IMMUNE PLATELET DESTRUCTION Autoimmune (ITP) Childhood Adult Drug-induced Heparin Quinine, others Immune complex (infection, etc) Alloimmune Post-transfusion purpura Neonatal purpura

ITP Childhood ITP (most < 10 yrs old) May follow viral infection, vaccination Peak incidence in fall & winter ~50% receive some treatment ≥75% in remission within 6 mo Adult ITP No prodrome Usually chronic, recurrences common Spontaneous remission rate about 5%

Childhood (acute) ITP Adult (chronic) ITP

Epidemiology (adults) ITP Epidemiology (adults) Prevalence: ~10/100,000 Incidence: ~3/100,000/yr Bimodal age distribution Young adults (women > men) Elderly (men = women) About 20% have an associated disorder (secondary ITP)

Secondary ITP: associated disorders SLE Antiphospholipid syndrome CLL Large granular lymphocyte syndrome Autoimmune hemolytic anemia (Evans syndrome) Common variable immune deficiency Autoimmune lymphoproliferative disorder (ALPS) Autoimmune thyroid disease Sarcoidosis Carcinomas Lymphoma HIV, Hep C infection H pylori infection (geographic variation) Following stem cell or organ transplantation Following vaccination

ITP AND H PYLORI Some patients with ITP and concomitant H pylori infection improve after eradication of infection Confirm infection via breath test, stool antigen test or endoscopy Higher response rates in: Patients from countries with high background rates of infection (Asia, some parts of Europe; response rates low in US) Patients with less severe thrombocytopenia

ITP Pathogenesis ITP plasma induces thrombocytopenia in normal subjects Platelet-reactive IgG autoantibodies present in most cases Often specific for a platelet membrane glycoprotein Antibody coated platelets cleared by tissue macrophages Most destruction in spleen (extravascular) T-cell mediated platelet destruction can occur Many patients have impaired platelet production Immune injury to megakaryocytes? Inadequate TPO response Increased clearance? Disrupted link between platelet clearance and TPO production?

ITP Pathogenesis - 2 Some antibodies affect platelet function Interference with platelet function may increase risk of bleeding Platelet activation by antibodies may decrease bleeding risk but increase risk of thrombosis ITP patients have an increased risk of thromboembolism (~1.6 x higher)

Splenectomy specimen from a patient with chronic ITP Splenectomy specimen from a patient with chronic ITP. Left: (40x) Activated lymphoid follicles with expanded marginal zone (short arrow), a well-defined dark mantle zone (long arrow), and a germinal center containing activated lymphocytes (arrowhead). Right: (1000x) PAS stain showing histiocytes with phagocytized platelet polysachharides (arrows). Transfusion 2005;45:287

Infusion of ITP plasma into a normal person causes dose-dependent thrombocytopenia Infusion of ITP plasma into normal subject causes dose-dependent thrombocytopenia.

Clinical features and diagnosis ITP Clinical features and diagnosis Petechiae, purpura, sometimes mucosal bleeding Major internal/intracranial bleeding rare Mortality rate < 5% Absence of constitutional symptoms or splenomegaly Other blood counts and coagulation parameters normal No schistocytes or platelet clumps on blood smear Marrow shows normal or increased megakaryocytes (optional) Rule out other causes of thrombocytopenia (HIV, Hepatitis C, etc)

The immature platelet fraction reflects rate of platelet production ITP + iron deficiency Marrow failure Higher numbers indicate more rapid production

Confirmatory laboratory testing ITP Confirmatory laboratory testing Serum antiplatelet antibody assay (poor specificity) Test for specific anti-platelet glycoprotein antibodies (more specific, negative in 10-30%) Confirmatory testing not necessary in most cases

