Topic 1 - Idiopathic thrombocytopenic purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP).docx

**HEME-IMMUNE** **WEEK 8: PLATELET DISORDERS, DISORDERS OF HAEMOSTASIS, MYELOFIBROSIS & MYELOPROLIFERATIVE DISORDERS** **Topic 1: Idiopathic thrombocytopenic purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP)** TLO 8.1.1. Classify bleeding disorders in terms of vessel wall abnormalities,...

**HEME-IMMUNE** **WEEK 8: PLATELET DISORDERS, DISORDERS OF HAEMOSTASIS, MYELOFIBROSIS & MYELOPROLIFERATIVE DISORDERS** **Topic 1: Idiopathic thrombocytopenic purpura (ITP) and Thrombotic thrombocytopenic purpura (TTP)** TLO 8.1.1. Classify bleeding disorders in terms of vessel wall abnormalities, platelet disorders (quantitative, qualitative or both), coagulation disorders (inherited & acquired) TLO 8.1.2. Discuss the aetiology and pathogenesis of ITP. TLO 8.1.3. Describe the clinical features of ITP. TLO 8.1.4. Discuss the evaluation and outline the management of ITP. TLO 8.1.5. Compare acute and chronic ITP in terms of age, clinical features, platelet count and prognosis. TLO 8.1.6. Understand and discuss qualitative platelets disorders: Glanzmann thrombasthenia and Bernard-Soulier (giant platelet) syndrome. TLO 8.1.7. Discuss the aetiology and epidemiology of TTP. TLO 8.1.8. Describe the clinical features and evaluation of TTP. TLO 8.1.9. Outline the management and prognosis of TTP. **BLEEDING DISORDERS CLASSIFICATION**  **TERMINOLOGY USED IN BLEEDING DISORDER** Petechiae: Small (1 to 2 mm in diameter), red to purple haemorrhagic spots in the skin, mucous membranes, or serosal surfaces. Result from blood leaking through intact endothelial lining or the capillaries. Most commonly found with a low platelet count, thrombocytopenia, or a defect in platelet function. Purpura: The term purpura means purple. They are slightly larger (\> 3 mm) than petechiae. - Note: Purpura may be classified as thrombocytopenic and non-thrombocytopenic (vascular) purpura. Ecchymoses: They are larger (\>1 to 2 cm) and result from blood escaping through endothelium into intact subcutaneous tissue. The RBCs in the lesion are degraded and release haemoglobin, giving rise to the red/blue colour. Hematoma: Formed when blood leaks from a vessel and collects within a tissue. Blue or purple and slightly raised. Easy bruisability: Term used when petechiae and ecchymoses develop with less than usual trauma (minimal trauma). Excess bleeding: bleeding occurs for a longer time and is more profuse than normal. Normally seen in severe Haemophilia A. **IMMUNE THROMBOCYTOPENIC PURPURA (ITP)** **IMMUNE THROMBOCYTOOENIC PURPURA (ITP) =** is an autoimmune disorder characterized by a low platelet count and a mucocutaneous bleeding. There is an increase in the destruction of platelets by an autoimmune mechanism. Autoantibodies or immune complexes bind to the platelets and cause their premature peripheral destruction. - Most common cause of thrombocytopenia. Megakaryocytes are normal or increased in bone marrow (compensatory mechanism). ITP is classified as primary or as secondary to an underlying disorder and as acute (of six months or less in children) or chronic as in adult. Acute ITP: - Self-limited disease of children between 2 to 6 years. M:F ratio 1:1. - Presents 1-3 weeks post viral illnesses (measles, rubella, EBV) or vaccination. - Platelet destruction is caused by antiplatelet autoantibodies in the spleen- IgM antibody that combine with platelets and result of their destruction in the spleen. - Platelet count \< 10,000/mm3 - Onset is sudden or abrupt. - Presents as petechia over the skin, gum bleeding, epistaxis, and ecchymosis (especially in legs). Intracranial haemorrhage- fatal - Resolve spontaneously- 6 months- severe cases- treated with steroid or intravenous immunoglobulin. - 20% of children (usually without viral prodrome) will have persistent thrombocytopenia beyond 6 months and this will change to chronic ITP. Chronic ITP: - Indolent disorder of insidious onset - Multiple remissions and relapses - Predominantly in adult women aged 20-40. (F:M ratio is 3:1) - Not preceded by infection or associated with any underlying disease. - Persistent thrombocytopenia lasting more than 6 to 12 months. - Pathogenesis: autoimmune disorder with formation of antiplatelet antibodies, directed against membrane glycoproteins most often IIb-IIIa or Ib-IX of platelets- 80% of patients are of IgG type. In addition to causing the destruction of platelets, these autoantibodies also induce platelet dysfunction by blocking the glycoprotein receptors. The antibody/platelet can be demonstrated in about 80% of patients, and they are of IgG type. Similar to what is seen in autoimmune haemolytic anaemia. - Clinical features are not specific but are due to thrombocytopenia in general. - Splenomegaly and lymphadenopathy are uncommon in primary ITP. **ACUTE VS. CHRONIC ITP** **CAUSES OF SECONDARY ITP**  **PATHOGENESIS OF ITP** **MULTI-DYSFUNCTIONAL PATHOPHYSIOLOGY IN ITP** Recognition of self-antigen - Molecular mimicry and cross-reaction - Cryptic epitope and epitope spreading Tolerance failure - T cell tolerance failure - B cell tolerance failure Altered cell communication - B7/CD28 interaction - CD40/CD40L interaction - Fas/FasL pathway - Fc receptor Type-1/type-2 cytokines - Increased IL-2 - Low TGF-β - Increased IL-10 - Increased M-CSF Cell-mediated cytotoxicity Megakaryocytopoiesis **DIAGNOSTIC EVALUATION OF ITP** Complete blood counts: - Platelet count: Markedly reduced (10-100 x 109/L) and is below 80,000/mm3 (80 × 109/L). - Haemoglobin: The level varies depending on the duration and amount of bleeding and ranges from 7 to 12 gm/dL. Peripheral smear: - Platelets: thrombocytopenia, and because of the accelerated compensatory thrombopoiesis, large or giant platelets seen - Red blood cells: chronic blood loss- hypochromic microcytic anaemia - White blood cells: Usually within normal range Coagulation study: - Bleeding time (BT): Prolonged, but PT and PTT are normal - Clotting time (CT): Normal Tests for platelet autoantibodies: - May be positive. Specific anti‐glycoprotein GPIIb/IIIa or GPIb antibodies on the platelet surface or in the serum Bone marrow examination: - Hypercellular, shows normal or increased numbers of megakaryocytes. - Tests for HCV, HIV and Helicobacter Pylori testing **IMMUNE THROMBOCYTOPENIC PURPURA CLINICAL PICTURE**  **ITP PERIPHERAL BLOOD SMEAR AND BONE MARROW ASPIRATES** Peripheral blood film: Peripheral smear in a patient with ITP showing an almost total absence of platelets. A large, young platelet is seen in the centre of the smear. BM aspirate: A high-power view shows that some of the megakaryocytes appear relatively immature with hypolobulated nuclei and hypogranular cytoplasm. **MANAGEMENT APPROACH FOR ITP** **TREATMENT OF ITP** Acute ITP: Acute ITP is a self-limited disorder with spontaneous remission occurring in majority of patients within 2 to 6 months. Therefore, the management of acute ITP is mainly supportive and monitoring. Chronic ITP: aim of treatment should be to maintain a platelet count above the level at which spontaneous bruising or bleeding occurs with the minimum of intervention or trauma. Emergency treatment: - General measures: stop drugs that reduce platelet function, control blood pressure, minimize trauma. - Corticosteroids: 1st line; 80% show complete remission - Intravenous immunoglobulin: used as first line if corticosteroids are contraindicated. Useful in patients with life‐threatening haemorrhage - Platelet transfusion: for refractory, major bleeding, or need for urgent surgery. - Antifibrinolytic: tranexamic acid if mucosal bleeding - Emergency splenectomy: may be considered, vaccinations prior if possible. - Management of intracranial bleeding: IV steroids, IVIg, platelet transfusion is important to avoid further damage. Non-urgent treatment (platelet count \ - Infection - autoimmune/connective tissue disease - certain drugs - stem cell transplantation or cardiac surgery **THROMBOTIC THROMBOCYTOPENIC PURPURA (TTP)** - TTP is an infrequent condition, with an annual incidence of 1.5 to 6 cases per million adults annually. - \~ 90% of cases are in adults and 10% in children. It is more common in females, with an incidence of 2 - 3 times that in males. - It is also 8-fold more likely in African-Americans compared to White-Americans. - The peak incidence is in the fifth decade of life in the United States; meanwhile, in Europe, the peak incidence is in the third decade. - The classic five symptoms of TTP are microangiopathic haemolytic anaemia (MAHA), thrombocytopenia, transient neurologic symptoms, fever and renal failure. **PATHOGENESIS OF TTP**  **CLINICAL FEATURES OF TTP** TTP has traditionally been described as a pentad of: 1. Microangiopathic haemolytic anaemia. Clinically patients have pallor and frequently icterus. 2. Bleeding manifestations secondary to severe thrombocytopenia such as petechiae, ecchymoses, epistaxis, and gastrointestinal/genitourinary bleeding. 3. Fluctuating neurologic dysfunction such as altered level of consciousness, seizures, visual field abnormalities, and hemiparesis, which may terminate in coma. 4. Renal abnormalities: proteinuria, haematuria, azotemia. 5. Fever **TTP VS HAEMOLYTIC UREMIC SYNDROME: LABORATORY INVESTIGATION & MANAGEMENT** **PERIPHERAL SMEAR: TTP** **ALGORITHM FOR DIFFERENTIATINF TTP FROM ATYPICAL HUS & THEIR THERAPEUTIC MODALITIES** Prognosis: most patients respond to transfusions of fresh frozen plasma or to plasmapheresis. In untreated cases mortality may approach 90%. Early treatment (with plasma exchange and corticosteroids) decreases the mortality to 15% Relapses are frequent. Low ADAMTS13 or anti-ADAMTS13 antibodies are used to differentiate TTP from other Microangiopathy. TTP is treated with plasmapheresis and anti-CD20 antibody.