Part XIII HEMATOLOGIC DISEASES - 札幌医科大学tatsumi/std2009/184... · part xiii hematologic diseases part xiii: hematologic diseases part xiii hematologic diseases select an

Part XIII HEMATOLOGIC DISEASES

Part XIII: HEMATOLOGIC DISEASES

Part XIII HEMATOLOGIC DISEASES Select an item below

● Chapter 158 HEMATOPOIESIS AND HEMATOPOIETIC GROWTH FACTORS ● Chapter 159 APPROACH TO THE ANEMIAS ● Chapter 160 APLASTIC ANEMIA AND RELATED BONE MARROW FAILURE

SYNDROMES ● Chapter 161 NORMOCHROMIC, NORMOCYTIC ANEMIAS ● Chapter 162 MICROCYTIC AND HYPOCHROMIC ANEMIAS ● Chapter 163 MEGALOBLASTIC ANEMIAS ● Chapter 164 HEMOLYTIC ANEMIAS: RED CELL MEMBRANE AND METABOLIC

DEFECTS ● Chapter 165 HEMOLYTIC ANEMIAS: AUTOIMMUNE ● Chapter 166 HEMOLYTIC ANEMIAS: INTRAVASCULAR ● Chapter 167 HEMOGLOBINOPATHIES: THE THALASSEMIAS ● Chapter 168 HEMOGLOBINOPATHIES: METHEMOGLOBINEMIAS, POLYCYTHEMIAS,

AND UNSTABLE HEMOGLOBINS ● Chapter 169 SICKLE CELL ANEMIA AND ASSOCIATED HEMOGLOBINOPATHIES ● Chapter 170 BLOOD TRANSFUSION ● Chapter 171 DISORDERS OF PHAGOCYTE FUNCTION ● Chapter 172 LEUKOPENIA AND LEUKOCYTOSIS ● Chapter 173 EOSINOPHILIC SYNDROMES ● Chapter 174 MYELOPROLIFERATIVE DISEASES ● Chapter 175 MYELODYSPLASTIC SYNDROME ● Chapter 176 THE CHRONIC LEUKEMIAS ● Chapter 177 THE ACUTE LEUKEMIAS ● Chapter 178 APPROACH TO THE PATIENT WITH LYMPHADENOPATHY AND

SPLENOMEGALY ● Chapter 179 NON-HODGKIN'S LYMPHOMAS ● Chapter 180 HODGKIN'S DISEASE ● Chapter 181 PLASMA CELL DISORDERS ● Chapter 182 STEM CELL TRANSPLANTATION ● Chapter 183 APPROACH TO THE PATIENT WITH BLEEDING AND THROMBOSIS ● Chapter 184 HEMORRHAGIC DISORDERS: ABNORMALITIES OF PLATELET AND

VASCULAR FUNCTION ● Chapter 185 COAGULATION FACTOR DEFICIENCIES ● Chapter 186 HEMORRHAGIC DISORDERS: MIXED ABNORMALITIES ● Chapter 187 THROMBOTIC DISORDERS: HYPERCOAGULABLE STATES ● Chapter 188 ANTITHROMBOTIC THERAPY

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Chapter 184 HEMORRHAGIC DISORDERS: ABNORMALITIES OF PLATELET AND VASCULAR FUNCTION


Chapter 184: HEMORRHAGIC DISORDERS: ABNORMALITIES OF PLATELET AND VASCULAR FUNCTION

Chapter 184 HEMORRHAGIC DISORDERS: ABNORMALITIES OF PLATELET AND VASCULAR

FUNCTION

Marc Shuman

The normal sequence of events leading to clotting is initiated by trauma to the vessel, which constricts reflexively to reduce bloodflow. Platelets adhere to the subendothelial matrix in the injured vessel, and platelet aggregation and thrombus formation begin simultaneously (see Chapter 183). A variety of drugs can interfere with different aspects of hemostasis (Table 184–1), and therefore a medication history is particularly important.

TABLE 184–1. DRUGS THAT MAY ALTER HEMOSTASIS

Select an item below

● PATHOLOGIC HEMOSTASIS. ● BLOOD PLATELETS ● ABNORMALITIES IN PLATELET COUNT ● ABNORMALITIES IN PLATELET FUNCTION ● PLATELET TRANSFUSIONS ● VASCULAR DISORDERS (TABLE 184–5) ● BIBLIOGRAPHY ● FIGURES● TABLES

Notes

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Chapter 184: PATHOLOGIC HEMOSTASIS.



PATHOLOGIC HEMOSTASIS.

Thrombus formation is similar to normal hemostasis except that abnormalities in activation, inhibition, or fibrinolysis result in pathologic clots. Derangements may occur in (1) the vessel wall, e.g., atherosclerosis; (2) platelets, e.g., myeloproliferative disorders; and (3) regulation of the coagulation system, e.g., antithrombin III deficiency, Factor V Leiden, etc. Anatomic and/or biochemical alterations of the vascular intima are by far the most frequent causes of pathologic thrombosis. A variety of pathologic alterations of the vessel wall modify endothelial function in a prothrombotic fashion. At one extreme, the endothelial lining may be physically disrupted with exposure of circulating blood to extracellular matrix and tissue factor. Also, several substances may induce intact endothelium to promote thrombosis. Thus interleukin-1 (IL-1), tumor necrosis factor, and endotoxin increase both endothelial plasminogen activator inhibitor type 1, inhibitor of fibrinolysis, and endothelial tissue factor. Moreover, endothelial cells express receptors for several of the coagulation factors, including Factors Va, IXa, and Xa, so that once coagulation is initiated, it can be amplified on the endothelial cell surface. It is not difficult to imagine how rupture of an atherosclerotic plaque results in pathologic initiation of clotting that terminates in vascular occlusion. Thrombosis is an important event in atherosclerotic vascular disease: (1) platelet thrombi are found in the coronary circulation in fatal myocardial infarction, and (2) fibrinolytic therapy can restore blood flow early in coronary occlusion.

Notes

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Chapter 184: BLOOD PLATELETS



BLOOD PLATELETS


● FORMATION AND KINETICS. ● PLATELET FUNCTION. ● PLATELET FUNCTION TESTS.

Notes


Chapter 184: FORMATION AND KINETICS.



FORMATION AND KINETICS.

Platelets are disk-shaped cells 2 to 4 mm in diameter normally found in the peripheral blood (150,000 to 300,000 per microliter). In Wright-stained blood smears, they are identified by their blue-gray cytoplasm and red (lysosomal) granules and by lack of a nucleus.

