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Plt disorders 2015

Platelet disorders

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Plt disorders 2015

  1. 1. Prapti Patel Resident Lecture Series 2.4.15 PLATELET DISORDERS: ITP, TTP, HIT
  2. 2. IMMUNE THROMBOCYTOPENIC PURPURA
  3. 3. • Barnes-Jewish Hospital, 1950: postulated that patients with ITP had a “blood factor” that caused destruction of platelets • To test this hypothesis, Harrington received a transfusion of 500 ml of blood from a patient with ITP.[ • Within three hours, his platelets dropped to dangerously low levels • platelet count remained extremely low for four days, finally returning to normal levels by the fifth day PATHOPHYSIOLOGY OF ITP: HARRINGTON- HOLLINGSWORTH EXPERIMENT
  4. 4. PATHOPHYSIOLOGY OF ITP • Platelets phagocytized  Membrane GPIIb/IIIa or GPIb/IX digested into a peptide and presented to macrophages  CD4+ T cell is activated  T cell secretes IL-6  activate antibody producing B cells  autoantibodies bind to platelets  platelets are phagocytized by splenic macrophages • Antibodies can bind to megakaryocytes, thus decreasing overall platelet production
  5. 5. PATHOPHYSIOLOGY OF ITP: WHAT CAUSES IGG PRODUCTION? • Infections: anti-viral antibodies cross react with platelet glycoproteins • CMV, EBV • HIV: molecular mimicry of HIV proteins and GPIIb/IIIa • Hep C: molecular mimicry between HCV core envelope protein 1 and GP IIb/IIIa • Bacterial products (LPS) attach to platelet surface and increase phagocytosis • Autoimmune disorders • SLE, antiphospolipid syndrome, post-HSCT thrombocytopenia, sarcoidosis • Lymphoproliferative disorders • CLL • Drug associated ITP • Fludarabine
  6. 6. • Purpura • NOT palpable and asymptomatic • Mucosal bleeding • Blood blisters • Asymptomatic ITP: A VARIABLE CLINICAL PRESENTATION
  7. 7. EPIDEMIOLOGY • Observational study in Denmark from 1973 to 1995 and UK from 1990 to 2005 • Incidence 22-44 per million per year • 70% are Women • 70% are under age 40 • Typically chronic disease and asymptomatic, lasting for years • Acute and symptomatic in children • Death from bleeding is rare • Death more likely related to immunosuppression
  8. 8. • Evaluate for systemic disease • Coagulation studies • DIC, TTP • MAHA: heart valves • Splenomegaly • Splenic sequestration • hematologic malignancy • Other cytopenias • Marrow failure: MDS • Lypmhoproliferative or myeloproliferative disorders • EDTA dependent platelet agglutination • Pregnancy • Drugs • Heparin, quinine, sulfas, antibiotics • Viral infections • HIV, EBV, rubella, CMV • Autoimmune disorders • SLE • Congenital platelet disorder DIAGNOSIS OF EXCLUSION Must have isolated thrombocytopenia and no other signs of systemic disease
  9. 9. DIAGNOSIS BY PERIPHERAL BLOOD SMEAR
  10. 10. DIAGNOSIS BY PERIPHERAL BLOOD SMEAR Schistocytes: TTP, DIC, HUS Clumping: EDTA
  11. 11. INDICATIONS TO TREAT • Major bleeding is rare in ITP • Mostly occurs at <10,000 • Goal of treatment: • Reach a platelet count that will prevent bleeding • Prevent toxicity of treatment itself • When to treat • Asymptomatic with moderate thrombocytopenia does not require treatment • General cutoff: 30,000/µL • Watch for worsening thrombocytopenia or new onset of symptoms
  12. 12. FIRST LINE TREATMENT: STEROIDS • Prednisone 1 mg/kg/day • 40-60% response rate with a response by 2 weeks • Taper after initial response occurs, with most flares occurring during taper • Goal oft therapy • Keep plt’s at 50,000 or greater • Minimize steroid induced side effects • Give calcium and vitamin D • Check DEXA scan
  13. 13. INTRAVENOUS IMMUNOGLOBULIN • Quick, but temporary response • Can be used in life threatening bleeding or preparing for splenectomy/surgery • Helps to prevent platelet destruction after transfusion • 2 forms • IVIg: 1 g/kg for 1-2 days • Anti-Rh(D) in Rh+ patients: 50-75 mcg/kg/day
  14. 14. • Mechansm is unknown • Inhibit the autoantibody and cause steric hinderance so antibody can’t bind to platelets • Inhibit the Fc receptor of the macrophages, decreaseing uptake of antibody coated platelets • Clinical Data (Br J Haematol. 1999;107(4):716.) • 1g/kg dose resulted in platelet count >80,000 in 28% of patients by day 2 and 67% by day 4 (N=35) IVIG
  15. 15. FAILURE OF TREATMENT • Failure to respond to high dose gluccocorticoids • No response after 2 weeks of therapy • Continued symptomtatic thrombocytopenia • Failure to maintain response • Case sereies of 208 patients with ITP: • 39% complete response rate with prednisone • Only 18% sustained complere response at 6 months • Am J Med. 1995;98(5):436.
