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The Clinical Approach to Disorders of Platelet Number and Function
C H A P T E R
39 The Clinical Approach to Disorders of Platelet Number and Function Alan D. Michelson Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
I. INTRODUCTION This chapter discusses the clinical approach to patients with disorders of platelet number and/or function (Tables 39-1 through 39-3). As in all of clinical medicine, the history and physical examination are the keys to unlocking the diagnosis. The characteristic clinical features that differentiate primary hemostatic disorders (thrombocytopenia, platelet function defects, and von Willebrand disease [VWD]) from coagulation disorders (e.g., hemophilia) are listed in Table 39-4. Three of these clinical features are particularly helpful. First, petechiae are a very strong pointer toward a primary hemostatic disorder and away from a coagulation disorder. Second, hemarthroses are a very strong pointer toward a coagulation disorder and away from a primary hemostatic disorder. Third, in the setting of an injury, immediate excessive bleeding suggests a primary hemostatic disorder (because the initial platelet plug does not form correctly), whereas delayed bleeding suggests a coagulation disorder (because the lack of a well-formed fibrin clot results in gradual breakdown of the initial platelet plug). The clinical approaches to thrombocytopenia during pregnancy and in the neonatal period are discussed separately in Chapters 44 and 45, respectively. The clinical approach to thrombocytosis is discussed in Chapter 49.
II. CLINICAL HISTORY A. Bleeding Spontaneous bleeding, or excessive bleeding during or after an injury, is suggestive of an underlying hemo-
Platelets, 3rd edition
static disorder. The clinician must obtain a history of the patient’s responses to hemostatic challenges: surgery (including circumcision), dental procedures (especially tooth extractions), trauma, injections, menses, labor and delivery, and tooth brushing. Immediate bleeding suggests a primary hemostatic disorder, whereas delayed bleeding suggests a coagulation disorder (Table 39-4). Easy bruising is common in hemostatic disorders but does not help distinguish disorders of platelet number and function from other disorders of hemostasis. However, epistaxes, gingival bleeding, and menorrhagia are all more common in primary hemostatic disorders than in coagulation disorders. The age of onset of the excessive bleeding may help to distinguish inherited bleeding disorders from acquired bleeding disorders.
B. Gender and Family History Some disorders of platelet number and function are X-linked recessive (e.g., Wiskott Aldrich syndrome [Chapters 47 and 50]) and therefore present almost exclusively in males. Other disorders of platelet number and function are autosomal recessive (e.g., Bernard Soulier syndrome and Glanzmann thrombasthenia) or autosomal dominant (e.g., MYH9-related disorder) (Chapters 47 and 50). Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are common X-linked recessive coagulation disorders that occur almost exclusively in males.
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© 2013 Elsevier Inc. All rights reserved.
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39. THE CLINICAL APPROACH TO DISORDERS OF PLATELET NUMBER AND FUNCTION
TABLE 39-1 Causes of Thrombocytopenia in the Absence of Leukopenia or Anemia
TABLE 39-2
Causes of Platelet Function Defects
Acquired Increased Platelet Destruction: Immune thrombocytopenic purpura Disseminated intravascular coagulation Heparin-induced thrombocytopenia Other drug-induced thrombocytopenias Systemic lupus erythematosus HIV-1-related thrombocytopenia Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome Common variable immunodeficiency Post-transfusion purpura Type 2B von Willebrand disease Platelet-type von Willebrand disease Wiskott Aldrich syndrome/X-linked thrombocytopenia
Uremia Myeloproliferative disorders Essential thrombocythemia Polycythemia vera Chronic myeloid leukemia Primary myelofibrosis Acute leukemias and myelodysplastic syndromes Dysproteinemias Extracorporeal perfusion Acquired von Willebrand disease Acquired storage pool deficiency Antiplatelet antibodies Liver disease Drugs and other agents Inherited
Decreased Platelet Production: Normal-sized Platelets Congenital amegakaryocytic thrombocytopenia (CAMT) Thrombocytopenia with absent radii (TAR) Amegakaryocytic thrombocytopenia with radio-ulnar synostosis (ATRUS) Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) Paris Trousseau thrombocytopenia/Jacobsen syndrome Familial thrombocytopenia 2 Large Platelets Bernard Soulier syndrome DiGeorge syndrome (velocardiofacial syndrome) Benign Mediterranean macrothrombocytopenia Platelet-type von Willebrand disease MYH9-related disease Gray platelet syndrome GATA-1 mutation of X-linked thrombocytopenia and thalassemia Macrothrombocytopenia with platelet expression of glycophorin A Macrothrombocytopenia with mutations in platelet β1 tubulin Macrothrombocytopenia with filamin A mutations Sequestration Hypersplenism Kasabach Merritt syndrome Increased Platelet Destruction and Hemodilution Extracorporeal perfusion
