Idiopathic Thrombocytopenic Purpura

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Idiopathic Thrombocytopenic Purpura
By Dr. Manhal Alsamady
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Immune Mediated Thrombocytopenic Purpura

• ITP is defined as isolated thrombocytopenia with
  no clinically apparent associated conditions or
  other causes of thrombocytopenia
• ITP is a high prevalence disease 16 to 27 per
  million per year
• Incidence increases with age
• Female predominance under the age of 60 but not
  over the age of 60
• It can have an abrupt onset or insidious onset.
  It is generally abrupt in onset with children

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Classification
Acute ITP
Chronic ITP

• Mostly children
• Acute onset
• Spontaneous
• remission frequent

• Mostly adults
• Usaully gradual onset
• Spontaneous remission rare
• Chronic recurrent course

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Aetiology in children

• Often after infection (viral or bacterial)
• Theories
• antibody cross-reactivity
• H. pylori
• bacterial lipopolysaccharides

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Pathogenesis of ITP

• ITP is an autoimmune disease during which pt.
  bodys immune system attacks and destroys his
  platelets.
• The body releases auto-antibodies which
  chemically tag its own cells as foreign
• ITP is mediated by IgG autoantibodies.
• Glycoprotein IIb/IIIa, Ib/Ix, Ia/IIa, IV and V
  ...
• Accelerated clearance through Fc? receptors that
  are expressed by tissue macrophages (spleen
  liver).
• This causes a rapid drop in the level of
  platelets in a persons body

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• 100 cases per 1 milion persons per year.
• About half of these cases occur in children.
• Primary vs Secondary .
• Acute vs Chronic ( gt6 months).

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• Affected children are young (peak age 5 yrs)
  and previously healthy, and they typically
  present with the sudden onset of petechiae or
  purpura a few days or weeks after an infectious
  illness.
• Boys and girls are equally affected.

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Presentation

• Petechiae, purpura, and easy bruising - very
  common
• Epistaxis, gingival bleeding, and menorrhagia
  -common
• Overt gastrointestinal bleeding and gross
  hematuria are rare
• Intracranial hemorrhage - very rare

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• In more than 70 of children, the illness
  resolves within six months, irrespective of
  whether they receive therapy.
• By contrast, ITP in adults is generally chronic.

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Evaluation of ITP

• Features consistent with the diagnosis of ITP
• Thrombocytopenia with normal or slightly large
  platelets
• Normal RBC morphology and number (may have
  associated iron def or thallasemia etc.)
• Normal white cell number and morphology
• Splenomegaly rare
• Features not consistent with the diagnosis of ITP
• Giant platelets
• RBC abnormalities ie schisotocytes
• Leukocytosis or Leukopenia

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Diagnosis (of Exclusion)

• Rule out other causes
• lab error / PLT clumping
• drug / medication interaction
• infections (HIV, Hepatitis C)
• destructive / consumptive processes (TTP/HUS)
• bone marrow disease (leukemias, MDS)

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• The diagnosis of ITP remains one of exclusion.
• Secondary forms of the disease occur in
  association with SLE, the antiphospholipid
  syndrome, immunodeficiency states (IgA
  deficiency and common variable hypogammaglobulinem
  ia), Lymphoproliferative disorders (CLL, Large
  granular lymphocytic leukemia, and lymphoma),
  infection with HIV and hepatitis c virus, and
  therapy with drugs such as heparin and quinidine.
  

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To Marrow or Not to Marrow?

• Bone marrow aspiration biopsy if
• Patient 60 yrs. or older
• Poorly responsive to tx
• Unclear clinical picture
• The bone marrow in patients with ITP
• contains normal or increased numbers of
• megakaryocytes.

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• There is consensus, that bone marrow examination
  is not necessary in children if management
  involves observation or IVIG.
• Although it is not mandatory, many pediatric
  hematologists recommend that an aspiration be
  performed before starting corticosteroids to rule
  out the rare case of acute leukemia.

