrated to produce a normal result if each of the relevant factor levels are 50 percent of normal or greater. If the mixture still yields a significantly prolonged PT or aPTT, an inhibitor probably is present. Some inhibitors, such as antibodies to factorVIII, require time to inhibit the factor VIII activity in the assay, whereas other inhibitors, such as lupus anticoagulant or heparin, do not. Consequently, incubating the mixture for 1 or 2 hours at 37°C before performing the coagulation assay is desirable.

When none of the initial test results (PT, aPTT, and platelet count) is abnormal and the patient exhibits bleeding manifestations, ristocetin cofactor (RCF) or von Willebrand factor activity and examination of the blood film can be helpful for distinguishing among various candidate hemostatic abnormalities. The bleeding time is not used anymore because the test is highly operator and situational (room temperature, skin circulation, etc.) dependent and is not sufficiently reliable to be useful in the diagnostic process. Instead, many laboratories have introduced the platelet function analyzer (PFA) to detect qualitative defects in primary hemostasis. Figure 116–2 shows an algorithm that includes these secondary tests. Patients with type 1 and type 2 von Willebrand disease often have normal findings on initial laboratory tests because factor VIII levels are sufficiently high (>30 U/dL) for a normal aPTT result (Chap. 126). Examination of the blood film is helpful for distinguishing between Bernard-Soulier syndrome and von Willebrand disease because giant platelets are characteristic of the former (Chap. 120). Distinguishing mild-type von Willebrand disease from normal is difficult because levels of von Willebrand factor in the normal population is highly variable, partly accounted for by differing von Willebrand factor levels in individuals with different ABO blood types. In fact, some investigators have questioned whether patients with von Willebrand factor levels as low as 35 percent should be labeled as having von Willebrand disease.¹⁰ The likelihood of having von Willebrand disease is a function of bleeding history, the von Willebrand factor level, and the number of first-degree family members with reduced von Willebrand factor levels.¹¹

The ristocetin-induced platelet aggregation test is useful for distinguishing type 2B and platelet-type von Willebrand disease from the other types of von Willebrand disease. In type 2B and platelet-type von Willebrand disease, an enhanced response to low concentrations of ristocetin is observed, 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 non–anticoagulated blood and absent clot retraction are characteristic of Glanzmann thrombasthenia (Chap. 120).

Another simple test that may be useful for distinguishing among hemostatic disorders is the thrombin time (i.e., time for plasma to clot after adding thrombin). The thrombin time is prolonged in (1) afibrinogenemia, hypofibrinogenemia, and dysfibrinogenemias (Chap. 125), (2) the presence of heparin, (3) disseminated intravascular coagulation (DIC) causing increased levels of fibrin(ogen) degradation products, which inhibit fibrin monomer polymerization (see Fig. 116–1D and Chap. 129), and (4) patients with amyloidosis and an immunoglobulin inhibitor of thrombin.¹²

Because surgical procedures are a great challenge to the hemostatic system, careful assessment of the risk of bleeding in every patient is important. The risk assessment is based on the bleeding history, physical examination, the underlying disorder if any, the type and site of surgery that is planned, and the results of basic hemostatic tests (PT, aPTT, platelet count). Several studies indicate that unselected coagulation tests have no significant predictive value of perioperative bleeding, and that patients with a negative bleeding history do not require routine coagulation screening.¹³ However, this conclusion does not consider that patients with mild to moderate bleeding disorders who can bleed excessively following surgery may have a negative bleeding history because they have not been challenged; obtaining a good bleeding history is an expertise that is not shared by all physicians; and if bleeding occurs during or after surgery for whatever reason, the basic tests performed preoperatively are an essential reference for determining the cause of bleeding.

Table 116–3 lists low-risk and high-risk conditions. A critical analysis of each potential cause of bleeding should be undertaken for the high-risk conditions. In addition to the extent of the surgical trauma, the magnitude of the fibrinolytic activity at the surgical site must be considered. For example, prostatectomy carries considerable risk of prolonged bleeding because of the presence of high fibrinolytic activity in the urine. Some surgical procedures can be anticipated to cause hemostatic abnormalities, such as operations in which extracorporeal circulation is used (because 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 DIC. Finally, the ability to institute local hemostatic measures should be considered. Thus, liver, lung, and kidney biopsies, although considered minor procedures, have a significant risk of bleeding because local measures, such as direct pressure, cannot be used to control bleeding.