Platelets are formed in the bone marrow from giant polyploid cells called megakaryocytes. Megakaryocytes mature by a series of nuclear replications within a common cytoplasm (endomitosis) that lead to four- to six-lobed nuclei, as well as by elaboration of specific granules in the cytoplasm. Following maturation, the megakaryocyte cytoplasm becomes demarcated into platelet subunits, and the platelets are released into the circulation through the marrow sinusoids. A hematopoietic growth factor specific for megakaryocytes, thrombopoietin, has been identified. Various forms of the recombinant protein are currently being tested in clinical trials. The expectation is that it will be approved for the treatment of patients with thrombocytopenia caused by inadequate production of platelets. IL-11 also stimulates platelet production. IL-11 has been approved for use in patients with thrombocytopenia secondary to treatment of malignancy with high-dose chemotherapy.

Ordinarily, each megakaryocyte produces 1000 to 3000 platelets. Normally, 3 to 10 megakaryocytes are seen in bone marrow smears under low-power magnification, but none appear in peripheral blood. Platelets circulate for 9 to 10 days. Approximately one third reside in a splenic pool, which exchanges freely with the circulating pool. In diseases associated with platelet antibodies, the spleen is frequently the site of destruction. In addition, in disorders causing secondary splenic enlargement, thrombocytopenia may result from splenic sequestration (see Chapter 178). Conversely, following splenectomy, the platelet count may

increase transiently to 106 per microliter.

An estimate of platelet number in the peripheral blood film (normal, increased, decreased) is useful in detecting patients with abnormally low platelet counts. Normally, 3 to 10 platelets per high-power (oil immersion) field appear on peripheral smears. Platelets are counted directly by an automated particle counter.

Notes



Chapter 184: PLATELET FUNCTION.



PLATELET FUNCTION.

Platelets contain three types of secretory granules: lysosomes, α-granules, and dense bodies (electron-dense organelles) (Fig. 184–1). α-Granules contain platelet-specific proteins: platelet factor 4, β-thromboglobulin, and several growth factors, including platelet-derived growth factor, platelet-derived endothelial cell growth factor, and transforming growth factor β. α-Granules also contain several hemostatic proteins, including fibrinogen, Factor V, and von Willebrand factor, which is synthesized by megakaryocytes. Dense bodies (δ-granules) contain adenosine triphosphate, adenose diphosphate (ADP), Ca2+, and serotonin.

FIGURE 184–1 Electron micrograph of an unstimulated platelet. α = α-granule; d = dense body (×24,000). (Courtesy of Dr. Dorothy Bainton, University of California, San Francisco.)

In addition to release of potent vasoconstrictors from intracellular granules in response to a variety of substances and aggregation to form a plug at the site of vessel injury, platelets provide a surface for the activation of soluble coagulation factors (Fig. 184–2). Activated platelets expose specific receptors that bind Factor Xa and Va and in this way increase their local concentration, thus accelerating prothrombin activation. Factor X is also activated by Factors IXa and VIII (antihemophilic factor) on the platelet surface.

FIGURE 184–2 Platelet aggregation, adhesion, and enhancement of coagulation. A, Platelet aggregation. Activation of platelets by several physiologic stimuli results in fibrinogen binding to specific receptors, GPIIb-IIIa. Binding of fibrinogen is followed by platelet aggregation. B, Platelet adhesion. Injury to the vascular endothelium results in exposure of extracellular matrix. Under high shear, von Willebrand factor (vWf) binds to the platelet receptor GPIb. The platelet-vWf complex then binds to the subendothelium. C, Amplification of thrombin formation by platelets. Coagulation Factors IXa, VIIIa, and X form a Ca2+-dependent trimolecular complex on the platelet surface. Activation of Factor X is amplified several hundred thousand–fold. Coagulation Factors Xa, Va, and prothrombin form a Ca2+-dependent trimolecular complex on platelets. Thrombin formation is amplified several hundred thousand–fold.

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Chapter 184: PLATELET FUNCTION.

Platelets contain a membrane phospholipase C that, upon stimulation by activating agents, hydrolyzes endogenous phosphatidylinositol to form a diglyceride. The diglyceride, in turn, is converted to arachidonic acid by a diglyceride lipase. Arachidonic acid is a substrate for prostaglandin synthetase (cyclooxygenase), a reaction inhibited by aspirin and non-steroidal anti-inflammatory drugs, and is subsequently converted to prostaglandins. The prostaglandin endoperoxide PGG2 is required for ADP-induced aggregation and release; both PGG2 and

thromboxane A2 are potent platelet-aggregating agents.

Notes


Chapter 184: PLATELET FUNCTION TESTS.



PLATELET FUNCTION TESTS.

BLEEDING TIME.

(See Chapter 183.) The bleeding time is prolonged when the platelet count falls below 90,000 per microliter or when a functional platelet abnormality exists. Von Willebrand disease prolongs the bleeding time not as a result of a platelet defect but rather because of the lack of a plasma factor important for normal platelet function. Although imperfect, the bleeding time is the only test of platelet function that correlates with susceptibility to bleeding. Even though patients with a prolonged bleeding time may be at risk for increased bleeding with surgery, not all have abnormal bleeding.

PLATELET AGGREGOMETRY.

The response of platelets to a variety of aggregating agents can be quantitated in platelet-rich plasma or whole blood. The aggregometer measures temporal, semiquantitative, and qualitative parameters of in vitro aggregation. This technique is of greatest value in diagnosing congenital qualitative platelet disorders.

Notes



Chapter 184: ABNORMALITIES IN PLATELET COUNT



ABNORMALITIES IN PLATELET COUNT


● Thrombocytopenia ● Thrombocytosis

Notes


Chapter 184: Thrombocytopenia



Thrombocytopenia

Low platelet counts (thrombocytopenia) (Fig. 184–3) can be caused by disturbances in production, distribution, or destruction. The consequences are entirely hemostatic. With normally functioning platelets, the following is expected: when the platelet count is 100,000 per microliter or greater, patients have no abnormal bleeding even with major surgery; with a platelet count of 50,000 to 100,000 per microliter, patients may bleed longer than normal with severe trauma; with a platelet count of 20,000 to 50,000 per microliter, bleeding occurs with minor trauma, but spontaneous bleeding is unusual; with a platelet count less than 20,000 per microliter, patients may have spontaneous bleeding; and when the platelet count is less than 10,000 per microliter, patients are at high risk for severe bleeding.

FIGURE 184–3 Evaluation of thrombocytopenia. Abn = abnormal; N = normal; PT = prothrombin time; aPTT = activated partial thromboplastin time; LDH = lactate dehydrogenase; BUN = blood urea nitrogen.

Decreased Production of Platelets

Hypoplasia of hematopoietic stem cells may cause thrombocytopenia (Table 184–2). Examination of the bone marrow reveals decreased numbers of megakaryocytes and either an overall decrease in cellularity or infiltration by abnormal cells.