C. Medications The history of the patient’s intake of medications is important. Thrombocytopenia can result from drugs, including heparin (Chapter 42), quinidine, quinine, sulfonamides, rifampin, penicillin, vancomycin, gold salts, procainamide, valproic acid, carbamazepine, chlorothiazide, abciximab, tirofiban, and eptifibatide (Chapter 41). Furthermore, a platelet function defect can be caused by many drugs, including aspirin and
Abnormalities of the platelet receptors for adhesive proteins GPIb-IX-V complex (Bernard Soulier syndrome, platelet-type von Willebrand disease) GPIIb-IIIa (αIIbβ3) (Glanzmann thrombasthenia) GPIa-IIa (α2β1) GPVI Abnormalities of the platelet receptors for soluble agonists P2Y12 receptor Thromboxane A2 receptor α2-adrenergic receptor Abnormalities of the platelet granules δ-granules (nonsyndromic δ-storage pool deficiency, Hermansky Pudlak syndrome, Chediak Higashi syndrome, MRP4 deficiency, thrombocytopenia with absent radii syndrome, Wiskott Aldrich syndrome) α-granules (gray platelet syndrome, Quebec platelet disorder, 11q terminal deletion disorder, White platelet syndrome, Medich platelet disorder, X-linked macrothrombocytopenia with thalassemia, arthrogryposis renal dysfunction and cholestasis [ARC] syndrome) α- and δ- granules (α,δ-storage pool deficiency) Defects of signal transduction Abnormalities of the arachidonate/thromboxane A2 pathway (defects in phospholipase A2, cyclooxygenase, thromboxane synthetase) Abnormalities of GTP binding proteins (Gαq deficiency, Gαi1 defect, hyperresponsiveness of platelet Gsα) Defects in phospholipase C activation (partial selective PLC-β2 isozyme deficiency) Abnormalities in transcription factors Abnormality in GPVI/FcRc signaling Leukocyte adhesion deficiency-III (LAD-III) Abnormalities of membrane phospholipids Scott syndrome Stormorken syndrome Miscellaneous abnormalities of platelet function Primary secretion defects Other (osteogenesis imperfecta, Ehlers Danlos syndrome, Marfan syndrome, hexokinase deficiency, glucose-6-phosphate deficiency)
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
III. PHYSICAL EXAMINATION
TABLE 39-3
Causes of Thrombocytosis
Primary Thrombocytosis Essential thrombocythemia Chronic myeloproliferative disorders (including polycythemia vera, myelofibrosis with myeloid metaplasia) Chronic myeloid leukemia Myelodysplastic syndrome Congenital thrombocytosis Reactive Thrombocytosis Infection Rebound thrombocytosis (e.g., after chemotherapy or immune thrombocytopenic purpura) Tissue damage (e.g., surgery) Chronic inflammation Malignancy Renal disorders Hemolytic anemia Iron deficiency Asplenia (postsplenectomy, postinfarction, or congenital)
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hydroxychloroquine, miconazole), cardiovascular drugs (propranolol, nitroprusside, nitroglycerin, furosemide, calcium channel blockers), psychotropics (tricyclic antidepressants, phenothiazines, selective serotonin reuptake inhibitors), chemotherapeutic agents (mithramycin, BCNU, daunorubicin, dasatinib), ethanol, and food items and supplements (omega-3 fatty acids, vitamin E, onions, garlic, ginger, cumin, turmeric, clove, black tree fungus, Gingko) (Chapter 51).
D. Medical History A history of renal disease, liver disease, myeloproliferative disorder, acute leukemia, myelodysplastic syndrome, or dysproteinemia suggests an acquired platelet function defect (Table 39-2 and Chapter 51).
E. Transfusion History TABLE 39-4 Characteristic Clinical Features that Differentiate Primary Hemostatic Disorders from Coagulation Disorders Primary Hemostatic Disorder
Coagulation Disorder
Prototypic Disorders
Thrombocytopenia platelet function defect von Willebrand disease*
Hemophilia
Bleeding
Immediate
Delayed
Petechiae
Yes
No
Hemarthroses
No
Yes
Intramuscular hematomas
Uncommon
Common
Epistaxes
Common
Uncommon
Menorrhagia
Common
Uncommon
The sudden development of profound thrombocytopenia 5 to 10 days after the transfusion of blood products (not necessarily platelet concentrates) strongly suggests the diagnosis of post-transfusion purpura (Chapter 46).
F. Social-Sexual History Homosexual persons, intravenous narcotic addicts, and their sexual partners are at risk for HIV-1 infection and the subsequent development of chronic immune thrombocytopenic purpura. The thrombocytopenia can present in the presence or absence of other clinical manifestations of AIDS (Chapter 40).
*
In the uncommon type 3 von Willebrand disease, the factor VIII coagulant level is low enough for the clinical features to be those of a combined primary hemostatic and coagulation disorder.
III. PHYSICAL EXAMINATION A. Hemorrhage
other nonsteroidal anti-inflammatory drugs (e.g., indomethacin, ibuprofen, naproxen), ADP receptor antagonists (ticlopidine, clopidogrel, prasugrel, ticagrelor), glycoprotein (GP) IIb-IIIa antagonists (abciximab, tirofiban, eptifibatide), phosphodiesterase inhibitors (dipyridamole, cilostazol), antimicrobial agents (penicillins, cephalosporins, nitrofurantoin,
Petechiae very strongly suggest a primary hemostatic disorder rather than a coagulation disorder (Table 39-4). Petechiae can also be a sign of vasculitis or, in a sick patient, bacteremia (including meningococcemia) and disseminated intravascular coagulation (DIC). In contrast, hemarthroses very strongly suggest a coagulation disorder rather than a primary hemostatic disorder (Table 39-4). Intramuscular hematomas are more typical of a coagulation disorder than a primary hemostatic disorder.
