Immune Thrombocytopenia
GENERAL PRINCIPLES
Immune thrombocytopenia (ITP) is an acquired immune disorder in which antiplatelet antibodies cause shortened platelet survival and suppress megakaryopoiesis leading to thrombocytopenia and increased bleeding risk.3 Etiologies of ITP include idiopathic (primary), associated with coexisting conditions (secondary), or drug induced.
Epidemiology
Adult primary ITP has an incidence of 3.3 cases per 105 persons.4
Etiology
• In primary ITP, autoantibodies bind to platelet surface antigens and cause premature clearance by the reticuloendothelial system in addition to immune-mediated suppression of platelet production.
• Secondary ITP occurs in the setting of systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome (APS), HIV, hepatitis C virus (HCV), Helicobacter pylori, and lymphoproliferative disorders.3
• Drug-dependent ITP results from drug-platelet interactions prompting antibody binding.5 Some common medications linked to thrombocytopenia include quinidine and quinine; platelet inhibitors abciximab, eptifibatide, tirofiban, and ticlopidine; antibiotics linezolid, rifampin, sulfonamides, and vancomycin; the anticonvulsants phenytoin, valproic acid, and carbamazepine; analgesics acetaminophen, naproxen, and diclofenac; cimetidine; and chlorothiazide.
DIAGNOSIS
Clinical Presentation
ITP typically presents as mild mucocutaneous bleeding and petechiae or incidental thrombocytopenia. Occasionally, ITP can present as major bleeding. Risk of bleeding is highest with platelet counts lt;30 ? 109#8725;L.6
Diagnostic Testing
Normalization of platelet counts with discontinuation of suspected drug and confirmation if thrombocytopenia recurs when rechallenged support the diagnosis of drug-induced ITP.
LABORATORIES
• Review a peripheral blood smear to confirm automated platelet count, assess for platelet clumping and to determine platelet, red cell, and white cell morphologies.
• Laboratory tests do not confirm the diagnosis of primary ITP, although they help to exclude secondary causes. Primary ITP often has the scenario of isolated thrombocytopenia in the absence of a likely underlying causative disease or medication.
• Test for infection-associated causes (e.g., HIV, HCV).6
• Serologic tests for antiplatelet antibodies generally do not help diagnose ITP because of poor sensitivity and low negative predictive value (NPV).
DIAGNOSTIC PROCEDURES
Diagnosis of ITP does not typically require bone marrow examination, although it can help to exclude other causes in select patients with additional CBC abnormalities, unresponsiveness to immune suppression therapy, or atypical signs or symptoms.6
TREATMENT
• The decision to treat primary ITP depends on the severity of thrombocytopenia and bleeding risk. The therapeutic goal is a safe platelet count to prevent major bleeding (typically #8805;30 ? 109#8725;L) and minimization of treatment-related toxicities.
• Initial therapy, when indicated, consists of glucocorticoids (e.g., dexamethasone 40 mg orally for 4 days, followed by an additional 4 days in nonresponders or prednisone 1 mg/kg daily with prolonged taper).7 Patients may also receive IV immunoglobulin (IVIG; 1 g/kg for one to two doses) to hasten response.
• Rh-positive patients may also receive anti-D immunoglobulin (WinRho) (ineffective postsplenectomy). WinRho may cause severe hemolysis and requires postinfusion monitoring (black box warning). Given effective therapies, WinRho is rarely used for ITP treatment at this time.
• Most primary ITP cases respond to therapy within 1-3 weeks; however, 30%-40% of patients will develop relapsed/refractory ITP.
• Choices for second-line therapy of ITP include rituximab (anti-CD20 monoclonal antibody), thrombopoietin receptor agonists (TPO-RA), and splenectomy.
î There are three TPO-RA for treatment of refractory primary ITP patients: romiplostim,8 dosed subcutaneously weekly; eltrombopag9 and avatrombopag,10 taken orally once a day.
TPO-RA produce durable platelet count improvements in gt;90% ITP patients beginning 5-7 days after initiation. Potential complications include thromboembolic events.î Rituximab is associated with a remission (platelet gt; 100 ? 109#8725;L at 12 months) in ~25%.
î Two-thirds of patients with refractory ITP will obtain a durable complete response following splenectomy. Administer pneumococcal, meningococcal, and Haemophilus influenzae type B vaccines before (preferred) or after splenectomy.
• Fostamatinib, a tyrosine kinase inhibitor (TKI) that inhibits the spleen tyrosine kinase Syk, increases platelet count by reducing platelet phagocytosis by macrophages. While response rates were low (18% achieved a stable platelet count gt; 50 ? 109#8725;L) in trial, most patients had tried multiple prior therapies (median 3, range 1-13).11
• Additional treatment options for patients with relapsed/refractory disease include single or combined therapies with prednisone, IVIG, androgen therapy with danazol, other immunosuppressive agents.
• Management of secondary ITP may include a combination of treatment for the underlying disease and therapies similar to those used for primary ITP.
• Platelet transfusion for severe drug-induced thrombocytopenia may decrease risk of bleeding. IVIG, steroids, and plasmapheresis have uncertain benefit.