TABLE 184–2. DISORDERS ASSOCIATED WITH THROMBOCYTOPENIA

Decreased production of platelets may also be due to abnormal maturation of megakaryocytes. Deficiency of either vitamin B12 or folate can cause thrombocytopenia

owing to ineffective thrombocytopoiesis (see Chapter 163). Similarly, abnormal platelet production is common in hematopoietic dysplasias (see Chapter 175). In both disorders, megakaryocytes are usually increased. In hematopoietic dysplasia, megakaryocytes may be abnormal in appearance, such as micromegakaryocytes occasionally with a single-lobed nucleus.

Increased Peripheral Destruction of Platelets (see Table 184–2)

IMMUNE DISORDERS.

Three types of immunologic reactions cause premature destruction of platelets: (1)





development of autoantibodies against platelet-membrane antigens, (2) binding of immune complexes to platelet Fc receptors, and (3) lysis of platelets because of fixation of complement on their surface.

IDIOPATHIC THROMBOCYTOPENIC PURPURA.

Idiopathic thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder characterized by the development of antibodies to one's own platelets, which are then destroyed by phagocytosis in the spleen and, to a lesser extent, the liver. The spleen is the principal reticuloendothelial site of platelet destruction, as well as the major site of synthesis of antibody production in ITP. Childhood ITP is usually acute and follows recovery from a viral infection. The incidence is equal in boys and girls. In adults, the onset is usually more gradual, without a preceding illness and with a chronic course. In a small percentage of adult cases, the disease has an acute onset. Ninety per cent of adults with ITP are younger than 40 years, and the ratio of women to men is 3 to 4:1. Some patients' sera contain antibodies against platelet glycoproteins IIb and IIIa. Petechiae, ecchymoses, and epistaxis develop in this patients. Menorrhagia may develop in women. The incidence of death, reported in older series to be about 5%, is likely to be significantly lower now. Adverse risk factors are severe thrombocytopenia (platelet count, <15,000), advanced age, and concomitant bleeding diatheses. Cerebral bleeding occurs in approximately 1% of cases.

The diagnosis of ITP depends on the exclusion of underlying systemic disorders that result in increased peripheral destruction or decreased production of platelets. On physical examination, the spleen is not enlarged, although it may be in childhood ITP as a consequence of viral infection. In ITP the hemoglobin is normal unless the patient has significant bleeding. Peripheral blood smears reveal normochromic, normocytic red blood cells. Similarly, the leukocyte count and differential are normal, although these values may reflect a preceding viral illness in children. The value of assays for detecting antiplatelet antibodies on the platelet surface is unclear; most of the tests do not distinguish between autoantibodies and immune complexes that bind to the platelet Fc receptor. Furthermore, the assays do not differentiate between specific antiplatelet antibodies and non-specifically adsorbed IgG. In most cases of ITP the diagnosis is clear-cut, thus making it unnecessary to confirm the presence of antiplatelet antibodies. In complex cases, the antibody test may be helpful. The level of platelet-associated IgG does not correlate with the severity of thrombocytopenia. In over 90% of cases of chronic ITP, the antibody is IgG.

If the general clinical evaluation and blood tests do not identify a systemic cause of thrombocytopenia, the bone marrow should be examined. In ITP the marrow is normal, although megakaryocytes may be increased in number.

In children, ITP is self-limited. Approximately 70% recover within 4 to 6 weeks. In adults, indications for treatment depend on the severity of bleeding and the degree of thrombocytopenia. Asymptomatic patients with platelet counts greater than 40,000 per microliter can be observed with periodic evaluation to determine the natural fluctuations of their disease. Patients with platelet counts less than 20,000 per microliter are usually symptomatic and require treatment. Patients with platelet counts over 30,000 per microliter who have bleeding may have an acquired platelet function abnormality caused by the antibody. Initially, bleeding associated with ITP is treated with prednisone at a dose of 1 to 2 mg/kg/day. Prednisone inhibits macrophage ingestion of antibody-coated platelets, in addition to suppressing antibody synthesis. Prednisone has also been shown to have a



stabilizing effect on small blood vessels in thrombocytopenic animals. In 80 to 90% of patients, the platelet count rises to hemostatic levels within 2 to 3 weeks. Failure to respond to steroids is indicated by a platelet count lower than 50,000 per microliter after 4 weeks of treatment or a subnormal platelet count after 6 weeks. Once the platelet count has reached its apex and is stable, the steroid dose should be tapered slowly. When the dose of prednisone is tapered, however, most patients (>90%) exhibit a relapse of thrombocytopenia. Thus the primary benefit of prednisone is in the acute management of bleeding.

Another effective approach to managing patients who are actively bleeding or for whom major surgery is necessary is the use of intravenous γ-globulin. Intravenous immune globulin (IVIG) concentrates raise the platelet count within 3 to 5 days in most patients and is the most rapidly active agent. Unfortunately, the therapeutic effect is usually transient because the platelet count falls to baseline levels over the next month. In rare instances, repeated infusions of IVIG have led to sustained remissions after discontinuation of therapy. It is proposed that IVIG works by blocking Fc receptors on macrophages, thereby inhibiting phagocytosis. The dosage is 1 g/kg/day on 2 successive days. In 80% of patients, subsequent platelet counts rise above 50,000 per microliter. A less expensive alternative is RhoGAM, anti-Rh antibody. The principle is the same as that in IVIG, reticuloendothelial blockade.

Owing to the lack of a sustained remission in most patients with severe thrombocytopenia treated with steroids or IVIG, a more definitive approach is necessary. Splenectomy improves the platelet count in 70% of patients with ITP and induces sustained remission in approximately 60%, but no test can reliably predict which patients will respond. The platelet count rises, usually within a few days or at most 1 to 2 weeks after splenectomy.

A variety of other therapies can induce partial or complete remissions in chronic ITP when splenectomy has failed. Danazol, 200 mg three times per day, induces a remission in approximately 40% of cases of chronic ITP. Response is delayed and takes 4 to 6 weeks. The mechanism remains unknown. Intravenous vincristine and vinblastine also raise the platelet count in ITP, usually within 1 to 2 weeks. Responses are transient and remissions are not sustained.

Immunosuppressive agents—cyclophosphamide and azathioprine—improve the platelet count in 20 to 30% of cases of chronic ITP. The potential benefit of these drugs must be weighed against the risks of toxicity. In one small series, 60% of patients with refractory ITP had complete remissions with combination chemotherapy. Pulsed, high-dose dexamethasone has also been reported to be effective therapy in patients with refractory ITP.

Management of ITP in pregnancy is complicated by the additional risk to the fetus of thrombocytopenia secondary to maternal antibodies. Intraventricular hemorrhage, gastrointestinal bleeding, and death have been reported in newborns. Whether the mother had ITP before pregnancy is critical. When ITP initially develops in women during pregnancy, the risk of serious bleeding in the newborn is negligible. Conversely, neonates born to women with a history of ITP preceding pregnancy have a 20% risk of severe thrombocytopenia. In addition to treating the underlying ITP, cesarean delivery is recommended to decrease the risk of intracranial bleeding in these newborns.