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
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39. THE CLINICAL APPROACH TO DISORDERS OF PLATELET NUMBER AND FUNCTION
B. Other Physical Signs
B. Blood Smear
Splenomegaly may indicate hypersplenism (e.g., Gaucher disease) or malignancy. Fluctuating global or focal neurological signs suggest thrombotic thrombocytopenic purpura (Chapter 43). Bilateral absent radii are observed in the thrombocytopenia with absent radii (TAR) syndrome (see Fig. 47-1 in Chapter 47). Eczema in a boy suggests the possibility of Wiskott Aldrich syndrome (Chapters 47 and 50). Giant hemangiomas suggest Kasabach Merritt syndrome (Chapter 45). Oculocutaneous albinism is observed in Hermansky Pudlak syndrome (Chapters 18 and 50) and Chediak Higashi syndrome (Chapters 18 and 50). Deafness, cataracts, deafness, and/or hypertension suggest the possibility of an MYH9-related disorder (Chapter 47). Cardiac defects, delayed development, otorhinolaryngological manifestations, psychiatric disturbances, and mental retardation suggest the velocardiofacial syndrome that is associated with Bernard Soulier syndrome (Chapters 47 and 50).
1. Platelets Large platelets may be observed in immune thrombocytopenic purpura (ITP, Chapter 40). Giant platelets are observed in essential thrombocythemia and other causes of primary thrombocytosis (Table 39-3) (see Fig. 49-1 in Chapter 49) and in inherited giant platelet syndromes (Table 39-1) (e.g., Bernard Soulier syndrome [Fig. 50-2A in Chapter 50] and MYH9-related disorders [Fig. 47-3 in Chapter 47]). Agranular, gray platelets are observed in the gray platelet syndrome (Fig. 50-2B in Chapter 50) (see Chapters 47 and 50). Although the platelets are small in Wiskott Aldrich syndrome (Chapter 47), this may not be appreciated on conventional blood smears. In addition to the blood smear, the mean platelet volume (MPV) obtained from an automated cell counter is useful in the differentiation of disorders with giant, large, normal, or small platelets (see Chapter 27).
IV. CLINICAL TESTS A. Platelet Count The causes of a low platelet count in the absence of leukopenia or anemia are shown in Table 39-1. Aplastic anemia and infiltrative disorders of the bone marrow, including leukemia and solid tumor metastases, do not usually cause an isolated thrombocytopenia of major degree in the absence of any leukopenia or anemia. Pseudothrombocytopenia (Chapter 48), the result of platelet clumping ex vivo, can cause erroneously low platelet counts reported by electronic counters. The platelet clumping can be observed in the peripheral blood smear by light microscopy (see Figs. 48-1 through 48-7 in Chapter 48). In most cases, drawing the blood into citrate anticoagulant rather than the standard EDTA will circumvent, and therefore diagnose, the problem of pseudothrombocytopenia. The causes of a high platelet count are shown in Table 39-3 and discussed in Chapter 49. The immature platelet fraction (i.e., the number of young or “reticulated” platelets) can now be measured on some automated cell counters (see Chapter 27 for details). This may be helpful in differentiating thrombocytopenia secondary to lack of production (low number of “reticulated” platelets) from thrombocytopenia secondary to increased destruction (high number of “reticulated” platelets).
2. Leukocytes Myeloblasts or lymphoblasts suggest the diagnosis of leukemia or myeloproliferative disorder. Do¨hle bodies are observed in the neutrophil cytoplasm in MYH9related disorders (see Fig. 47-3 in Chapter 47). Giant cytoplasmic granules are observed in the neutrophils, monocytes, and lymphocytes in Chediak Higashi syndrome (Chapters 18 and 50), but these granules may be more easily recognized in leukocyte precursors in the bone marrow rather than in leukocytes in the peripheral blood. 3. Erythrocytes Red cell fragmentation (schistocytes) suggests thrombotic thrombocytopenic purpura, hemolyticuremic syndrome, or DIC (see Fig. 43-8 in Chapter 43). Spherocytes may be observed in Evans syndrome (Chapter 40).
C. Platelet Function Tests Chapter 28 discusses platelet aggregometry, and Chapter 26 discusses other clinical tests of platelet function.
D. Other Tests Bone marrow aspiration with or without biopsy may be useful in the diagnosis of leukemia and other malignancies, aplastic anemia, ITP (especially in adults), amegakaryocytic thrombocytopenia, and Gaucher disease. Furthermore, bone marrow
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
V. DIFFERENTIAL DIAGNOSIS
examination may be necessary in the evaluation of thrombocytosis, if reactive thrombocytosis (Table 39-3) has not been confirmed by history, physical examination, or noninvasive laboratory tests (as discussed in Chapter 49). Other tests used in the specific diagnosis of disorders of platelet number and function are discussed in the context of the differential diagnosis (see Section V next) and in the other chapters of this book (Chapters 40 52) that discuss these disorders in detail.
V. DIFFERENTIAL DIAGNOSIS The presence of a disorder of platelet number and/ or function can usually be determined from the clinical history, physical examination (Table 39-4), and complete blood count (including examination of the blood smear). The following sections (V.A, V.B, and V.C.) provide an overview of the clinical approach to establishing the specific cause of the thrombocytopenia or platelet function defect.
