Presentation on theme: "Immune Mediated Thrombocytopenic Purpura ITP is defined as isolated thrombocytopenia with no clinically apparent associated conditions or other causes."— Presentation transcript:
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
Aetiology in children Often after infection (viral or bacterial) Theories: *antibody cross-reactivity *H. pylori *bacterial lipopolysaccharides
Pathogenesis of ITP ITP 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 foreign ITP is mediated by IgG autoantibodies. Glycoprotein IIb/IIIa, Ib/Ix, Ia/IIa, IV and V... Accelerated clearance through Fc ү receptors that are expressed by tissue macrophages (spleen & liver). This causes a rapid drop in the level of platelets in a person’s body
100 cases per 1 milion persons per year. About half of these cases occur in children. Primary vs Secondary. Acute vs Chronic ( >6 months).
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.
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
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.
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
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.
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.
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.
Anti-Platelet Antibody Testing NOT recommended by ASH Practice Guidelines Poor positive/negative predictive values, poor sensitivity with all current testing methods… …and doesn’t change the management!
General Principles of Therapy The decision to treat ITP is based on the platelet count, the degree of bleeding, and the patient ’ s lifestyle Major bleeding rare if PLT > 10,000 Goal = get PLT count to safe level to prevent bleeding…
“Safe” Platelet Counts “moderately” = 30-50,000 Probably safe if asymptomatic Caution with elderly (CNS bleeds)
The incidence of intracranial hemorrhageis ~ between 0.2-1%. Almost all intracranial hemorrhages occur at platelet counts below 20.000/mm 3, and generally below 10.000/mm3. Risk factors : head trauma and exposure to antiplatelet drugs.
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.
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.
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.
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).
Randomized clinical trials have demonstrated that therapy with IVIG shortens the duration of severe thrombocytopenia ( platelet < 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.
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.
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.
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.
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%) !!!! Bacterial sepsis ( ~ 3%) !!!!
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.
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 ???
Should the Patient be Hospitalized? ITP Practice Guideline – American Society of Hematology Patients 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.
Options for Treatment Steroids IVIG Anti-D Splenectomy Rituximab Thrombopoietin receptor agonists Others: danazol, cyclophosphomide, azathioprine, vincristine, cyclosporine A, dapsone.
Does the Pt need to be treated? ASH Guideline Patients with counts >50,000 do not routinely require treatment However, 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.
Initial Therapy Prednisone 1 mg/kg/day *usually response within 2 weeks Taper off after PLT response Duration of use = controversial
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
Treatment Side-Effects Steroids *bone density loss *GI effects *muscle weakness *weight gain IVIG/anti-D *hypersensitivity *headache *renal failure *nausea/vomiting *alloimmune hemolysis
Emergency Therapy – serious bleeding
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”
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
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.”
Chronic Refractory ITP Persistent > 3 months PLT < 50,000 Failure to respond to splenectomy
When all else fails… Steroids IVIg / anti-D Rituximab (anti-CD20) Cyclophosphamide Danazol Accessory splenectomy H. pylori eradication
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