Objectives by wpr1947


									   Approach to
 Morey A. Blinder, M.D.
Associate Professor of Medicine
 and Pathology & Immunology
    Washington University
         St. Louis, MO
   Megakaryocyte – 3000 platelets
   Adult must make 1 x 1011/day

   20–30% pooled in spleen
   Lifespan 9–10 days
Sites of bleeding in thrombocytopenia
   Skin and mucous membranes
    •   Petechiae
    •   Ecchymosis
    •   Hemorrhagic vesicles
    •   Gingival bleeding and epistaxis
 Menorrhagia
 Gastrointestinal bleeding
 Intracranial bleeding
 (typical of platelet disorders)

Do not blanch with pressure
Not palpable (vasculitis)
Bleeding Manifestations in Relation to
Platelet Count
   WHO Bleeding Grade and Characteristics

Grade 1            Grade 2              Grade 3              Grade 4
Mucocutaneous      Ecchymosis           Melena*              Debilitating
   bleed              >10cm             Hematemesis*         Non-fatal CNS
Petechiae          Hematoma             Hemoptysis*          Any fatal
Ecchymosis                              Hematuria*
                   Epistaxis packing                           bleeding
 <10 cm                                 Vaginal bleeding*
Orophayngeal                            Epistaxis*
Conjunctival          w/o visual        Oropharyngeal*
Epistaxis                               Musculoskeletal/
                   Bleeding w/o
 No intervention                          Soft tissue
                    RBC transfusion
Vaginal spotting
 (<2 pads/day)                          * With transfusion

Miller et al. Cancer 1981; 47:207-214
Thrombocytopenia and Platelet
   Volunteer whole blood donors
    • Platelet rich plasma (Random
    • Buffy coat

   Volunteer single donors
    • Apheresis platelets
Platelet Transfusions: Targeted Therapy

   What is the trigger for prophylactic platelet

   What is the recommended dose of platelets
    needed for a transfusion?
     ASCO Recommendations for Prophylactic
     Platelet transfusions
           Condition                      Platelet count trigger
           Acute leukemia                 <10,000/µl

           Stem cell transplant           <10,000/µl

           Chronic stable                 Not defined
           Solid tumors                   <10,000/µl
                                          <20,000/µl for bladder or
                                          necrotic tumors
           Surgical procedures            <40-50,000/µl

Schiffer, CA et al. J Clin Oncol 2001; 19:1519-38
  Standard compared to low dose Platelet
  transfusion (SToP)

                        R          Standard dose platelets
                        A             3-6 x 1011/product
    Hypoproliferative   N                    N=61
   Thrombocytopenia     O
      Hematologic              Transfusion for Platelet count <10,000/µl/day
       malignancy       I
                                       Low dose platelets
                        E              1.5-3 x 1011/product

Heddle, NM Blood 2009; 113:1564-1573
   Standard Compared to Low Dose Platelet
   Transfusion (SToP): Results

    Platelet dose    n    Grade 2-4      Days     Grade 4
                           bleeding    bleeding   bleeding
    Low              58     30/58      111/918    3 (5.2%)
                           (51.7%)     (12.1%)
    Standard         61     30/61       73/854       0
                           (49.2%)      (8.5%)

Heddle, NM Blood 2009; 113:1564-1573
   Platelet Dose to Prevent Bleeding in
   Thrombocytopenic Patients (PLADO)
                                  Transfuse for Platelet count <10,000/µl/day

                         R               High dose platelets
    Hypoproliferative    A
                                        4.4 x 1011/M2/product
   thrombocytopenia      N
     Hematologic         O
                                      Medium dose platelets
    malignancy/SCT       I             2.2 x 1011/M2/product
       n=1,272           Z
                                         Low dose platelets
                                        1.1 x 1011/M2/product

Slichter, SJ et al. N Engl J Med 2010; 362:600-13
   Platelet Dose to Prevent Bleeding in
   Thrombocytopenic Patients (PLADO): Results

     Platelet dose    Grade 2-4     Grade 4         No. of platelet
                      bleeding      bleeding        transfusions
     Low                  71%           3%                 5
     Medium               69%            2%                3
     High                 70%            2%                3

    Low dose of platelets required more transfusions
    Number of platelets had no effect on the incidence of bleeding

Slichter, SJ et al. N Engl J Med 2010; 362:600-13
          Do patients actually benefit from
         prophylactic platelet transfusions?
Previous studies of prophylactic vs. therapeutic platelet transfusions
are >25 yrs old: No reported difference (insufficient power??)

