Overview of Acquired and Inherited Clinical Platelet Disorders

Joel S. Bennett

An insufficient number of platelets (thrombocytopenia) or impaired platelet function (thrombocytopathia) can produce bleeding. Both situations are encountered frequently in clinical practice, engendering substantial and appropriate concern about the risk and prevention of bleeding. A summary of key points to be taken from this overview are listed in Table 59.1.

QUANTITATIVE PLATELET DISORDERS

Definition of Thrombocytopenia and Risk of Bleeding

The normal range for platelet counts in healthy individuals is 150,000 to 350,000/µL. However, as discussed in Chapter 60, mean platelet counts are higher in women than men, independent of the presence of iron deficiency, and decline with age, especially after age 60.¹ Although the significance of severe thrombocytopenia is usually readily apparent, the significance of borderline thrombocytopenia, defined as a platelet count between 100,000 to 150,000/µL, is often unclear. Some platelet counts in this range are outliers of the normal platelet count distribution, but they can also represent an early manifestation of an unrecognized disease. Many patients with borderline thrombocytopenia carry a diagnosis of autoimmune thrombocytopenia (ATP), but in a prospective study of 217 healthy individuals with incidental borderline thrombocytopenia, 88% still had a platelet count of >100,000/µL after 5 years without a specific diagnosis being established.² Based primarily on this study, the International Working Group of the Vicenza Consensus Conference has set the threshold for the diagnosis of idiopathic thrombocytopenia (ITP) as a platelet count of <100,000/µL.³

The number of circulating platelets is the composite of the rate of platelet production, the rate of platelet destruction, and platelet sequestration in the spleen. In humans, the platelet lifespan is 7 to 10 days and reflects both nonrandom platelet senescence and random platelet consumption.⁴ Platelet senescence is likely explained by an intrinsic apoptotic pathway that acts as an “internal timer,” determining when an aged platelet should be removed from the circulation.⁵^,⁶ Based on measurements of platelet kinetics in patients with marrow hypoplasia, it has been predicted that there is a fixed platelet requirement of approximately 7,100 platelets/µL/d and that these platelets are used to support the integrity of the vasculature.⁷ There is also a pool of platelets in the spleen that accounts for approximately 30% of the platelet volume in normal individuals and that is in dynamic equilibrium with platelets in the circulation.⁸^,⁹ However, >30% of the platelet volume may be sequestered in an enlarged spleen due to conditions such as portal hypertension or infiltrative diseases such as in myeloproliferative neoplasms.¹⁰

The normal platelet count is far in excess of the number of platelets required for hemostasis. Although the cutaneous bleeding time, a measure of platelet function in vivo, can be increased at platelet counts <100,000/µL,¹¹ significant spontaneous bleeding does not usually occur in an otherwise hemostatically normal individual until the platelet count declines to <5,000/µL.¹² Clinical trials of patients receiving chemotherapy or being treated for aplastic anemia indicate that a threshold of 10,000 platelets/µL is sufficient to minimize the risk of spontaneous bleeding,¹³ and hemorrhage following trauma or surgery usually does not occur if the platelet count is >50,000/µL.¹⁴^,¹⁵ Nonetheless, there is no absolute threshold for spontaneous bleeding due to thrombocytopenia, and it can occur at higher platelet counts when fever, sepsis, severe anemia, or other hemostatic defects are present or when platelet function is impaired, for example, by medications.

Differential Diagnosis of Thrombocytopenia

From a practical clinical standpoint, thrombocytopenic disorders can be divided into those having an immunologic basis and those that do not.