A. Thrombocytopenia Although the list of causes of thrombocytopenia may appear dauntingly long (Table 39-1), the diagnosis of the specific cause of thrombocytopenia in a patient is often straightforward. ITP (Chapter 40) is a diagnosis of exclusion in a patient with acquired thrombocytopenia: a normal hemoglobin level, white blood cell count and differential, and blood smear (except for the thrombocytopenia and possibly enlarged platelets), in the absence of hepatosplenomegaly, lymphadenopathy, abnormalities of the radii, or other underlying disease. Anemia in the presence of ITP may signify either significant bleeding or autoimmune hemolytic anemia (Evans syndrome, Chapter 40). DIC can essentially be excluded if a thrombocytopenic patient is generally well without a clear precipitating cause for DIC (e.g., sepsis, hypoxia, or shock). If suspected, DIC can be diagnosed by D-dimer and fibrin split products. Heparin-induced thrombocytopenia (Chapter 42) or other drug-induced thrombocytopenia (Chapter 41) can be excluded or suspected based on the clinical history. Systemic lupus erythematosus (SLE)-related thrombocytopenia (Chapter 40) may be initially difficult to diagnose if the thrombocytopenia precedes other manifestations of SLE. HIV-1-related thrombocytopenia (Chapter 40) may be suspected from the clinical history, and HIV can be tested for if this diagnosis is not already known. Patients with thrombotic thrombocytopenic purpura or hemolytic-uremic
817
syndrome, although listed in Table 39-1, usually have anemia and fragmented red cells on blood smear (see Fig. 43-8 in Chapter 43). In addition, blood urea nitrogen and serum creatinine are elevated in hemolytic-uremicsyndrome. Common variable immunodeficiency is diagnosed by measuring quantitative serum immunoglobulins. Post-transfusion purpura (Chapter 46) is strongly suggested by the sudden development of profound thrombocytopenia 5 to 10 days after the transfusion of blood products. Type 2B VWD and platelet-type VWD, both rare causes of thrombocytopenia, can be suspected by increased ristocetin-induced platelet agglutination at low ristocetin concentrations (Chapter 28).1 The absent radii in the TAR syndrome (see Fig. 47-1 in Chapter 47) are all too evident by examination of the patient. Amegakaryocytic thrombocytopenia (Chapter 47) is diagnosed by examination of the bone marrow. Giant platelet syndromes (Chapters 47 and 50) are evident on peripheral blood smear (see Fig. 47-3 in Chapter 47 and Fig. 50-2A in Chapter 50). Wiskott Aldrich syndrome (Chapter 47) can be suspected in a male patient with thrombocytopenia and eczema. In hypersplenism, which can occur in any patient with an enlarged spleen from any cause, the thrombocytopenia is usually not severe, and anemia and leukopenia are often present. The giant hemangiomas of Kasabach Merritt syndrome (Chapter 45) are often, but not always, evident on physical examination.
B. Platelet Function Defects The list of specific causes of platelet function defects is also long (Table 39-2). However, acquired defects are the most common and the underlying medical condition is usually evident. With the exception of VWD1 and, to a lesser extent, storage pool disease (Chapters 18 and 50), inherited platelet function defects are all rare. These rare disorders (Chapter 50) usually require specialized research laboratories to make a specific diagnosis, with the exception of Bernard Soulier syndrome and Glanzmann thrombasthenia, which are easily diagnosed by platelet aggregometry (Chapter 28) and flow cytometry (Chapter 29). Platelet aggregation (Chapter 28) is useful for the diagnosis of platelet function defects. In Glanzmann thrombasthenia (Chapter 50), the platelets do not aggregate in response to adenosine diphosphate (ADP), epinephrine, arachidonic acid, or collagen, but do agglutinate in response to ristocetin. In Bernard Soulier syndrome (Chapters 47 and 50), the platelets do not agglutinate in response to ristocetin, but do aggregate in response to all other agonists.
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
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39. THE CLINICAL APPROACH TO DISORDERS OF PLATELET NUMBER AND FUNCTION
Patients with storage pool disease or defects in platelet secretion (Chapters 18 and 50) show decreased platelet aggregation or absence of the second wave of aggregation in response to ADP, epinephrine, arachidonic acid, or collagen. Some patients with storage pool disease cannot be reliably diagnosed by standard platelet aggregometry; the diagnosis is made by measuring the granule adenine nucleotides by lumiaggregometry (Chapter 28), biochemical assays, or by labeling the platelets with the fluorescent dye mepacrine and then measuring platelet fluorescence by microscopy or flow cytometry (Chapter 29).
C. von Willebrand Disease
clinically indistinguishable from disorders of platelet number and function. VWF has a second major role: it is the carrier molecule for factor VIII. In the uncommon setting of type 3 VWD, the factor VIII coagulant activity is low enough for the clinical features to be those of a combined primary hemostatic disorder and coagulation disorder (Table 39-4). VWD is usually diagnosed by a decrease in plasma levels of ristocetin cofactor activity, VWF antigen, and factor VIII coagulant activity. However, not all patients with VWD have a decrease in the plasma levels of all three of these parameters.1
VI. SPECIFIC DISORDERS
A primary hemostatic disorder in the absence of thrombocytopenia or morphological evidence of a platelet function disorder may require testing for VWD. VWD is not primarily a disorder of platelet function, but a disorder of von Willebrand factor (VWF).1 Because of the key role of VWF in platelet adhesion via its binding to the GPIb-IX-V complex (Chapters 10 and 20), VWD results, however, in a platelet adhesion defect. Therefore, VWD usually presents clinically as a primary hemostatic disorder (Table 39-4) that, without laboratory testing, may be
The specific disorders of platelet number and function (Tables 39-1 through 39-3), including their pathophysiology, clinical features, differential diagnosis, definitive diagnostic tests, and treatment, are discussed in detail in the chapters that follow (Chapters 40 52).
Reference [1] Sadler JE. New concepts in von Willebrand disease. Annu Rev Med 2005;56:173 91.