PLATELET ANTIBODIES ASSOCIATED WITH SYSTEMIC DISORDERS.

Antibodies directed against platelets and causing thrombocytopenia occur in several types of disorders in which bone marrow megakaryocytes are normal or increased in number. Antibody-mediated destruction of platelets occurs in lymphoproliferative disorders such as chronic lymphocytic leukemia and lymphoma. Generally, thrombocytopenia improves with treatment of the underlying malignancy. Immune thrombocytopenia has also been associated with non-hematologic tumors, but it is unclear whether these have been chance associations. The platelet count improves with immunosuppressive therapy such as prednisone.

Immune thrombocytopenia is common in systemic lupus erythematosus (SLE) (see Chapter 289). Whether this association is due to specific antiplatelet antibodies, to antibodies against common antigens also found on platelets, or to immune complexes is unclear. The platelet count is usually mildly to moderately decreased. Treatment is usually directed at SLE because other manifestations of the disease are present in most cases. Occasionally, immune thrombocytopenia occurs in patients who have serologic evidence of SLE but fail to meet all the criteria for the diagnosis. The decision to treat such patients with splenectomy is difficult because other manifestations of SLE may appear subsequently. If the platelet count is severely decreased (<30,000 per microliter) and no other complications of SLE exist, splenectomy is a reasonable choice. If the platelet count is moderately decreased (230,000 to 40,000 per microliter) and major bleeding problems are absent, careful observation may be the best course. Monthly intravenous cyclophosphamide, 0.75 to 1.0 g/m2 body surface area, normalizes platelet counts within 2 to 18 weeks in patients with SLE who are also taking prednisone. Such therapy allows a substantial reduction in steroid dosage.

Thrombocytopenia associated with antiplatelet antibodies has been reported in patients with viral illnesses, including infectious mononucleosis, human immunodeficiency virus (HIV) infection, and cytomegalovirus (CMV) infection. In the case of infectious mononucleosis and CMV infection, thrombocytopenia is usually self-limiting, with recovery in 3 to 4 weeks. For patients with severe thrombocytopenia, a short course of glucocorticoids may be indicated. The nature of the immune reaction has not been characterized. In HIV-infected patients, thrombocytopenia is frequent with or without the full acquired immune deficiency syndrome (AIDS). Frequently the causes are multifactorial: (1) infection causing increased platelet destruction and/or inhibition of platelet production secondary to granulomatous replacement of the bone marrow, (2) suppression of hematopoiesis by drugs used to treat AIDS or associated infections, and (3) immune destruction of the patient's own platelets. Antibodies associated with platelets have been demonstrated in these patients, although the cause is unclear. Treatment with prednisone is hazardous because of the immunocompromised status of these patients. Splenectomy has the disadvantage of further compromising the immune system. Zidovudine treatment sometimes raises the platelet count in mild to moderate thrombocytopenia. For acute bleeding, IVIG raises the platelet count within a few days.

More than 50 drugs (see Table 184–1) have been reported to cause immune thrombocytopenia, but infrequently with conclusive confirmation. Quinine and quinidine often cause immune thrombocytopenia, and drug-dependent antibodies have been demonstrated. Sulfa compounds, including sulfisoxazole, sulfonamide, sulfamethoxypyridazine, and sulfamethazine, have also been demonstrated to cause immune thrombocytopenia. Multiple





reports describe immune thrombocytopenia caused by hydrochlorothiazide, phenytoin, methyldopa, heparin, and digitalis derivatives. In most instances the drug must be present to cause antibody binding and thrombocytopenia, and the platelet count returns to normal within a few days after discontinuation of treatment. Glucocorticoids do not accelerate recovery. Platelet antibody tests with and without the putative offending agent are useful in determining the cause of thrombocytopenia but cannot be performed until the drug clears from the plasma. In addition, a drug metabolite rather than the parent compound may be responsible for antibody formation and binding to platelets. Unless the metabolite is specifically tested, a negative result will be obtained.


The incidence of thrombocytopenia associated with heparin therapy appears to be 3 to 5%, with a higher percentage of cases associated with bovine than with porcine preparations. The platelet count usually decreases gradually after the first few days of treatment and seldom induces bleeding. The count corrects rapidly after heparin therapy is discontinued. Nevertheless, if the platelet count falls below 50,000 per microliter, heparin therapy should be discontinued. Thrombocytopenia has been reported with the usual therapeutic doses, as well as with the very low doses used for procedures such as hemodialysis and "flushing" of vascular catheters or during revascularization procedures. The antibody appears to be against a complex of heparin and platelet factor 4, a glycosaminoglycan α-granule component with high affinity for heparin. Immune thrombocytopenia also occurs with low-molecular-weight heparins as well (e.g., enoxaparin and dalteparin [Fragmin]). In approximately 50% of patients with immune thrombocytopenia secondary to heparin, the antibody cross-reacts with low-molecular-weight heparins. Patients with heparin-induced thrombocytopenia are at risk for either arterial or venous thrombosis and pose an extremely difficult challenge inasmuch as treatment with either unfractionated or low-molecular-weight heparin is contraindicated. Moreover, warfarin should not be used acutely as the sole anticoagulant. Alternatives to heparin for acute anticoagulation of patients with active thrombosis include new thrombin inhibitors or heparinoids.

NON-IMMUNE DISORDERS ASSOCIATED WITH INCREASED CONSUMPTION OF PLATELETS.

DISSEMINATED INTRAVASCULAR COAGULATION.

(See Chapter 186). In this syndrome, pathologically activated coagulation results in thrombin formation and the subsequent removal of platelets from the circulation.

THROMBOTIC THROMBOCYTOPENIC PURPURA.

A rare disease of unknown etiology, thrombotic thrombocytopenic purpura (TTP) is characterized by severe thrombocytopenia, microangiopathic hemolytic anemia (>96% of patients), and neurologic abnormalities (>92% of patients). Fever and renal involvement—proteinuria, hematuria, azotemia, and casts—are present in 98 and 88% of patients, respectively. Renal abnormalities are usually mild; the creatinine rarely exceeds 3.0 mg/dL. Azotemia usually reverses as remission occurs, in contrast to the hemolytic-uremic syndrome (HUS) (see below). In the involved organs, arterioles and capillaries become occluded by a hyaline material consisting principally of platelet thrombi plus fibrin deposits in the vessel wall. Virtually any organ may be involved. Symptoms frequently wax and wane,




presumably because of platelet aggregation and disaggregation. Thus patients may have evanescent headache, aphasia, or stupor one moment and be alert the next.

