Acute ITP

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

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/mm 3 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/mm 3 ) 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

4. Secondary ITP

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 ≥30×10 9 /L and/or to avoid bleeding. Durable response : Platelet count ≥30×10 9 /L and at least doubling of the baseline count at 6 months. Early response : Platelet count ≥30×10 9 /L and at least doubling baseline at 1 week Initial response : Platelet count ≥30×10 9 /L and at least doubling baseline at 1 month Remission : Platelet count >100 ×10 9 /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.

11. Clinical Features

12. Clinical features

13. Clinical grading Asymptomatic: Incidentally detected low platelet count Mild symptoms: Bruising/ petechiae, minor epistaxis, little/no interference with daily living Moderate symptoms: Skin bleed, epistaxis, mucosal bleeds more troublesome, menorrhagia. Severe symptoms: Bleeding episodes requiring hospitalisation and/ or transfusions, interfering with daily living and QOL (Bolton- Maggs and Moon. Lancet 1997;35:620-23)

14. Diagnosis History Clinical Examination- Signs of malignant disease or congenital thrombocytopenia syndromes. CBC -Isolated Thrombocyopenia (< 100 ×10 9 /L ) Peripheral Smear - Large Platelets and to exclude abnormal cells. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia

15. 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

16. Recommendation s 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 201 9 evidence-based practice guideline for immune thrombocytopenia

17. 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.

18. 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

19. 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.

20. 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)

21. 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.

22. Recommendations for Surgical Procedure

23. Intracranial Hemorrahge The most significant complication. Incidence in children: 0.1-0.5% Mortality: 25% Potential risk factors include Platelet counts below 10 to 20x10 9 /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

24. 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

25. 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

26. 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

27. 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 1/3 rd patients after 6 weeks Longer duration infusion Not easily available

28. 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.

29. 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 : c auses anemia, renal failure, DIC and death Advantages over IVIG: Less expensive Easily available I.v . infusion over 3-5min Headache, fever, chills less common

30. 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

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