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CME: Bleeding Disorders - Management
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CME: Bleeding Disorders - Management

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  • 1. Prof.Dr.G.Sundaramurthy’s unit Dr.K.Senthamizh selvan
  • 2.  
  • 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
  • 6.  
  • 7.  
  • 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
  • 10.  
  • 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
  • 27.  
  • 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
  • 31.  
  • 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
  • 33.  
  • 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
  • 36.  
  • 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.
  • 43.  
  • 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
  • 52.  
  • 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
  • 61.  
  • 62.  
  • 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
  • 66.  
  • 67.  
  • 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.
  • 72.  

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