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
39 The Clinical Approach to Disorders of Platelet Number and Function Alan D. Michelson Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
I. INTRODUCTION This chapter discusses the clinical approach to patients with disorders of platelet number and/or function (Tables 39-1 through 39-3). As in all of clinical medicine, the history and physical examination are the keys to unlocking the diagnosis. The characteristic clinical features that differentiate primary hemostatic disorders (thrombocytopenia, platelet function defects, and von Willebrand disease [VWD]) from coagulation disorders (e.g., hemophilia) are listed in Table 39-4. Three of these clinical features are particularly helpful. First, petechiae are a very strong pointer toward a primary hemostatic disorder and away from a coagulation disorder. Second, hemarthroses are a very strong pointer toward a coagulation disorder and away from a primary hemostatic disorder. Third, in the setting of an injury, immediate excessive bleeding suggests a primary hemostatic disorder (because the initial platelet plug does not form correctly), whereas delayed bleeding suggests a coagulation disorder (because the lack of a well-formed fibrin clot results in gradual breakdown of the initial platelet plug). The clinical approaches to thrombocytopenia during pregnancy and in the neonatal period are discussed separately in Chapters 44 and 45, respectively. The clinical approach to thrombocytosis is discussed in Chapter 49.
II. CLINICAL HISTORY A. Bleeding Spontaneous bleeding, or excessive bleeding during or after an injury, is suggestive of an underlying hemo-
Platelets, 3rd edition
static disorder. The clinician must obtain a history of the patient’s responses to hemostatic challenges: surgery (including circumcision), dental procedures (especially tooth extractions), trauma, injections, menses, labor and delivery, and tooth brushing. Immediate bleeding suggests a primary hemostatic disorder, whereas delayed bleeding suggests a coagulation disorder (Table 39-4). Easy bruising is common in hemostatic disorders but does not help distinguish disorders of platelet number and function from other disorders of hemostasis. However, epistaxes, gingival bleeding, and menorrhagia are all more common in primary hemostatic disorders than in coagulation disorders. The age of onset of the excessive bleeding may help to distinguish inherited bleeding disorders from acquired bleeding disorders.
B. Gender and Family History Some disorders of platelet number and function are X-linked recessive (e.g., Wiskott Aldrich syndrome [Chapters 47 and 50]) and therefore present almost exclusively in males. Other disorders of platelet number and function are autosomal recessive (e.g., Bernard Soulier syndrome and Glanzmann thrombasthenia) or autosomal dominant (e.g., MYH9-related disorder) (Chapters 47 and 50). Hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency) are common X-linked recessive coagulation disorders that occur almost exclusively in males.
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© 2013 Elsevier Inc. All rights reserved.
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39. THE CLINICAL APPROACH TO DISORDERS OF PLATELET NUMBER AND FUNCTION
TABLE 39-1 Causes of Thrombocytopenia in the Absence of Leukopenia or Anemia
TABLE 39-2
Causes of Platelet Function Defects
Acquired Increased Platelet Destruction: Immune thrombocytopenic purpura Disseminated intravascular coagulation Heparin-induced thrombocytopenia Other drug-induced thrombocytopenias Systemic lupus erythematosus HIV-1-related thrombocytopenia Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome Common variable immunodeficiency Post-transfusion purpura Type 2B von Willebrand disease Platelet-type von Willebrand disease Wiskott Aldrich syndrome/X-linked thrombocytopenia
Uremia Myeloproliferative disorders Essential thrombocythemia Polycythemia vera Chronic myeloid leukemia Primary myelofibrosis Acute leukemias and myelodysplastic syndromes Dysproteinemias Extracorporeal perfusion Acquired von Willebrand disease Acquired storage pool deficiency Antiplatelet antibodies Liver disease Drugs and other agents Inherited
Decreased Platelet Production: Normal-sized Platelets Congenital amegakaryocytic thrombocytopenia (CAMT) Thrombocytopenia with absent radii (TAR) Amegakaryocytic thrombocytopenia with radio-ulnar synostosis (ATRUS) Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) Paris Trousseau thrombocytopenia/Jacobsen syndrome Familial thrombocytopenia 2 Large Platelets Bernard Soulier syndrome DiGeorge syndrome (velocardiofacial syndrome) Benign Mediterranean macrothrombocytopenia Platelet-type von Willebrand disease MYH9-related disease Gray platelet syndrome GATA-1 mutation of X-linked thrombocytopenia and thalassemia Macrothrombocytopenia with platelet expression of glycophorin A Macrothrombocytopenia with mutations in platelet β1 tubulin Macrothrombocytopenia with filamin A mutations Sequestration Hypersplenism Kasabach Merritt syndrome Increased Platelet Destruction and Hemodilution Extracorporeal perfusion
