Acute ITP
- 1. Acute Immune Thrombocytopenia Dr. Liza Bulsara
- 2. Immune Thrombocytopenia(ITP) • Also known as Werlhof Disease • ITP is immune mediated acquired hemorrhagic disorder of adults and children characterized by transient or persistent thrombocytopenia and depending upon severity of thrombocytopenia, increased risk of bleeding – Cut off platelet count < 100,000/mm3 – 3-8 children/million/year Rodeghiero et al, BLOOD, 12 MARCH 2009 VOLUME 113, NUMBER 11
- 3. TYPES PRIMARY • An autoimmune disorder characterized by isolated thrombocytopenia (peripheral blood platelet count < 100,000/mm3) in the absence of other causes or disorders that may be associated with thrombocytopenia • Diagnosis of exclusion SECONDARY • All forms of immune- mediated thrombocytopenia except primary ITP • Example Secondary ITP (HIV Induced) Secondary ITP (Drug Induced) Secondary ITP (malignancy Induced) Rodeghiero et al, BLOOD, 12 MARCH 2009 VOLUME 113, NUMBER 11
- 5. Phases of disease American Society of Hematology 2019 Guidelines • Newly Diagnosed ITP: ITP duration of < 3 months. • Persistent ITP: ITP duration of 3-12 months. • Chronic ITP: ITP duration of >12 months.
- 6. Definitions of terms • Corticosteroid-dependent: Ongoing need for continuous prednisone >5 mg/d (or corticosteroid equivalent) or frequent courses of corticosteroids to maintain a platelet count ≥30×109 /L and/or to avoid bleeding. • Durable response: Platelet count ≥30×109 /L and at least doubling of the baseline count at 6 months. • Early response: Platelet count ≥30×109 /L and at least doubling baseline at 1 week • Initial response: Platelet count ≥30×109 /L and at least doubling baseline at 1 month • Remission: Platelet count >100×109 /L at 12 months. American Society of Hematology 2019 Guidelines
- 7. Bleeding Definitions • Major Bleeding : 1. WHO grade 3 - Epistaxis, Bleeding from mucous membranes, vaginal bleeding, malena, hematemesis, hemoptysis, hgematochezia,hematuria,bleeding from puncture sites. 2. WHO grade 4 - Retinal hemorrage with vision impairement, CNS bleeding, hemorrahges in other organs with functional impairement (liver, kidneys, lungs etc.) 3. Buchanan severe grade - Mucosal bleeding or suspected internal hemorrhage (brain, lung,muscle, joint, etc) that requires immediate medical attention or intervention. 4. Bolton-Maggs and Moon severe bleeding - Bleeding episodes requiring hospitalisation and/ or transfusions, interfering with daily living and QOL. 5. ITP Bleeding Scale (IBLS) grade 2 or higher. 6. Life-threatening or intracerebral hemorrhage bleeding. American Society of Hematology 2019 Guidelines
- 8. ITP Bleeding Scale (IBLS)
- 9. • Minor Bleeding - Any bleeding not meeting the criteria for “major bleeding”. American Society of Hematology 2019 Guidelines
- 10. Pathogenesis • Immune thrombocytopenia is caused by increased platelet destruction and impaired platelet production • involves alterations in cellular immunity and immune-mediated megakaryocyte injury. • antibodies directed against specific platelet glycoproteins (GPs), specifically GPIIb/IIIa or GPIb/IX, • rapid destruction in the RES, particularly the spleen. • Peptides released from phagocytosed platelets processed and presented to specific T cells, stimulate B cells produce additional platelet autoantibodies. known as epitope spreading, • platelet production does not compensate for increased platelet destruction s/o BM megakaryocytes may also be impaired. • Megakaryocytes also express GP receptors, which may render them targets of ITP autoantibodies • mechanisms invoked to explain the development of thrombocytopenia in the face of platelet autoantibodies include opsonization and clearance, direct activation of complement, or cellular destruction via apoptosis.
- 14. Diagnosis • History • Clinical Examination- Signs of malignant disease or congenital thrombocytopenia syndromes. • CBC-Isolated Thrombocyopenia (<100×109 /L) • Peripheral Smear - Large Platelets and to exclude abnormal cells. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia
- 17. Bone Marrow Examination NOT DIAGNOSTIC, it only: – Supports the diagnosis with findings of normal or increased meagkaryocytes – Excludes the aplasia, infiltration, other causes BMA should be done if • Very young age(<2 years) • Family history of thrombocytopenia or bleeding • Anemia disproportionate to the degree of bleeding • Abnormalities of WBC count/Morphology • Fever, bone or joint pains • Non Petechial Rashes • Systemically unwell child • Significant lymphadenopathy, hepato-splenomegaly • Deranged clotting screen The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia
- 18. Recommendations for investigations • BMA is not necessary in children and adolescents with the typical features of ITP • BMA is not necessary in children who fail IVIg therapy • BMA is also not necessary in similar patients prior to initiation of treatment with corticosteroids or prior to splenectomy • No indication of: Routine use of anti-platelet, antiphospholipid and anti- nuclear antibodies, thrombopoietin levels,Ig levels,reticulate platelets or platelet parameters obtained on automated analyzers The American Society of Hematology 2019 evidence-based practice guideline for immune thrombocytopenia
- 19. Management Recommendations Outpatient vs inpatient management • In children with newly diagnosed ITP who have no or mild bleeding (skin manifestations) only, the ASH guideline panel suggests against admission to the hospital rather than outpatient treatment. • Remark: For patients with uncertainty about the diagnosis, those with social concerns, those who live far from the hospital, and those for whom follow-up cannot be guaranteed, admission to the hospital may be preferable.
