THROMBOCYTOPENIA

1. THROMBOCYTOPENIA By DR NAGANATH NARASIMHAN PRE M

2. Platelets Released from megakaryocytes under the influence of flow in capillary sinuses Normal Platelet count 1.5-4.5 Lakhs/micro liter.

3. Liver -? Thrombopoetin hormone? major regulator of platelet production Increase in synthesis occurs with inflammation,especially with Interleukin 6 production. TPO binds to receptor on platelets & megakaryocytes ? removed from circulation. Decrease in platelets,megakaryocyte mass?increased TPO,causing platelet production.

4. Average lifespan�> 7� 10 days One third platelets? spleen Platelets anucleate,limited capacity to produce proteins,physiologically very active

5. Vascular endothelium injured?inhibitory effects are overcome? platelets adhere to exposed intimal surface primarily through vWF Platelet adhesion?aggregation of intracellular signals? activation of platelet glycoprotein(Gp IIb/IIIa receptor ?platelet aggregation. Activated Platelets? release of granules?nucleotides,adhesive proteins,growth factors,procoagulants -?serve to promote platelet aggregation,blood clot formation. Platelet plug?stabilised by fibrin mesh.

6. Elements of hemostasis Adequate Platelet count Adequate Platelet function: Bleeding Time Adequate levels of Von Willebrand�s Factor Adequate levels of Clotting Factors:Pt/INR,PTT Adequate Blood vessel response

7. Thrombocytopenia Defined as a reduction in the peripheral blood platelet count below the normal limit of 1.5lakhs/micro liter Reconfirmation of the platelet count should be done Confirmation by Blood film

8. 1) Decreased bone marrow production. (2) Sequestration, usually in an enlarged Spleen. (3) Increased platelet destruction.

9. Classification ACQUIRED More Common Causes Less Common Causes Rare causes NEONATAL/CONGENITAL

10. Acquired More common causes Idiopathic Thrombocytopenic Purpura Drugs/Chemicals Leukemias Hypersplenism Aplastic Anemia Disseminated Lupus erythematosus Bone marrow infiltration� Secondary carcinoma Multiple myeloma Malignant lymphomas Myelofibrosis

11. Less common Infection including HIV Megaloblastic macrocytic anaemia Liver diesease Alcoholism Massive blood transfusion Disseminated intravascular caogulation

12. Rare Causes Thrombotic thrombocytopenic purpura Post partum Thrombocytopenia Post tranfusion thrombocytopenia Haemangiomas Food allergy Idiopathic cryoglobulinaemia

13. Neonatal/congenital IMMUNE Auto immune-mothers with chronic idiopathic thrombocytopenic purpura Iso immune(allo immune)-platelet group incompatibility INFECTIONS Congenital /Neonatal Drug administered to mother

14. Congenital Megakaryocytic hypoplasia Isolated Associated with congenital abnormalities/Pancytopenia Hereditary Sex linked-pure form,Aldrich�s Syndrome Autosomal dominant/recessive Congenital Leukaemia Giant haemangioma

15. Symptoms/signs Purpura-purple colored skin manifestations-leaked blood Ecchymoses(purplish patch on skin),petechiae(minute hemorrhagic spots) Splenomegaly(sequestration) Depends on cause of thrombocytopenia Most patients with platelets >50K/ul have no symptoms Many patients live without symptoms with platelets 30-50k/ul for years Concern for platelets<30k/ul Especially with platelet dysfunction Intracerebral hemorrhage <10-15K/ul

16. Malaise Fatigue Weakness with/without blood loss

17. Signs Splenomegaly Cirrhosis Bleeding gums Cerebral haemorrhage Petechaie Spontaneous bleeding Bruising characteristics Oral/nasal/GIT/genitourinary bleeding Optic fundal hemorrhage Prolonged bleeding from cuts Unusually heavy menstrual flow Malaena Prolonged bleeding during surgery

18. Approach Proper history Whether there is easy bruising h/o bleeding manifestations h/o epistaxis/oral bleeding/hematemesis/hemoptysis Overall health of the patient h/o receiving any drugs h/o any reduced platelets in the past Any family history of decreased platelets h/o ingestion of herbal drugs

19. h/o recent infections h/o recurrent infections Previous h/o cancers Liver diseases Autoimmune disorders

20. Young healthy adult with thrombocytopenia�limited diagnosis Ill hospitalized patients with multiple medications�can be difficult to diagnose

21. Physical examination Vitals should be seen Pallor Icterus Any petechiae,purpura Excessive bruising Wet purpura,blood blisters(oral mucosa) Can be life threatening Throat for any congestion/bleeding spots Skin ,mucous membranes thoroughly examined

22. Splenomegaly Evidence of Chronic liver disease Other underlying disorders Systems Abdomen �Splenomegaly,CLD features Per Rectal examination Pelvic examination in females Respiratory-to rule out any foci of bleeding CVS

23. Thorough neurological examination should be done,to rule out any bleeding intracranially. Fundus examination should be done.