C. Medications The history of the patient’s intake of medications is important. Thrombocytopenia can result from drugs, including heparin (Chapter 42), quinidine, quinine, sulfonamides, rifampin, penicillin, vancomycin, gold salts, procainamide, valproic acid, carbamazepine, chlorothiazide, abciximab, tirofiban, and eptifibatide (Chapter 41). Furthermore, a platelet function defect can be caused by many drugs, including aspirin and
Abnormalities of the platelet receptors for adhesive proteins GPIb-IX-V complex (Bernard Soulier syndrome, platelet-type von Willebrand disease) GPIIb-IIIa (αIIbβ3) (Glanzmann thrombasthenia) GPIa-IIa (α2β1) GPVI Abnormalities of the platelet receptors for soluble agonists P2Y12 receptor Thromboxane A2 receptor α2-adrenergic receptor Abnormalities of the platelet granules δ-granules (nonsyndromic δ-storage pool deficiency, Hermansky Pudlak syndrome, Chediak Higashi syndrome, MRP4 deficiency, thrombocytopenia with absent radii syndrome, Wiskott Aldrich syndrome) α-granules (gray platelet syndrome, Quebec platelet disorder, 11q terminal deletion disorder, White platelet syndrome, Medich platelet disorder, X-linked macrothrombocytopenia with thalassemia, arthrogryposis renal dysfunction and cholestasis [ARC] syndrome) α- and δ- granules (α,δ-storage pool deficiency) Defects of signal transduction Abnormalities of the arachidonate/thromboxane A2 pathway (defects in phospholipase A2, cyclooxygenase, thromboxane synthetase) Abnormalities of GTP binding proteins (Gαq deficiency, Gαi1 defect, hyperresponsiveness of platelet Gsα) Defects in phospholipase C activation (partial selective PLC-β2 isozyme deficiency) Abnormalities in transcription factors Abnormality in GPVI/FcRc signaling Leukocyte adhesion deficiency-III (LAD-III) Abnormalities of membrane phospholipids Scott syndrome Stormorken syndrome Miscellaneous abnormalities of platelet function Primary secretion defects Other (osteogenesis imperfecta, Ehlers Danlos syndrome, Marfan syndrome, hexokinase deficiency, glucose-6-phosphate deficiency)
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
III. PHYSICAL EXAMINATION
TABLE 39-3
Causes of Thrombocytosis
Primary Thrombocytosis Essential thrombocythemia Chronic myeloproliferative disorders (including polycythemia vera, myelofibrosis with myeloid metaplasia) Chronic myeloid leukemia Myelodysplastic syndrome Congenital thrombocytosis Reactive Thrombocytosis Infection Rebound thrombocytosis (e.g., after chemotherapy or immune thrombocytopenic purpura) Tissue damage (e.g., surgery) Chronic inflammation Malignancy Renal disorders Hemolytic anemia Iron deficiency Asplenia (postsplenectomy, postinfarction, or congenital)
815
hydroxychloroquine, miconazole), cardiovascular drugs (propranolol, nitroprusside, nitroglycerin, furosemide, calcium channel blockers), psychotropics (tricyclic antidepressants, phenothiazines, selective serotonin reuptake inhibitors), chemotherapeutic agents (mithramycin, BCNU, daunorubicin, dasatinib), ethanol, and food items and supplements (omega-3 fatty acids, vitamin E, onions, garlic, ginger, cumin, turmeric, clove, black tree fungus, Gingko) (Chapter 51).
D. Medical History A history of renal disease, liver disease, myeloproliferative disorder, acute leukemia, myelodysplastic syndrome, or dysproteinemia suggests an acquired platelet function defect (Table 39-2 and Chapter 51).
E. Transfusion History TABLE 39-4 Characteristic Clinical Features that Differentiate Primary Hemostatic Disorders from Coagulation Disorders Primary Hemostatic Disorder
Coagulation Disorder
Prototypic Disorders
Thrombocytopenia platelet function defect von Willebrand disease*
Hemophilia
Bleeding
Immediate
Delayed
Petechiae
Yes
No
Hemarthroses
No
Yes
Intramuscular hematomas
Uncommon
Common
Epistaxes
Common
Uncommon
Menorrhagia
Common
Uncommon
The sudden development of profound thrombocytopenia 5 to 10 days after the transfusion of blood products (not necessarily platelet concentrates) strongly suggests the diagnosis of post-transfusion purpura (Chapter 46).
F. Social-Sexual History Homosexual persons, intravenous narcotic addicts, and their sexual partners are at risk for HIV-1 infection and the subsequent development of chronic immune thrombocytopenic purpura. The thrombocytopenia can present in the presence or absence of other clinical manifestations of AIDS (Chapter 40).
*
In the uncommon type 3 von Willebrand disease, the factor VIII coagulant level is low enough for the clinical features to be those of a combined primary hemostatic and coagulation disorder.
III. PHYSICAL EXAMINATION A. Hemorrhage
other nonsteroidal anti-inflammatory drugs (e.g., indomethacin, ibuprofen, naproxen), ADP receptor antagonists (ticlopidine, clopidogrel, prasugrel, ticagrelor), glycoprotein (GP) IIb-IIIa antagonists (abciximab, tirofiban, eptifibatide), phosphodiesterase inhibitors (dipyridamole, cilostazol), antimicrobial agents (penicillins, cephalosporins, nitrofurantoin,
Petechiae very strongly suggest a primary hemostatic disorder rather than a coagulation disorder (Table 39-4). Petechiae can also be a sign of vasculitis or, in a sick patient, bacteremia (including meningococcemia) and disseminated intravascular coagulation (DIC). In contrast, hemarthroses very strongly suggest a coagulation disorder rather than a primary hemostatic disorder (Table 39-4). Intramuscular hematomas are more typical of a coagulation disorder than a primary hemostatic disorder.