- 20. Treatment vs observation • In children with newly diagnosed ITP who have no or minor bleeding, the ASH guideline panel suggests observation rather than corticosteroids, IVIG or anti-D immunoglobulin
- 21. First line therapy • In children with newly diagnosed ITP who have non–life threatening mucosal bleeding and/or diminished HRQoL, the ASH guideline panel suggests corticosteroids rather than anti-D immunoglobulin or IVIG. • If corticoseroids are not given then either anti- D immunoglobulin or IVIG is recommended.
- 22. Corticosteroid duration and type • In children with newly diagnosed ITP who have non–life threatening bleeding and/or diminished HRQoL, the ASH guideline panel recommends courses of corticosteroids 7 days or shorter. • Prednisone (2-4 mg/kg per day; maximum, 120 mg daily, for 5-7 days) rather than dexamethasone (0.6 mg/kg per day; maximum, 40 mg/kg per day, for 4 days)
- 23. • Management of children with ITP who do not have a response to first-line treatment • In children with ITP who have non–life-threatening mucosal bleeding and/or diminished HRQoL and do not respond to first-line treatment, the ASH guideline panel suggests the use of TPO-RAs (eltrombopag, romiplostim) rather than rituximab or splenectomy • If TPO-RA is not used, then the ASH guideline panel suggests rituximab rather than splenectomy.
- 24. Intracranial Hemorrahge • The most significant complication. • Incidence in children: 0.1-0.5% • Mortality: 25% • Potential risk factors include – Platelet counts below 10 to 20x109/L, – Nonsteroidal anti-inflammatory drugs (NSAIDs) – Head trauma – Vasculitis associated with systemic lupus erythematosis (SLE), Varicella infection – Cerebral arteriovenous malformations (AVMs) Psaila et al. Blood 2009
- 25. General Measures • Educate parents about nature of disease & signs /symptoms of bleeding • Expected gain vs side effects of drugs • Avoid drugs interfering with platelet function • Avoid contact sports/IM Injections • Routine activities, schooling, walking, jogging should be encouraged • 24 hrs hospital contact point • Monitoring
- 26. Treatment of Newly Diagnosed ITP Oral Corticosteroid Dose: Prednisone (2-4 mg/kg per day; maximum, 120 mg daily, for 5-7 days) Mech of action: • Decreasing production of antiplatelet antibodies • Decreasing binding of antibodies to the platelets • Decreasing phagocytosis of opsonised platelets Adverse effects: • Mood Changes • Gastritis • Hypertension • Immunosupression
- 27. IVIG • Highly effective in increasing the platelet counts (PC) – A single dose of IVIg (0.8-1 g/kg) to be given if corticoseroids are not given. – Can be used if a more rapid increase in the PC is desired • Response rate : Up to 80% within 24 hrs lasting up to 1-2 weeks • Mechanism of action: – Blockade of receptors on RE cells, resulting in survival of opsonised platelets – Inhibition of binding of antibodies to platelet antigens – Decreased antibody production by suppressing B cells
- 28. Disadvantages of IVIG • Higher doses associated with side effects: – Allergic reaction – Fever, headache, nausea, vomiting – Neutropenia and hemolytic anemia – Acute kidney injury – Aseptic meningitis • Expensive • Relapse in 1/3rd patients after 6 weeks • Longer duration infusion • Not easily available
- 29. Anti-D immunoglobulin Role of anti-D: • Anti-D Ig can be used intravenously to treat pt with acute and chronic ITP who have not undergone splenectomy Dose and response: • The recommended infusion dose is 50-75 mcg/kg given as single dose or two divided doses on separate days • Significant response in 50-77% cases within 1 to 3 days, peaking at a mean of eight days after infusion. • The duration of response may last 3 weeks or longer. Mechanism of action: • Phagocytic cell blockade due to occupancy of the phagocytic cell Fc receptors by the IgG-sensitized RBCs, which prevents the platelets from binding to these receptors.