TTP must be considered when thrombocytopenia and anemia occur acutely with microangiopathic changes of red blood cells on the peripheral blood smear and the absence of evidence of other disorders (Tables 184–3 and 184–4; Color Plate 6L). Although findings in disseminated intravascular coagulation are similar, patients with TTP have minimal changes in coagulation tests. Evans' syndrome, which is autoimmune hemolytic anemia and thrombocytopenia, is characterized by a positive Coombs' test and by microspherocytes rather than schistocytes on peripheral smear. Rarely, TTP has been reported to complicate SLE. More commonly, patients with SLE have immune thrombocytopenia and anemia of chronic disease or immune hemolytic anemia (see Chapter 289). TTP has also been reported in association with oral contraceptives and pregnancy. In most cases the diagnosis of TTP is straightforward. When the diagnosis is uncertain, gum, skin, or bone marrow biopsy may be helpful, with positive results reported in 40 to 60% of cases. It is critical to establish the diagnosis and begin treatment rapidly inasmuch as delay can result in severe morbidity or mortality. Most untreated patients die within 3 months. Large-volume plasmapheresis, approximately two plasma volumes with replacement infusion of normal plasma, is the treatment of choice for TTP and cures approximately 70% of patients. The best indication of a successful response is a rise in the platelet count. Plasmapheresis/infusion should be continued until the platelet count becomes normal and stable. Normalization of anemia and neurologic abnormalities usually follows. Approximately 10% of patients have a chronic, relapsing form of TTP. The plasma of patients with chronic TTP in remission contains abnormally large multimers of von Willebrand factor.

TABLE 184–3. DIFFERENTIAL DIAGNOSIS OF ANEMIA AND THROMBOCYTOPENIA

TABLE 184–4. DISORDERS ASSOCIATED WITH THROMBOCYTOPENIA AND MICROANGIOPATHIC ANEMIA

COLOR PLATE 6–L, Thrombotic thrombocytopenic purpura (TTP). Peripheral smear shows fragmented red cells alongside larger, polychromatophilic cells and a nucleated red cell that reflect hemolysis, as well as a paucity of platelets.

HEMOLYTIC-UREMIC SYNDROME.

Primarily a disorder of infants and young children, HUS rarely occurs in adults. Like TTP, HUS produces a microangiopathic hemolytic anemia, but thrombocytopenia is mild to moderate and neurologic abnormalities are absent. Unlike TTP, acute renal failure is a prominent feature in HUS, frequently necessitating hemodialysis. Severe hypertension is also a prominent feature. Children typically have gastrointestinal signs and symptoms—abdominal pain and diarrhea. HUS may occur in women who are in the postpartum period or are taking oral contraceptives. HUS has also been reported in cancer patients receiving mitomycin or cisplatin chemotherapy.

SEPSIS.




Gram-negative (more commonly than gram-positive) sepsis causes accelerated platelet destruction, presumably a result of binding of bacterial immune complexes to the platelet. Severe thrombocytopenia may follow.

Disorders of Distribution of Platelets

With splenic enlargement, platelet pooling increases (e.g., Gaucher's disease, congestive splenomegaly, lymphoma) and may cause thrombocytopenia (see Chapter 178). Platelet counts lower than 30,000 to 50,000 per microliter are unusual.

Dilutional Thrombocytopenia

When packed erythrocytes or non-fresh whole blood is transfused to replace blood loss, thrombocytopenia may ensue. Approximately 35 to 40% of platelets remain after replacement of one blood volume; microvascular bleeding secondary to thrombocytopenia occurs rarely after the replacement of one to two volumes. Platelets should be transfused only if thrombocytopenia and bleeding are present.

Notes



Chapter 184: Thrombocytosis



Thrombocytosis

Elevation of the platelet count above the normal range reflects increased production, either reactive or the result of a myeloproliferative disorder. Most thrombocytosis occurs secondary to an underlying disorder unassociated with complications. When caused by a primary disorder of hematopoiesis, however, thrombocytosis can cause serious bleeding and/or thrombotic complications, which makes it important to determine its cause.

ESSENTIAL THROMBOCYTHEMIA.

Essential thrombocythemia (see Chapter 174) and other myeloproliferative diseases such as agnogenic myeloid metaplasia and polycythemia vera are also associated with an elevated platelet count. The count may be elevated in chronic myelogenous leukemia but rarely results in complications.

REACTIVE THROMBOCYTOSIS.

Elevated platelet counts occur secondarily in a number of unrelated disorders (counts higher than 106 per microliter are unusual): iron deficiency anemia; hemorrhage; splenectomy (see Chapter 178); inflammatory disorders, particularly inflammatory bowel disease; neoplasms (e.g., lung, gastrointestinal); and leukemoid reaction (see Chapter 172).

No convincing evidence exists that reactive thrombocytosis increases the risk of thrombosis. Therefore it should not be treated. With successful treatment of the primary disease, the count returns to normal.

Notes





Chapter 184: ABNORMALITIES IN PLATELET FUNCTION



ABNORMALITIES IN PLATELET FUNCTION


● Acquired Disorders of Platelet Function ● Hereditary Disorders of Platelet Function

Notes


Chapter 184: Acquired Disorders of Platelet Function



Acquired Disorders of Platelet Function

DRUGS THAT INHIBIT PLATELET FUNCTION.

(See Table 184–1.) Non-steroidal anti-inflammatory agents inhibit platelet function by blocking platelet synthesis of prostaglandins. Aspirin (acetylsalicylic acid) irreversibly acetylates prostaglandin synthetase (cyclooxygenase) and, as a result, impairs platelet function for its lifespan. One aspirin tablet (300 mg) is sufficient to cause this effect. Fortunately, in normal people this dose does not result in excessive bleeding, but in patients with von Willebrand disease or those with severe coagulation factor deficiency (Factor VIII or IX), serious bleeding can result. For this reason, aspirin is contraindicated in these disorders.


High doses of β-lactam antibiotics such as penicillin and related compounds induce an abnormality in platelet function that persists for 2 to 3 days after treatment with the drug is discontinued. The mechanism is unclear. The bleeding time is prolonged, and patients may have increased bleeding.

RENAL FAILURE.

Platelets function abnormally in patients with renal failure. The uremic metabolites responsible for this dysfunction are uncertain. Guanidinosuccinic acid and phenolic compounds that accumulate in uremia may inhibit platelet aggregation. Abnormal platelet adhesion and activation may occur in uremia as well as thrombocytopenia. The latter is usually mild and may be due to the underlying cause of the renal disease.

