Larry Waterbury
Philip D. Zieve
In a healthy person, a number of different processes interact to ensure that blood is maintained in a fluid state until the integrity of a blood vessel wall is compromised. At that point, a plug is rapidly formed to prevent exsanguination. Three major systems are involved in this process: the vasculature itself, the blood platelets, and the coagulation system.
Evaluation of Patients
The history is the most important aid in determining whether a patient has a hemorrhagic diathesis (1). Patients with congenital disorders of hemostasis or acquired disorders of long standing almost certainly have a history of unexpectedly excessive bleeding in response to minor trauma or to surgery. The clinician should ask specifically whether the patient has required transfusion after an operative procedure or a seemingly minor trauma.
Bleeding caused by injury to the vasculature is overwhelmingly more common than bleeding caused by defective hemostasis. Therefore, patients with gastrointestinal or genitourinary hemorrhage, for example, are more likely to have a lesion (e.g., peptic ulcer, carcinoma, diverticulum, or tumor of the kidney or bladder) that has bled than a disorder of hemostasis. Similarly, nosebleeds, bleeding gums, or excessive menstrual flow probably reflect local (usually benign) problems. Furthermore, even if patients have hemostatic dysfunction, they are likely to bleed from local lesions, the propensity to bleed of which has been accentuated by the hemostatic abnormality.
Specific disorders of hemostasis may be strongly suspected based on the patient's history and because of characteristic findings on physical examination (Fig. 56.1), but in almost all instances, laboratory tests are required before a specific diagnosis can be made. Screening tests, procedures that are extremely sensitive to alterations in hemostasis, ordinarily are relied on first in a patient with a suspected hemorrhagic diathesis (Table 56.1). More specific tests are indicated if any of these screening test results are abnormal or if a disorder of hemostasis is strongly suspected, even if the test results are not abnormal. These more specific tests are best performed in consultation with a hematologist.
Disorders of Blood Vessels
Vascular disease is diagnosed uncommonly as a cause of a hemorrhagic diathesis, in part because, except for trauma, disorders of the vasculature that result in untoward bleeding are rare (2) and in part because there is no reliable screening test to detect generalized vascular dysfunction. The primary hemorrhagic manifestation of vascular disease is purpura, a confluent purplish discoloration of the skin caused by extravasation of blood from cutaneous and subcutaneous blood vessels. Although patients with an abnormal vasculature occasionally experience bleeding from large blood vessels, most commonly they bleed into the skin or mucous membranes. Because purpura is a common response to minor trauma, it cannot in itself be taken as evidence of an underlying hemorrhagic diathesis.
Cutaneous Lesions
Unexplained bruises, especially on the lower extremities, are common and usually are not associated with an underlying disease process. Therefore, a history of easy bruising is unlikely, by itself, to lead to a diagnosis of a disorder of hemostasis. Similarly, senile purpura, which occurs characteristically on the dorsum of the hand and the extensor surfaces of the forearms, does not represent a generalized hemorrhagic diathesis but results from the loss of connective tissue support to intracutaneous blood vessels, which then are easily traumatized and bleed within the substance of the skin. Identical lesions are seen sometimes in patients with Cushing syndrome or in patients who have received corticosteroid therapy.
Allergic purpura is a hypersensitivity reaction to an antigenic stimulus that usually cannot be identified (although sometimes a drug or an infection can be incriminated as a provocative agent) (3,4). Characteristically, patients
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develop a symmetrical petechial rash, which is most prominent on the extremities. The lesions are slightly raised, distinguishing them from the petechiae of thrombocytopenia. No hemostatic dysfunction is associated with this condition. The cutaneous manifestations of the disorder are part of a widespread small-vessel vasculitis, the manifestations of which may include arthralgias (sometimes with evidence of joint effusions), fever, malaise, abdominal pain, gastrointestinal bleeding, and renal disease caused by a focal glomerulonephritis that occasionally progresses to chronic renal failure. There is no specific treatment for this condition. If the patient is taking a drug that is suspected of being a sensitizing agent, the drug should be discontinued. In fact, because the offending agent often is not readily identified, all drugs that are not absolutely essential to care should be discontinued. Most patients recover spontaneously within 3 to 4 weeks, but signs and symptoms of the disease may continue or recur for up to 1 year. Patients should be reassured while they are symptomatic that unless they have evidence of progressive renal disease, they ultimately will recover.
