Thrombocytopenia

Thrombocytopenia

1. ThrombocytopAenia Modarator : Prof (Dr.) Tushar Kanti Das, HOD by Dr Sweta Biswas Das 2 nd Year PGT

2. Thrombocytopaenia Subnormal amount of platelets in peripheral blood Normal range: 1.5 lakhs to 4.5 lakhs per µl * Abnormal: <50,000 per µl ** Count between 20,000 to 50,000 per µl # Bleeding with trauma or surgery or mild spontaneous bleeding Count <20,000 per µl # Spontaneous and severe haemorrhage * "Platelet count: MedlinePlus Medical Encyclopedia".  www.nlm.nih.gov . Retrieved 2015-05-01. ** "What Is Thrombocytopenia? - NHLBI, NIH".  www.nhlbi.nih.gov . Retrieved 2015-05-01. # Kawthalkar Shirish M, Essentials of Haematology,Second edition 2013, pg: 402-403

3. Causes of Thrombocytopaenia

4. Thrombocytopaenia : Increase destruction of platelets Immune Idiopathic thrombocytopaenic purpura Systemic lupus erythemaetosus Drugs: Heparin, gold salts, penicillin, quinidine, quinine Infections: HIV, malaria, dengue, HCV, Helicobacter pylori Post transfusion purpura Neonatal alloimmune purpura Non-immune Disseminated intravascular coagulation Thrombotic thrombocytopaenic purpura/ Haemolytic Uremic syndrome Giant haemangioma

5. Thrombocytopaenia : Decrease production of platelets Hereditary Fanconi’s anaemia Wiskott-Aldrich syndrome Acquired Aplastic anaemia Bone marrow infiltration (leukemia, myelodysplasia, myelofibrosis Megaloblastic anaemia Drugs (cytotoxic drugs, ethanol), radiation Viral infections

6. Thrombocytopaenia : Others Dilutional thrombocytopaenia Massive blood transfusion Increased sequestration Hypersplenism

7. Idiopathic thrombocytopaenic purpura (ITP) Autoantibodies or immunocomplexes binds with platelets Causes premature peripheral destruction Two types Acute ITP Chronic ITP

8. Idiopathic thrombocytopaenic purpura (ITP): Pathogenesis of Acute ITP Immune complex of viral antigen Host anti-viral antibodies Binds with Fc receptors of platelets Immune destruction of platelets by macrophage at spleen Thrombocytopaenia Anti-viral antibodies cross reacts with platelets antigen

9. Idiopathic thrombocytopaenic purpura (ITP): Pathogenesis of Chronic ITP Thrombocytopaenia Antibodies Glycoprotein IIb / IIIa on platelet Megakaryocytes Decrease platelets formation Antibody-platelets complex Binds with Fc receptors of Macrophages Immune destruction of platelets by macrophage at spleen Hampers fibrinogen binding with platelets Causes platelets malfunction

10. Idiopathic thrombocytopaenic purpura (ITP): Clinical features of acute and chronic ITP Parameter Acute ITP Chronic ITP Age Childhood Young adults Sex No sex preference Common in females H/o preceding viral infection or vaccination Common No Onset of bleeding Sudden Insidious Degree of thrombocytopenia Severe Moderate Duration of disease Self-limited (2-6 months) Many years Spontaneous remission Usual Rare

11. Anaemia: due to bleeding In Child: Lymphocytosis, Eosinophilia Platelets: Acute ITP < 20,000/ cmm Chronic ITP <50,000/ cmm Morphology: Megathrombocyte Chronic ITP: Hyperactive giant platelets mild bleeding manifestation Number of Giant platelets Proportional to Megakaryocytes in bone marrow Laboratory examination of ITP: Peripheral blood smear ITP: Idiopathic Thrombocytopaenic Purpura

12. Laboratory examination of ITP: Bone Marrow examination Megakaryocytes Number- normal or increase Morphology- Hypogranular cytoplasm Vacuolisation Lack of platelets budding Nuclear hypolobulation Dense nuclear chromatin ITP: Idiopathic Thrombocytopaenic Purpura

13. Laboratory examination of ITP: Others Coagulation profile Bleeding time- increased Clot retraction- deficient Platelets antibodies Increased platelet-associated immunoglobulin Not sufficient sensitive Not sufficient specific ITP: Idiopathic Thrombocytopaenic Purpura