    Trial of Prophylactic Platelet Study (TOPPS)
      Pts with         A          Prophylactic platelet transfusions
  hypoproliferative    N            For platelet count <10,000/µl
(Chemotherapy for      M
    haematologic       I             Therapeutic platelet
                       Z              transfusions only
  malignancy) (UK)

     …Ongoing as of April 2010 (Jan. 2006-Dec. 2011)
    Platelet Transfusions: Summary

 Thrombocytopenia due to most causes increases the
  risk of bleeding
 The optimal use of platelet transfusions in patients at
  risk is still unclear
    • Insufficient studies exist to make conclusions about platelet
    • Uncertainty exists and platelets are increasingly scarce
    • Adequate alternatives to platelet transfusions do not exist
   Platelet transfusions are generally not recommended
    for patients with many forms of thrombocytopenia
    particularly with increased platelet destruction
Approach to the patient with a suspected
platelet disorder
   History
    • Is the patient bleeding?
    • Are there symptoms of a secondary illness? (neoplasm, infection,
      autoimmune disease)
    • Is there a history of medications, alcohol use, or recent transfusion?
    • Are there risk factors for HIV infection?
    • Is there a family history of thrombocytopenia?
    • Do the sites of bleeding suggest a platelet defect?

   Assess the number and function of platelets
    • CBC with peripheral smear
    • Platelet function study (if platelet number adequate)
    • Von Willebrand studies
 Classification of Platelet Disorders

Quantitative Disorders     Qualitative Disorders

 Abnormal distribution     Inherited disorders (rare)
                            Acquired disorders
 Dilution effect
                               • Medications
 Decreased production         • Chronic renal failure
 Increased destruction        • Cardiopulmonary bypass
Thrombocytopenia associated with
shortened survival (increased destruction)
    Immune mediated thrombocytopenia
     •   Drug-induced thrombocytopenia
     •   Heparin induced thrombocytopenia
     •   ITP
     •   TTP (most)
    Non-immune destruction
     • DIC
     • Sepsis-associated
    Multifactorial thrombocytopenias
     • Hospital (ICU)-associated thrombocytopenia
     • Cancer associated thrombocytopenia
Acquired thrombocytopenia with
shortened platelet survival

    Associated with bleeding      Associated with thrombosis

     • Immune-mediated              • Thrombotic
       thrombocytopenia (ITP)         thrombocytopenic purpura
     • Most drug-induced            • DIC
       thrombocytopenias            • Trousseau’s syndrome
     • Most others                  • Heparin-associated
Drug-induced thrombocytopenia
What is the frequency of drug-induced
Estimates vary:
~1% of patients receiving GPIIb/IIIa antagonists
~1% of patients receiving unfractionated heparin
<1:10,000 for most other drugs (causal relationship is often uncertain)

Which drugs are most likely to cause thrombocytopenia?
Case-control study
      Kaufman et al., Blood 1993; 82: 2714-2718
Individual case reports
   Reviewed in
      George et al., Ann Intern Med 1998; 129: 886-890
      Ann Intern Med 2001; 134: 346
      Ann Intern Med 2003; 138: 239
      Ann Intern Med 2005; 142: 474-475
    Thrombocytopenic purpura in relation to
    the use of drugs
Case-control study
   ~90 East Coast hospitals, 1983-1991

Identified 62 patients >16 yo admitted for
   (1) acute onset of bleeding
          (1st day of bleeding = “index day”)
   (2) platelets ≤30,000 (other counts normal)
   (3) rapid recovery of platelets to ≥150,000
          without splenectomy or steroids (7 pts)
          with steroids rapidly tapered (55 pts)
   Median age 49, 65% female

   chemotherapy, radiotherapy, splenomegaly, SLE,
   mononucleosis, malignant blood disease,
   megaloblastic anemia, renal failure, cirrhosis,
   granulomatous disease, DIC, HIV, etc., etc.

