This document summarizes various causes and management of thrombocytopenia and bleeding disorders. It discusses evaluation and treatment of conditions that cause decreased platelet count or function such as immune thrombocytopenia, thrombotic thrombocytopenic purpura, hemophilia, von Willebrand disease, and liver disease. Treatment options include steroids, IV immunoglobulins, platelet transfusions, desmopressin, coagulation factor concentrates, cryoprecipitate, splenectomy and plasma exchange.

1. Prof.Dr.G.Sundaramurthy’s unit Dr.K.Senthamizh selvan

3. ARTEFACTUAL THROMBOCYTOPENIA INCREASED PLATELET DESTRUCTION DECREASED PLATELET SYNTHESIS ABNORMALITY IN PLATELET FUNCTION

4. autoimmune- primary/idiopathic -secondary causes(SLE,drugs) alloimmune non-immunologic(TTP,DIC,HUS) Abnormal vascular surfaces

5. ---- treatment options STEROIDS : -reduces Ab production -increases marrow platelet production -reduces intramedullary platelet destruction -reduces splenic sequestration -down regulates macrophage Fc R

8. SPLENECTOMY : removes primary destruction site of platelets reduces antibody production IV Ig: - blocks Fc R in macrophages ,B cells - improves cell survival by modulating growth factors ANTI –D immunoglobulin : - coats RBCs of Rh +ve patients ,causes Fc R mediated destruction in spleen - hence spares platelets - efficacy is low after splenectomy

9. DANAZOL: - down regulates Fc R on phagocytic cells RITUXIMAB: - anti CD 20 antibody –causing selective B cell depletion in vivo -mechanism- apoptosis ADCC complement mediated VINCA ALKALOIDS: - inhibition of microtuble dependant events required for monocytes/macrophages

11. children adults Asymptomatic --------------------------- Prednisone 1-2mg/kg/d Minor purpura IVIg 1g/kg single dose ; High dose oral steroids ; Prednisone 1-2mg/kg/d ; Mucosal bleeding Hospital care ; IVIg 2g/kg over 2-5 days; High dose oral steroids ; Hospital care ; Prednisone 1-2mg/kg/d ; Life threatening bleed Hospital care ; IVIg 2g/kg over 2-5 days; High dose oral steroids ; Hospital care ; IVIg 1-2g/kg over 2-5 days ; Prednisone 1-2mg/kg/d ;

12. if refractory to steroid course and splenectomy options : long term IV Ig pulse methylprednisolone anti D immunoglobulin danazol vinca alkaloids IFN α rituximab

13. ROMIPLASTIM: - an Fc peptide fusion protein -acts on TPO- R - pathways similar to endogenous TPO - given as S.C.inj - used in chronic ITP ELTROMBOPAG : - TPO- R agonist - oral route - used in chronic and refractory ITP -acquired amegakaryocytic TP

14. gestational thrombocytopenia is a close mimicker ITP is difficult to manage in pregnancy anti platelet Ab – cross placenta ,causing TP in fetus treatment options : IVIg low dose steroids splenectomy mode of termination is determined by obstetric indications.

15. LEVEL :1 evidence quinidine,quinine,rifampicin,sulfonamides,danazol,methyldopa,acetaminophen,digoxin LEVEL:2 evidence goldsalts,procainamide,carbamazepine, thiazides ,ranitidine,chlorpropamide

16. antibody mediated -complement -non complement idiosyncrasy

17. TREATMENT OPTIONS: withdrawal of offending drug IV Ig plasmapheresis steroids --- recovery within 1 wk exception :gold salts induced tp which takes several months for recovery ---dimercaprol can be tried

18. 3-5% of pts receiving UF heparin antibody to heparin- platelet factor4 attaches to Fc R causing platelet activation -hypercoagulable state -thrombocytopenia

19. TYPE :1 -occurs within 2 days -non immune mechanism -direct effect of heparin on platelets - count normalises even if treatment continued TYPE :2 -occurs within 4-10 days -immune mechanism -life threatening thrombotic events -we actually mean this as HIT in clinical practice.