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TABLE 56.1 Laboratory Evaluation of Hemostatic Function |
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FIGURE 56.1. Bleeding caused by thrombocytopenia compared with bleeding caused by abnormal coagulation. A: Immune thrombocytopenic purpura with typical petechial lesions. B: Hemophilia A with extensive purpuric bleeding. (From D Levin J. Disorders of hemostasis. Philadelphia: WB Saunders, 1976 , with permission.) |
Autoerythrocyte sensitization (5) is a disorder, predominantly of women, characterized by apparently spontaneous painful ecchymoses, usually on the lower extremities and anterior trunk. The disorder is so named because of a one-time belief that the disorder arose as the result of a hypersensitivity response to patients’ red cells or red cell stroma. In fact, the lesions can sometimes be produced by injection of autologous red cells into the skin of these patients. It has become apparent, however, that virtually all patients with the disorder are severely psychoneurotic and, in some instances, frankly psychotic. Many people now believe that the lesions are self-inflicted.
Cryoglobulinemia (6) as a primary abnormality or as a special feature of an underlying disease such as dysproteinemia (seeDysproteinemia), lymphoma, or collagen vascular disease may cause purpuric bleeding, especially on the lower extremities. The cryoglobulins may be isolated monoclonal proteins or may be immune complexes of monoclonal immunoglobulin IgG or IgM and polyclonal IgG or of mixed polyclonal immunoglobulins. There often is an associated glomerulonephritis and, in the patient with immune complex formation, sometimes evidence of hepatitis B or hepatitis C infection.
The diagnosis of cryoglobulinemia can be made by placing a sample of the patient's serum in a refrigerator overnight and then inspecting the serum for the formation of a white gel or precipitate that disappears when the specimen is warmed. The blood for this test should be drawn in a warm syringe and the clot that forms should be allowed to retract in a 37°C water bath. Primary cryoglobulinemia is poorly responsive to treatment. Secondary cryoglobulinemia may respond to treatment of the underlying disease.
Patients with other vasculitides sometimes also present with petechialike lesions and systemic disease (e.g., renal or pulmonary disease) typically much more severe than in patients with allergic purpura. These conditions are sometimes associated with antineutrophilic cytoplasmic
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antibodies (ANCAs). Such patients are best managed in consultation with a rheumatologist.
Mucocutaneous Lesions
Some patients with vascular disease are prone to bleeding from the oral, nasal, or gastrointestinal mucosa, as well as from the skin. Such patients may present to their providers not only with cutaneous hemorrhage but also with bleeding gums, epistaxis, hematemesis, or melena.
Amyloidosis
Mucocutaneous bleeding may be a symptom of amyloidosis because of the deposition of amyloid within the walls of blood vessels (7). Periorbital bleeding and bleeding in skin folds are especially common. The skin in the areas of hemorrhage sometimes appears thickened because of palpable amyloid deposits within it. Patients suspected of having this disorder should have biopsies with appropriate staining and serum and urine electrophoresis in an attempt to make a specific diagnosis.
Dysproteinemia
Myeloma or macroglobulinemia may be associated with untoward bleeding, either because of increased viscosity of the blood or because the coating of blood vessels and platelets with the abnormal protein interferes with normal hemostatic function (8). Abnormal coagulation is common in patients with these disorders. Patients suspected of having dysproteinemia should have samples of their serum and urine examined by electrophoresis in an attempt to demonstrate a monoclonal protein. If the diagnosis of dysproteinemia seems likely based on the result of this test and the clinical presentation, consultation with a hematologist or oncologist is appropriate.