2625 age/sex matched controls admitted for
   trauma (47%)
   acute infections (31%)
   other conditions (22%)
                                                     Kaufman DW et al. Blood 1993; 82: 2714-2718
Drug-induced Thrombocytopenia
A Systemic Review of Published Case Reports

                                                                      Criteria for review of case reports:

                                                                      1. The candidate drug (a) preceded thrombocytopenia and (b)
    Possible – Level III

                                                                         recovery from thrombocytopenia was complete and sustained
                                                                         after the drug was discontinued (unlikely if criterion 1 not met –
                           Probable – Level II

                                                                         Level IV)
                                                 Definite – Level I

                                                                      2. The candidate drug was (a) the only drug used prior to the
                                                                         onset of thrombocytopenia or (b) other drugs were continued or
                                                                         reintroduced after discontinuation of the candidate drug with a
                                                                         sustained normal platelet count

                                                                      3. Other etiologies for thrombocytopenia were excluded

                                                                      4. Re-exposure to the candidate drug resulted in recurrent
                                                                         thrombocytopenia (strongest evidence)
Drug-induced Thrombocytopenia
A Systemic Review of Published Case Reports

Included in the review:

515 patient case reports
48% of which supported “definite” (Level I) or “probable” (Level II) association between a drug
   and thrombocytopenia

For Level I drugs:                        Median (days)           Range (days)

   Time to onset of thrombocytopenia:             14              1-1000
   Time to recovery after stopping the drug:      7               1-60
   Time to platelet nadir after re-challenge:     3               <1-60
   Time to recovery after re-challenge:           5               <1-60
     Drug-induced Thrombocytopenia is
            constantly evolving

Level I                                           Level II

2001 Indinavir (Crixivan) (2 case reports)        2001Ticlopidine (Ticlid) (2 case reports)
  Atorvastatin (Lipitor) (1 case report)            Acetazolamide (Diamox) (2 case reports)
  Pentoxifylline (Trental) (1 case report)        2003Lotrafiban (5 case reports)
  Mesalamine (Asacol, Pentasa, Rowasa)              Naproxen (Aleve and others) (3 case reports)
  (1 case report)                                   Sulfamethoxypyridine (3 case reports)
2003Octreotide (Sandostatin) (1 case report)        Chlorpropamide (Diabinese) (2 case reports)
  Abciximab (ReoPro) (group data)                   Roxifiban (2 case reports)
  Eptifibatide (Integrilin) (group data)            Sulfapyridine (2 case reports)
2005Rituximab (Rituxan) (1 case report)           2005Chlordiazepoxide-clidinium (Librax) (2 case reports)
  Tirofiban (Aggrastat) (group data)                Clopidogrel (Plavix) (2 case reports)
2007Adefovir dipivoxil (Preveon, Hepsera) (1        Terbinafine (Lamisil) (2 case reports)
  case report)                                      Simvastatin (Zocor) (2 case reports)
  Lopinavir/ritonavir (Kaletra) (1 case report)   2007Efalizumab (Raptiva) (5 case reports)
  Teicoplanin (Targocid) (1 case report)            Etretinate (Tegison) (2 case reports)
                                                    Oxaliplatin (Eloxatin) (2 case reports)
                                                    Famotidine (Pepcid) (group data)
             Drug-induced Thrombocytopenia:
                    Available databases

   Database of case reports and case series Updated in Oct. 2008

   1468 drugs listed
   Clinical data from case reports
   Laboratory evidence of drug-dependent antibody
   Data mining case reports with no clear causal association

   Royer DJ et al. Eur J Haematol 2010; 48:421-9
     • Data base of thrombocytopenia associate with complementary and
       alternative medicines, herbal remedies, nutritional supplements and
       beverages (only 5 agents clearly associated with thrombocytopenia: cow’s
       milk, cranbery juice, Jui, Lupini bean and tahini)
Heparin Induced Thrombocytopenia
     Heparin usage

   One of the most commonly administered
    parenteral therapies in the hospital setting
   One trillion units of heparin used per year in
    the USA
   Twelve million patients exposed to heparin
    per year

   Indications for anticoagulation are
   Heparin documentation is frequently
      Clinical Suspicion of HIT

   Normal platelet count prior to heparin with a decline to
    • (or reduction of platelet count by >50%)
 Onset of thrombocytopenia by day 14
 Exclusion of other causes of thrombocytopenia
 Any new thrombotic event while on heparin
 Skin inflammation or necrosis at heparin      injection
    Distribution of Platelet Count