- 30. • Adverse effects: – Fever, chills, nausea, vomiting, headache – Hemolysis : Fall in Hb occurs within 1 week, recovers by day 21. (more with higher dose) – Intravascular hemolysis: causes anemia, renal failure, DIC and death • Advantages over IVIG: – Less expensive – Easily available – I.v. infusion over 3-5min – Headache, fever, chills less common
- 31. Emergency Treatment • Increase the circulating platelet count rapidly • Larger than usual (two to threefold) infusion of donor platelets ranging from transfusions every 30 minutes to 8 hours • IVIG infusion(1g/kg) • IV administration of methylprednisolone (30 mg/kg, maximum dose 1 g) over 20 to 30 minutes • Efficacy of antifibrinolytic agents is unproven • Consider recombinant factor VIIa • Consider emergency splenectomy in truly life- threatening bleeding
- 32. THANK YOU!
Editor's Notes
- #3: This threshold was preferred to the more commonly used level of less than 150 109/L, based upon a prospective cohort of otherwise healthy subjects with a platelet count between 100 and 150 109/L, showing that the 10-year probability of developing more severe thrombocytopenia (persistent platelet count below 100 109/L) is only 6.9% (95% confidence interval [CI], 4.0%-12.0%).19 some non-Western populations, platelet count values between 100 and 150 109/L are frequently found in apparently healthy people
- #27: All 3 patients had plt <20,000 at diagnosis and 2 of 3 had received treatment at diagnosis…. Data from 2540 patients were analyzed, including 203 infants (7.6%), 1860 children ≥1 to <10 years of age (69.1%), and 477 children and adolescents between ≥10 and <16 years of age (17.7%). The mean platelet count at diagnosis was similar in all three groups, as was the percentage of patients with initial platelet count <20×109/L. The male/female ratio was highest in infants and decreased with age (P=.009). Immunoglobulin therapy was used more often in infants and corticosteroids in patients ≥10 years of age. Follow-up information at 6 months was available for 1742 children (68.6%). Chronic ITP was seen less frequently in infants (23.1%) than in children >10 years of age (47.3%, P<.0001). Intracranial hemorrhage occurred in 3 of 1742 children during the first 6 months after the diagnosis of ITP. No prospective studies clearly indicate decrease in incidence of ICH associated with treatment…. Several children who had Itp-associated Ich were receiving platelet enhancing therapy at the time of hemorrhage….
- #29: Many randomized studies support the benefit of prednisone in children with ITP....73 children ages 10 months to 14 years who had newly diagnosed ITP were randomized to receive oral prednisolone (60 mg/m2 per day for 21 days) or a placebo. Platelet responses were significantly faster in the corticosteroid-treated group, with 90% of children achievinga platelet count of 30 109/L within the first 10 days of treatment compared with 45% of children in the placebo no-treatment group. The number of childrenwho developed chronic thrombocytopenia, although small in both groups, appeared to be uninfluenced by steroid therapy. No side effects or serious complications were noted in this trial....... A commonly used high-dose corticosteroid regimen is that reported by van Hoff and Ritchey.42 The investigators treated 21 consecutive children who had ITP using IV methylprednisolone (30 mg/kg, maximum dose 1 g) given daily for 3 days. The median time to achieving a platelet count greater than 20 109/L was 24 hours. Ten children (48%) had transient glycosuria but no cases of hyperglycemia were observed. ASH: inNo evidence to support any one dose or dosing regimen over other…. Long term steroid should be avoided children because of side effects… Steroids have been used for the treatment of patients with primary immune thrombocytopenia since the 1950s. Their mechanism of action involves a broad immunosuppressive effect, as well as a protective effect on the vascular endothelium. Durable responses to short-term first-line treatment with steroids are seen in 70–80% of children and only 15–40% of adults. Response rates are much lower in chronic and refractory immune thrombocytopenia, where high doses of steroids are often used. Steroids are associated with significant dose-dependent toxicities that should limit their use in the long-term. Current investigational approaches to increase the long-term results involve the combination of steroids with other drugs, such as rituximab.
- #31: 5gm vial: Rs. 8000 to 20,000
- #33: Few instances of intravascular hemolysis, DIC and renal failure have been reported.
- #34: IVIG has the most rapid onset of action…and should be considerd….. infusion will increase the survival of infused platelets…. Recombinant factor VIIa (rfVIIa)160 has been used in several patients with ITP who were either bleeding or undergoing surgery. In all 18 cases reported, the bleeding stopped but 3 patients died. Care must be taken when using recombinant factor rfVIIa because of a risk of thrombosis….. high concentrations of FVIIa induce platelet activation, generate platelet surface factor IXa and Xa which lead to thrombin generation on the platelet surface, and also to the formation of hemostatic plaque despite low platelet numbersMoreover, very high concentrations of rFVIIa may also result in a saturation of all available tissue factor exposed at the site of injury, as well as in extravascular spaces, Moreover, very high concentrations of rFVIIa may also result in a saturation of all available tissue factor exposed at the site of injury, as well as in extravascular spaces, leading to local thrombin generation and thrombus formation….This process tends to occur without systemic activation of anticoagulation…