  16. 16. • Mechanism of action: • Spleen is major site of platelet destruction • Spleen is 25% of total lymphoid mass, which produced autoantibodies • Response rates • Usually occurs within 2 weeks of surgery • Complete remission rate of 60- 70% • Durable remissions • Partial remission rate of 15-20% SPLENECTOMY FOR REFRACTORY ITP
  17. 17. • Prospective controlled phase II trial (Blood. 2008;112(4):999.) • 60 patients with ITP >6 months and platelet count of <30,000 • Given rituximab 375 mg/m2 Q week x 4 • 40% able to maintain a plt count of >50,000 at one year • 33% at two years • No trial comparing rituximab to splenectomy RITUXIMAB FOR REFRACTORY ITP
  18. 18. THROMBOPOIETIN RECEPTOR AGONISTS FOR REFRACTORY ITP
  19. 19. • 118 patients with plt<50,000 and failed one prior therapy randomized to oral eltrombopag vs placebo • End point: plt count >50K by day 43 • Eltrombopag 75 mg: 81%, mean platelet count 183,000 • Placebo: 11%, mean platelet counts 16,000 • Patients with ITP randomized (2:1) to romiplostim vs placebo • ½ had a splenectomy • Given SQ weekly therapy for 24 wks to maintain plt count b/w 50-200K • Assessed durable plt response: Goal platelet count maintained for >6 weeks • Splenectomized:38% vs 0% (p<0.0013) • Nonsplenectomized: 56% vs 0% (p<0.0001) THROMBOPOIETIN RECEPTOR AGONISTS VS PLACEBO Romiplostim: Lancet. 2008;371(9610):395. Eltrombopag: N EJM. 2007;357(22):2237.
  20. 20. THROMBOPOIETIN STIMULATING AGENTS • FDA approved for ITP in adults with insufficient response to steroids, IVIG, or splenectomy • ASH 2011 guidelines: use in patients at risk for bleeding who have a contraindication to splenectomy and have failed at least one other therapy other than steroids • EMA: approved these agents for "splenectomized adults who are refractory to other treatments." • Expensive: one year of Romiplostim is >$55,000 • Long term effects not known • Increase risk of clotting/bleeding? • Increase bone marrow fibrosis?
