Thrombocytopenia: Pathophysiology and Classification

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Wintrobes Clinical Hematology 12th Edition

2009 Lippincott Williams & Wilkins

Chapter 50 Thrombocytopenia: Pathophysiology and Classification

George M. Rodgers It was not until the 16th century (Lusitanus) and the early part of the 17th century (La Riviere) that purpura in the absence of fever was recognized (1). In 1735, Werlhof distinguished morbus maculosus hemorrhagicus as a separate entity, and in 1808, Willan classified purpura under the headings simplex, hemorrhagica, urticans, and contagiosa, thus separating the types later described by Schnlein (1829) and Henoch (1868) that now bear their names. The marked diminution in hematoblasts (platelets) in purpura hemorrhagica was recognized by Krauss (1883) and Denys (1887). Hayem (1895) noted the nonretractility of the blood clot, and Duke (1912) demonstrated the prolonged bleeding time. Abnormal capillary fragility was observed by writers in different countries ( le signe du lacet , Grocco-Frugoni sign, and the Rumpel-Leede phenomenon).

Pathophysiology
Thrombocytopenia may be defined as a subnormal number of platelets in the circulating blood. It is the most common cause of abnormal bleeding. Despite the number and diversity of disorders that may be associated etiologically, thrombocytopenia results from only four processes: Artifactual thrombocytopenia, deficient platelet production, accelerated platelet destruction, and abnormal distribution or pooling of the platelets within the body (Fig. 50.1). The changes in the basic parameters of thrombopoiesis that are characteristic of each of these processes are summarized in Table 50.1.

Artifactual Thrombocytopenia
Artifactual thrombocytopenia , or falsely low platelet counts, occurs ex vivo when platelets are not counted accurately. This mechanism should be considered in patients who have thrombocytopenia but no petechiae or ecchymoses. Although inaccurate counting may occur in the presence of giant platelets (2) or with platelet satellitism (3), the most common cause of artifactual thrombocytopenia is platelet clumping (pseudothrombocytopenia) (4). Platelet clumping in pseudothrombocytopenia appears to be caused by anticoagulant-dependent platelet agglutinins that are immunoglobulins (Igs) of IgG, IgA, or IgM subtypes. Although clumping is most commonly seen when blood is collected into ethylenediaminetetraacetic acid anticoagulant, other anticoagulants may cause clumping, even hirudin or Phe-Pro-Arg chloromethyl ketone (5). Platelet clumping is also time dependent and varies with the type of instrumentation used for automatic counting (5). There is evidence that the autoantibodies bind to glycoprotein IIb/IIIa (6), and in one study, there was over 80% concordance between the presence of anticardiolipin antibody and platelet agglutinins in individual patient plasmas (7). These autoantibodies have no known associations with disease or drugs and have been noted in some patients for over 10 years (8).

Accelerated Platelet Destruction

Accelerated platelet destruction is the most common cause of thrombocytopenia. It leads to stimulation of thrombopoiesis and, consequently, to an increase in the number, size, and rate of maturation of the precursor megakaryocytes (Fig. 50.1) (9). When the rate of platelet destruction exceeds this compensatory increase in platelet production, thrombocytopenia develops.

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Compensated platelet destruction without thrombocytopenia also may occur in patients with prosthetic heart valves and in patients with idiopathic thrombocytopenic purpura after splenectomy (10,11,12). Platelet destruction may result from both intracorpuscular defects and extracorpuscular abnormalities. Intracorpuscular defects are rare but have been demonstrated in certain forms of hereditary thrombocytopenia, such as Wiskott-Aldrich syndrome (see Chapter 53) (13). In such disorders, the survival of affected platelets is shortened in the circulation of both the patient and normal recipients. Platelets injured by either intracorpuscular or extracorpuscular processes usually are removed from the circulation by the spleen, liver, and reticuloendothelial system. Platelet destruction most often is the result of extracorpuscular factors; various immunologic phenomena are the most common. Immunologic platelet destruction is discussed in Chapter 51. Platelet consumption in intravascular thrombi or on damaged endothelial surfaces is another cause of thrombocytopenia. This occurs in disseminated intravascular coagulation (see Chapter 58) and in thrombotic thrombocytopenic purpura (see Chapter 52) and other microangiopathic processes. Thrombocytopenia caused by other nonimmunologic platelet destruction is discussed in Chapter 52.