Warkentin. Semin Hematol 1998;35(4):9-16.
Clinical sequelae of HIT
Outcome          Incidence

New thrombosis   up to 50%

Amputation       ~10%
                 Associated with arterial thrombosis
                 Associated with venous limb gangrene

Death            10-20%
Delayed-onset HIT
                                                     Day 21
49 year old woman with a DVT
Treated with heparin and warfarin

Day 5: Discharged on warfarin;
INR 2.2

Day 19: Returned with pain and
swelling in leg; INR 1.9

Day 21: Progression of DVT to
Venous limb gangrene
Pedal pulses intact
 Warkentin et al. Ann Intern Med 1997;127:804–812.
Heparin-indcued Thrombocytopenia (HIT):
Clinical Presentation - Temporal aspects

                                     Typical-onset HIT HIT
                                         (within days)
                                     (within 4-144 to 14 days)

               Rapid-onset HIT
               (previous heparin exposure)

                                                      Delayed-onset HIT
                                         (average of 9 days after heparin is stopped)

  0    1   2   3   4     5   6   7   8     9 10 11 12 13 14 15 21            40

      Heparin exposure
Idiopathic Thrombocytopenic
        Purpura (ITP)
    Definition of ITP
   Primary ITP
     •   Isolated thrombocytopenia with a platelet count <100,000/µl
     •   No other causes or disorders associated with thrombocytopenia
     •   Diagnosis of primary ITP is a diagnosis of exclusion
     •   Main clinical problem is bleeding but not always present

   Secondary ITP
     • All forms of immune-mediated thrombocytopenia except primary ITP
      Pathophysiology of ITP
   Increased platelet destruction mediated by autoantibodies

   Auto-antibodies that react with major membrane glycoproteins can be identified in
    ~80% of patients

   Antibody concentrations diminish with effective treatment and increase with
Initial Treatment of ITP
     Platelet Count
       (per µl)                  Symptoms                  Treatment
     > 50,000                   None                       None
     20-50,000                  Not bleeding               None
                                Bleeding                   Glucocorticoids
                                                           IVIG or Anti-D
     < 20,000                   Not bleeding               Glucocorticoids
                                Bleeding                   Glucocorticoids
                                                           IVIG or Anti-D
George et al. ITP: A practice guideline developed by explicit methods for the American
Society of Hematology. Blood 1996; 88:3
Approach to the Treatment of ITP

 Initial treatment   IVIG/Anti-D
 Curative therapy    Glucocorticoids

 Rescue therapy      High dose glucocorticoids
 Chronic therapy     Many agents
                     Thrombopoietin-receptor agonists
     Initial Treatment of ITP with Prednisone:
      Initial therapy
        • prednisone 1-2 mg/kg/day for 2-4 weeks
           then taper.
        • 0.25 to 0.5 mg/kg/day may be as effective.
        • Initial response rate is 50-60% with ~ 50% demonstrating
           normalization of counts
        • Majority will see a decline in platelet counts on weaning.
        • Long-term complete remission rate after therapy discontinued

Porteilje et al. Blood 2001; 97:2549.
Chronic therapy
      Relapsed after previous therapy

      Decline/poor surgical candidate

      Delay surgery
                                                            Production is constant



   receptor receptor
                                 Transcription      JAK2,
                                   signaling       STAT5
         TPO-R                                                 Feese et al. PNAS 2004;101:1816-1821
    Tpo-receptor Agonists

   rTpo                               Tpo or agonist
    • stimulated platelet production
    • stimulated anti-Tpo antibody
 Romiplostim
 Eltrombopag
 AKR 501
 LGD-4665                             transduction
  Treatment with recombinant human TPO
Recombinant Tpo

Halted production of rhTpo as a therapeutic agent

                                                    Li et al. Blood 2001; 98:3241-48

                                  Peptide Receptor Binding
                  FC Carrier Domain        Domain

 • Unique platform peptibody              • 4 receptor binding sites
 • Expressed in E. coli                   • Targets thrombopoietin receptor
 • Molecular weight = 60,000 D            • No sequence homology with TPO
                                          • t1/2 120 hrs

                    Bussel et al. N Engl J Med. 2006;355:1672-1681
Romiplostim: Pivotal Trials
Romiplostim: Effect on Median Platelet Count
     Median Platelet Count x 109/L

