MANAGEMENT OF PATIENTS WITH THROMBOCYTOPENIA ELSHAMI M. ELAMIN, MD CENTRAL CARE CANCER CENTER

ITP DITP HIT TTP ITP during pregnancy

INTROCUCTION Hemostasis encompasses a series of interrelated and simultaneously occurring events involving: Blood vessels Platelets Coagulation system Defects affecting any of these major participants may lead to a hemostatic defect and a bleeding disorder

INTRODUCTION The number of circulating platelets is tightly regulated by the hormone thrombopoietin (TPO) TPO is produced by the liver Free TPO removed from circulation by plts

THROMBOCYTOPENIA IMMUNE CAUSES NON-IMMUNE CAUSES

IMMUNE THROMBOCYTOPENIA 1 IMMUNE THROMBOCYTOPENIA

ITP TERMINOLOGY NEW OLD (ABANDONED) Idiopathic Purpura Immune: Primary Secondary

IMMUNE CAUSES Primary Immune Thrombocytopenia (ITP) Secondary Immune Thrombocytopenia

Primary Immune Thrombocytopenia (ITP)

Primary Immune Thrombocytopenia (ITP) Isolated thrombocytopenia Plt count <100,000 (100k) In children: ITP is typically self-limited Follows viral/infectious illness In adults: ITP is typically becomes persistent or chronic with no obvious precipitating events

Old Classification of ITP Acute ITP (≤ 6 months) Chronic ITP (> 6 months)

New Classification of ITP Duration Classification < 3 month Newly diagnosed 3-12 months Persistent > 12 months Chronic Source: Rodeghiero 2009.1

PATHOPHYSIOLOGY Now: Historically: ITP was thought to be due to increased plt destruction caused by autoantibodies (anti– GPIIb-IIIa and anti–GPIb-IX) Now: It is recognized that ITP is also a result of suboptimal platelet production Plasma level of endogenous thrombopoietin (eTPO) is suboptimal because of: Accelerated clearance by accelerated removal of eTPO bound to antibody-coated plts Binding to megakaryocytes in the BM Absence of increased synthesis in response to thrombocytopenia

CLINICAL PRESENTATION No symptoms Minimal bruising Serious bleeding Mucocutaneous bleeding is the hallmark of severe primary ITP and manifests as: Petechiae, purpura, ecchymosis, epistaxis, menorrhagia, oral mucosal bleeding, GI bleeding, or rarely, intracranial hemorrhage Bleeding is not expected with plt >30,000

DIAGNOSIS Exclude other causes There is no “gold standard” diagnostic test CBC Peripheral blood film BM HIV HCV H. pylori

The International Consensus Report (ICR) DIAGNOSIS ASH The International Consensus Report (ICR) Does not recommend routine measurement of antiplt, antiphospholipid, or ANA Considers measurement of TPO of unproven or uncertain benefit Did not find sufficient evidence to recommend or suggest the routine use of anti-plt, antiphospholipid, ANA, and TPO levels in evaluation of pts with suspected ITP BM test only to exclude other causes of thrombocytopenia

TREATMENT OF ITP

TREATMENT GOAL To achieve a platelet count that will prevent major bleeding To attain a sustained increase of the platelet count that is considered hemostatic It is NOT the goal to normalize platelet count

MANAGEMENT OF CHILDERN WITH PRIMARY ITP During the first month of diagnosis: Severe hemorrhage occurs in approximately 1 in 200 Intracerebral hemorrhage occurs in approximately 1 in 800 Recovery of the platelet count ultimately occurs in 80% of children. The remaining 20% have persistent thrombocytopenia Major bleeding is uncommon.

MANAGEMENT OF CHILDERN WITH PRIMARY ITP Family counseling Supportive care rather than specific drug therapy Because spontaneous recovery is expected in most children Drug therapy (Steroids, IVIG, Anti-D)

MANAGEMENT OF CHILDERN WITH PRIMARY ITP Splenectomy: Persistent thrombocytopenia/bleeding CR in ~ 75% of children Deferred until after 5 yrs of age Risk for overwhelming sepsis Vaccines for Strep pneumoniae, Neisseria meningitides, and H influenzae type b PCN prophylaxis is recommended until adulthood

TREATMENT OF ADULTS WITH PRIMARY ITP ITP in adults: Recurs and persists Asymptomatic pts with mild-moderate thrombocytopenia require no specific treatment Who should be treated?