Uremic bleeding is usually mucocutaneous and reflects abnormal platelet and/or vascular hemostatic functions. The bleeding time is commonly prolonged, but other causes of prolongation must be excluded (e.g., medication, congenital platelet disorders, and von Willebrand disease). Low hematocrits (<24%) prolong the bleeding time in uremia. Transfusion of packed red blood cells or recombinant erythropoietin to elevate the hematocrit above 26% shortens the bleeding time and corrects abnormal platelet aggregation in hemodialysis patients. Although the mechanism for improved hemostasis is uncertain, it may be due in part to increased platelet radial movement and interaction with the endothelium. Tests of coagulation are normal.

When a uremic patient bleeds, a structural lesion or other hemostatic abnormalities must be suspected; platelet abnormalities are seldom the cause. When the hemostatic defect of renal failure is believed to be a significant contributing factor in bleeding, either peritoneal dialysis or hemodialysis can usually reverse the hemostatic defect. If the bleeding time remains prolonged and the patient is bleeding, low-dose estrogens, 1-deamino-8-D-arginine


Chapter 184: Acquired Disorders of Platelet Function

vasopressin (DDAVP), or cryoprecipitate can be tried. All three raise the plasma levels of Factor VIII (antihemophilic factor/von Willebrand factor), but their efficacies have not been firmly established. Platelet transfusion usually has no benefit.

HEPATIC FAILURE.

(See Chapter 154.) Platelet function is sometimes abnormal in liver disease, but why this is so and the extent to which it contributes to bleeding are unclear. The bleeding time may be prolonged in moderately severe liver disease when the platelet count is greater than 90,000 per microliter. DDAVP has been reported to improve the bleeding time in these circumstances. More commonly in hepatic failure, a bleeding diathesis is due to deficiencies in coagulation factors.

PARAPROTEINEMIAS.

(See Chapter 181.) Abnormal platelet function occurs in a subset of patients with multiple myeloma or Waldenström's macroglobulinemia. The bleeding time is usually prolonged, and bleeding can be moderately severe. If the level of the paraprotein is lowered by plasmapheresis and/or chemotherapy, the bleeding time and bleeding improve, thus suggesting a direct effect of the paraprotein on platelet function. Paraproteins may impair platelet function by inhibiting platelet-fibrinogen interaction.

ACQUIRED STORAGE POOL DISEASE.

Mild platelet function abnormalities may develop from loss of storage granules. Some of the disorders in which this finding has been reported include cardiopulmonary bypass surgery, hairy cell leukemia, and conditions with antiplatelet autoantibodies. Platelet dysfunction following bypass surgery is transient and not of clinical importance beyond the initial 24 hours after surgery.

MYELOPROLIFERATIVE DISORDERS.

Patients with essential thrombocythemia and, less commonly, agnogenic myeloid metaplasia and polycythemia vera may have abnormalities of platelet function. In essential thrombocythemia, abnormalities usually occur at platelet counts greater than 106 per microliter and may lead to abnormal bleeding, thrombosis, or both. Although the functional abnormalities are not specific, a prolonged bleeding time indicates that the patient is at risk for bleeding. Treatment of bleeding patients with thrombocytosis should be directed at lowering the platelet count as rapidly as possible.

Notes




Chapter 184: Hereditary Disorders of Platelet Function



Hereditary Disorders of Platelet Function

The bleeding history is similar among these rare diseases. Patients provide a lifelong history of easy bruising, epistaxis, and prolonged oozing after venipuncture, dental extractions, and other challenges to hemostasis.

GLANZMANN'S THROMBASTHENIA.

This autosomal recessive bleeding disorder is characterized by a prolonged bleeding time and platelets that fail to aggregate normally when stimulated with ADP, epinephrine, collagen, or thrombin. In Glanzmann's thrombocytopenia, two membrane glycoproteins (GPIIb, GPIIIa) that normally serve as the receptor for fibrinogen in activated platelets are markedly deficient (see Fig. 184–2). Fibrinogen binding to platelets is required for platelet aggregation. The diagnosis is confirmed by demonstrating a deficiency of platelet GPIIb-IIIa. The platelet count is always normal.


BERNARD-SOULIER SYNDROME.

This autosomal recessive disorder is caused by deficiency of a platelet membrane glycoprotein complex, GPIb-IX. As a result, "giant" platelets appear in the peripheral blood smear. Frequently, the platelet count is mildly decreased. In laboratory studies, platelets aggregate normally in response to ADP, collagen, or epinephrine but fail to aggregate in response to ristocetin. Physiologically, platelets fail to adhere normally to subendothelial connective tissue because of defective binding of von Willebrand factor.

STORAGE POOL DISEASE.


Chapter 184: Hereditary Disorders of Platelet Function

In this autosomal dominant disorder, platelet storage granules are decreased in number and/or content, presumably because of abnormal granule formation in megakaryocytes. The bleeding diathesis is mild and affects mostly women. With the deficiency in dense granules, platelets aggregate abnormally because of inadequate secretion of ADP. Dense-granule storage pool disease is also associated with several other congenital disorders, including oculocutaneous albinism in both the Hermansky-Pudlak and Chédiak-Higashi syndromes, the Wiskott-Aldrich syndrome, and a syndrome that includes thrombocytopenia and absent radii. Patients may also be deficient in α-granules, either in combination with denser-granule deficiency or independently. The gray platelet syndrome refers to the latter situation, in which the absence of granule staining confers a gray color to the platelets. Mild thrombocytopenia may also be present.

VON WILLEBRAND DISEASE.

This disease, the most common congenital bleeding disorder that also affects platelet function, is discussed in Chapter 185.

Notes



Chapter 184: PLATELET TRANSFUSIONS



PLATELET TRANSFUSIONS


● INDICATIONS. ● CHRONIC THROMBOCYTOPENIA. ● DOSAGE. ● ALLOANTIBODIES AGAINST PLATELETS.

Notes


Chapter 184: INDICATIONS.



INDICATIONS.

When serious bleeding complicates thrombocytopenia, platelet transfusions are effective only when the cause is decreased production. Thrombocytopenia caused by increased peripheral destruction or sequestration is usually refractory to platelet transfusion. Bleeding caused by qualitative platelet disorders ordinarily responds to platelet transfusions except when secondary to uremia or hepatic failure or when an offending drug remains in the circulation.

For patients with congenital platelet disorders, platelet transfusion must be given judiciously because repeated transfusions stimulate alloantibodies. Eventually it may become impossible to raise the platelet count through transfusion. Accordingly, platelet transfusions should be reserved for serious bleeding or in preparation for surgery on patients with moderately severe platelet defects.

Platelet transfusions are indicated for patients who are bleeding actively and have either a platelet count lower than 50,000 per microliter or a qualitative platelet abnormality as manifested by a prolonged bleeding time. Platelet transfusions may also be indicated prophylactically before surgery or other invasive procedures. Before surgery, platelet counts should be greater than 50,000 per microliter in most cases and greater than 90,000 per microliter for procedures such as neurosurgery or ophthalmologic surgery in which any abnormal bleeding may cause excessive morbidity. For invasive procedures such as kidney or liver biopsies, a platelet count over 50,000 per microliter is probably sufficient, assuming normal platelet function.