24. investigations CBC Hb-if there is associated anemia Platelet count WBC �to rule out any infections,if increased Also when decreased to rule out pancytopenia if there other cell lines are also reduced ESR LFT-To rule out any liver disease RFT

25. Mean platelet volume-estimates average size of platelets Coagulation profile PT PTT Bleeding Time Metabolic parameters Urinalysis

26. Evaluation of platelet function Peripheral Smear �number,size,manual platelet count,Schistocytes(TTP/HUS) Bleeding time Mainly measures platelet function(clot formation) Normal 3-7mins Useful for platelet counts >100K/ul Maybe affected by fibrinogen levels.other anticoagulants Prolonged �Uremia,liver disease

27. Bone Marrow biopsy Number and appearance of megakaryocytes Rapid test for antif-heparin/platelet factor 4 antibodies in development Specific tests for different types

28. Torniquet test Performed by placing a sphygmomanometer cuff around upper arm,raising the pressure to 100mm hg for 5-7mins If systolic pressure is <100mm hg,the pressure is raised to halfway between systolic and diastolic pressure. 2-3mins after the cuff has been deflated,the congestion disappeared,no of petechiae in an area with a 3cm diameter ,1cm below the cubital fossa is counted

29. Normal-upto 10-20 More than 20 is abnormal In severe thrombocytopenia >100 or more Test is positive in severe cases Negative sometimes in mild/moderate thrombocytopenia

30. Platelet Transfusion It should be done only if the platelets go below 10,000 Persistant epistaxis Life threatening hemorrhage�GI bleeding A tranfusion is termed as successful if the bleeding manifestation for which it has been given is contolled for more than 48 hrs

31. Infection Induced Viral infections Parvovirus Rubella Mumps Varicella Hepatitis C Epstein Barr Virus HIV Bacterial Infections Seen in Gram negative septicemia

32. Affect Platelet production/survival Immune Mechanisms in IMN and early HIV Late HIV-Pancytopenia Bone marrow examination-for evaluating occult infection Required only if there is Urgency Other non invasive methods have failed Treatment of underlying cause of infection

33. Drug Induced Due to bone marrow suppression by T/t with lot of drugs. In thrombocytopenia without any apparent cause,all drugs should be suspected,maybe stopped or substituted Herbal Over the counter drugs

34. Drug dependant antibodies? specific platelet antigens-?thrombocytopenia(only when drug is present) Induction of antibodies Drug dependant antibodies?assays provided drug is present in assay Occurs after period of initial exposure And also rexposure

35. Platelet GpIIb IIIa inhibitory drug(abciximab) Thrombocytopenia?24hrs after initial exposure Due to antibodies that cross react with drug bound to platelet

36. Abciximab Digoxin Acetaminophen Eptifibatide Acyclovir Hydrochlorothiazide Aminosalicylic acid Ibuprofen Amiodarone Levamisole Amphotericin B Octreotide Ampicillin Phenytoin Carbamazepine Quinine Chlorpropamide Rifampin Danazol Tamoxifen Tirofiban Trimethoprim/sulfamethoxazole

37. Inherited Rare Isolated/part of syndrome Autosomal Dominant Associated with mutations in non muscle myosin heavy chain MYH9 gene May Hegglin Anomaly Sebastein,Ebstein�s,Fechtner syndromes Common Feature? Large Platelets

38. Autosomal Resistant Congenital Amegakaryocytic Thrombocytopenia Thrombocytopenia with absent radii Bernard Soulier Syndrome Functional platelet disorder X Linked Wiskott Aldrich Syndrome Dyshematopoetic syndrome(mutation in transcription regulator of hematopoesis)

39. ITP Acquired disorder Immune mediated destruction of platelets/inhibition of platelet release from megakryocytes Children-Acute Adults �Chronic exact nature of immune reaction unkown

40. Secondary to Systemic Lupus Erythematosus HIV,Hepatitis C Helicobacter Pylori infection Presentation Mucocutaneous bleeding-oral.GIT,heavy menstrual bleeding Low platelet count with normal Peripheral Smear Also ecchymoses,petechiae Thrombocytopenia�Incidental finding

41. Wet purpura/Blood Blisters Retinal Hemorrhages (life threatening bleeding)

42. LAb Bone marrow examination Peripheral smear�large platelets Associated iron deficiency can be present Tests for secondary causes HIV,Hep C SLE Protein Electrophoresis Immunoglobulin levels?to r/o Hypogammaglobulinemia IgA deficiency Monoclonal gammopathies

43. Anemia present then Coomb�s test to r/o Evan�s Syndrome

44. Treatment Diagnosed ITP does not mean,immediate t/t Initial Treatment i.e in patients without Bleeding symptoms Severe thrombocytopenia <5000/ul Signs of impending bleeding Drugs Prednisolone 1mg/kg Rho(D)Immunoglobulin theraphy@ 50-75ug/kg

45. I.V IgG Blocks Fc receptor system 2g/kg total,divided doses over 5days Severe ITP High Dose Glucocorticoids with I.V IgG or antiRhoD theraphy. Rituximab useful in Refractory ITP

46. Splenectomy In relapses Vaccinations-Pneumococcal,Meningococcal,H.influenzae must be given New drugs� TPO receptor antagonists S/C and Oral preparation.

