1. Diana Girnita, MD, PhD The Christ Hospital December 2011

2. Definition Platelets < 150,000/ml 2.5% of normal people < 150,000/ml Recent drop 50%, even if normal platelets count 3. Increased risk of bleeding if < 60,000 -with minor trauma if < 12,000 spontaneous If < 6,000 - severe, life threatening 4. Initial approach of the patient Clinical: 1. epistaxis 2. gingival bleeding 3. meno/ metrorrhagia 4. tend to bleed immediately after minor trauma 5. cerebral bleeding Cutaneous: petechiae, purpura, ecchymoses 5. Clinical presentation A: Dense, cutaneous petechiae on the foot and ankle. B:Bullous hemorrhages on the buccal mucosa PURPURA - purplish discoloration of the skin due to the presence of confluent petechiae Ecchymoses nontender areas of bleeding into the skin, usually associated with multiple colors 6. PMH ?Bleeding history ?Hematologic disease (acute /chronic leukemias, MDS) ?Recent new drugs or drugs that are only taken intermittently (ASA, NSAID, herbal, plavix, heparin) ?Recent live virus vaccination ?Recent infection (viral, bacterial, rickettsial) /sepsis ?Recent travel malaria /dengue virus, leptospirosis, meningococcemia, hantavirus, hemorrhagic fevers (eg, Ebola, Lassa ). 7. PMH- cont ?Recent massive transfusion (PRBCs /platelets) in an allo-sensitized recipient ? Recent organ transplantation by sensitization to platelet allo-antigens /GVHD ?Pregnancy especially late in the 3rd trimester or at onset of labor , +/- ITP or TTP-HUS, or preeclampsia/ eclampsia FH: ++ for bleeding and/or thrombocytopenia 8. The physical examination Examination in critical areas 1. Ocular fundus -CNS bleeding 2. Lymphadenopathy 3. Hepatosplenomegaly 4. Stool for occult blood 5. Skin -feet and ankles , presacral area, areas of previous trauma Outline areas of bleeding with a marking pen (changes in the number/pattern of petechiae) 9. Labs CBC -WBC, RBC, Plt count -r/o TTP and acute leukemia PERIPHERAL SMEAR Plt # Ptl morphology- large? +/- Plt clumping +/- scystocytes If anemia: ? Hemolytic ? (LDH, haptoglobin, Bilirubin) 10. Bone marrow examination Evaluate megakariocytes BM could be Hypocellular Cellular BM replacement 11. Mechanisms of thrombocytopenia 1. Pseudothrombocytopenia 2. Decreased platelet production 3. Increased platelet destruction 4. Dilutional thrombocytopenia 5. Distributional thrombocytopenia 12. Pseudothrombocytopenia EDTA-induced platelet clumping Drugs Abciximab - directed against the GP IIb/IIIa receptor 13. Decreased platelet production Hypocellular BM Infections (MMR, varicella, parvovirus, hepatitis C EBV, HIV, rickettias) Live attenuated vaccines Drugs Aplastic anemia Alcohol Autoantibody - against the thrombopoietin receptor (SLE) 14. Decreased platelet production Cellular BM Leukemias MDS Severe vit B12 /folate deficient anemia MDS 15. Decreased platelet production Marrow replacement Myelofibrosis Solid malignancies Granulomas Myelofibrosis 16. Increased platelet destruction 1.Immune mediated Primary ITP Secondary: infectious, CLL, drugs (heparin), APL sdr, lymphoma Allo-immunization (post-transfusion) 2. Non-immune mediated MAHA (TTP-HUS, DIC) Evan Sdr: thrombocytopenia + hemolytic anemia Vascular prostheses/ bypass; trauma Drugs: ticlopidine/clopidogrel, Cavernous hemangioma HELLP syndrome -in pregnant women 17. Other causes: Dilutional thrombocytopenia massive blood transfusion with PRBC (> 20 units of PRBCs /24H) Distributional thrombocytopenia caused by splenic sequestration Portal hypertension Cirrhosis Splenomegaly Hypothermia 18. Thrombocytopenia in the ICU patient Sepsis/septic shock - one-half of the cases Use of heparin DIC Massive blood transfusion Post-transfusion purpura Cardiopulmonary resuscitation Cardiopulmonary bypass ARDS PE Use of intravascular catheters Solid organ allograft rejection Drugs (antibiotics, chemotherapy, antiplatelet agents - abciximab) 19. Heparin induced thrombocytopenia (HIT) HIT I HIT II 20. HIT II an immune-mediated