20. MANAGEMENT OF HIT: stop UF and LMW heparin start - direct thrombin inhibitors : ARGATROBAN, LEPIRUDIN - factor 10a inhibitors - DANAPAROID only these drugs are FDA approved for HIT they are given for 2 weeks

21. platelet count may normalise but thrombotic tendency may persist . hence continued with warfarin for 3-6 months warfarin induced protein C and S deficiency aggravates thrombotic potential -----start warfarin later avoid heparin products in future for atleast 6 months.

22. SLE: -TP in SLE correlates with disease activity -auto antibodies in SLE can bind GP1b9/2b/3a - treatment guidelines same as that of ITP Thymoma,myasthenia,CLL,hodgkin’s disease INFECTIONS : HIV,IMN,CMV,Hep B and C H.pylori,varicella ------ to treat the primary cause

23. platelets can express some epitopes due to polymorphism of gene for PL GPs no natural antibodies occurs 1)neonatal alloimmune thrombocytopenia. 2)post transfusion purpura. Treatment options: - self limiting - steroids - plasmapheresis - IV Ig

24. ADAMTS13 --- cleaves VWF when it is conformationally unfolded defect in ADAMTS13 ---causes TTP 1)TP 2)Microangiopathic hemolysis 3)Renal failure acquired TTP hereditary TTP

25. ACQUIRED TTP HEREDITARY TTP hemodialysis plasma exchange with FFP plasmapheresis corticosteroids IV Ig Immunosuppresants Rituximab FFP plasma exchange plasmapheresis

26. INFECTION: - Shigella dysentriae type 1 - E.coli O157:H7 ATYPICAL HUS: no prodrome ,no apparent cause MANAGEMENT -BP control -fluid and electrolyte balance -packed cell/platelet/FFP –transfusion - hemodialysis

28. presents with mild bleeds detected incidentally not responsive to steroids/ IV Ig supportive measures usually suffices in most of the cases wiskott-aldrich syndrome ---requires stem cell transplantation

29. 1) ACQUIRED AMEGAKARYOCYTIC TP: as a component of aplastic anaemia CMV,Parvovirus- B19 Toxins-benzene TPO antibodies ----options Platelet transfusion vincristine IV Ig danazol Steroids ATG Cyclophosphamide allogenic BMT

30. 2) MARROW SUPRESSANTS : Immunosupressants cancer chemotherapy selective megakaryocyte suppressants: thiazides ,estrogens,alcohol -----withdrawal of offending agent usually corrects platelet counts 3 ) INEFFECTIVE THROMBOPOIESIS: in B12,Folate deficiency -----treat the cause

32. ABNORMAL PLATELET POOLING: - N- 1/3 RD of platelets sequestered in spleen, in hypersplenism this fraction increases -splenectomy,embolic occlusion of splenic vasculature - shunt surgeries in case of cirrhosis corrects platelet counts MASSIVE BLOOD TRANSFUSION: -replacement of pt blood volume in 24 hrs./ or > 10 units of PCT - platelet /FFP to supplemented in massive transfusions

34. BERNARD SOULLIER SYNDROME GLANZMAN’S THROMBASTHENIA Gp 1b9 defect adhesion to vesselwall impaired to avoid trauma,antiplatelets pl.transfusion desmopressin r factor 7a antifibrinolytics bonemarrow/stem cell tx Gp 2b/3a defect aggregation of platelets impaired pl. transfusion r factor 7a antifibrinolytics bonemarrow/stem cell tx

35. URAEMIA: -coagulopathy is an indication for dialysis -erythropoietin -cryo ppt -blood transfusion ANTI-PLATELET DRUGS: ---- withdraw offending drug

37. -----principles HEMOSTATIC LEVELS: - lowest plasma conc. Of a given coagulation factor required for normal hemostasis IN VIVO RECOVERY: - after infusion of factors –loss from intra vascular space. - adsorption of coagulation factors by platelets and various vascular surfaces

38. phase 1: -rapid loss of via diffusion phase 2: -biological half life -determines frequency and dose