WHAT IS THE PLATELET COUNT THRESHOLD? ASH ICR Plat >50,000 rarely need treatment in the absence of: Bleeding due to plt dysfunction or another hemostatic defect Comorbidity for bleeding Trauma Surgery Anticoagulation Lifestyle/profession predisposing the patient to trauma Treat new cases if Plat < 30,000 However, no evidence for minimum plt count threshold

EMERGENCY TREATMENT

Emergency conditions Active hemorrhage: CNS GIT GUT Limb- or sight-threatening High risk of significant bleeding Need for surgical procedure

EMERGENCY TREATMENT GENERAL INITIAL TREATMENT Cessation of drugs reducing plt function Blood pressure control Menses inhibition Minimizing trauma High-dose IV steroids + IVIg Plt transfusion +/- IVIg

Alternative Emergency Treatment Options ASH ICR Plt transfusion + continuous IVIg Splenectomy +/- IVIg and/or corticosteroids Recombinant factor VIIa Risk of thrombosis Antifibrinolytics (aminocaproic acid and tranexamic acid) Anti-D Vinca alkaloids Antifibrinolytics with first- line therapy Splenectomy

FIRST-LINE TREATMENT

FIRST-LINE ASH IRC Prednisone 1 mg/kg/d X3 wk IVIg + Steroids when a rapid response required When Steroids are contrain- dicated: IVIg or anti-D (WinRho) Steroids X 4 wk or longer Pts with bleeding, high risk of bleeding, or contraindications to steroids: IVIg (0.4 g/kg/dX5 or IVIg 1 g/kg/d X1-2 days or Anti-D (50-75 μg/kg single dose)

YOUR STEROIDS’ CHOICES Prednisone: Starting at 1 mg/kg daily Tapering over a period of 4 - 8 weeks) OR High-dose dexamethasone in cycles: 40 mg daily for 4 days Repeated monthly for up to 6 cycles or every other week for 4 cycles Methylprednisolone: 1 g IV daily X 2–3

A.E. OF THERAPY Corticosteroids: IVIg: Anti-D (WinRho): Behavioral changes IVIg: Headache Anti-D (WinRho): Hemolysis Pts with a positive Coombs test should not receive it

!! WHEN FIRST-LINE FAILS !!

SECOND-LINE TREATMENT

SECOND-LINE ASH ICR TPO: TPO: Recommended: After splenectomy If contraindications to splenectomy and failed at least one other therapy Considered: If failed one line of therapy such as corticosteroids or IVIg TPO: Recommended: After failing at least one line of therapy such as corticosteroids or IVIg

NOVEL APPROACH TO TREAT CHRONIC ITP increase production to outpace destruction

Thrombopoietin (TPO) receptor agonists Romiplostim (Nplate): SC Eltrombopag (Promacta): PO Bind and activate the TPO receptor  increase plt production They have no structural similarity to endogenous TPO They do not stimulate cross-reactive TPO antibodies They are effective in up to 70% of pts with ITP before and after splenectomy Responses appear to be more pronounced before splenectomy Plt count responses are generally maintained as long as the drug is administered

Serious A.E. of TPO Worsening thrombocytopenia after D/C Bone marrow reticulin formation/Fibrosis with cytopenias Thrombosis Hematologic malignancy risk Hepatotoxicity, cataracts (Promacta)

Nplate (Romiplostim) SC wkly 1 mcg/kg (actual body wt) Common A.E. is headache 1 mcg/kg (actual body wt) Lowest dose to maintain plt > 50,000 Do not attempt to normalize plt counts Wkly CBC and smear until counts are stable > 50k, then monthly D/C Nplate if no clinical benefit after 4 wks of max dose

SECOND-LINE ASH ICR Anti-CD20 (Rituxan): Anti-CD20 (Rituxan): Considered for pts at risk of bleeding who have failed one line of therapy, such as corticosteroids, IVIg, or splenectomy Anti-CD20 (Rituxan): Considered in pts with refractory or relapsed ITP Contraindicated in pts with active HBV

SECOND-LINE ASH ICR Immunosuppressives and corticosteroid- sparing drugs (azathioprine): Evidence-based recommendations on appropriate indications or timing of use are not made due to inadequate research Immunosuppressives and corticosteroid- sparing drugs (azathioprine): Elderly pts and when splenectomy is contra- indicated Single agent or in combination with steroids

Surgical treatment (Splenectomy)

Splenectomy is recognized by both the ASH 2011 guideline and the ICR recommendations as the only treatment to provide sustained off-treatment remissions lasting ≥1 year in approximately two-thirds of patients

SPLENECTOMY ASH ICR For pts who fail steroids Laparoscopic = open When? No optimal timing Second-line When? Wait ≥6 months after diagnosis due to potential for spontaneous improvement or late remission

VACCINATION Splenectomized pts at risk of infection from: Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenzae Vaccination preferably 4 wks before or 2 wks after splenectomy Follow CDC recommendations Revaccination is based on country-specific recommendations

REFRACTORY IMMUNE THROMBOCYTOPENIA

REFRACTORY ITP Pts are considered to have refractory ITP if they do not attain hemostatic platelet count either: After splenectomy OR After first- and second-line medical treatment OR After initially responding to splenectomy and relapsing thereafter AND Either exhibit severe ITP or have a risk of bleeding that requires therapy based on the clinical judgment