  21. 21. EMERGENT TREATMENT OF ITP • Platelet transfusion • IVIG: 1g/kg for 1-2 days • High dose IV steroids • Methylprednisolone 1 gram or 30 mg/kg/day for 2-3 days
  22. 22. THROMBOTIC THROMBOCYTOPENIC PURPURA
  23. 23. HISTORICAL PERSPECTIVE • First described in 1924 by Eli Moshcowitz • 16 year old girl that presented with fever, anemia leukocytosis, petechiae, hemiparesis • Urine had albumin and granular casts • Died 2 weeks later • Autopsy showed hyaline thrombi in terminal arterioles, especially heart and kidney • 1966: First clinical review • 272 patients with TTP • Classic pentad of: thrombocytopenia, hemolytic anemia, neurological symptoms, fever, renal damage • Mortality 90% • No one was treated with plasma
  24. 24. HISTORICAL PERSPECTIVE OF TREATMENT • Transfusion therapy not looked at until 1976 • 14 patients had whole blood transfusions • 8/14 had clinical response • Plasmapheresis • Response if replacement fluid was plasma • No response if replacement fluid was albumin • Conclusion: There’s something in the plasma that can ameliorate TTP
  25. 25. PATHOGENESIS • Link between TTP and vWF made in 1982 • Based on study of 4 patients • Had much larger vWF multimers • Proposed a defect in depolymerase activity that would normally cleave vWF • Plasma exchange provides this missing depolymerase activity • 1996: metalloprotease in plasma shown to cleave vWF multimers • Children with congenital TTP had a deficiency in this metalloprotease and adults with acquired TTP had an antibody to it • Metalloprotease was purified, cloned, and named ADAMTS13
  26. 26. STRUCTURE OF VWF
  27. 27. IDIOPATHIC TTP • Polyclonal IgG autoantibody to ADAMTS13 • Associated with 30% relapse after initial remission • Incidence 3.8 million a year in the US • Peak incidence of idiopathic TTP is ages 30-50 • African ancestry • Obesity • Genetic predisposition
  28. 28. CLINICAL PRESENTATION-THE PENTAD • Must haves: • Hemolytic anemia • Thrombocytopenia • Purpura or petechiae • Rarely bleeding • Maybes: present in 50% • Fever • Renal failure • Neurologic findings • Headache • Visual disturbances • Vertigo • Personality changes • Confusion/lethargyComa • Siezures • Focal sensory or motor deficits/aphasia • PRES
  29. 29. • Thrombocytopenia -50% of patients have platelets <20,000 • Evidence of hemolysis • 33% of patients have Hgb <6 • Schistocytes : >5 per high powered field • Elevated retic count • Evidence of tissue ischemia • Elevated LDH: median LDH is 1200 • Ruled out AIHA, DIC LABORATORY PRESENTATION ADAMTS13 activity level is NOT a criteria
  30. 30. ADAMTS13 TESTING AS A DIAGNOSTIC TOOL • ADAMTS13 activity correlates with clinical presentation, but not clinical course • Study of 48 patients with clinical diagnosis TTP-HUS • 16 had severe ADAMTS 13 deficiency • Clinical course was variable and no different than other 32 patients • Assay techniques are not standardized • Levels vary with pregnancy, age, cirrhosis, CKD, postoperative course, acute inflammatory states, sepsis, acute hepatitis, VOD after HSCT • Activity level <5% is consistent with TTP • Only 5% needed to maintain homeostasis
  31. 31. SECONDARY THROMBOTIC MICROANGIOPATHY (TMA) • Infection and DIC • Malignancy • Postop • Malignant Hypertension • Bone Marrow Transplant Patients • Allografts • Total body irradiation • GVHD • Autoimmune disorders • Lupus vasculitis (TMA) • Antiphospholipid Sx (TMA) • Evans Sx • Pregnancy • HELLP (TMA) • Eclampsia (TMA) Not associated with ADAMTS13 deficiency Can be associated with ADAMTS13 deficiency
  32. 32. DRUGS AS A CAUSE OF TMA • Quinine • Chemotherapy • Mitomycin C • Bleomycin • Gencitabine • Cisplatin • Immunosuppression • Cyclosporine • Tacrolimus • Ticlopidine • Clopidogrel • Treat like TTP with plasma exchange • No relapse reported after stopping drug Associated without ADAMTS13 antibody Associated with ADAMTS13 antibody
  33. 33. TREATMENT • Plasma infusion (FFP): giving back ADAMTS13 • More effective in congenital TTP • Temporizing measure in acquired TTP • Plasma exchange: giving ADAMTS13 and removing antibody and large vWF multimers • Exchange of single plasma volume • Larger volume exchanges may have benefit