Vitamin C Deficiency
In the United States, symptomatic vitamin C deficiency (scurvy) might be seen in three specific groups: chronic alcoholics, food faddists, and chronically ill or debilitated patients (9). Because humans, unlike most animals, are unable to synthesize vitamin C, they depend on exogenous sources such as fruits and leafy vegetables. People who cannot, or will not, eat an adequate diet of foods that contain the vitamin are subject to the manifestations of scurvy. The signs and symptoms of scurvy are attributable largely to the formation of defective connective tissue, because of the human body's absolute dependence on vitamin C for the synthesis of normal collagen. Mucocutaneous bleeding is common in patients with vitamin C deficiency who characteristically have large ecchymoses on their extremities, bleeding gums, and, very suggestive of this disorder, perifollicular hemorrhages that commonly appear on the lower extremities and anterior trunk. Sometimes patients with vitamin C deficiency develop hemarthroses similar to those seen in patients with severe coagulation disorders. All manifestations of scurvy are readily reversed by administration of vitamin C, so scurvy should be considered in patients with compatible signs and symptoms even though the disorder is uncommon. Vitamin C deficiency can be confirmed by assay of the blood, but this test usually is unnecessary because, if the diagnosis is suspected, a therapeutic trial of vitamin C (250 mg once per day) is innocuous.
Hereditary Hemorrhagic Telangiectasia
Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease) is an inherited abnormality of blood vessels (an autosomal dominant condition) in which there is dilation of abnormally thin-walled venules and capillaries (10). The dilations result in characteristic telangiectases, which are small, flat, red, or purple lesions that blanch on pressure. They occur throughout the body but most commonly are seen externally on the lips, tongue, hand, and mucous membranes of the nose. Lesions of larger blood vessels also occur in this disease, most commonly pulmonary arteriovenous fistulas, which develop in up to one third of patients and may cause high-output heart failure. Vascular malformations of the liver or the brain may occur. The mucocutaneous lesions may bleed excessively when traumatized. Recurrent epistaxis is the most common symptom of patients with the disorder, but the most troublesome problem is recurrent gastrointestinal bleeding, which is difficult to manage. Accessible lesions ordinarily can be treated by local compression. No pharmacologic agent will alter the course of the condition, but symptoms are variable. Many patients experience little difficulty during the course of their lives.
Disorders of Platelets
Platelets provide a cellular defense against the loss of blood from traumatized vessels, especially where blood flow is relatively rapid, as on the arterial side of the circulation and the left side of the heart. Platelets are particularly effective in sealing leaks from small arterioles and capillaries. When platelets are abnormal, either quantitatively or qualitatively, these vessels bleed most prominently. The platelet plug is initiated by contact of platelets with subendothelial collagen, which is exposed by injury to the vascular intima. The absorption of a protein, von Willebrand factor (see below), to specific receptor sites on the platelet surface is important in the mediation of this process. Thereafter, aggregating agents such as thrombin and adenosine diphosphate cause the accretion of platelets at that site,
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eventually forming an adhesive plug that within minutes prevents the further flow of blood. Eventually, the plug is replaced by fibrin laid down by the activation of the coagulation mechanism, which occurs simultaneously with the initiation of platelet plug formation.
Thrombocytopenia is one of the most common acquired disorders of hemostasis. The normal platelet count is between 150,000 and 400,000/mm3, but the platelet count ordinarily must be reduced to <50,000/mm3 before untoward bleeding is observed, and even then bleeding usually does not occur unless the patient is traumatized. So-called spontaneous bleeding is unlikely unless the platelet count is reduced to <20,000/mm3. There is a general impression that there is a higher risk of bleeding when thrombocytopenia is secondary to decreased bone marrow production rather than to decreased survival of platelets. For example, patients with immune thrombocytopenia may not have significant bleeding even with platelet counts as low as 5,000/mm3. At any given platelet count, the risk of bleeding varies with the cause of thrombocytopenia.