                                     Placebo    n=
                                     Romiplostim n =

                                     Placebo    n=
                                     Romiplostim n =

Kuter DJ; Lancet: 2008:371:395-403
    Response to Romiplostim

          Overall             Placebo

 Median number
    of weeks with
platelet response
Proportion of Romiplostim Who Discontinued
or Reduced Concurrent ITP Therapy


      Romiplostim                 Romiplostim   Romiplostim
Long-term Treatment with Romplostim in patients with
chronic ITP: 3-year update from an open-extension study
             Extension study
             Female                         67%
             Splenectomy                    60%
             Baseline platelet count        17,000/µl
             Median duration of treatment   65 weeks

                                            Kuter et al, Abstract 402, ASH 2008

     Small molecule (MW = 546)
     Orally bioavailable
     Once-daily dosing
     Not immunogenic
     Binds to transmembrane portion
      of TPO receptor

     Stimulates megakaryocyte
      proliferation and differentiation
     Increases platelet count in

Jenkins et al. Blood. 2007;109:4739-4741.
          Eltrombopag: Placebo-controlled
                  Phase III Study

     ITP patients            A                       Eltrombopag
       N=114                 N                      50 mg PO q.d.*
  50% Platelet count
                             O          *Dose adjusted to maintain platelet count 50-400,000/µl
       <15,000               M
 35% splenectomized          I
  15% ≥3 treatments          Z          Placebo with standard of care
                             E                    PO daily

Primary endpoint
   A platelet count 50,000/mcL at any time during the 42 day treatment period
Eltrombopag Boosts Platelet Counts to ≥50,000/µL

                         Percentage of respondents

59% on eltrombopag achieved primary efficacy endpoint versus 16% on placebo (P
In general, increases in platelet counts were detected 1 week following initiation of
eltrombopag and the maximum response was observed after 2 weeks of therapy
Platelet counts generally decreased within 1 to 2 weeks after discontinuing
Oral Eltrombopag for the Long-term Treatment of Patients
with Chronic ITP: Results of a Phase III, Double-blind,
Placebo-controlled Study (RAISE)

                              A                        Eltrombopag
          ITP patients        N                       50 mg PO q.d.*
            N=211             D
 Platelet count <15,000 50%   O          *Dose adjusted to maintain platelet count 50-200,000/µl
    35% splenectomized        M
     15% ≥3 treatments        I
                              Z                            Placebo
                              E                            PO daily

    Primary endpoint:
     Incidence of durable platelet response (without rescue medications).
     I.e. platelet count 50x109/L for 6 weeks during final 8 weeks of therapy

                                                               Cheng et al., Abstract 400, ASH 2008
Oral Eltrombopag for the Long-term Treatment of Patients
with Chronic ITP: Results of a Phase III, Double-blind,
Placebo-controlled Study (RAISE)

                                          Mean platelet count:
                                          Week 1: 36,000/µl
                                          After: 52-91,000/µl

                                 Cheng et al., Abstract 400, ASH 2008
Safety concerns of thrombopoietin-
receptor agonists

      Rebound thrombocytopenia
      Thrombosis/thromboembolic events
      Clonal thrombopoiesis/malignancy
      Bone marrow fibrosis
Evaluation of Bone Marrow Reticulin Formation
in Romiplostim-treated Patients with ITP
Background:           Fibrosis: Stromal structural fibers:
                      Reticulin fibrosis - type III collagen (Reticulin stain)
                      Collagen fibrosis - type I collagen (Trichrome stain)

    Mild reticulin fibrosis      Severe reticulin fibrosis        Collagen fibrosis

 Design: 2 groups of patients:
       Prospective studied baseline + follow up bone marrow (n=6)
       Retrospective studied for cause (n=5)
                                                             Kuter et al, Abstract 3416, ASH 2008
Evaluation of Bone Marrow Reticulin Formation
in Romiplostim-treated Patients with ITP
                                           Prospective       Retrospective
                            Fibrosis   Pre-      Post-      Pre-         Post-
0 -absent                   grade
1- fine fibers              0-1        6         5          5            1
2- diffuse fine fibers      1-2        0         1 (wk 15) 0             1
3- diffuse with scattered   2-3                             0            2
coarse fibers
4- Collagen fibrosis        4                               0            1

