First Quarter 2008 - Issues in Hematology - ION Solutions

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oncologistics volume 7, issue 1 - spring 2008 18the available clinical information. For instance, patientswith appropriate risk factors should undergo testing forHuman Immunodefi ciency Virus (HIV). In older patients withunexplained thrombocytopenia, or in individuals in whomstandard therapy has not been effective, a bone marrowbiopsy may be in order. Correct diagnosis of the etiologyof thrombocytopenia is essential in order to provide thecorrect treatment, and to avoid unnecessary proceduresand treatments.MANY PATIENTS WITH THROMBOCYTOPENIAHAVE INCREASED PLATELET DESTRUCTIONNon-immune and immune processes can lead to ashortened platelet lifespan. Immune mediated plateletdestruction can occur due to medication, autoimmunity,or alloimmune antibodies following sensitization.Medications should always be scrutinized as a possiblecause of thrombocytopenia, since the pharmaceuticallist of offending agents is extensive. Drugs with strongevidence of antibody-mediated platelet destruction includequinine, quinidine, sulfonamides, and gold salts. In additionto the cessation of the offending medication, there aretreatments for severe thrombocytopenia with bleedingthat may need to be given emergently. These treatmentsmay include platelet transfusion, corticosteroids, andintravenous immunoglobulin (IVIG).A special case of drug-induced immune-mediatedthrombocytopenia that is associated with arterial andvenous thrombosis rather than bleeding is Heparin-inducedthrombocytopenia (HIT). HIT occurs in 2-5% of patientsgiven unfractionated heparin by any route for fi ve to 10days. Antibodies develop to a complex of heparin boundto PF4 (a protein secreted by activated platelets.) Whenthrombocytopenia is detected in a hospitalized patient,HIT must always be considered. If a patient has HIT, allheparin administration should be promptly stopped. Thisincludes subcutaneous injections of “minidose” heparin,heparin fl ushes of IV lines, low molecular weight heparin,and even heparin coating of intravenous catheters.Additionally, at least until the platelet count normalizes,alternative anticoagulation, such as the direct thrombininhibitors like recombinant hirudin and argatroban shouldbe administered. Warfarin should not be used in cases ofacute HIT because of its delayed therapeutic effect, and itsassociation with venous limb gangrene. Sincepatients rarely become profoundly thrombocytopenicby this disease alone, platelet transfusions are typicallynot required. In fact, the administration of platelettransfusions in this disease is controversial, and somereports suggest platelet transfusions can actuallyprecipitate thrombotic complications.Alloimmune thrombocytopenia is due to sensitization toalloantigens such as Pl A1 , and can result from transfusion(post-transfusion purpura or PTP) or maternal sensitizationduring pregnancy (neonatal alloimmune thrombocytopeniaor NAIT). PTP causes profound thrombocytopenia 7-10days after exposure to platelets that contaminate redblood cell transfusions, and can be treated withintravenous immunoglobulin or plasma exchange.NAIT can cause severe thrombocytopenia and bleedingin neonates, and is treated with transfusion of plateletsderived from the newborn’s mother, corticosteroids,and intravenous immunoglobulin.Autoimmune thrombocytopenia, also known asidiopathic thrombocytopenic purpura, is caused bycirculating anti-platelet autoantibodies. An ITP-likepicture can also occur in autoimmune diseases suchas systemic lupus erythematosis, in patients withlow-grade lymphoproliferative disorders such as chroniclymphocytic leukemia, and in patients with HIV infections.ITP can occur in patients of either sex, at any age, andmay present with either mucocutaneous bleeding orunexplained asymptomatic thrombocytopenia. Exceptfor thrombocytopenia, the CBC is completely normal.Splenomegaly is absent in this disorder, and peripheralblood smears are only remarkable for a decreased numberof platelets, some of which may be larger in size thannormal. Bone marrow examination is usually not necessaryin the absence of other fi ndings suggesting myelodysplasia.When done, the bone marrow biopsy typically showsnormal or increased numbers of megakaryocytes, but isotherwise normal.Management of ITP is guided by both symptoms andplatelet count. Asymptomatic patients with plateletcounts of greater than 30,000/µL can be followedwithout treatment. With bleeding and/or a platelet
