cme: bleeding disorders - management
DESCRIPTION
TRANSCRIPT
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Prof.Dr.G.Sundaramurthy’s unit
Dr.K.Senthamizh selvan
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ARTEFACTUAL THROMBOCYTOPENIA
INCREASED PLATELET DESTRUCTION
DECREASED PLATELET SYNTHESIS
ABNORMALITY IN PLATELET FUNCTION
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autoimmune- primary/idiopathic -secondary
causes(SLE,drugs)
alloimmune
non-immunologic(TTP,DIC,HUS)
Abnormal vascular surfaces
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---- treatment options STEROIDS : -reduces Ab production -increases marrow platelet
production -reduces intramedullary platelet
destruction -reduces splenic sequestration -down regulates macrophage Fc R
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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
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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
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children adultsAsymptomatic --------------------------- 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 ;
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if refractory to steroid course and splenectomy
options : long term IV Ig pulse methylprednisolone anti D immunoglobulin danazol vinca alkaloids IFN α rituximab
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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
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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.
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LEVEL :1 evidence
quinidine,quinine,rifampicin,sulfonamides,danazol,methyldopa,acetaminophen,digoxin
LEVEL:2 evidence goldsalts,procainamide,carbamazepine, thiazides ,ranitidine,chlorpropamide
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antibody mediated
-complement -non complement
idiosyncrasy
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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
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3-5% of pts receiving UF heparin
antibody to heparin-
platelet factor4 attaches to Fc R causing platelet activation -hypercoagulable state -thrombocytopenia
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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.
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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
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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.
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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
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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
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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
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ACQUIRED TTP HEREDITARY TTP
hemodialysis plasma exchange
with FFP plasmapheresis corticosteroids IV Ig Immunosuppresant
s Rituximab
FFP plasma exchange plasmapheresis
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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
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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
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1) ACQUIRED AMEGAKARYOCYTIC TP: as a component of aplastic anaemia CMV,Parvovirus- B19 Toxins-benzene TPO antibodies ----optionsPlatelet transfusion vincristineIV Ig danazolSteroids ATGCyclophosphamide allogenic
BMT
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2) MARROW SUPRESSANTS : Immunosupressants cancer chemotherapy selective megakaryocyte suppressants: thiazides ,estrogens,alcohol -----withdrawal of offending agent usually
corrects platelet counts3) INEFFECTIVE THROMBOPOIESIS: in B12,Folate deficiency-----treat the cause
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ABNORMAL PLATELET POOLING: - N- 1/3RD 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
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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
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URAEMIA: -coagulopathy is an indication for
dialysis -erythropoietin -cryo ppt -blood transfusion ANTI-PLATELET DRUGS: ---- withdraw offending drug
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-----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
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phase 1: -rapid loss of via
diffusion phase 2: -biological half life -determines
frequency and dose
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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
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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 .
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PURIFIED CONC. COAGULATION FACTORS:
RECOMBINANT FACTORS
PORCINE FACTORS
PROTHROMBIN COMPLEX CONCENTRATES:
- contains factor 2,7,9,10,protein c,s, - high thrombogenic potential
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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.
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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.
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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 kgχ0.5
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----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
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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.
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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)χbody wt.in kg therapy is complicated by inhibitor
formation DDAVP, EACA,tranexamic acid
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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
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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
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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
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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
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Thrombocytopenia Decreased synthesis of coagulation
factors Increased fibrinolysis ----options are 1)Inj. Vitamin k2) fresh frozen plasma 3) prothrombin complex concentrates4) recombinant factor 7a5) cryoprecipitate
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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.
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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.
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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
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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
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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
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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
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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
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EHLER-DANLOS SYNDROME MARFAN SYNDROME OSTEOGENESIS IMPERFECTA PSEUDOXANTHOMA ELASTICUM
----To avoid contact sports,isometric exercises,antiplatelets
----to undergo regular screening
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pt can present with purpura,hematuria,hemoptysis etc
options : - steroids - plasmapheresis - immunosuppresants
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Whether treatment should be withdrawn abruptly or gradually withdrawn ("tailed off") is still debatable.
Theoretically, the "rebound hypercoagulability" 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.
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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
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----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
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-- 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.
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