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Anti-Platelet Antibody Testing

• NOT recommended by ASH Practice Guidelines
• Poor positive/negative predictive values, poor
  sensitivity with all current testing methods
• and doesnt change the management!

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General Principles of Therapy

• The decision to treat ITP is based on the
  platelet count, the degree of bleeding, and the
  patients lifestyle
• Major bleeding rare if PLT gt 10,000
• Goal get PLT count to safe level to prevent
  bleeding

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Safe Platelet Counts

• moderately 30-50,000
• Probably safe if asymptomatic
• Caution with elderly (CNS bleeds)

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• The incidence of intracranial hemorrhageis
  between 0.2-1.
• Almost all intracranial hemorrhages occur at
  platelet counts below 20.000/mm3, and generally
  below 10.000/mm3.
• Risk factors head trauma and exposure to
  antiplatelet drugs.

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• Most intracranial hemorrhagrs occur within four
  weeks after presentation with ITP, often within
  the first week.
• Most children with typical acute ITP recover
  completely within a few weeks without treatment
  and that there is no proof that therapy prevents
  intracranial hemorrhage.

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• ITP in many children certainly those without
  hemorrhage is managed on an outpatient basis
  with minimal investigation, short-term therapy in
  select cases, and the avoidance of activities
  that predispose the patient to trauma and of
  medications that impair platelet function.

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• American Society of Hematology
• (ASH) recommends drug therapy for
• children with platelet counts of less
• than 10.000/mm3 with little or no purpura.
• The UK guidelines state only patients who
  experience significant mucous membrane bleeding
  receive treatment.

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TREATMENT

• Watch Wait strategy.
• Corticosteroids (high, standard or low dose).
• IVIG (high or low dose, 2 day or 1 day).
• IV anti-D immunoglobulin in Rh(D) positive
  patients (high or low dose).

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• Randomized clinical trials have demonstrated that
  therapy with IVIG shortens the duration of severe
  thrombocytopenia ( platelet lt 20.000 /mm3) .
• Adverse reactions headache, fever, nausea, and
  aseptic meningitis.
• The response to IVIG is more rapid than the
  response to IV anti-D.
• The average decrease in the hemoglobin level is
  1.3 g per deciliter, and intravascular hemolysis
  is rare.

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Urgent Treatment

• Neurologic symptoms, internal bleeding, or
  emergency surgery demands immediate intervention.
• IV.Methylprednisone (30 mg/Kg/d max 1 gr/d for
  2-3 days) / 20-30min IVIG (1 gr/kg/d for 2-3
  days) infusion of platelets that is 2-3 times
  the usual amount infused Vincristine may be
  considered.

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• Splenctomy should be considered if it has not yet
  been performed.
• Plasmapheresis is of limited benefit.
• Antifibrinolytic therapy (e.g. Aminocaproic acid)
  may reduce mucosal bleeding, and recombinant
  factor VIIa should be considered.

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Management of first Relapse

• Approximately 25 of children with ITP have a
  relapse after initial treatment.
• One third of children have spontaneous remission
  and only 5 still have severe thrombocytopenic
  requiring therapy one year after diagnosis.

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• Guidelines from the American Society of
  Hematology recommended that splenctomy be
  considered for children who have had ITP for at
  least one year with symptomatic, severe
  thrombocytopenia.
• In children, the rate of complete remission after
  splenectomy is 70-80.
• Bacterial sepsis ( 3) !!!!

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Chronic Refractory ITP

• Achallenge is posed by the occasional symptomatic
  child in whom splenectomy fails or is
  containdicated and in whom the platelet count
  cannot be sustained with acceptable doses of
  corticosteroids, anti-D immune globulin.
• American Soceity of Hematology guidelines
  recommend treatment for such children if they
  have symptomatic thrombocytopenia and platelet
  counts of less than 30.000/mm3.
• No regimen is universally effective.
• Vincristine, azathioprine, cyclophosphamide or
  cyclosporine.