Antibody-Mediated Thrombocytopenia

Immune Thrombocytopenia

Immune thrombocytopenia, also known as ITP or ATP, is an acquired disorder caused by antiplatelet antibodies.¹⁶^,¹⁷^,¹⁸ As discussed in Chapter 61, ITP is characterized by the presence of an isolated platelet count of <100,000 in the context of normal red and white cell counts, a peripheral blood smear only remarkable for a decreased number of platelets, and the absence of splenomegaly.¹⁷ In addition, a diagnosis of ITP requires that there be no family history of thrombocytopenia and no use of medications that can cause thrombocytopenia.¹⁷^,¹⁹ Because there is no standard diagnostic laboratory test for ITP, it is a diagnosis of exclusion.²⁰ Thus, when a patient’s clinical presentation deviates from the paradigm given above, the diagnosis of
ITP must be reconsidered. ITP can occur at any age, in either sex, and can present with either spontaneous mucocutaneous bleeding or unexplained asymptomatic thrombocytopenia. Characteristically, the bone marrow of patients with ITP is normal, except for a compensatory increase in megakaryocytes, so that bone marrow examination is rarely necessary or helpful. Although assays are available to detect antiplatelet antibodies, they lack sensitivity and specificity and are rarely useful diagnostically.

Table 59.1 Key points regarding thrombocytopenia and thrombocytopathia

•	The platelet count of most asymptomatic patients with borderline thrombocytopenia (platelet counts of 100,000-150,000/µL) remains stable without a specific diagnosis.
•	Significant spontaneous bleeding usually does not occur in an otherwise hemostatically normal individual until the platelet count declines to <5,000/µL.
•	ATP is characterized by an isolated platelet count <100,000 in the context of normal red and white cell counts, a peripheral blood smear only remarkable for a decreased number of platelets, and the absence of splenomegaly. When a patient’s clinical presentation deviates from this paradigm, the diagnosis of ATP must be reconsidered.
•	The differential diagnosis of ATP includes pseudothrombocytopenia, drug-induced thrombocytopenia, underlying autoimmune disease, lymphoproliferative disorders, immunodeficiency, myelodysplasia, and infections with hepatitis C virus, human immunodeficiency virus, or H. pylori.
•	Although many medications impair platelet function in vitro, only a few, including aspirin, the thienopyridines and the α_IIbβ₃ antagonists, regularly cause clinically significant bleeding.
•	Nonimmune mechanisms can cause thrombocytopenia by decreasing platelet production by the bone marrow, platelet sequestration in an enlarged spleen, or by decreasing the lifespan of circulating platelets.
•	Inherited thrombocytopenia is rare but must be considered in the differential diagnosis of a thrombocytopenic patient.
•	Hereditary disorders of platelet adhesion, aggregation, and platelet secretion must be considered in the evaluation of easy bruising, menorrhagia, and excessive postoperative and postpartum blood loss.
•	Abnormal hemostasis specifically due to perturbed platelet function is a feature of the chronic myeloproliferative disorders (PV, ET) and of dysproteinemias (multiple myeloma).

In approximately half of the patients who are considered to have ITP, platelet antibodies are secondary to another disorder, for example, autoimmune diseases (systemic lupus erythematosus), lymphoproliferative disorders (chronic lymphocytic leukemia), immunodeficiency disorders (common variable immunodeficiency), myelodysplasia, and infections with hepatitis C virus, human immunodeficiency virus, or Helicobacter pylori.²⁰

In adults, ITP is generally a chronic disease; only 15% of patients remit within a year of onset. By contrast, childhood ITP is often preceded by a febrile illness and more than 70% remit within 6 months, regardless of treatment; only 5% to 10% of children go on to develop chronic disease.²⁰ The goal of treatment of ITP is to maintain a safe, but not necessarily normal, platelet count with minimal toxicity from therapy.¹⁷ As bleeding is usually minimal or absent until the platelet count is <30,000/µL, asymptomatic patients with a platelet count >30,000/µL can be followed with no treatment. Nonetheless, maintenance of a hemostatically effective platelet count may require the chronic administration of a low dose of corticosteroids (i.e., 10 mg of prednisone daily), splenectomy, or immunosuppression with drugs such rituximab, azathioprine, or cyclophosphamide. For patients refractory to therapy, treatment with the thrombopoietin receptor agonists romiplostim or eltrombopag can be considered.²¹ When patients with ITP present emergently with severe thrombocytopenia (<5,000/µL) and/or major or lifethreatening hemorrhage, treatment usually includes high-dose corticosteroids and/or intravenous immunoglobulin (IVIgG).²² Anti-D immune globulin may be substituted for IVIgG in Rh-positive patients who have not undergone splenectomy. Platelet transfusions are generally unable to increase platelet counts in patients with severe ITP because of the rapid clearance of antibody-coated transfused platelets, but the concurrent transfusion of IVIgG and platelets has been reported to increase platelet counts in most patients.²³^,²⁴