The characteristic lesion of thrombocytopenia is the petechia, a small purpuric hemorrhage occurring on the skin or mucous membranes, especially at sites of elevated capillary pressure, such as the lower extremities, the forearm after inflation of a blood pressure cuff, or the face after prolonged crying or coughing. In fact, if capillary pressure is raised high enough or if capillaries are damaged after sunburn, for example, petechiae may be seen in otherwise normal people. Although cutaneous bleeding may be the first clue to the diagnosis of thrombocytopenia, morbidity from the disorder is more likely to result from gastrointestinal or genitourinary hemorrhage. If bleeding occurs from these sites, the patient should be examined at an appropriate time to determine whether an organic lesion, such as carcinoma of the colon or kidney, has bled in association with defective hemostasis. The most feared complication of thrombocytopenia is intracerebral bleeding that, although it occurs infrequently, is still one of the major causes of death in patients with the disorder.
Evaluation of the Thrombocytopenic Patient
The best screening test for evaluation of the numbers of platelets in the blood is observation of a stained smear of the peripheral blood. With relatively little experience it is easy to determine whether the platelet count is unusually low or high. In unanticoagulated blood (e.g., from a fingerstick), at least one clump of platelets, on the average, should be seen in every oil immersion field. In anticoagulated blood, one platelet should be seen for every 10 to 20 red cells. If a quantitative abnormality is suspected, a precise platelet count can be obtained. The bleeding time is not useful as a screening test for detecting quantitative abnormalities of platelets or for predicting which patients are likely to bleed excessively when traumatized (11). However, despite its limitations, the bleeding time still is used commonly to evaluate qualitative abnormalities of platelet function (described later in this chapter).
Patients with an immune thrombocytopenia (see below) characteristically have increased amounts of γ-globulin adsorbed to their platelets. Tests to detect these proteins are widely available but have proved to be nonspecific and therefore of little value in establishing a precise diagnosis.
In ambulatory practice, many patients with mild thrombocytopenia are encountered. The precise pathophysiology of the condition is not clear. Many patients are found to have thrombocytopenia during the course of routine hematologic studies performed to obtain baseline data or as part of an evaluation of an apparently unrelated condition. The first task for the clinician is to rule out spurious thrombocytopenia secondary to marked platelet clumping affecting the accuracy of the automated platelet count. This artifact usually is secondary to antibodies to the anticoagulant used to obtain blood for a complete blood count. When spurious thrombocytopenia is suspected, blood should be collected using another anticoagulant (usually citrate) and the platelet count repeated. The technician should inspect a smear from anticoagulated blood for increased clumping. Once spurious thrombocytopenia has been ruled out, if the platelet count is >50,000/mm3 and the history, physical examination, and other hematologic evaluations do not suggest an underlying disease that urgently requires diagnosis and treatment, it probably is justifiable simply to follow the patient with serial platelet counts performed monthly until the stability of the counts are determined.
Symptomatic thrombocytopenia caused by decreased production of platelets usually is observed in conjunction with processes such as aplastic anemia, leukemia, myelodysplasia, disseminated tuberculosis, or metastatic carcinoma that affect other hematologic cell lines. In contrast, severe thrombocytopenia caused by increased destruction of platelets does not necessarily indicate the presence of a disease process that is affecting parts or systems of the body other than the blood platelets or their precursors. To be reasonably certain about the pathophysiology of thrombocytopenia, however, it sometimes is necessary to perform an aspiration of the bone marrow and to evaluate the numbers of megakaryocytes and the appearance of the other blood cell precursors. Patients who have thrombocytopenia because of diseases involving the bone marrow, except in cases of megaloblastic anemia, have reduced numbers of megakaryocytes. If the thrombocytopenia is severe, abnormalities of production of, or qualitative changes in, other cell lines likely will be noted. On the other hand, if the patient is thrombocytopenic because of increased destruction of platelets, the numbers of megakaryocytes will be increased and the marrow will otherwise appear normal (although increased erythroid
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activity might be seen in those patients who are bleeding). It has been proposed that bone marrow aspiration need not be done routinely in patients with isolated thrombocytopenia (thought to be immune mediated) (12,13). In any case, patients with severe thrombocytopenia (<30,000/mm3) require consultation with a hematologist.