39. FRESH FROZEN PLASMA: -contain all coagulation factors , 5and 8 slightly low - thawed FFP used upto 5 days. -ABO compatibility to be tested ,Rh neednot be tested CRYOPRECIPITATE: -contains fibrinogen,VWF,factor 8 and 9,fibronectin -contains small amt of plasma -ABO compatibility to be tested ,Rh neednot be tested

40. PLATELETS: -pooled random donors----upto 8 units can be pooled from different patients -apherised platelet----from single donor - lifespan after pooling -4 hrs ,unless properly stored. - in emergencies ABO incompatibility can be compromised except for mild reactions .

41. PURIFIED CONC. COAGULATION FACTORS: RECOMBINANT FACTORS PORCINE FACTORS PROTHROMBIN COMPLEX CONCENTRATES: - contains factor 2,7,9,10,protein c,s, - high thrombogenic potential

42. vasopressin analogues releases VWF,factor 8 and 9 from vascular endothelial cells also releases endothelium derived plasminogen activators ---causes fibrinolysis so antifibrinolytics like EACA to be combined repeated dosing causes depletion of sources of VWF. used carefully in SHT,CCF.

44. to avoid trauma, isometric exercises to avoid anti-platelets to avoid IM injections caution regarding infections via blood products HIV,HEP B,C,prions,CMV. therapy is complicated by development of inhibitors to clotting factors. difficulty in treating these conditions.

45. inherited factor 8 deficiency depending on factor levels- -severe <1% -moderate 1-5% -mild 6-30% mainstay of treatment to maintain hemostatic levels dose required=(target levels-baseline levels)×body wt.in kg χ 0.5

46. ----replacement therapy mild bleeds,uncomplicated hemarthroses,superficial hematomas: initial ---30-50% maintenance --- 15-25% for 2-3 d large hematomas,bleed into muscle: >50% for 1 wk oropharyngealspaces, retroperitoneum,CNS bleeds : 50-100% for 7-10 days surgical prophylaxis : 100% for 7-10 days dental procedures : 50-100% for 3 days

47. Other measures ….. DDAVP : -0.3 µg/kg infused over 20 min -nasal spray 150µg in each nostril -2to3 fold rise in factor 8,with peak at 30-60 min Tranexamic acid : 25 mg/kg qid EACA : loading dose -200 mg/kg maintenance-100mg/kg every 6 hr.

48. inherited deficiency of factor 9 less frequent and less severe than hemophilia A during replacement factor 9 has low in vitro survival , 30-50% dose required =(target levels-baseline lines) χ body wt.in kg therapy is complicated by inhibitor formation DDAVP, EACA,tranexamic acid

49. VWF stabilises factor 8, assists in platelet aggegation VWD – types 1- partial defect 2-qualitative defect 3-severe quantitative defect platelet type(pseudo) VWD- defect in platelet GP 1b causing abnormal binding with VWD

50. TYPE I : DDAVP (infusion/spray) TYPE 2 A/B: DDAVP+VWF containing factor 8 conc. TYPE 2 M/N and TYPE 3: - VWF containing factor 8 conc. - prophylaxis is required only in TYPE3 - replacement of factor 8 wont suffice as its half life is very low in the absence of VWF

51. VWF REPLACEMENT: 50-80% -In major trauma,surgery,CNS bleeds 30-50%-minor surgery,dental procedures peri partum bleeds type 3 VWD patients develop antibodies against VWF NON –REPLACEMENT THERAPY: estrogen ,OCP EACA Tranexamic acid

53. HEMORRHAGIC DISEASE OF NEW BORN: - vitamin k 0.5 to 10 mg im to babies -prophylactic administration of vit k to mothers before delivery MALABSORPTION OF VITAMIN K/ DRUGS: -vitamin k 10mg im vit, - coagulopathy reverts in 12-24 hrs. if not so there is a coexistent liver disease or DIC

54. Thrombocytopenia Decreased synthesis of coagulation factors Increased fibrinolysis ----options are Inj. Vitamin k fresh frozen plasma prothrombin complex concentrates recombinant factor 7a cryoprecipitate

55. presents as coagulopathy in acute DIC and Thrombotic complications in chronic DIC -----management of DIC stabilise the patient treatment of the primary cause platelet transfusion if <20,000/cumm fresh frozen plasma packed cell transfusion low molecular wt. heparin,antithrombin in chronic DIC cryoppt .in hypofibrinogenemia.