Alloimmune Thrombocytopenia

Alloimmune thrombocytopenia results from sensitization to platelet alloantigens such as Pl^A1 following platelet or red cell transfusion to a patient lacking this antigen (post-transfusion purpura, PTP) or maternal sensitization to a foreign platelet antigen during pregnancy, similar to Rh incompatibility (neonatal alloimmune thrombocytopenia, NATP).²⁵^,²⁶ PTP causes profound thrombocytopenia 7 to 10 days after transfusion and can be treated with IVIgG or plasma exchange. NATP causes severe thrombocytopenia and bleeding in neonates and is treated with platelet transfusion, corticosteroids, and IVIgG.

Drug-Induced Thrombocytopenia

Antiplatelet antibodies induced by sensitization to drugs can cause acute platelet destruction and must be considered in the differential diagnosis of thrombocytopenia²⁷ (see Chapter 62). Although there is a long list of drugs reported to cause antibodymediated platelet destruction, the evidence for the 24 drugs listed in Table 59.2 is particularly strong.¹⁹ In general, drug-dependent antibody binding to platelets requires initial reversible binding
of a drug to platelet membrane glycoproteins.²⁸^,²⁹ Uncommonly, drugs such as penicillin act as haptens by covalently binding to platelet membrane glycoproteins or drugs such as gold salts, levodopa, and procaine amide induce platelet-specific neoantigens and a clinical scenario mimicking ITP.³⁰ In another variation of drug-induced thrombocytopenia, platelet counts may decrease immediately after administration of the chimeric human/murine anti-α_IIbβ₃ monoclonal antibody fragment abciximab due to preexisting antibodies against the murine portion of the drug, or thrombocytopenia can be delayed for 5 to 10 days during which time new antibodies are generated.³¹ Similarly, acute thrombocytopenia can follow the administration of the small molecule α_IIbβ₃-antagonists eptifibatide and tirofiban.³¹ Here, the thrombocytopenia is thought to be due to naturally occurring antibodies recognizing platelet neoepitopes induced by antagonist binding. Emergent treatment for severe drug-induced thrombocytopenia with bleeding includes stopping the likely offending medication, platelet transfusion, corticosteroids, and IVIgG, similar to the emergent treatment for severe ITP.

Table 59.2 Drugs associated with antibody-mediated thrombocytopenia

Abciximab

Acetaminophen

Amiodarone

Ampicillin

Carbamazepine

Eptifibatide

Haloperidol

Ibuprofen

Irinotecan

Naproxen

Oxaliplatin

Phenytoin

Piperacillin

Quinidine

Quinine

Ranitidine

Rifampin

Simvastatin

Sulfisoxazole

Tirofiban

Trimethoprim/Sulfamethoxazole

Valproic acid

Vancomycin

Adapted from Reese JA, Li X, Hauben M, et al. Identifying drugs that cause acute thrombocytopenia: an analysis using 3 distinct methods. Blood 2010;116:2127-2133, with permission.

Heparin-induced thrombocytopenia (HIT) is a special case of drug-induced thrombocytopenia since it is associated with arterial and venous thrombosis rather than bleeding (see Chapter 108). Depending on the clinical population at risk, HIT occurs in approximately 1% to 5% of patients given unfractionated heparin for 5 to 10 days and is due to the formation of antibodies against a complex of heparin and the platelet a granule protein platelet factor 4.³² HIT is a clinical diagnosis with criteria that include an acute decrease in platelet count of 50% or to >150,00/µL; the diagnosis is confirmed by appropriate testing for heparin-related antibodies.³²^,³³ If HIT is a possibility, all heparin administration should be stopped and alternative anticoagulation instituted with a direct thrombin inhibitor such as argatroban, at least until the platelet count returns to normal.³³ Warfarin should not be used for acute HIT because it can be associated with venous limb gangrene, a syndrome similar to warfarin-induced skin necrosis that may lead to amputation.³⁴

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