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TABLE 56.2 Etiology of Thrombocytopenia by Mechanism |
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Decreased Production of Platelets
Decreased production of platelets is a common mechanism for thrombocytopenia in ambulatory patients (Table 56.2). Apparent suppression of thrombopoiesis often is associated with viral infections such as upper respiratory infections, infectious mononucleosis, and childhood exanthems. In most cases, bone marrow aspirates show megakaryocytes in normal or reduced numbers, although they sometimes appear morphologically abnormal. At other times, increased numbers of megakaryocytes are found in patients with thrombocytopenia in association with viral infections, suggestive of a destructive process (perhaps immunologic) to which the marrow has responded with increased production of platelets. In general, patients with benign viral infections are not likely to have severe thrombocytopenia and so are not at major risk for bleeding. The process ordinarily dissipates as the infection resolves.
Certain drugs predictably produce thrombocytopenia by affecting thrombopoiesis. Among these drugs, cytotoxic agents are unlikely to be administered by the general practitioner. Although thiazide diuretics have been reported to produce mild to moderate thrombocytopenia commonly, a clear-cut cause-and-effect relationship has not been demonstrated. In the reported studies, platelet counts have fallen several weeks after the beginning of therapy, sometimes associated with morphologically abnormal megakaryocytes. Rarely, however, thiazides have been clearly implicated in immunologically induced destructive thrombocytopenia (see Increased Destruction of Platelets). Thiazide diuretics also are a common cause of allergic purpura (see above), but patients with this condition have normal platelet counts.
A large number of drugs have been implicated, on occasion, in the production of thrombocytopenia by the suppression of thrombopoiesis. Therefore, if patients are symptomatic from thrombocytopenia or have counts <50,000/mm3 and the cause of thrombocytopenia is unknown, it would be reasonable to discontinue the administration of all drugs that are not considered absolutely essential.
Management
Clearly, the cause of decreased platelet production should be removed, if possible (e.g., discontinuing administration of an offending drug). If there is no evidence of mucous membrane or internal bleeding, treatment of the thrombocytopenia itself usually is unnecessary. Patients with severe bleeding should receive platelet transfusions when thrombocytopenia is due to decreased platelet production and counts are <50,000/mm3. Some patients with chronic diseases of the bone marrow, such as myelodysplasia or aplastic anemia, require periodic platelet transfusions. Such patients should be followed by a hematologist or oncologist, as well as by a primary caregiver.
Increased Destruction of Platelets
In ambulatory practice, probably the most common cause of thrombocytopenia seen is thrombocytopenia secondary to an immune mechanism (Table 56.3). Patients with autoimmune thrombocytopenia characteristically present with petechiae (12–14). Physical examination reveals no other evidence of disease; in particular, the spleen usually is not palpable. It is helpful to look at platelet morphology on a peripheral blood smear. Typically, platelets are large and sometimes elongated in severe destructive thrombocytopenia as opposed to the small platelets seen when the
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thrombocytopenia is due to decreased production. The smear should be made with blood from a fingerstick because anticoagulants cause platelets to swell. Bone marrow aspirates appear normal except for increased numbers of megakaryocytes. An acute disease, often preceded by an otherwise benign viral infection, is seen more commonly in children and, by definition, lasts <6 months. The chronic illness (often still called idiopathic thrombocytopenic purpura) lasts >6 months and is seen more often in women than men (ratio of 3:1 or 4:1). It sometimes is associated with an underlying lymphoproliferative disorder or a collagen vascular disease, especially systemic lupus erythematosus and, more rarely, autoimmune hemolytic anemia. There is an increased incidence of immune thrombocytopenia in association with human immunodeficiency virus (HIV) infection (15) (see Chapter 39). Autoimmune thrombocytopenia is caused by an antibody adsorbed to the surface of circulating platelets that results in their premature destruction by the reticuloendothelial system. The disorder is characterized by ineffective production of platelets as well (16).