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
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39. THE CLINICAL APPROACH TO DISORDERS OF PLATELET NUMBER AND FUNCTION
B. Other Physical Signs
B. Blood Smear
Splenomegaly may indicate hypersplenism (e.g., Gaucher disease) or malignancy. Fluctuating global or focal neurological signs suggest thrombotic thrombocytopenic purpura (Chapter 43). Bilateral absent radii are observed in the thrombocytopenia with absent radii (TAR) syndrome (see Fig. 47-1 in Chapter 47). Eczema in a boy suggests the possibility of Wiskott Aldrich syndrome (Chapters 47 and 50). Giant hemangiomas suggest Kasabach Merritt syndrome (Chapter 45). Oculocutaneous albinism is observed in Hermansky Pudlak syndrome (Chapters 18 and 50) and Chediak Higashi syndrome (Chapters 18 and 50). Deafness, cataracts, deafness, and/or hypertension suggest the possibility of an MYH9-related disorder (Chapter 47). Cardiac defects, delayed development, otorhinolaryngological manifestations, psychiatric disturbances, and mental retardation suggest the velocardiofacial syndrome that is associated with Bernard Soulier syndrome (Chapters 47 and 50).
1. Platelets Large platelets may be observed in immune thrombocytopenic purpura (ITP, Chapter 40). Giant platelets are observed in essential thrombocythemia and other causes of primary thrombocytosis (Table 39-3) (see Fig. 49-1 in Chapter 49) and in inherited giant platelet syndromes (Table 39-1) (e.g., Bernard Soulier syndrome [Fig. 50-2A in Chapter 50] and MYH9-related disorders [Fig. 47-3 in Chapter 47]). Agranular, gray platelets are observed in the gray platelet syndrome (Fig. 50-2B in Chapter 50) (see Chapters 47 and 50). Although the platelets are small in Wiskott Aldrich syndrome (Chapter 47), this may not be appreciated on conventional blood smears. In addition to the blood smear, the mean platelet volume (MPV) obtained from an automated cell counter is useful in the differentiation of disorders with giant, large, normal, or small platelets (see Chapter 27).
IV. CLINICAL TESTS A. Platelet Count The causes of a low platelet count in the absence of leukopenia or anemia are shown in Table 39-1. Aplastic anemia and infiltrative disorders of the bone marrow, including leukemia and solid tumor metastases, do not usually cause an isolated thrombocytopenia of major degree in the absence of any leukopenia or anemia. Pseudothrombocytopenia (Chapter 48), the result of platelet clumping ex vivo, can cause erroneously low platelet counts reported by electronic counters. The platelet clumping can be observed in the peripheral blood smear by light microscopy (see Figs. 48-1 through 48-7 in Chapter 48). In most cases, drawing the blood into citrate anticoagulant rather than the standard EDTA will circumvent, and therefore diagnose, the problem of pseudothrombocytopenia. The causes of a high platelet count are shown in Table 39-3 and discussed in Chapter 49. The immature platelet fraction (i.e., the number of young or “reticulated” platelets) can now be measured on some automated cell counters (see Chapter 27 for details). This may be helpful in differentiating thrombocytopenia secondary to lack of production (low number of “reticulated” platelets) from thrombocytopenia secondary to increased destruction (high number of “reticulated” platelets).
2. Leukocytes Myeloblasts or lymphoblasts suggest the diagnosis of leukemia or myeloproliferative disorder. Do¨hle bodies are observed in the neutrophil cytoplasm in MYH9related disorders (see Fig. 47-3 in Chapter 47). Giant cytoplasmic granules are observed in the neutrophils, monocytes, and lymphocytes in Chediak Higashi syndrome (Chapters 18 and 50), but these granules may be more easily recognized in leukocyte precursors in the bone marrow rather than in leukocytes in the peripheral blood. 3. Erythrocytes Red cell fragmentation (schistocytes) suggests thrombotic thrombocytopenic purpura, hemolyticuremic syndrome, or DIC (see Fig. 43-8 in Chapter 43). Spherocytes may be observed in Evans syndrome (Chapter 40).
C. Platelet Function Tests Chapter 28 discusses platelet aggregometry, and Chapter 26 discusses other clinical tests of platelet function.
D. Other Tests Bone marrow aspiration with or without biopsy may be useful in the diagnosis of leukemia and other malignancies, aplastic anemia, ITP (especially in adults), amegakaryocytic thrombocytopenia, and Gaucher disease. Furthermore, bone marrow
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
V. DIFFERENTIAL DIAGNOSIS
examination may be necessary in the evaluation of thrombocytosis, if reactive thrombocytosis (Table 39-3) has not been confirmed by history, physical examination, or noninvasive laboratory tests (as discussed in Chapter 49). Other tests used in the specific diagnosis of disorders of platelet number and function are discussed in the context of the differential diagnosis (see Section V next) and in the other chapters of this book (Chapters 40 52) that discuss these disorders in detail.
V. DIFFERENTIAL DIAGNOSIS The presence of a disorder of platelet number and/ or function can usually be determined from the clinical history, physical examination (Table 39-4), and complete blood count (including examination of the blood smear). The following sections (V.A, V.B, and V.C.) provide an overview of the clinical approach to establishing the specific cause of the thrombocytopenia or platelet function defect.