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Splenectomy in children with chronic ITP

• The aim of the study was to determine whether the
  response to splenectomy is related to the
  response to previous treatments ???

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Should the Patient be Hospitalized?

• ITP Practice Guideline American Society of
  Hematology
• Patients with platelet counts gt20,000 should not
  be hospitalized if they are either asymptomatic
  or have only minor purpura.
• Hospitalization is appropriate for patients with
  platelet counts lt20,000 who have significant
  mucous membrane bleeding.

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Options for Treatment

• Steroids
• IVIG
• Anti-D
• Splenectomy
• Rituximab
• Thrombopoietin receptor agonists
• Others danazol, cyclophosphomide, azathioprine,
  vincristine, cyclosporine A, dapsone.

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Does the Pt need to be treated?

• ASH Guideline
• Patients with counts gt50,000 do not routinely
  require treatment
• However, treatment is indicated in patients with
  platelet counts lt20,000 to 30,000, and those with
  counts lt50,000 and significant mucous membrane
  bleeding (or risk factors for bleeding, such as
  hypertension, peptic ulcer disease, or a vigorous
  lifestyle).
• When ITP symptoms persist after primary treatment
  (glucocorticoid) and splenectomy, further therapy
  is recommended in patients with platelet counts
  lt30,000 who have active bleeding.

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Initial Therapy

• Prednisone 1 mg/kg/day
• usually response within 2 weeks
• Taper off after PLT response
• Duration of use controversial

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Second-Line Therapy

• IV Immune Globulin (IVIg)
• 1 gram/kg/day x 2 days
• WinRho (anti-D) if pt is Rh
• 50-75 mcg/kg/day
• Anti-D as effective as IVIG in Rh,
  non-spelectomized patients response rate 70
• Anti-D infusion time is 5 - 10 minutes instead of
  several hours over 2 5 days

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Treatment Side-Effects

• Steroids
• bone density loss GI effects
• muscle weakness weight gain
• IVIG/anti-D
• hypersensitivity headache
• renal failure nausea/vomiting
• alloimmune hemolysis

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Emergency Therapy serious bleeding
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• Long term prognosis excellent in children with
  acute ITP
• In adults 12-25 will require chronic or
  recurrent therapies .
• 5 or less will develop chronic refractory ITP

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Splenectomy

• Predictors of response younger age found to
  correlate with response but this finding is not
  consistent
• Durability while there are reports of late
  relapses, analysis of 21 case series with
  follow-up of more than 5 years, suggest that the
  response to splenectomy is durable.
• Toxicity operative mortality 0.2 1,
  complications 9 13 (? Related to willingness
  to operate on older patients?) fatal asplenic
  sepsis 0.73 per 1000 pt yrs

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Splenectomy

• Splenectomy remains the single best option to
  convert a patient with ITP into a nonpatient,
  that is, one who is unlikely to need frequent
  monitoring or intervention, and it minimizes
  interference with a normal lifestyle.

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Chronic Refractory ITP

• Persistent gt 3 months
• PLT lt 50,000
• Failure to respond to splenectomy

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When all else fails

• Steroids
• IVIg / anti-D
• Rituximab (anti-CD20)
• Cyclophosphamide
• Danazol
• Accessory splenectomy
• H. pylori eradication

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Rituximab

• Anti CD20 monoclonal antibody targeting B-cells
• Many uncontrolled trials showing response rates
  (Plts gt 50K) from 40 60.
• Time to response is 3-7 weeks.
• Follow up is short (median in one systematic
  review 9.5 mos) though one study of
  unsplenectomized patients found 33 still
  responding at 2 yrs.
• Toxicities Infusion reactions rare cutaneous,
  pulmonary and infectious events described (In
  rare cases fatal), reactivation of hepatitis B

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