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TABLE 56.3 Immune Thrombocytopenia |
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Many drugs are associated with thrombocytopenia on an immunologic basis (17). Heparin is the drug most commonly implicated (seeChapter 57). Many other drugs (e.g., quinine, quinidine, sulfa, β-lactam antibiotics, carbamazepine, phenytoin, rifampin, sulfonylureas, ticlopidine, valproic acid) have been less frequently implicated (for a review of drugs associated with thrombocytopenia, seehttp://www.moon.ouhsc.edu/jgeorge). If a patient presents to the practitioner with severe thrombocytopenia caused by increased destruction of circulating platelets, it is important to ask what drugs the patient is taking and to consider stopping them if there is any question that the drugs are involved in the process.
It is not unusual for alcoholics to develop thrombocytopenia, usually to a moderate degree, after a binge. Alcohol appears to damage platelet membranes, causing their premature destruction, and to inhibit the compensatory increase in platelet production by marrow megakaryocytes. Once the binge is over, the platelet count returns to normal (or transiently higher than normal) in 4 to 5 days. Alcoholics of long standing who have developed cirrhosis of the liver and portal hypertension may have chronic thrombocytopenia because of increased sequestration of platelets in their spleens.
Management
An American Society of Hematology Practice Guidelines Panel has made recommendations for treatment of autoimmune thrombocytopenia (12,13). The panel found no experimental evidence on which to base recommendations, so they resorted to achieving a consensus among experts. The following recommendations are not precisely those of the panel but are consistent with its views. If the platelet count is <20,000/mm3, treatment should be instituted immediately with the equivalent of 60 to 100 mg (1 mg/kg of body weight) prednisone, even if the patient is asymptomatic or has only a few petechiae. Patients with mucous membrane or internal bleeding should be hospitalized, and patients with severe internal bleeding should receive intravenous γ-globulin (which corrects immune thrombocytopenia more rapidly than do corticosteroids) in the hospital. Such bleeding usually will not occur if the platelet count is >30,000/mm3. In general, the risk of major bleeding appears greater in elderly patients (18,19).
Most patients with platelet counts of 20,000 to 30,000/mm3 or less because of chronic immune thrombocytopenia ultimately require splenectomy. Treatment of immune thrombocytopenia in patients with HIV infection is the same as it is for patients who do not have HIV infection.
Although approximately 70% of patients respond within days to corticosteroids with a rise in platelet count sufficient to maintain adequate hemostasis, many relapse as the dosage is tapered. (A reasonable schedule is to reduce the dosage by 10 mg/day each week to half the initial dosage and then by 5 mg/day each week.) If patients do not respond to corticosteroids initially, if mucous membrane or internal bleeding recurs, or if the platelet count falls below 30,000/mm3 as the dosage of corticosteroids is tapered, splenectomy frequently is indicated. Adequate platelet counts (>50,000/mm3) are maintained in approximately 80% of splenectomized patients. Patients with symptomatic refractory immune thrombocytopenia may respond to an immunosuppressive drug (other than a corticosteroid) and should be treated by a hematologist.
Increased Sequestration of Platelets
Patients with large spleens often have thrombocytopenia because of redistribution of platelets within a larger splenic pool, most commonly because of congestive splenomegaly associated with portal hypertension. Splenectomy reverses thrombocytopenia but is rarely indicated, because usually the thrombocytopenia is not severe and splenectomy should be considered only if there is a clear-cut hemorrhagic diathesis and the underlying disease responsible for the enlarged spleen permits an operation to be performed.
