3 Immune Mediated Thrombocytopenic Purpura ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopeniaITP is a high prevalence disease 16 to 27 per million per yearIncidence increases with ageFemale predominance under the age of 60 but not over the age of 60It can have an abrupt onset or insidious onset. It is generally abrupt in onset with children
5 Aetiology in children Often after infection (viral or bacterial) Theories:*antibody cross-reactivity*H. pylori*bacterial lipopolysaccharides
6 Pathogenesis of ITPITP is an autoimmune disease during which pt. body’s immune system attacks and destroys his platelets.The body releases auto-antibodies which chemically tag its’ own cells as foreignITP is mediated by IgG autoantibodies.Glycoprotein IIb/IIIa, Ib/Ix, Ia/IIa, IV and V ...Accelerated clearance through Fcү receptors that are expressed by tissue macrophages (spleen & liver).This causes a rapid drop in the level of platelets in a person’s body
7 100 cases per 1 milion persons per year. About half of these cases occur in children.Primary vs Secondary .Acute vs Chronic ( >6 months).
8 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.
9 Presentation Petechiae, purpura, and easy bruising - very common Epistaxis, gingival bleeding, and menorrhagia -commonOvert gastrointestinal bleeding and gross hematuria are rareIntracranial hemorrhage - very rare
14 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.
15 Evaluation of ITP Features consistent with the diagnosis of ITP Thrombocytopenia with normal or slightly large plateletsNormal RBC morphology and number (may have associated iron def or thallasemia etc.)Normal white cell number and morphologySplenomegaly rareFeatures not consistent with the diagnosis of ITPGiant plateletsRBC abnormalities ie schisotocytesLeukocytosis or Leukopenia
16 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)*note both hyper- and hypothyroidism can cause tpenia; also autoimmune diseases like lupus
17 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 hypogammaglobulinemia), 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.
18 To Marrow or Not to Marrow? Bone marrow aspiration & biopsy if…Patient 60 yrs. or olderPoorly responsive to txUnclear clinical pictureThe bone marrow in patients with ITPcontains normal or increased numbers ofmegakaryocytes.*note can be an area of controversy in the community and actually between hematologists*always need to r/o MDS, leukemias in older pts; but if you have a younger pt and the clinical picture is confusing, it’s advisable to check the marrow.
19 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.
20 Anti-Platelet Antibody Testing NOT recommended by ASH Practice GuidelinesPoor positive/negative predictive values, poor sensitivity with all current testing methods……and doesn’t change the management!*ASH guidelines = published in 1996, based on 1994 study*several studies have looked at use of antiPLT ab’s in pts with suspected ITP… and although the tests can be + in ITP, can also be + in non-immune etiologies (i.e. pregnancy, MDS, congenital tpenia)*…despite this, it’s kind of a “knee-jerk” in the community and often among internists to order the test; but will generally still come down to clinical judgment while waiting for the test to come back.
21 General Principles of Therapy The decision to treat ITP is based on the platelet count, the degree of bleeding, and the patient’s lifestyleMajor bleeding rare if PLT > 10,000Goal = get PLT count to safe level to prevent bleeding…*again, this talk deals w/ITP in adults – and although 80%+ of children will go into a remission and likely recover normal PLT counts, only 9-10% of adults will
22 “Safe” Platelet Counts “moderately” = 30-50,000Probably safe if asymptomaticCaution with elderly (CNS bleeds)*data suggest if pts are asymptomatic at this PLT count, this is probably a safe level – fewer than 10% develop lower counts in follow up if they present at this level (although still need close f/u)*as with all tx, need to tailor to your specific patient
23 Risk factors : head trauma and exposure to antiplatelet drugs. The incidence of intracranial hemorrhageis ~ between 0.2-1%.Almost all intracranial hemorrhages occur at platelet counts below /mm3, and generally below /mm3.Risk factors : head trauma and exposure to antiplatelet drugs.
24 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.
25 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.
26 American Society of Hematology (ASH) recommends drug therapy forchildren with platelet counts of lessthan /mm3 with little or no purpura.The UK guidelines state : only patients who experience significant mucous membrane bleeding receive treatment.
27 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).
28 Randomized clinical trials have demonstrated that therapy with IVIG shortens the duration of severe thrombocytopenia ( platelet < /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.
29 Urgent TreatmentNeurologic 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.
30 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.
31 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.
32 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%) !!!!
33 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 /mm3.No regimen is universally effective.Vincristine, azathioprine, cyclophosphamide or cyclosporine.
34 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 ???
35 Should the Patient be Hospitalized? ITP Practice Guideline – American Society of HematologyPatients with platelet counts >20,000 should not be hospitalized if they are either asymptomatic or have only minor purpura.Hospitalization is appropriate for patients with platelet counts <20,000 who have significant mucous membrane bleeding.
36 Options for TreatmentSteroids IVIG Anti-D Splenectomy Rituximab Thrombopoietin receptor agonists Others: danazol, cyclophosphomide, azathioprine, vincristine, cyclosporine A, dapsone.*e.g. Higher-risk pt = elderly, prone to falls, hx PUD, construction worker, etc.
37 Does the Pt need to be treated? ASH GuidelinePatients with counts >50,000 do not routinely require treatmentHowever, treatment is indicated in patients with platelet counts <20,000 to 30,000, and those with counts <50,000 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 <30,000 who have active bleeding.
38 Initial Therapy Prednisone 1 mg/kg/day *usually response within 2 weeksTaper off after PLT responseDuration of use = controversial*most adults respond within 2 weeks (majority within 1 week)*duration = often 4-6 weeks as spontaneous remissions are ususally in that time period*no set answers even among the ITP Practice Panel of hematologists who set the ASH guidelines, as there isn’t any hard data to help determine.
39 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/dayAnti-D as effective as IVIG in Rh+, non-spelectomized patients; response rate – 70%Anti-D infusion time is minutes instead of several hours over 2 – 5 days*winRho ->only in Rh+ patients*Immune-mediated clearance of the sensitized erythrocytes occupies the Fc receptors in the reticuloendothelial system, minimizing removal of antibody-coated platelets*NOTE neither tx is long-term but can provide rapid response if someone is acutely bleeding, needs to go into surgery, etc. (usually in days)
40 Treatment Side-Effects Steroids*bone density loss *GI effects*muscle weakness *weight gainIVIG/anti-D*hypersensitivity *headache*renal failure *nausea/vomiting*alloimmune hemolysis
42 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”
43 SplenectomyPredictors of response – younger age found to correlate with response but this finding is not consistentDurability – 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
44 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.”
45 Chronic Refractory ITP Persistent > 3 monthsPLT < 50,000Failure to respond to splenectomy
46 When all else fails… Steroids IVIg / anti-D Rituximab (anti-CD20) CyclophosphamideDanazolAccessory splenectomyH. pylori eradication
47 Rituximab Anti CD20 monoclonal antibody targeting B-cells Many uncontrolled trials showing response rates (Plts > 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