Deficient Platelet Production

Deficient platelet production may result from any of a number of processes. Those that depopulate the stem cell or megakaryocyte compartments are the most common, such as marrow injury by myelosuppressive drugs or irradiation, and aplastic anemia. Deficient platelet production also may be the consequence of disordered proliferation within a precursor compartment of normal or even increased size. For example, in disorders characterized by megaloblastic hematopoiesis, hypertrophy of the precursor compartment occurs in response to thrombopoietic stimuli, but thrombopoiesis is ineffective and platelet production is insufficient. Rarely, abnormalities of the processes that normally regulate thrombopoiesis appear to underlie deficient platelet production, such as deficiency of thrombopoietin and cyclic thrombocytopenia.

Abnormal Pooling
Abnormal pooling or abnormal in vivo distribution of an essentially normal total platelet mass may produce thrombocytopenia. P.1290 This type of thrombocytopenia is seen in the various disorders associated with splenomegaly (see Chapter 53), in which platelet production is normal or even increased but most of the platelets are sequestered in the vastly enlarged extravascular splenic pool. Thrombocytopenia may also be caused by dilution of platelets when patients are massively transfused during blood loss. A discussion of various forms of thrombocytopenia attributable to deficient or ineffective thrombopoiesis or abnormal platelet pooling is included in Chapter 53.

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Figure 50.1. The pathophysiology of thrombocytopenia. A simplified diagram of the biodynamics of the megakaryocyteplatelet system (solid lines) and the mechanisms (dashed lines) by which pathologic processes (shaded blocks) produce thrombocytopenia.

Table 50.1 Thrombokinetic Patterns in Various Forms of Thrombocytopenia

Decreased Production Measurement Hypoproliferation or Hypoplasia a Ineffective Thrombopoiesis b Accelerated Destruction c Pooling Abnormal

Total megakaryocyte mass d

Decreased

Increased

M increased

V increased

Megakaryocyte number

Decreased

M increased

Increased

V increased

Megakaryocyte volume

Increased

Normal or V decreased

Increased

V increased

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Platelet turnover rate or production rate e

Decreased

Decreased

Increased

V increased

Total platelet mass

Decreased

Decreased

Decreased

? Normal

Splenic platelet pool

Decreased

Decreased

Decreased f

Increased

Platelet survival

Normal

V shortened

Shortened

V shortened

M, markedly; V, variably.
a b

Includes myelophthisic processes. Mainly in megaloblastic hematopoiesis; component of accelerated destruction present in Minor component of ineffective thrombopoiesis present in some cases. Equated to total thrombopoiesis. Equated to effective thrombopoiesis. Not representative of sequestered antibody-sensitized platelets.

some cases.
c d e f

Based on Harker LA. Megakaryocyte quantitation. J Clin Invest 1968;47:452457; Harker LA. Thrombokinetics in idiopathic thrombocytopenic purpura. Br J Haematol 1970;19:95 104; and Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest 1969;48:963974.

Classification
A classification of thrombocytopenia based on pathophysiologic criteria is presented in Table 50.2. It should be recognized that multiple pathogenetic factors may simultaneously or sequentially play a role in the production of thrombocytopenia. The discussion and various tables included in Chapters 51, 52, and 53 are based on the most suitable features of both the etiologic and the P.1291 pathophysiologic classifications because neither alone is entirely satisfactory.