Is testing for platelet autoantibodies useful Is testing for platelet autoantibodies useful? Test results & patient outcomes from 2016-2017 at UWHC All testing done at Blood Center of Wisconsin Patient Test result Outcome/diagnosis M, 66 Positive Probable ITP (response to IVIG) M, 83 Negative Myelodysplasia F, 38 ITP (response to IVIG) F, 81 ITP (response to steroids) F, 57 Viral-induced thrombocytopenia (zoster) M, 56 Chemotherapy-induced thrombocytopenia (colon CA) M, 57 Probable aplastic anemia Drawn 3 days after platelet transfusion

ITP IS A RELATIVELY BENIGN DISEASE A PROSPECTIVE STUDY OF ITP IN 245 ADULTS Overall incidence 1.6/100,000/yr Median age 56, F:M 1.2:1 12% presented with bleeding, 28% asymptomatic 18% needed no treatment Only 12% needed splenectomy 63% in remission (plts > 100K) at end of followup period (6-78 mo, median 60) 87% had at least partial remission (plts >30K) and freedom from symptoms 1.6% died from complications of disease or its treatment Age-specific incidence This study challenges the notion of ITP as a chronic disease that preferentially affects women. The age of patients was also higher than in many other published series. Brit J Haematol 2003;122:966

4.5 x higher risk of infection in year 1 1.8 x higher risk years 2-5 3.2 x higher risk of intrancranial bleeding in years 1-5 Increased risk of subsequent hematologic malignancy Therapy-related (lymphoma) or misdiagnosis (AML, MDS) This risk not confirmed in other studies 5 year all-cause mortality rate 2.3 x higher Risk highest in older patients, those with comorbid conditions Blood 2011; 117:3514

Indications for treatment ITP Indications for treatment Platelets < 20-30K Active bleeding or high bleeding risk, platelets <50K

First line treatment options ITP First line treatment options First line treatment options: Glucocorticoids (daily vs pulse dose) IVIG Anti-Rh globulin (WinRho) Rituximab? Thrombopoietin receptor agonists? Hospitalization often not necessary Splenectomy rarely used as first line Rx

Glucocorticoid therapy ITP Glucocorticoid therapy Mechanism of action: Slows platelet destruction, reduces autoantibody production Prednisone, 1-2 mg/kg/day (single daily dose) Begin slow taper after 2-4 weeks (if patient responds) Consider alternative therapy if no response within 3-4 weeks About 2/3 of patients respond (plts > 50K) within 1 week Most patients relapse when steroids withdrawn Advantages: high response rate, outpatient therapy Disadvantages: steroid toxicity (increases with time and dose), high relapse rate

Prednisone attenuates the effect of ITP plasma infusion on platelet count Prednisone blunts the decrease in platelet count caused by ITP plasma infusion.

Intravenous immunoglobulin therapy ITP Intravenous immunoglobulin therapy Possible mechanisms of action: Slowed platelet consumption by Fc receptor blockade Accelerated autoantibody catabolism Reduced autoantibody production Dose: 0.4 g/kg/d x 5 days (alternative: 1 g/kg/d x 2 days) About 75% response rate, usually within a few days to a week Over 75% of responders return to pre-treatment levels within a month Advantages: rapid acting, low toxicity Disadvantages: high cost, short duration of benefit, high relapse rate Indications: Lifethreatening bleeding; pre-operative correction of platelet count, steroids contraindicated or ineffective

Second line treatment options ITP Second line treatment options Rituximab TPO receptor agonists Romiplostim (Nplate) Eltrombopag (Promacta) Splenectomy

ITP Splenectomy Sustained remission in 2/3 of patients Almost all responses occur within 7-10 days of splenectomy Operative mortality < 1% Severe intra- and postoperative hemorrhage rare (about 1% of patients) Laparoscopic splenectomy usually preferable technique Advantage: High sustained response/cure rate Disadvantages: Operative risk (mainly older pts with comorbid disease); post-splenectomy sepsis (fatality rate 1/1500 patient-yrs); increased risk of thrombosis & cardiovascular events Indication: Steroid failure or relapse after steroid Rx (persistent severe thrombocytopenia or significant bleeding)

Splenectomy attenuates the effect of ITP plasma infusion on platelet count More antibody needed to cause thrombocytopenia in asplenic subject.