47. Heparin Induced Thrombocytopenia 1>Thrombocytopenia never very severe 2>not associated with bleeding but increase risk of thrombosis. Antibody formation to complex of platelet specific protein platelet factor 4 and heparin. Platelets exposed to heparin develop antibodies to heparin/Platelet factor 4 without consequences. Fraction develop thrombocytopenia Around 50% develop Heparin induced thrombocytopenia and thrombosis.

48. HIT develops after exposure to heparin for 5-10days. It can occur before 5 days in those exposed to heparin in prior weeks/months(<100 days) Delayed onset HIT can occur sometimes after several days of stopping heparin.

49. Diagnostic for HIT Thrombocytopenia Timing of platelet drop Thrombosis and other sequelae Other cause of thrombocytopenia not evident.

50. LAB testing HIT antibodies detected by 2 assays 1..ELISA with PF4/polyanion complex as antigen 2.Platelet Activation Assay

51. Thrombosis is a complication of HIT Imaging studies should be done to rule it out

52. Treatment Switching over to another anticoagulant Argatroban ,Lepirudin(Direct Thrombin Inhibitors) effective . Direct Thrombin Inhibitor,bivalirudin and the antithrombin-binding pentasaccharide , Fondaparinux appear to be effective Danaparoid, a mixture of glycosoaminoglycans with anti-Xa activity,effective

53. For patients with thrombosis,can be maintained with Warfarin for 3-6months Introduction of warfarin alone in the setting of HIT or HITT may precipitate thrombosis, particularly venous gangrene, presumably due to clotting activation and severely reduced levels of proteins C and S. Warfarin should only be started after alternative anticoagulation has been given for several days and the prothrombotic state has lessened.

54. Thrombotic Thrombocytopenic purpura Described in 1924 by Eli Moschcowitz Characterised by pentad of findings Thrombocytopenia Microangiopathic hemolytic anemia Neurologic manifestations Renal function abnormalities Fever

55. Pathogenesis Inherited (Upshaw-Schulman syndrome) Idiopathic TTP Normally the ultra-high molecular-weight multimers of von Willebrand factor (vWF) produced by the endothelial cells are processed into smaller multimers by a plasma metalloproteinases called ADAMTS13. In TTP the activity of the protease is inhibited, and the ultra-high molecular-weight multimers of vWF initiate platelet aggregation and thrombosis

56. IDIOPATHIC TTP More common in Women than men HIV Infection and pregnant females. Medication related TTP secondary to antibody formation,(ticlopidine and possibly clopidogrel direct endothelial toxicity(cyclosporine, mitomycin C, tacrolimus, quinine) Withdrawal of agents might decrease the microangiopathy.

57. LAbs HCT Low Microangiopathic anemia Reticulocyte Elevated WBC Normal Peripheral Smear Schistocytes/polychromasia PT Normal PTT Normal Fibrinogen Normal D-Dimer Normal Direct Coombs Negative LDH Elevated Indirect Bilirubin Elevated Haptoglobin Reduced Creatinine Elevated

58. Level of ADAMTS13 activity, as well as antibodies, can now be detectedvby laboratory assays. However sensitivity and specificity not well known

59. Differentiation TTP&DIC TTP DIC Associated with Bloody diarrhea Pregnancy/postpartum Meds Isolated platelet consumption No change in PT/PTT No fibrinogen change No D-dimer change Associated with Sepsis Obstetric complications Shock Coagulation cascade activation Big change in PT/PTT Reduction in fibrinogen Elevation in D-dimer

60. treatment Plasma exchange Can infuse Fresh Frozen Plasma if plasmapheresis not done Steroids-prednisolone Platelet transfusion(Contraindicated) Injection Rituximab

61. Hemolytic Uremic syndrome Acute renal failure, microangiopathic hemolytic anemia, thrombocytopenia. Children,episode of diarrhoea Hemorrhagic in nature Escherichia coli O157:H7 is the most frequent Treatment is supportive HUS not associated with diarrhoea has poor prognosis.

62. Pseudothrombocytopenia An in vitro artifact resulting from platelet agglutination via antibodies (usually IgG, but also IgM and IgA) when the calcium content is decreased by blood collection in ethylenediamine tetraacetic (EDTA) tubes. If low platelet count is obtained,peripheral smear should help in distinguishing.

65. Normal Peripheral Blood Smear

66. Platelet Clumping Psuedothrombocytopenia

67. Abnormal Large Platelets

68. Schistocytes/decreased plateletsMicroangiopathic hemolytic anemia