Table 50.2 Pathophysiologic Classification of Thrombocytopenia

Artifactual thrombocytopenia Platelet clumping caused by anticoagulant-dependent immunoglobulin (pseudothrombocytopenia) Platelet satellitism Giant platelets Decreased platelet production (see Chapter 53) Hypoplasia of megakaryocytes Ineffective thrombopoiesis Disorders of thrombopoietic control Hereditary thrombocytopenias Increased platelet destruction Caused by immunologic processes (see Chapter 51) Autoimmune Idiopathic Secondary: Infections, pregnancy, collagen vascular disorders, lymphoproliferative

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disorders, drugs, miscellaneous Alloimmune Neonatal thrombocytopenia Posttransfusion purpura Caused by nonimmunologic processes Thrombotic microangiopathies Disseminated intravascular coagulation (see Chapter 58) Thrombotic thrombocytopenic purpura (see Chapter 52) Hemolytic-uremic syndrome (see Chapter 52) Platelet damage by abnormal vascular surfaces (see Chapter 53) Miscellaneous (see Chapter 53) Infection Massive blood transfusions Abnormal platelet distribution or pooling (see Chapter 53) Disorders of the spleen (neoplastic, congestive, infiltrative, infectious, of unknown cause) Hypothermia Dilution of platelets with massive transfusions

Methods for the measurement of serum thrombopoietin concentrations or reticulated platelets have been reported. These techniques may both elucidate the pathophysiology of thrombocytopenia in various disease states and determine the mechanism of thrombocytopenia in individual patients. Reticulated platelets can be identified with fluorescent dyes that bind to nucleic acids, especially RNA. Measurement of the percentage of reticulated platelets identifies platelets that have recently been released from the bone marrow. There is an increased percentage of reticulated platelets in patients with thrombocytopenia caused by increased destruction and a normal to reduced percentage of reticulated platelets in patients with deficient production (14,15). The sensitivity and specificity of this method of distinguishing between these categories are reported to be more than 95% (16).

References
1. Jones HW, Tocantins LM. The history of purpura hemorrhagica. Ann Med Hist 1933;5:349 359.

2. Kjeldsberg CR, Hershgold EJ. Spurious thrombocytopenia. JAMA 1974;227: 628630.

3. Bizzaro N. Platelet satellitosis to polymorphonuclears: cytochemical, immunological, and ultrastructural characterization of eight cases. Am J Hematol 1991;36:235242.

4. Gowland E, Kay HE, Spillman JC, et al. Agglutination of platelets by a serum factor in the presence of EDTA. J Clin Pathol 1969;22:460464.

5. Schrezenmeier H, Mller H, Gunsilius E, et al. Anticoagulant-induced pseudothrombocytopenia and pseudoleukocytosis. Thromb Haemost 1995;73: 506513.

6. Pegels JG, Bruynes EC, Engelfriet CP, et al. Pseudothrombocytopenia: an immunologic study on platelet antibodies dependent on ethylene diamine tetra-acetate. Blood 1982;59:157161.

7. Bizzaro N, Brandalise M. EDTA-dependent pseudothrombocytopenia: association with antiplatelet and antiphospholipid antibodies. Am J Clin Pathol 1995;103:103107.

8. Bizzaro N. EDTA-dependent pseudothrombocytopenia: a clinical and epidemiologic study of

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112 cases, with 10-year follow-up. Am J Hematol 1995;50: 103109.

9. Harker LA. Megakaryocyte quantitation. J Clin Invest 1968;47:452457.

10. Harker LA. Thrombokinetics in idiopathic thrombocytopenic purpura. Br J Haematol 1970;19:95104.

11. Branehg I. Platelet kinetics in idiopathic thrombocytopenic purpura (ITP) before and at different times after splenectomy. Br J Haematol 1975;29: 413426.

12. Hope AF, Heyns ADP, Ltter MG, et al. Kinetics and sites of sequestration of indium 111labeled human platelets during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1981;81:880886.

13. Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest 1969;48:963974.

14. Rinder HM, Munz UJ, Ault KA, et al. Reticulated platelets in the evaluation of thrombocytopenic disorders. Arch Pathol Lab Med 1993;117:606610.

15. Watanabe K, Takeuchi K, Kawai Y, et al. Automated measurement of reticulated platelets in estimating thrombopoiesis. Eur J Haematol 1995;54: 163171.

16. Richards EM, Baglin TP. Quantitation of reticulated platelets: methodology and clinical application. Br J Haematol 1995;91:445451.

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