LAPAROSCOPIC SPLENECTOMY IS THE PROCEDURE OF CHOICE IN ADULT ITP A Systematic Review 66% complete response rate (2632 patients) No preoperative characteristic consistently predicted response Type of procedure Mortality Complication rate Open 1% 12.9% Laparoscopic 0.2% 9.6% Blood 2004;104:2623

Intervention: Rituximab, 375 mg/m2 weekly x 4 doses Background: Most patients treated for ITP with corticosteroids relapse when steroids are withdrawn. Many patients can be cured by splenectomy, but some are not. Treatments for relapsed and chronic ITP and adults have variable efficacy. Subjects: 57 adults with chronic ITP, with platelet counts <30K. All had at least 2 prior ITP treatments and 31 had been splenectomized. Intervention: Rituximab, 375 mg/m2 weekly x 4 doses Outcome: Overall 54% response rate (32% with plts >150K, 22% with plts 50-150K). 89% of complete responders remained in remission a median of 72.5 weeks after treatment. Toxicity was minimal. Conclusion: Rituximab is a promising treatment for chronic/refractory ITP The most effective treatment for patients with ITP who relapse after corticosteroid treatment and/or splenectomy has not been established. This paper shows that Rituximab is effective in a majority of these patients, with minimal toxicity. British Journal of Haematology 2004; 125: 232–239

Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia Vivek L. Patel, Matthieu Mahévas, Soo Y. Lee, Roberto Stasi, Susanna Cunningham-Rundles, Bertrand Godeau, Julie Kanter, Ellis Neufeld, Tillmann Taube, Ugo Ramenghi, Shalini Shenoy, Mary J. Ward, Nino Mihatov, Vinay L. Patel, Philippe Bierling, Martin Lesser, Nichola Cooper, and James B. Bussel 26% of children and 21% of adults with ITP who had an intial response (CR or PR) to rituximab remained in remission without further treatment after 5 years No major toxicity observed Children did not relapse after 2 years, but adults did The most effective treatment for patients with ITP who relapse after corticosteroid treatment and/or splenectomy has not been established. This paper shows that Rituximab is effective in a majority of these patients, with minimal toxicity. Blood 2012;119:5989

TPO Receptor Agonists for ITP Overall response rate 75% or higher Modest toxicity Transaminase increases (~10%) Marrow fibrosis (~10%), asymptomatic 5-6% incidence of thromboembolism Can switch drugs if intolerant to one Expense remains a barrier for some patients

ROMIPLOSTIM FOR CHRONIC ITP Patients: 125 patients with chronic ITP (about half had been splenectomized) Intervention: Random assignment to treatment with romiplostim (AMG 531) or placebo Endpoint: Durable platelet response (platelets at least 50K during at least 6 of last 8 wks of treatment) Outcome: 16/42 splenectomized patients had durable response with romiplostim, vs 0/21 with placebo. 25/41 non-splenectomized pts had durable response with romiplostim vs 1/21 with placebo. 20/23 pts on romiplostim stopped or reduced concurrent treatment for ITP, vs 6/16 on placebo. No significant toxicity from romiplostim Lancet 2008;371:395

Lancet 2008;371:395

Responses to oral eltrombopag in ITP Lancet 2010

EMERGENCY TREATMENT OF ITP Platelet transfusion + high dose steroids Platelet transfusion + continuous IVIG rVIIa (risk of thrombosis) Antifibrinolytics Emergent splenectomy

ITP IN PREGNANCY Mild cases indistinguishable from gestational thrombocytopenia Rule out eclampsia, HIV etc Indications for treatment platelets < 10K platelets < 30K in 2nd/3rd trimester, or with bleeding Treatment of choice is IVIg corticosteroids may cause gestational diabetes, fetal toxicity Splenectomy for severe, refractory disease some increased risk of preterm labor; technically difficult in 3rd trimester Potential for neonatal thrombocytopenia (approx 15% incidence) consider fetal blood sampling in selected cases consider Cesarian delivery if fetal platelets < 20K