Increased Use of Platelets
Patients with disseminated intravascular coagulation characteristically have thrombocytopenia, almost always in association with multiple defects in coagulation. Such patients often present acutely ill because of the underlying disease that has incited the hemostatic disorder. For example, in women with various complications of pregnancy, patients with disseminated carcinoma, or in some
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patients with septicemia, hemostatic mechanisms have been activated because of exposure of the circulating blood to thromboplastic material. The hemorrhagic diathesis is manifest most commonly by widespread bruising, petechiae, and mucous membrane bleeding, occasionally, but not often, associated with venous or arterial thrombosis. In addition to thrombocytopenia, patients have disordered coagulation, which can be identified by measuring the prothrombin time (PT), the partial thromboplastin time (PTT), and the concentration of fibrinogen in the plasma, and by demonstrating increased titers of fibrinogen and fibrin degradation products in the plasma or serum. These products are formed by the lysis of fibrinogen and fibrin by plasmin, the major proteolytic enzyme of the blood. Patients who are strongly suspected of having disseminated intravascular coagulation or in whom the diagnosis has been made should be hospitalized for further treatment and for identification and treatment of the underlying disease.
Qualitative Disorders of Platelets
A number of inherited abnormalities of platelets result in impaired hemostasis even though platelet counts often are within normal limits. In general, the hemorrhagic diathesis associated with these conditions is milder than it is in patients with severe thrombocytopenia. Practitioners are unlikely to see these patients, but if patients have unexplained bleeding, such as purpura, epistaxis, or menorrhagia, with apparently normal coagulation and normal or slightly reduced platelet counts, it is reasonable to perform a bleeding time (see below), which often is abnormal in patients with qualitatively abnormal platelets. Similar abnormalities may be acquired in patients with various disease states, most commonly uremia. In fact, patients with chronic renal failure who have a tendency to bleed often improve after hemodialysis. Perhaps the most common acquired qualitative disorder of blood platelets occurs after the ingestion of aspirin, which often prolongs the bleeding time and irreversibly interferes with platelet aggregation and the release of certain intracellular platelet constituents. Although untoward bleeding is unusual in patients who have taken aspirin, the drug may intensify a pre-existing tendency to bleed. Other nonsteroidal anti-inflammatory drugs may impair platelet function, but, compared with aspirin, the effect is even less predictable and is more quickly reversible when the drug is stopped.
Patient Experience
The bleeding time should be performed using a commercially available, spring-loaded, disposable device (Simplate) that makes a small incision in the forearm. The examiner should puncture the skin with the disposable lancet. A blood pressure cuff should be inflated to 40 mm Hg above the elbow during the test. The time between the instant the puncture is made and the point at which blood from the wound can no longer be adsorbed onto a piece of filter paper is the bleeding time (normally 2–9 minutes). The patient should be warned of the very transient sharp pain that will be experienced when the wound is made and of the small scar, usually inapparent, that may form when the wound heals.
Thrombocytosis
Platelet counts >400,000/mm3, unless associated with a myeloproliferative disorder such as polycythemia vera, myeloid metaplasia, or chronic granulocytic leukemia, are not in themselves associated with an increased risk for morbidity from excessive bleeding or clotting. However, they may signify the presence of an underlying disease that requires attention. If thrombocytosis exists, the most common causes are inflammatory disease and solid tumor malignancies. Other causes include the postsplenectomy state, acute bleeding, and severe chronic iron deficiency. In secondary thrombocytosis, the platelet count usually (but not always) is <1,000,000/mm3.
Patients with chronic myeloproliferative disorders (polycythemia vera, primary myelofibrosis, essential thrombocythemia), if they have thrombocytosis, usually have large distorted platelets on smear and other hematologic abnormalities typical of the particular disease. Many of these patients also have splenomegaly. The platelet counts may be >1,000,000/mm3. Treatment of thrombocytosis associated with chronic myeloproliferative disease should be planned in consultation with a hematologist.
Coagulation Disorders
The generation of a solid fibrin clot from circulating soluble fibrinogen is the body's major defense against the loss of blood from the vasculature, especially from blood vessels larger than the capillary, arteriole, and venule. Coagulation is initiated by the exposure of proteins to thromboplastic substances (tissue factor) when blood vessels are injured. Thereafter, a series of enzymatic reactions occurs that results in the conversion of fibrinogen by the proteolytic enzyme thrombin to fibrin. The best screening tests for detecting abnormalities of clotting are the activated partial thromboplastin time (aPTT) and PT. The aPTT and the PT measure different phases of the early parts of the coagulation process, but both measure the later phase of the process—the conversion of prothrombin to thrombin and the subsequent conversion of fibrinogen to fibrin.