Notes


Chapter 184: CHRONIC THROMBOCYTOPENIA.



CHRONIC THROMBOCYTOPENIA.

In the absence of active bleeding, recommendations are based on the cause of the thrombocytopenia. When thrombocytopenia is due to decreased production, the platelet count should be maintained at 10,000 to 20,000 per microliter. When accelerated destruction of platelets exists, transfusion is seldom effective. Patients with ITP frequently tolerate low platelet counts with little bleeding because of the excellent function of the younger platelets available in the circulation.

Notes


Chapter 184: DOSAGE.



DOSAGE.

For patients who require platelet transfusions chronically, platelets should be obtained from a single donor for each transfusion (generally 6 to 7 U) to reduce the risk of formation of multiple alloantibodies (see below). In a 70-kg patient, 1 U of platelets usually raises the platelet count by approximately 10,000 per microliter. The count should be repeated 10 to 60 minutes after transfusion to assess the compatibility of the transfused platelets and to determine whether the desired count has been achieved. In actively bleeding patients, the platelet count should be maintained above 50,000 per microliter.

Notes


Chapter 184: ALLOANTIBODIES AGAINST PLATELETS.



ALLOANTIBODIES AGAINST PLATELETS.

In approximately 50 to 60% of patients who become refractory to random donor platelets, anti-HLA antibodies appear to be responsible. The other presumed antigens have not yet been identified. In one rare form of alloimmunization, antibodies develop against the PL antigen, an epitope on platelet glycoprotein IIIa. The difference between PLAI positive and negative (PLA2) is a single amino acid. Of the normal population, 98% have PLAI-positive platelets.

When PLAI-negative patients are transfused with PLAI-positive blood, they produce anti-PLAI antibodies and post-transfusion purpura may develop. Previous immunization is necessary, either by transfusion or by pregnancy. Why this syndrome is rare and selectively high in women despite the frequency of PLAI negativity in the population is unknown. These patients not only rapidly clear transfused platelets from their circulation but also destroy their own platelets and become thrombocytopenic usually 5 to 10 days after transfusion. If patients with antibodies against the PLAI antigen become severely thrombocytopenic, treatment with plasmapheresis or exchange transfusion is necessary because bleeding from thrombocytopenia can be life-threatening.

NEONATAL ALLOIMMUNE THROMBOCYTOPENIA.

Thrombocytopenia caused by maternal alloantibodies against fetal platelet antigens occurs in approximately 1 in 2000 to 4000 fetuses. Affected infants may have intracranial hemorrhage (estimated at between 10 and 30%); in families with an affected infant, the risk of recurrence is at least 75%. PLAI antibodies have been identified in most cases as being responsible for thrombocytopenia. Affected infants are treated by transfusion with washed maternal platelets. Women with a prior history of an affected infant should give birth by cesarean section. Also, IVIG given to pregnant mothers with a prior affected infant raises fetal platelet counts and reduces the rate of intracranial hemorrhage.

Notes


Chapter 184: VASCULAR DISORDERS (TABLE 184-5)



VASCULAR DISORDERS (TABLE 184–5)

Normal vascular function is necessary for effective hemostasis (see Fig. 184–1). Alteration in the integrity or structure of blood vessels can lead to a bleeding diathesis, the symptoms and signs of which are indistinguishable from those of a platelet disorder.


TABLE 184–5. VASCULAR DISORDERS ASSOCIATED WITH BLEEDING


● Congenital Vascular Disorders Associated with Bleeding ● Acquired Disorders of Blood Vessels Causing Bleeding ● Miscellaneous Disorders

Notes


Chapter 184: Congenital Vascular Disorders Associated with Bleeding



Congenital Vascular Disorders Associated with Bleeding

HEREDITARY HEMORRHAGIC TELANGIECTASIA (RENDU-OSLER-WEBER DISEASE).

This disorder, the most common genetic cause of vascular bleeding, is inherited as an autosomal dominant trait. Its most frequent symptom is spontaneous epistaxis. More than half of these patients have epistaxis by 20 years of age and 90% by age 45. Telangiectasia occurs most frequently on the face in two thirds of patients, on the mouth in half, and on the cheeks, tongue, nose, and lower lip in approximately one third. In about 40%, the hands and wrists are also involved. Beyond this cutaneous or mucosal involvement, the organ system affected most often is the gastrointestinal tract (15%). Death from intestinal bleeding occurs in 12 to 15% of patients with symptomatic gastrointestinal involvement. The liver, lungs, central nervous system, and urinary tract are involved in decreasing order of frequency. Pulmonary arteriovenous fistulas, present in approximately 5% of patients, are manifested by cyanosis, dyspnea, clubbing, and thoracic murmurs. Hemoptysis is unusual. Surgical resection is successful in managing this complication in most instances. Coil embolization of these fistulas has also been used successfully. Stroke may occur with central nervous system involvement, a complication that tends to affect younger patients (mean age, 33 years ). Careful inspection of the nose and mouth usually reveals the diagnosis. In other cases, endoscopy or angiography may be necessary. Pathologic examination of involved tissue demonstrates dilated capillaries with loss of subendothelial structures.

Tests of platelet function and bleeding time are normal. Although no therapy is consistently effective, based on a few case reports and one small series of patients, conjugated estrogen-progestin therapy appears to be efficacious in decreasing the number of bleeding episodes. Generally, the prognosis is relatively good.

CAVERNOUS HEMANGIOMA (KASABACH-MERRITT SYNDROME).

Congenital subcutaneous and visceral hemangiomas may be associated with thrombocytopenia and bleeding in infants and children. Bleeding occurs at the site of the lesions or systemically secondary to thrombocytopenia. Platelets are activated within the hemangioma and subsequently removed from the circulation. In addition, mild disseminated intravascular coagulation may occur with consumption of fibrinogen. Thrombocytopenia is more severe than the coagulation abnormalities. Spontaneous regression of hemangiomas may occur over a period of years. In cases in which thrombocytopenia is severe and tumors are few, surgery and/or radiation therapy may be effective. Intentional thrombosis of hemangiomas by the administration of inhibitors of fibrinolysis, with or without cryoprecipitate, has been successful in managing thrombocytopenia in a few cases. Also, interferon-α has been observed to cause significant regression of hemangiomas.

DISORDERS OF CONNECTIVE TISSUE.


Chapter 184: Congenital Vascular Disorders Associated with Bleeding

Genetic abnormalities in structural glycoproteins such as collagen can result in vascular fragility caused by weakening of the vessel wall. Bleeding may be limited to increased bruising or may be manifested as internal hemorrhaging. Ehlers-Danlos syndrome (see Chapter 216), osteogenesis imperfecta (see Chapter 217), and pseudoxanthoma elasticum (see Chapter 218), are examples of inherited disorders of connective tissue that may be associated with a bleeding diathesis on this basis.