TREATMENT OF REFRACTORY ITP

TREATMENT RECOMMENDATIONS ASH ICR Recommends: TPO-receptor agonists suggests: Anti-CD20 (Rituxan) TPO-receptor agonists Not FDA approved: Anti-CD52 (Campath) Combination chemo HSCT

SUMMARY Workup of patients with suspected ITP requires: Thorough search for nonimmune causes (secondary ITP) Primary ITP in children often resolves spontaneously or with minimal treatment Adult-onset primary ITP tends to relapse and often requires ongoing therapy Splenectomy is associated with a durable response in 2/3 of pts with primary ITP Relapses occur 15% of adults. TPO receptor agonists: Increase plt production Effective in 60 - 70% of pts with primary ITP

Secondary Immune Thrombocytopenia

Causes of secondary immune thrombocytopenia Drugs: DITP HIT Antiphospholipid syndrome SLE Common variable immune deficiency Post-BMT Post-vaccination Lymphoproliferative disorders Evans Syndrome Thyroiditis MGUS Infections CMV H. pylori HCV HIV Varicella zoster

Drug-Induced Thrombocytopenia (DITP)

Drug-Induced Thrombocytopenia (DITP) Most common: Seven days from exposure: Quinine and quinidine (tonic water, bitter melon, and meds) NSAIDs Sulfamethoxazole Rifampin Vancomycin Anticonvulsants Sedatives Within hours from exposure: Platelet GPIIb-IIIa inhibitors (Aggrastat, Integrilin, Preopro) http://www.ouhsc.edu/platelets

DITP MECHANISM: TREATMENT: Diagnosis: Antibodies: Quinine Gold, procainamide, sulfonamide, IFN TREATMENT: D/C drug Plt transfusion Diagnosis: Clinical ? Anti-plt Abs

Heparin-Induced Thrombocytopenia (HIT)

Abs against complexes of PF4 + Heparin Production of: 1- Platlets microparticles 2- Intensely prothrombotic state UFH or LMWH Abs against complexes of PF4 + Heparin HIT Abs binds to plt Fc receptors Activates: 1- Plts 2- Endothelial cells 3- Macrophages

H.I.T. NON-IMMUNE (TYPE-I) IMMUNE (TYPE-II) Thrombocytopenia: >50% plt reduction Timing: 5-10 day after heparin Thrombosis OTher: (exclusion of other causes) First 2 days after heparin Caused by plt agglutination because of heparin’s strong negative charge Spontaneous recovery or with heparin interruption No clinical significance 4T Score

Timing of platelet count fall 4T Score (low 0–3; intermed 4–5; high 6–8) To determine the pretest probability of HIT 4Ts 2 ponits 1 point 0 point Thrombocytopenia Plt decrease of >50% and platelet nadir > 20k Plt decrease of 30%–50% or platelet nadir of 10–19k Plt decrease of 30% or platelet nadir <10k Timing of platelet count fall Clear onset of thrombocytopenia 5–10 days after heparin administration; or platelet decrease within 1 day, with prior heparin exposure within 30 days Consistent with day 5–10 decrease but not clear (eg, missing platelet counts) or onset after day 10; or decrease within 1 day, with prior heparin exposure 30-100 days ago Platelet count decrease <4 days without recent exposure Thrombosis or other sequelae New thrombosis (confirmed); skin necrosis (lesions at heparin injection site); acute systemic reaction after intravenous unfractionated heparin bolus Progressive or recurrent thrombosis; nonnecrotizing skin lesions; suspected thrombosis (not proven) None OTher causes for thrombocytopenia None apparent Possible Definite

THROMBOSIS Occurs in 50% of pts with untreated HIT: DVT PE Arterial (including limb artery) MI Microvascular thrombosis resembling DIC Adrenal infarction Skin necrosis at the heparin inj sites Anaphylactoid reactions after an IV heparin bolus Due to PF4/heparin antibodies

DIAGNOSIS

HIT is caused by anti-PF4/heparin Ig-G that activates plts Although many susceptible patients form IgG, IgM, and IgA Abs to PF4/heparin complexes after exposure to heparin, only a few will have platelet-activating IgG Abs that cause HIT.