56. Recombinant activated protein C – drotecogin alfa , inhibits activated factor 5 and 8. tissue factor pathway inhibitor recombinant -activated factor 7 antiselectin antibodies – blocks platelet adhesion IL 10 inhibitors (IL 10 s involved in coagulation cascade) MAPK inhibitors (mitogen activated protein kinase involved in intracellular signalling in inflammation.

57. many patients develop allo-antibodies against clotting factors . these antibodies acts as inhibitors of coagulation common in hemophilia and very rare in other coagulation disorders present in 5-10% of all hemophiliacs 20% of severe hemophilia A 3-5% of hemophilia B

58. HIGH RISK GROUP: severe deficiency of factor 8,9 family history of inhibitors african descents mutations in factor 8 and factor 9 gene --- there is a negative correlation with HLA CW5

59. Plasma from normal individuals and pts are mixed in 1:1 ratio----aPTT is prolonged in presence of inhibitors BETHESDA ASSAY : detects specificity of inhibitors and its titre one BETHESDA UNIT (BU) is the amount of antibody that neutralises 50% of factor 8 or 9 in normal plasma after2 hr of incubation at 37’c NIJMEGEN ASSAY :here pH of the system is controlled on 2 hrs of incubation

60. high dose of clotting factors recombinant factor 7a –which bypasses factor 8 step prothrombin complex concentrates IMMUNE TOLERANCE INDUCTION: -based on daily infusion of the missing factor in small amounts until inhibitors disappears. -it may take 1 yr. RITUXIMAB GENE THERAPY LIVER TRANSPLANTATION

63. osler-weber –rendu syndrome screen for a-v malformations at cerebrum,pulmonary vessels,liver in case of recurrent epistaxis – laser therapy,arterial embolisation pulmonary AVMs –embolotherapy GI AVMs –endoscopic electrocautery -laser cerebral AVMs –steriotactic surgery - radiosurgery - embolotherapy

64. EHLER-DANLOS SYNDROME MARFAN SYNDROME OSTEOGENESIS IMPERFECTA PSEUDOXANTHOMA ELASTICUM ----To avoid contact sports,isometric exercises,antiplatelets ----to undergo regular screening

65. pt can present with purpura,hematuria,hemoptysis etc options : - steroids - plasmapheresis - immunosuppresants

68. Whether treatment should be withdrawn abruptly or gradually withdrawn (&quot;tailed off&quot;) is still debatable. Theoretically, the &quot; rebound hypercoagulability &quot; which results from sudden discontinuation might predispose to rebound thrombosis. Some clinicians tail off long term treatment over several weeks but withdrawal for short term treatment can be done suddenly.

69. In life threatening hemorrhage: - give inj.vit K-5-10 mg slow iv - FFP,cryo In minor bleeds-epistaxis,hematuria: -give inj.vit 0.5-2mg iv In asymptomatic individuals INR : 3-6 reduce dose of OAC, repeat INR after 2 days INR: >6 oral vit K 2.5-5 mg INR: >18 warrants admission and reversal

70. ---- PROTAMINE SULFATE protamine binds heparin to form a stable ion pair ,which is broken down by RES DOSE: 1mg iv for every 100 IU of heparin administered in large doses ,protamine itself has some anticoagulant effect

71. -- complications from thrombolytic therapy occur when patients receive higher dose per kg body wt. --In that case stop thrombolytic therapy EACA : - 4-5g infusion in 1 hr----1g/hr infusion over 8 hr. - has intrinsic thrombogenic potential FFP/CRYOPPT. APROTININ –banned by FDA.