14. Idiopathic thrombocytopaenic purpura (ITP)

15. Idiopathic thrombocytopaenic purpura (ITP): Differential diagnosis Isolated Thrombocytopaenia Thrombocytopaenia associated with other haematological disorders Secondary immune thrombocytopaenia (HIV, HCV, H. pylori , autoimmune disorders) Megaloblastic anaemia Drug induced thrombocytopaenia HELLP syndrome/ Pre- eclampsia Inherited thrombocytopaenia Hypersplenism Pseudothrombocytopenia Haematologic malignancies Aplastic anaemia Thrombotic thrombolytic purpura/ Haemolytic Uremic Syndrome Disseminated intravascular coagulation Evans syndrome Liver disease HELLP- Haemolysis, Elevated Liver enzymes and Low Platelets count

16. Causes of inherited thrombocytopaenia Small platelets Wiskott-Aldrich syndrome Normal-sized platelets Thrombocytopaenia absent radii syndrome Congenital amegakaryocytic thrombocytopaenia Giant platelets MYH-9 syndrome May- Hegglin anomaly Fechtner syndrome Epstein syndrome Sebastian syndrome Bernard- Soulier syndrome, Gray platelet syndrome, Montreal platelet syndrome

17. Normal and giant platelets Normal platelets Giant platelets

18. Idiopathic thrombocytopaenic purpura (ITP): Diagnosis Mucocutaneous type of bleeding Acute ITP: abrupt onset Chronic ITP: insidious onset Physical examination: all other normal Complete blood count: isolated thrombocytopaenia Bone marrow: normal Perform in unusual clinical feathers and course Exclusion of other causes of thrombocytopaenia

19. Idiopathic thrombocytopaenic purpura (ITP): Treatment (1/2) Isolated thrombocytopaenia with no other blood smear abnormalities No pervious or family history No organomegaly Normal bone marrow Immune - thrombocytopaenic purpura Mild to moderate thrombocytopaenia Follow up Severe thrombocytopaenia <30,000cmm Or Presence of bleeding Treatment

20. First line therapy Corticosteroids i . v. immunoglobulin i . v. Anti –D sera for Rh + cases Second line therapy Rituximab TPO receptor agonist- Romiplostim , Eltrombopage Splenectomy Life threatening bleeding i . v, immunoglobulin Platelets transfusion Idiopathic thrombocytopaenic purpura (ITP): Treatment (2/2)

21. Alloimmune Neonatal Thrombocytopenia (1/4) Foetal platelets having paternally derived antigen Lacking in mother Enter maternal circulation during gestation or delivery Stimulates alloantibody formation Destruction foetal platelets Including 1 st born, babies are affected Commonest platelets antigen: HPA-1a

22. Alloimmune Neonatal Thrombocytopaenia: Differential diagnosis (2/4) Increased peripheral destruction of platelets Immune destruction by maternal antibodies Auto immune antibodies (Maternal ITP or SLE) Alloimmune neonatal thrombocytopaenia Non-immune mechanism Disseminated intravascular coagulation Intrauterine infections Giant haemangioma

23. Alloimmune Neonatal Thrombocytopaenia: Differential diagnosis (3/4) Decreased production of platelets Thrombocytopaenia absent radii (TAR) syndrome Wiskott-Aldrich syndrome May- Hegglin anomaly Bernard- Soulier syndrome Fanconi anaemia Congenital malignancies

24. Alloimmune Neonatal Thrombocytopaenia (4/4) Self limiting- resolve in three weeks Intra cranial haemorrhage: due to trauma during vaginal delivery Severe cases: purpura and haemorrhage with in few hours of delivery Severe symptomatic thrombocytopaenia Treated with maternal derived platelets transfusion

25. Post transfusion purpura (1/2) Rare life threatening disorder Sudden onset thrombocytopaenia Bleeding occurs after 7-10 days of blood transfusion Common in mutiparous women Donor platelets: have HPA-1a antigen Patient’s platelets: lack HPA-1a antigen

26. Post transfusion purpura (2/2) May be previously sensitised by HPA-1a positive foetal platelets Treatment: i.v . gammaglobulin and plasmapheresis

27. Thrombotic microangiopatheis Characterised by Microvascular thrombosis Microangiopathc haemolytic anaemia (MAHA) Thrombocytopenia Classification Thrombotic thrombocytopaenic purpura (TTP) Haemolytic uraemic syndrome (HUS)