Notes





Chapter 184: Acquired Disorders of Blood Vessels Causing Bleeding



Acquired Disorders of Blood Vessels Causing Bleeding

SCURVY.

Severe vitamin C deficiency results in defective collagen formation in small blood vessels. Bleeding may occur in any tissue but is prominent in the lower extremities and is perifollicular in distribution. Other sites where bleeding is common include the gums, the subperiosteum in children, and muscle.

PURPURA ASSOCIATED WITH IMMUNOGLOBULIN DISORDERS.

CRYOGLOBULINEMIA.

(See Chapter 181.) Patients with any of the three types of cryoglobulinemia have purpura as a complication of their disease. In type I, bleeding may be due to obstruction of blood flow in the microcirculation at cold temperatures by cryoprecipitates, with subsequent increased vascular fragility. In type II and type III cryoglobulinemia, bleeding may be due to leukocytoclastic vasculitis associated with the immune complexes. Purpura occurs most commonly in the distal ends of the extremities.

BENIGN HYPERGLOBULINEMIA (WALDENSTRÖM'S PURPURA).

In this syndrome, patients have polyclonal hyperglobulinemia associated with purpura of the lower extremities. Leukocytoclastic involvement of the vessel wall may account for the increased vascular fragility and bleeding. Commonly, the onset of purpura is preceded by a stinging sensation in areas of involvement. Although generally no evidence of systemic vasculitis is seen, the disorder may evolve into Sjögren's syndrome or SLE.

AMYLOIDOSIS.

Amyloid deposition in the skin and subcutaneous tissue alters the normal structural support for small blood vessels and thereby results in increased vascular fragility. Purpura can occur at any site; for unclear reasons, periorbital hemorrhage is a characteristic finding.

WALDENSTRÖM'S MACROGLOBULINEMIA AND MULTIPLE MYELOMA.

(See Chapter 181.) Abnormalities in platelet function may occur with M proteins, as noted above. An additional contributing factor is hyperviscosity when it complicates these diseases. Slowing of blood flow and increased hydrostatic pressure may increase vascular fragility and lead to purpura.




Chapter 184: Acquired Disorders of Blood Vessels Causing Bleeding

HENOCH-SCHÖNLEIN PURPURA.

Symmetrical purpura and arthralgias of the lower extremities, abdominal pain, and melena characterize this childhood disorder. Rarely, adults are affected. Patients may give a history of a recent infectious illness. The disease has an acute onset with a maculopapular rash evolving into palpable purpura. Other complications include glomerulonephritis and hypertension (both of which are self-limiting) and intussusception. Involved tissues, including the skin, demonstrate vasculitis with IgA and complement deposition.

Henoch-Schönlein purpura usually remits spontaneously over a period of 1 to 2 months, although the course is often punctuated by flaring of symptoms and signs. Symptomatic improvement is obtained with glucocorticoids.

Notes


Chapter 184: Miscellaneous Disorders



Miscellaneous Disorders

CUSHING'S SYNDROME.

Cushing's disease or chronic administration of glucocorticoids results in increased bruising, particularly in the extremities. Abnormal bleeding probably results from alterations in the structure of the perivascular matrix, with loss of normal elasticity.

AUTOERYTHROCYTE SENSITIZATION (GARDNER-DIAMOND SYNDROME).

This bizarre syndrome is characterized by the development of purpura at any site on the body, preceded by pain and burning. It occurs almost exclusively in women. Usually, affected women have a history of severe stress and emotional problems. Tests for abnormalities in hemostasis are all normal.

The diagnostic test is the development of large ecchymoses within 24 to 48 hours at the site of subcutaneous injection of a small amount (~0.1 mL) of the patient's own blood or erythrocytes. Injection should be at sites inaccessible to the patient, and a concurrent control injection should be administered. The primary differential diagnosis is factitious purpura.

PURPURA SIMPLEX.

Purpura simplex denotes easy bruising, commonly observed in young children and middle-aged women and primarily affecting the lower extremities. Laboratory evaluation, including the bleeding time, is normal, and no evidence of vascular abnormalities is present. Affected women do not experience excessive bleeding with surgery, nor do they suffer from internal bleeding.

Notes


Chapter 184: BIBLIOGRAPHY



BIBLIOGRAPHY

Louwes H, Lathor OAZ, Vellenga E, deWolf JTLM: Platelet kinetic studies in patients with idiopathic thrombocytopenic purpura, Am J Med 106:430, 1999. Study suggesting that most patients with ITP have reduced platelet survival but some have decreased production. PUBMED Abstract

McMillan R: Therapy for adults with refractory chronic immune thrombocytopenic purpura. Ann Intern Med 126:307, 1997. Reviews experience with therapeutic options in ITP as well as experimental approaches. PUBMED Abstract

Ravandi-Kashani F, Schafer AI: Microvascular disturbances, thrombosis, and bleeding in thrombocythemia: Current concepts and perspectives. Semin Thromb Hemost 23:479, 1997. Review of the pathophysiology of thrombocytosis and its complications in myeloproliferative disorders. PUBMED Abstract

Rebulla P, Finazzi G, Marangoni F, et al: A multicenter randomized study of the threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337:1870, 1997. Establishes guidelines for platelet transfusion in hypoproliferative thrombocytopenia. PUBMED Abstract

Sarode R, Gottschall JL, Aster RH, et al: Thrombotic thrombocytopenic purpura: Early and late responders. Am J Hematol 54:102, 1997. Comprehensive examination of therapeutic efficacy of plasmapheresis. PUBMED Abstract

Notes


Chapter 184: FIGURES



FIGURES



FIGURE 184–3 Evaluation of thrombocytopenia. Abn = abnormal; N = normal; PT = prothrombin time; aPTT = activated partial thromboplastin time; LDH = lactate dehydrogenase; BUN = blood urea nitrogen.

COLOR PLATE 6–L, Thrombotic thrombocytopenic purpura (TTP). Peripheral smear shows fragmented red cells alongside larger, polychromatophilic cells and a nucleated red cell that reflect hemolysis, as well as a paucity of platelets.

Notes


Chapter 184: TABLES



TABLES


TABLE 184–2. DISORDERS ASSOCIATED WITH THROMBOCYTOPENIA

TABLE 184–3. DIFFERENTIAL DIAGNOSIS OF ANEMIA AND THROMBOCYTOPENIA

TABLE 184–4. DISORDERS ASSOCIATED WITH THROMBOCYTOPENIA AND MICROANGIOPATHIC ANEMIA

TABLE 184–5. VASCULAR DISORDERS ASSOCIATED WITH BLEEDING

Notes


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