disorder characterized by the formation of antibodies against the heparin-platelet factor 4 complex. UFH/LMWH 5-10 days after the heparin is started Heparin PF4 complex- Ab induce platelet aggregation and activation, endothelial cell activation (IL-6, vWF) Thrombosis (arterial and venous) + thrombocytopenia (>50% fall in Plt) DVT, PE (25%) Skin necrosis at injection site 21. Dg of HIT II Serotonin release assay Heparin-induced platelet aggregation The solid phase ELISA immunoassay- heparin-PF4- IgG antibodies 22. Treatment HIT II Stop the heparin UFH/LMWH Lepirudin Refludan Is a recombinant hirudin (anticoagulant action, similar to antithrombin III - the thrombin inhibitor) For HIT complicated by thrombosis, preventing new thromboses Not for renal failure patients Argatroban Is a direct thrombin inhibitor Metabolized in the liver Activity monitored by APTT Good for renal failure patients Warfarin when 1) patient stably anticoagulated with a thrombin-specific inhibitor 2) Plt > 150,000/microL 23. Challenges in bridging to long term anticoagulation The combination of argatroban and warfarin may raise the INR > 5.0 without a significant increased risk of bleeding complications. Measure the chromogenic factor X level A level < 40-45% typically indicates that the INR will be therapeutic (2-3) when the argatroban is discontinued. 24. HIT I Non-immune mechanism, appears to be due to a direct effect of heparin on platelet activation 1-4 days after heparin is started Platelets in the 100.000/mm3 range No thrombotic events No hemorrhage Management : observation 25. HIT I vs HIT II 26. Thrombotic thrombocytopenic purpura- hemolytic uremic syndrome (TTP-HUS) Thrombocytopenia Microangiopathic hemolytic anemia Neurologic symptoms and signs Renal function abnormalities +/- Fever TTP-HUS is associated with thrombi composed primarily of platelets in affected organs 27. Etiology TTP ADAMTS13 deficiency (vWf-cleaving protease) leads sequentially to the accumulation of unusual large vWf multimers, platelet aggregation, and the platelet clumping Genetic Acquired: DIC, HSCT, chemotherapy, severe sepsis, SLE, leukemia, acute inflammatory states, cirrhosis, uremia, drugs (ticlopidine, clopidogrel, quinine) 28. Etiology HUS Enterohemorrhagic E coli Shiga toxin binds and activates endothelial cells and platelets and induces formation of intra-renal thrombi Clinic: Children Bloody diarrhea Fever 29. Diagnosis TTP-HUS Peripheral smear: ++ Schystocytes Negative Coombs test Normal PT, PTT, fibrinogen Hemolysis : LDH increased (tissue ischemia + hemolysis), indirect bilirubin increased, decreased haptoglobin Increased creatinine Biopsy: arterioles filled with hyaline thrombi (DDx: vasculitis, DIC, HELLP, malignant HTN) 30. Treatment TTP-HUS 1. Plasma exchange Exceptions: Postdiarrheal HUS in children Cancer chemotherapy or transplantation Severe acute renal failure- cause fluid overload 2. Glucocorticoids: severe deficiency of ADAMTS13 Platelet transfusions are contraindicated 31. Immune thrombocytopenic purpura (ITP) Dg of exclusion ITP is related to a combination of increased platelet destruction along with inhibition of megakaryocyte platelet production via the production of specific IgG autoantibodies directed against platelet membrane GP (GPIIb/IIIa) 32. Diagnosis ITP CBC : ITP+AIHA = Evans Sdr Peripheral smear: large platelets Bone marrow aspirate >60 yo to r/o MDS Antiplatelet antibody testing not recommended by the ASH Platelets have HLA A, B-testing for anti-HLA ab to match platelets Consider ANA, viral serologies, H pylory Ab 33. Treatment ITP Initial : Steroids: PDN/ methylprednisolone (bleeding) IVIG WinRho (AntiRh-D) in Rh positive pt; ab coated RBC overwhelm Macrophages Fc receptor Refractory Splenectomy Rituximab (anti-CD20) Azathioprine, Cyclophosphamide Thrombopoiesis stimulant: Eltrombopag 34. References www.uptodate.com John Hopkins IM board review PG MGH handbook 35. Thank you! ALYSA & ANA