  34. 34. TREATMENT: CRYO-POOR PLASMA • Results from removal of cryoprecipitate from plasma • Depleted in factor VIII, vWF, factor XIII, fibrinogen • Can be used in patients with volume issues • Still has ADAMTS13 • RCT of 27 patients comparing CPP and FFP demonstrated equivalence • Time to response: 5.5 vs 6.0 days • Survival: 79% vs 77%
  35. 35. TREATMENT: PLASMA EXCHANGE • Continue daily until following is met for 3 days: • Platelet count >150K • LDH normal • Resolution of neurologic symptoms • Resolution of renal disease may be slow and incomplete • Then taper to QOD to twice a week • Average time on daily exchange: 7-16 days • Time on exchange (including taper) is variable • 3 to 145 exchanges
  36. 36. TREATMENT: STEROIDS • Rationale: need to eliminate antibody production • Benefit not clearly demonstrated • Common practice: 1 to 2 mg/kg/day during plasma exchange then taper • Alternative: methylprednisolone 1 gram IV daily for 3 days or 125 mg IV BID for 4 days • Or can be started if plasma exchange cannot be tapered
  37. 37. RESISTANT OR RELAPSING DISEASE • 10-20% of patients will have transient, incomplete, or no response to exchange • Can increase the frequency of exchange or: • Steroids • Rituximab • Cyclosporine • Cyclophosphamide
  38. 38. PLATELET TRANSFUSION IN TTP • Can correlate with acute decompensation and worsening thrombosis • Retrospective study: 89 pts received platelet transfusions in setting of TTP • 8% had new neurological event or death • Study from TTP registry in Oklahoma reviewed course of 54 patients • No difference in neurological events or death • Party line on platelet transfusions: • Do not need to transfuse platelets for procedures • Can transfuse platelets prior to emergency surgery after plasma exchange
  39. 39. HEPARIN INDUCED THROMBOCYTOPENIA (HIT)
  40. 40. COAGULATION CASCADE AND MECHANISM OF ACTION OF HEPARIN
  41. 41. PATHOPHYSIOLOGY OF HIT • Heparin causes thrombocytopenia: results in HIT • Type I: non-immune mediated • Platelet count falls 2 days after starting heparin and resumes to normal despite continued heparin use • Due to increased platelet activation • Type II: immune mediated • Due to formation of antibodies against heparin-platelet factor 4 complex
  42. 42. TYPE I VS TYPE II Type I Type II Frequency 10-20% 1-3% Timing of onset after starting heparin 1-4 days 5-10 days Nadir platelet count >100,000 >20,000 Antibody mediated No Yes Thromboembolic sequelae None 30-80% Hemorrhagic sequelae None Rare Management observe Stop heparin and start non- heparin anticoagulant to prevent arterial thromboses Brieger, DB, Mak, KH, Kohke-Marchant, K, et al. J Am Coll Cardiol 1998; 31:1449.
  43. 43. • Heparin and platelet factor 4 forms a highly immunogenic complex • PF4 is a heparin neutralizing protein contained in alpha granules of platelets • Heparin induces a conformational change in PF4, inducing a new epitope • Induces an antibody reaction • IgG, IgM, IgA is formed TYPE II IMMUNE MEDIATED HIT
  44. 44. • Once PF4-heparing complex forms, it binds to platelet surface • HIT ab (usually IgG) binds to the surface/complex • Fc portion of the antibody activates adjacent platelets, leading • 1. platelet activation and release of additional PF4 and procoagulant microparticles • 2. aggregated platelets, leading to increased removal by RES TYPE II IMMUNE MEDIATED HIT
  45. 45. EPIDEMIOLOGY AND RISK FACTORS • Seen in ~5% of patients treated with heparin • Risk factors for developing HIT (Blood. 2006;108(9):2937.) • Unfractionated heparin vs LMWH (RR 5.3; 95% CI 2.8-9.9) • Surgical patients vs medical patients (RR 3.2; 95% CI 2.0-5.4) • Female patients (RR 2.4; 95% CI 1.4-4.1) • Female surgical patients receiving UFH (RR 17; 95% CI 4.2-72)