 2 patients in retrospective study had >10 µg/kg
 All patients in retrospective group had follow up BM - improved
 Conclusion: Increased fibrosis (reticulin) was observed in BM of
 some romiplostim-treated patients; improved with drug withdrawal

                                                     Kuter et al, Blood 2009; 114:3722-3
Summary: Thrombopoietin-receptor
                      Romiplostim         Eltrombopag
Mechanism              TPOR: active site TPOR: TM domain
Indications            Chronic ITP                 Chronic ITP
Route                  SQ                          PO
Initial dose           1 mcg/kg/wk                 50 mg/day
                       ~80%                        ~80%
Overall response Borst et al. Ann Hematol 2004;83:764
Immunogenicity         Yes                         No
Hepatic toxicity       No                          Yes
Response in            Yes                         Yes
splenectomized pts.
REMS program           Yes                         Yes
Where do we go from here?
 1. Thrombopoietin receptor agonists are an effective treatment
    for chronic ITP with an acceptable toxicity profile
 2. When should these drugs be incorporated into current
    approach to treatment?
 3. Are there clinically significant differences in the side effect
    profiles between agents?
 4. How well defined are the long-term adverse reactions?
    (Thrombosis, BM fibrosis, clonal evolution)
 5. What is the role of Tpo-receptor agonists in other diseases?
    (Augmenting platelet donors, liver disease, BM failure,
    chemotherapy-associated thrombocytopenia)
Summary: Proposed Mechanism of
Immune-mediated Thrombocytopenias

                                Warkentin, NEJM 2007; 356: 891
Thrombotic Thrombocytopenic
       Purpura (TTP)
    Thrombotic Thrombocytopenic Purpura:
    Pentad of findings
   Clinical findings
    • Fever
    • Neurologic changes
    • Renal impairment

   Laboratory findings
    • Microangiopathic hemolytic
      anemia (schistocytes) Hgb
      <10 g/dl and laboratory
      findings of hemolysis
    • Thrombocytopenia (usually <
VWF and Platelet Adhesion

     Blood Flow
                                                VWF protease
  VWF          Platelet          Fibrinogen     (ADAMTS13)

    A1 domains            GPIb

 Adhesion           Rolling        Activation    Recruitment   Regulation
≈1000 µm s-1       ≈4 µm s-1       ≈0 µm s-1
     VWF, Proteolysis, and Platelet Adhesion
   Blood Flow

                          No Protease   Thrombus    Multimers

  Adhesion, Rolling,
Activation, Recruitment

Thrombotic Thrombocytopenic Purpura:
                                 Activity  Antibody

Congenital                       Low        Negative
Idiopathic/Relapsing             Low        Positive
Pregnancy-associated             Low        Positive
BMT-associated microangiopathy         Normal
Hemolytic uremic syndrome        Normal     Negative
Drug-associated TTP              Normal     Negative
Diarrheal-associated TTP-HUS     Normal     Negative
Thrombotic Thrombocytopenic Purpura:
   Initial treatment:
    • Plasma exchange (plasmapheresis) daily

   Relapsed or refractory disease:
    • Plasmapheresis ± Rituximab immunosuppressive therapy
    • Other (Vincristine; Splenectomy)

   Adjunctive therapy (unproven role)
    • Glucocorticoids
    • Aspirin
Response to Plasma Exchange

                      Protease Deficient
      Category Number Deficient + Inhibitor

     Idiopathic   13          10      5
    Cyclosporin    3           0      0
    Mitomycin      2           0      0
    Peripartum     2           0      0

        Total     20          10      5
Available Approaches for the Treatment
of Thrombocytopenia
   Pharmacologic agents to enhance hemostasis
     Tranexamic acid/EACA

   Biologic agents to enhance hemostasis
     Recombinant human factor VIIa

   Platelet transfusions
     Prophylactic transfusions
     Therapeutic transfusions

   Agents that improve the platelet count
     Thrombopoietic growth factors (Thrombopoietin-receptor agonists)

   PFA-100 has supplanted the bleeding time as a measure of platelet

   Drug-induced thrombocytopenia are variably defined and difficult to
    diagnose with certainty

   HIT remains an important cause of thrombocytopenia

   Treatment of HIT with Direct thrombin inhibitor is the standard
    approach to therapy
   Newer approaches to ITP are effective and may have a role in other

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