oncologistics thrombocytopeniacount of less than 30,000/µL, treatment withprednisone is recommended. Refractory patientsmay require splenectomy (60-75% remission rate),other immunosuppressive medications, or (pendingFDA approval) new thrombopoiesis stimulatingagents. Emergent presentations of ITP with severethrombocytopenia (less than 5,000/µL) and/or internalbleeding, should be treated with high doses of pulsecorticosteroids and intravenous immunoglobulin.Platelet transfusion may be given concurrently withthe intravenous immunoglobulin for critical bleeding.In Rh+ patients, who have not undergone splenectomy,anti-D immune globulin may be substituted forintravenous immunoglobulin. However, occasionalpatients will develop severe autoimmune hemolysisfrom the administration of this treatment.THROMBOCYTOPENIA DUE TO DIC, TTP/HUS,AND HYPERSPLENISMNon-immune mediated causes of platelet destructioninclude sepsis, disseminated intravascular coagulation(DIC), thrombotic thrombocytopenic purpura/hemolyticuremic syndrome (TTP/HUS), preeclampsia/eclampsia,cardiopulmonary bypass, and giant cavernoushemangiomas. The thrombocytopenia resolveswith treatment of the underlying disorder, andplatelet transfusion is rarely necessary. In TTP/HUS,thrombocytopenia is associated with thrombosis ratherthan bleeding, and controversial reports exist of clinicaldeterioration following platelet transfusion.Approximately 20% of the circulating platelet massis normally present in the spleen. Additional plateletsmay be sequestered when the spleen enlarges dueto portal hypertension or infi ltrative diseases, and thisresults in thrombocytopenia (although the platelet countis generally are not lower than 40,000-50,000/µL.)Consequently, bleeding due to thrombocytopenia fromhypersplenism alone is unusual.marrow is replaced by metastatic carcinoma,fi brosis, or other clonal hematopoietic disorders;following chemotherapy and/or radiation therapy;with ethanol toxicity; and during infections with virusessuch as HIV, cytomegalovirus (CMV), Epstein-Barrvirus (EBV), and varicella. Thrombocytopenia alsooccurs when normal megakaryocyte proliferation isimpaired by myelodysplasia.Overt bleeding in these disorders, when clearlydue to thrombocytopenia, is treated by platelettransfusion. However, in the absence of bleeding,prophylactic platelet transfusion is an area of controversy.When making the decision whether to treat a nonbleedingpatient with thrombocytopenia, the practitionermust consider the short lifespan of platelets (10 days),the fi ve-day shelf life of stored platelets, and the potentialof a transfusion inducing platelet alloantibodies. Inpatients undergoing treatment for acute leukemia,outcome is unchanged when platelet counts as lowas 5,000-10,000/µL are used as the threshold forprophylactic transfusion. Single donor apheresis platelets,and/or platelet donors who are HLA-identical to therecipient, should be used to prevent alloimmunization.The multi-center Platelet Dose trial is currently underwayand should help to clarify the ideal parameters for platelettransfusions in patients with malignancy.FINAL THOUGHTSThrombocytopenia remains a potentially life-threateningproblem that requires careful clinical assessmentand judgment. In recent years, signifi cant advanceshave been made in elucidating the pathogenesisof thrombocytopenia and the mechanisms ofthrombopoiesis. Drawing upon decades of basic scienceand clinical research, this has led to the application ofsafer and more effi cacious therapies for this disorder. ❚DECREASED PLATELET PRODUCTION INTHROMBOCYTOPENIADecreased platelet production occurs in primarydiseases of the bone marrow such as acute leukemiaand aplastic anemia; myelophthisic processes in whichCharles S. Abrams, M.D., is associate professorin the Department of Medicine at The Universityof Pennsylvania School of Medicine.oncologistics 19
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First Quarter 2008 - Issues in Hematology - ION Solutions

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