  46. 46. • Platelets decreased 30-50% from baseline during first 72 hours of bypass surgery • due in part to prolonged contact of platelets with the artificial surface of the extracorporeal circuit • usually receive large amounts of unfractionated heparin • incidence of HIT antibodies is as high as 25 to 70 percent by immunoassay and 4 to 20 percent by platelet activation assay. • several other potential causes of thrombocytopenia are often present CARDIAC SURGERY
  47. 47. CLINICAL PRESENTATION • Fall in platelet count >50% of baseline within 5-10 days of initiating heparin • It takes 5-10 days to produce IgG • Earlier onset can be seen be seen in prior exposure (due to preformed antibodies) • No other cause of thrombocytopenia • Platelet counts usually <20,000, median platelet count 60,000 • Bleeding is unusual • Venous and Arterial Thrombosis (platelet rich) • Due to activated platelets • Most common: PE, limb gangrene, cerebral sinus thrombosis, DVT • Less common: MI, CVA, organ infarction • Skin necrosis • Adrenal hemorrhage
  48. 48. • 0-3: low probablity of HIT (0.9%) • 4-5: intermediate probability (11.4%) • 6-8: high probability (34%) CLINICAL DIAGNOSIS: 4T SCORE 2 points 1 point 0 point Thrombocytopenia >50% fall and nadir ≥20k 30-50% fall, or nadir 10-19k; or >50% fall directly resulting from surgery <30% fall, or nadir <10k Timingb of Platelet Count Fall Clear onset between days 5- 14; or ≤1 day (prior heparin exposure within 30 days) Consistent with day 5-14 fall, but not clear (e.g. missing plt counts); or onset after day 14; or ≤1 day (prior heparin exposure 30-100 days ago) Platelet count fall ≤4 days without recent exposure Thrombosis or other sequelae New thrombosis (confirmed); skin necrosis; acute systemic reaction after iv UFH bolus Progressive or recurrent thrombosis; non-necrotizing (erythematous) skin lesions; suspected thrombosis (not proven) None Other causes of thrombocytopenia None apparent Possible Definite
  49. 49. • Heparin-PF4 complexes are coated on plate • Patient serum is added • If heparin IgG antibody is present, will bind to complex • Alkaline phosphatase-labeled anti-human globulin added to detect the IgG causing agglutination • The optical density (OD) is reported: OD values >0.40 are considered positive and indicate the presence of heparin-induced antibodies. • OD: measure of penetrance of light • Sensitivity: 91-97%, negative test rules out HIT • Specificity: 74-86%, (hemodialysis patients, cross reactivity of other antibodies or non-IgG HIT Ab) LABORATORY DIAGNOSIS: ELIZA TEST
  50. 50. LABORATORY DIAGNOSIS: SEROTONIN RELEASE ASSAY • Gold standard for HIT diagnosis • Platelets from normal donor are radiolabeled with 14C serotonin • Patient serum added with heparin • If HIT ab is present bind to heparinactivate plateletsgranules are emptied • Positive test: 14C serotonin is released • Sensitivity: >95% • Specificity: 97% • Not available in all centers
  51. 51. TREATMENT • First step: stop heparin and LMWH • Start anticoagulation with direct thrombin inhibitors to treat existing thromboses and prevent new ones • Lepirudin/Bivalirudin: renally cleared • Argatroban: hepatically cleared
  52. 52. • 2 mg/kg/hr CIVI • 3 trials let to FDA approval • Arch Intern Med. 2003;163(15): 1849 • Circulation. 2001;103(14):1838. • Chest. 2006;129(6):1407. • Reduction in thrombotic events • 0.1 to 0.15 mg/kg/hour CIVI • Prospective series of 82 patients: 89% of patients has increase in platelet counts (Circulation. 1999;99(1):73.) • Retrospective series of 205 patinets: less death, amputation, new thromboses than historical control, 25% vs 52% (J Thromb Haemost. 2005;3(11):2428.) TREATMENT Lepirudin Argatroban
  53. 53. LONG TERM THERAPY • Transition to long term therapy once platelets return to normal (>150,000) with direct thrombin inhibitors • Warfarin • Both DTI and warfarin increase INR • Goal INR is 2-3 • 5 days of overlapping therapy with warfarin and DTI before DTI is discontinued • Avoid induction of hypercoagulable state by lowering of protein C levels • No firm data on length of therapy • 3 months if no thrombosis • 6 months if thrombosis was present
  54. 54. THE END

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