28. Thrombotic thrombocytopaenic purpura (1/5) Uncommon disorder Hyaline microthrombi formation At microcirculation of various organs Due to platelets aggregation Idiopathic variety Autoantibodies against ADAMTAS13 Leads to deficiency of ADAMTAS13 Accumulation of ultra-large vWF multimers Bind large numbers of platelets ADAMTS13: A disintegrin and metalloprotease with thrombospondin 1 and 13

29. Thrombotic thrombocytopaenic purpura (2/5) Familial variety (Upshaw- Sohulman syndrome) ADAMTS13 deficiency: mutation in ADAMTS13 gene Affects young adults Common in female Manifestations Microangiopathic haemolytic anaemia Red cells passes through fibrin strands of microthrombi- haemolysis Clinically: pallor, icterus Peripheral blood smear: fragmented and nucleated RBC,reticulocytosis LDH and unconjugated bilirubin: increased in serum ADAMTS13: A disintegrin and metalloprotease with thrombospondin 1 and 13, RBC: Red Blood Cells, LDH: Lactose dehydrogenased

30. Thrombotic thrombocytopaenic purpura (3/5) Manifestations (Contd.) Bleeding secondary to severe thrombocytopaenia Petechiae Ecchymosis Epistaxis Gastrointestinal or genitourinary bleeding Coagulation profile: normal in most cases (PT, APTT) Fluctuating neurologic dysfunction Altered consciousness level Seizures Visual field abnormality Hemiparesis PT: Prothombin Time, APTT: Activated Partial Thromboplastin Time

31. Thrombotic thrombocytopaenic purpura (4/5) Manifestations (Contd.) Renal abnormalities Proteinuria Haematuria Azotaemia Fever Correct diagnosis is essential Platelets transfusion to correct thrombocytopaenia May aggravate predisposition to thrombosis

32. Thrombotic thrombocytopaenic purpura (5/5) Treatment Transfusion of fresh frozen plasma Plasmapheresis Antiplatelet drugs Corticosteroids Vincristine

33. Haemolytic Uraemic Syndrome (1/2) Characterised by Acute renal failure Thrombocytopenia Microangiopathic haemolytic anaemia (MAHA) Typical variety Children <5 yrs age Associated with Shiga toxin-producing Escherichia coli O157:H7 Diarrhoeal illness followed by MAHA, thrombocytopaenia and renal failure Atypical variety Diarrhoeal prodrome not occurs

34. Haemolytic Uraemic Syndrome (2/2) Microangiopathic haemolytic anaemia (MAHA) and thrombocytopaenia also occurs in Pre- eclampsia HELLP syndrome Autoimmune disorders Systemic infections Systemic malignancy Malignant hypertension HELLP- Haemolysis, Elevated Liver enzymes and Low Platelets count

35. Difference between TTP and HUS Features TTP HUS Age Adults Children <5 yrs MAHA Present Present Thrombocytopenia Present Present Fever Present Absent Severe renal failure Uncommon Common Major neurologic abnormalities Common Uncommon Prodrome bloody diarrhoea Absent Present (in typical HUS) Cause Severe deficiency of ADAMTS13 Infection by E. coli O157:H7 (in typical HUS) Coagulation test Normal Normal Treatment Plasma exchange Supportive TTP: Thrombotic Thrombocytopaenic Purpura, HUS: Haemolytic Uraemic Syndrome, MAHA: Microangiopathic Haemolytic Anaemia, ADAMTS13: A disintegrin and metalloprotease with thrombospondin 1 and 13

36. Thrombocytopaenia due to massive transfusion Factor V & VIII, viable platelets deficient in stored blood Massive stored blood transfusion Thrombocytopaenia Coagulation factor deficiency Bleeding Treatment Fresh frozen plasma and concentrated platelets transfusion

37. Thrombocytopaenia due to increased platelet sequestration or pooling Normally, 30% of total platelets sequestrated in spleen Splenic enlargement splenic pool expands up to 90% Compensatory increase in platelets in bone marrow Mild thrombocytopaenia

38. Sample collected with EDTA Falsely low reading in electronic cell counter Peripheral blood smear Large clamps of platelets Platelets rosetting around neutrophils EDTA alters Gp IIb / IIIa complex conformation EDTA depended anti-platelets antibody formation No clinical significance No bleeding manifestation Pseudothrombocytopaenia

39. Pseudothrombocytopaenia

40. References Kawthalkar Shirish M, Essentials of Haematology,Second edition 2013

41. Thank you