Enzymatic mechanisms oppose coagulation and prevent unwarranted widespread clotting of the blood when a blood vessel is injured. A number of cases of patients with an increased tendency to thrombosis and low levels of activity of one of the various protease inhibitors that normally circulate in the blood and regulate coagulation
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have been reported (see Chapter 57). Thefibrinolytic system generates the proteolytic enzyme plasmin, which adsorbs to the clots and results in their ultimate dissolution. Fibrinolytic therapy is commonly used in the treatment of various thrombotic diseases (e.g., acute myocardial infarction), but such therapy requires hospitalization.
Patients who have a deficiency of one or more of the coagulation proteins are more likely to have extensive soft-tissue bleeding or major hemorrhage in response to trauma than are patients with disorders of the vasculature or of blood platelets (petechiae, discussed earlier in this chapter, are never a sign of abnormal coagulation). Hereditary disorders of coagulation are rare. Ordinarily they are readily diagnosed because of the history of lifelong bleeding and, in the case of hemophilia, because of a history of characteristic hemorrhage into joints and soft tissues. Patients who have a severe hemorrhagic diathesis because of a hereditary abnormality of clotting almost always have markedly low levels of the deficient coagulation protein. Therefore, screening tests such as the aPTT almost always are abnormal and provide clues to the presence of the disorder. The practitioner likely will not encounter such patients because most of them are diagnosed in childhood and are treated by hematologists thereafter. However, if such a patient who is suspected of having a hereditary disorder of coagulation but who has not previously been diagnosed is encountered, referral to an appropriate center is warranted.
Von Willebrand disease is an inherited abnormality of hemostasis (20); the majority of cases are autosomal dominant. The condition is marked by a reduction in the concentration or a change in the structure of the protein von Willebrand factor, which ordinarily binds to platelets and mediates their adhesion to subendothelial collagen in the course of platelet plug formation (see above). Normally, von Willebrand factor forms a complex with antihemophilic globulin (factor VIII:c), the protein that is deficient in the blood of patients with classic hemophilia, so patients with von Willebrand disease often have reduced levels of factor VIII. The qualitative disorder of platelets is reflected in a prolonged bleeding time and decreased platelet adhesiveness. The platelets of these patients characteristically do not aggregate in vitro, as normal platelets do, when exposed to the obsolete antibiotic ristocetin. The course of the disease and the extent of the laboratory abnormalities vary among patients, but in general the hemorrhagic diathesis is milder than it is in hemophilia A. Patients bleed most commonly from the gastrointestinal tract. Symptoms of the disease usually are not apparent until the patient is an adult. The bleeding time and aPTT are useful screening tests. The diagnosis and treatment of patients with von Willebrand disease require the ongoing participation of a hematologist.
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TABLE 56.4 Advice To Give Patients with a Disorder of Hemostasis |
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Acquired disorders of coagulation are more common than are congenital disorders. By their nature they are more likely to be associated with multiple defects in hemostasis, such as those seen in patients with disseminated intravascular coagulation (discussed earlier in this chapter) or in patients taking anticoagulant drugs (see Chapter 57). The diagnosis and management of these problems are discussed in those sections.
Rarely, an isolated clotting factor deficiency is acquired, often in association with a lymphoproliferative or collagen vascular disease. Such a deficiency may or may not be revealed by a hemorrhagic diathesis but almost always is associated with an abnormal aPTT or PT. Patients with unexplained prolonged aPTTs or PTs should be referred to a hematologist for evaluation.
Advice to Patients Who Have a Disorder of Hemostasis
Table 56.4 lists some rules to give patients who have hemostatic dysfunction. It is important that the patient know the name of his or her disease and its clinical manifestations.
Specific References
For annotated General References and resources related to this chapter, visit http://www.hopkinsbayview.org/PAMreferences.
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