A. Thrombocytopenia Although the list of causes of thrombocytopenia may appear dauntingly long (Table 39-1), the diagnosis of the specific cause of thrombocytopenia in a patient is often straightforward. ITP (Chapter 40) is a diagnosis of exclusion in a patient with acquired thrombocytopenia: a normal hemoglobin level, white blood cell count and differential, and blood smear (except for the thrombocytopenia and possibly enlarged platelets), in the absence of hepatosplenomegaly, lymphadenopathy, abnormalities of the radii, or other underlying disease. Anemia in the presence of ITP may signify either significant bleeding or autoimmune hemolytic anemia (Evans syndrome, Chapter 40). DIC can essentially be excluded if a thrombocytopenic patient is generally well without a clear precipitating cause for DIC (e.g., sepsis, hypoxia, or shock). If suspected, DIC can be diagnosed by D-dimer and fibrin split products. Heparin-induced thrombocytopenia (Chapter 42) or other drug-induced thrombocytopenia (Chapter 41) can be excluded or suspected based on the clinical history. Systemic lupus erythematosus (SLE)-related thrombocytopenia (Chapter 40) may be initially difficult to diagnose if the thrombocytopenia precedes other manifestations of SLE. HIV-1-related thrombocytopenia (Chapter 40) may be suspected from the clinical history, and HIV can be tested for if this diagnosis is not already known. Patients with thrombotic thrombocytopenic purpura or hemolytic-uremic
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syndrome, although listed in Table 39-1, usually have anemia and fragmented red cells on blood smear (see Fig. 43-8 in Chapter 43). In addition, blood urea nitrogen and serum creatinine are elevated in hemolytic-uremicsyndrome. Common variable immunodeficiency is diagnosed by measuring quantitative serum immunoglobulins. Post-transfusion purpura (Chapter 46) is strongly suggested by the sudden development of profound thrombocytopenia 5 to 10 days after the transfusion of blood products. Type 2B VWD and platelet-type VWD, both rare causes of thrombocytopenia, can be suspected by increased ristocetin-induced platelet agglutination at low ristocetin concentrations (Chapter 28).1 The absent radii in the TAR syndrome (see Fig. 47-1 in Chapter 47) are all too evident by examination of the patient. Amegakaryocytic thrombocytopenia (Chapter 47) is diagnosed by examination of the bone marrow. Giant platelet syndromes (Chapters 47 and 50) are evident on peripheral blood smear (see Fig. 47-3 in Chapter 47 and Fig. 50-2A in Chapter 50). Wiskott Aldrich syndrome (Chapter 47) can be suspected in a male patient with thrombocytopenia and eczema. In hypersplenism, which can occur in any patient with an enlarged spleen from any cause, the thrombocytopenia is usually not severe, and anemia and leukopenia are often present. The giant hemangiomas of Kasabach Merritt syndrome (Chapter 45) are often, but not always, evident on physical examination.
B. Platelet Function Defects The list of specific causes of platelet function defects is also long (Table 39-2). However, acquired defects are the most common and the underlying medical condition is usually evident. With the exception of VWD1 and, to a lesser extent, storage pool disease (Chapters 18 and 50), inherited platelet function defects are all rare. These rare disorders (Chapter 50) usually require specialized research laboratories to make a specific diagnosis, with the exception of Bernard Soulier syndrome and Glanzmann thrombasthenia, which are easily diagnosed by platelet aggregometry (Chapter 28) and flow cytometry (Chapter 29). Platelet aggregation (Chapter 28) is useful for the diagnosis of platelet function defects. In Glanzmann thrombasthenia (Chapter 50), the platelets do not aggregate in response to adenosine diphosphate (ADP), epinephrine, arachidonic acid, or collagen, but do agglutinate in response to ristocetin. In Bernard Soulier syndrome (Chapters 47 and 50), the platelets do not agglutinate in response to ristocetin, but do aggregate in response to all other agonists.
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION
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39. THE CLINICAL APPROACH TO DISORDERS OF PLATELET NUMBER AND FUNCTION
Patients with storage pool disease or defects in platelet secretion (Chapters 18 and 50) show decreased platelet aggregation or absence of the second wave of aggregation in response to ADP, epinephrine, arachidonic acid, or collagen. Some patients with storage pool disease cannot be reliably diagnosed by standard platelet aggregometry; the diagnosis is made by measuring the granule adenine nucleotides by lumiaggregometry (Chapter 28), biochemical assays, or by labeling the platelets with the fluorescent dye mepacrine and then measuring platelet fluorescence by microscopy or flow cytometry (Chapter 29).
C. von Willebrand Disease
clinically indistinguishable from disorders of platelet number and function. VWF has a second major role: it is the carrier molecule for factor VIII. In the uncommon setting of type 3 VWD, the factor VIII coagulant activity is low enough for the clinical features to be those of a combined primary hemostatic disorder and coagulation disorder (Table 39-4). VWD is usually diagnosed by a decrease in plasma levels of ristocetin cofactor activity, VWF antigen, and factor VIII coagulant activity. However, not all patients with VWD have a decrease in the plasma levels of all three of these parameters.1
VI. SPECIFIC DISORDERS
A primary hemostatic disorder in the absence of thrombocytopenia or morphological evidence of a platelet function disorder may require testing for VWD. VWD is not primarily a disorder of platelet function, but a disorder of von Willebrand factor (VWF).1 Because of the key role of VWF in platelet adhesion via its binding to the GPIb-IX-V complex (Chapters 10 and 20), VWD results, however, in a platelet adhesion defect. Therefore, VWD usually presents clinically as a primary hemostatic disorder (Table 39-4) that, without laboratory testing, may be
The specific disorders of platelet number and function (Tables 39-1 through 39-3), including their pathophysiology, clinical features, differential diagnosis, definitive diagnostic tests, and treatment, are discussed in detail in the chapters that follow (Chapters 40 52).
Reference [1] Sadler JE. New concepts in von Willebrand disease. Annu Rev Med 2005;56:173 91.
IV. DISORDERS OF PLATELET NUMBER AND FUNCTION