A tentative diagnosis can be made by following the stepwise process of evaluation outlined in Figs. 116–1 and 116–2. However, further testing usually is required to establish a definitive diagnosis.

THROMBOCYTOPENIAS

When the laboratory reports an abnormally low platelet count, looking at the blood film to exclude pseudothrombocytopenia as a result of anticoagulant-induced platelet clumping (e.g., induced by ethylenediaminetetraacetic acid [EDTA]) is essential.¹⁴ Examination of the blood film also can reveal the presence of giant platelets, as in some inherited thrombocytopenias; giant platelets and Döhle bodies in leukocytes, as in May-Hegglin and other MYH9 platelet syndromes; moderately enlarged platelets, as in immune thrombocytopenia or other conditions associated with shortened platelet survival; small platelets, as in Wiskott-Aldrich syndrome; schistocytes and burr cells, as in the hemolytic uremic syndrome and thrombotic thrombocytopenic purpura, and occasionally in DIC; rouleaux formation, as in monoclonal gammopathies; macrocytosis and/or hypersegmentation, as in vitaminB₁₂ or folic acid deficiency; and abnormal white blood cells, as in leukemias and myeloproliferative disorders. Chapter 117 further discusses the evaluation and differential diagnosis of the thrombocytopenias.

FACTOR DEFICIENCIES

Coagulation factors usually are assayed by measuring their clotting activity. 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 being measured (substrate plasma). The results are 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 usually are determined in PT-based assays, whereas the activities of factors VIII, IX, XI, and XII, prekallikrein, and high-molecular-weight kininogen are measured in aPTT-based assays. The plasma level of fibrinogen most commonly is measured by assessing the time required for thrombin to clot the patient’s diluted plasma (Clauss method).¹⁵ Several assays of transglutaminase activity are available for measuring factor XIII activity,¹⁶ but a simple qualitative test based on dissolving a fibrin clot in 5 M urea usually is sufficient (Chap. 124). The RCF 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.¹⁷ This activity is defined as RCF activity. As with the coagulation factor assays, the results using patient plasma are compared to the results obtained with a normal reference plasma.

To determine whether a coagulation factor activity deficiency results from a quantitative decrease in protein or a qualitative abnormality in the protein, immunologic assays can be performed 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 all have been used successfully. Crossed immunoelectrophoresis measures both the immunologic reactivity and the mobility of the protein in an electric field; thus, it can detect protein abnormalities that affect electrophoretic migration. The abnormalities include the presence of antibody–antigen complexes that migrate differently from the protein itself, such as antiprothrombin–prothrombin complexes in patients with systemic lupus erythematosus or antiphospholipid syndrome. 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 aPTT performed on a 1:1 mixture of the patient’s plasma and normal plasma, further studies can help define the nature of the inhibitor and its titer. 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 cause can be verified by finding a prolonged thrombin time on a test of the patient’s plasma that is corrected with toluidine blue or other agents that neutralize heparin. The lupus anticoagulant also does not require incubation, and several methods for its detection are available (Chap. 131). However, with lupus anticoagulant, the PT usually is less prolonged than is the aPTT, and aPTT reagents have markedly different sensitivity to lupus-type anticoagulant depending on the amount of phosphatidyl serine present in each reagent.

Immunoglobulin inhibitors to specific coagulation factors may develop either after factor replacement therapy in patients with inherited deficiencies of coagulation factors (Chaps. 123 and 124) or spontaneously in patients without factor deficiencies (Chap. 127). Antibodies that neutralize factor activity frequently can be detected by incubating the patient’s plasma with normal plasma, usually for 2 hours at 37°C, and then assaying the specific factor. The Bethesda assay originally was designed to quantify factor VIII inhibitors but can be modified to detect other inhibitors of coagulation factors (Chap. 123).¹⁸ Some inhibitors do not directly neutralize clotting activity; instead they reduce factor levels by forming complexes with coagulation factors, which then are rapidly cleared from the circulation. Such plasmas do 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 deficiency of prothrombin in some patients with the antiphospholipid syndrome (Chap. 131) and deficiency of von Willebrand factor in some acquired forms of von Willebrand disease (Chap. 126).¹⁹

PLATELET FUNCTION DISORDERS

Some laboratories nowadays routinely use an automated PFA to detect qualitative defects in primary hemostasis. Use of the RCF activity assay, platelet aggregation, and/or clot retraction are useful for assessing whether the patient has von Willebrand disease or a platelet function disorder (see Fig. 116–2). Chapter 120 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.