H.I.T. Testing Subclinical Seroconversion HIT +/- Thrombosis Commercial anti-PF4/Heparin (PF4/polyanion) EIA: *IgG *IgA *IgM Anti-PF4/Heparin EIA: *IgG HIT +/- Thrombosis Washed plt activation assay: *SRA *HIPA

SEROTONIN RELEASE ASSAY (SRA) DIAGNOSIS ELISA SEROTONIN RELEASE ASSAY (SRA) Quantitative PF4/Heparin immunoassay Functional assay of HIT Abs Gold standard

TREATMENT

TREATMENT Stop heparin Do not wait for HIT testing results Start nonheparin anticoagulant: Direct Thrombin Inhibitors: Argatroban Lepirudin Bivalirudin (Angiomax) Factor Xa Inhibitors: Danaparoid (not available in US) (Arixtra) Fondaparinux (not approved) Start warfarin when plt >100k Overlap with direct thrombin inhibitor Continue warfarin for 30 days

NON-IMMUNE THROMBOCYTOPENIA 2 NON-IMMUNE THROMBOCYTOPENIA

NONIMMUNE CAUSES OF THROMBOCYTOPENIA Thrombotic Microangiopathies Familial thrombocytopenia: Wiskott- Aldrich syndrome May-Hegglin syndrome Thrombocytopenia with infection Hemophagocytic syndrome (EBV) 5. Hypersplenism 6. Myelodysplasia/Leukemia 7. BM suppression (valproic acid, alcohol, chemo) 8. von Willebrand disease type 2B 9. Thrombocytopenia in the critically ill

Thrombotic Microangiopathies Thrombotic Thrombocytopenic Purpura (TTP) Hemolytic Uremic Syndrome (HUS)

Thrombotic Microangiopathies TTP HUS Thrombocytopenia Microangiopathic HA ARF Majority caused by Shiga toxin–producing enterohemorrhagic E-coli Invasive pneumococcal infection Thrombocytopenia Microangiopathic H.A. Renal Failure Neurologic deficits Fever

PATHOGENESIS TTP HUS ADAMTS13 enzyme deficiency: Familial Acquired: Idiopathic Drugs: Quinine, Ticlopidine, Clopidgrel, Cyclosporine, Tacrolimus, Mitomycin C, Gemzar Others: Pregnancy, BMT, HIV, SLE, Malignancy Release of large multimers of vWF E-Coli/Inv pneumococci Shiga-toxin: Directly toxic to endothelial cell Prothrombotic state

DIAGNOSIS General Specific ADAMTS13 tests: Clinical CBC Peripheral blood film Hemolytic indices Negative Direct Coombs Normal Coagulation tests BUN/Cr. LFTs (T. Bili, LDH) ADAMTS13 tests: Quantitative (ELISA) Functional Complement factors test to confirm atypical HUS

Treatment of TTP No response to plasma exchange: Plasma exchange: 85% mortality  85% Survival 1 – 1.5 plasma volume Until: Plt >150k Normal LDH Symptoms resolved FFP and cryosupernant plasma (depleted of vWF) ? ASA/Anti-Plt No response to plasma exchange: Steroids Immunosuppressants Splenectomy Rituximab: Relapsed/Refractor y

Treatment of HUS HUS Atypical HUS Supportive Antibiotics Controversial Generally avoided Plasma exchange not required ? Plasma exchange Eculizumab (SOLIRIS): Inhibits complement-mediated thrombotic microangiopathy Be aware of: Life-threatening and fatal meningococcal infections Meningococcal vaccine at least 2 wks before 1st dose Vaccinate children against Strep and H influ

ITP DURING PREGNANCY

ITP DURING PREGNANCY INCIDENCE: 1 in 1000 to 1 in 10,000 Pregnant women may have lower plt counts than normal (Gestational Thrombocytopenia) May be due to a combination of hemodilution and increased platelet activation and clearance

DIAGNOSIS CBC Peripheral blood smear Retic count HIV and HCV tests (high-risk) Antiphospholipid antibodies Coagulation screening SLE serology LFTs

DIFFERENTIAL DIAGNOSIS Pregnancy-induced hypertension (Preeclampsia) Gestational thrombocytopenia HELLP syndrome (HemolysisElevatedLiverenzymesLowPlatelet) DIC Massive obstetrical hemorrhage Acute fatty liver Antiphospholipid antibody syndrome Folate deficiency

ITP DURING PREGNANCY TREATMENT Same as non-pregnant pts who have chronic ITP ASH: No platelet count threshold for treatment ICR: Treat pregnant women in the first two trimesters who are: Symptomatic Have 20-30k plt

ITP DURING PREGNANCY: TREATMENT ASH ICR Steroids as first-line IVIg if steroids are: Ineffective Produce significant AE OR If rapid plt increase is needed Limited evidence may support use of anti-D in Rh+, non-splenectomized women Steroids or IVIg as first- line therapy

ITP DURING PREGNANCY TREATMENT Steroids and IVIg: Considered to be safe to the fetus Steroids: May have maternal side effects including: exacerbation of gestational diabetes post- partum psychiatric disorders

Management during labor and delivery The ASH guidelines and ICR recommendations indicate that the mode of delivery should be based on obstetric indications