cme: bleeding disorders - management

Prof.Dr.G.Sundaramurthy’s unit

Dr.K.Senthamizh selvan

ARTEFACTUAL THROMBOCYTOPENIA

INCREASED PLATELET DESTRUCTION

DECREASED PLATELET SYNTHESIS

ABNORMALITY IN PLATELET FUNCTION

autoimmune- primary/idiopathic -secondary

causes(SLE,drugs)

alloimmune

non-immunologic(TTP,DIC,HUS)

Abnormal vascular surfaces

---- treatment options STEROIDS : -reduces Ab production -increases marrow platelet

production -reduces intramedullary platelet

destruction -reduces splenic sequestration -down regulates macrophage Fc R

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

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

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 ;

if refractory to steroid course and splenectomy

options : long term IV Ig pulse methylprednisolone anti D immunoglobulin danazol vinca alkaloids IFN α rituximab

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

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.

LEVEL :1 evidence

quinidine,quinine,rifampicin,sulfonamides,danazol,methyldopa,acetaminophen,digoxin

LEVEL:2 evidence goldsalts,procainamide,carbamazepine, thiazides ,ranitidine,chlorpropamide

antibody mediated

-complement -non complement

idiosyncrasy

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

3-5% of pts receiving UF heparin

antibody to heparin-

platelet factor4 attaches to Fc R causing platelet activation -hypercoagulable state -thrombocytopenia

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.

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

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.

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

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

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

ACQUIRED TTP HEREDITARY TTP

hemodialysis plasma exchange

with FFP plasmapheresis corticosteroids IV Ig Immunosuppresant

s Rituximab

FFP plasma exchange plasmapheresis

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

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

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

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

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

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

URAEMIA: -coagulopathy is an indication for

dialysis -erythropoietin -cryo ppt -blood transfusion ANTI-PLATELET DRUGS: ---- withdraw offending drug

-----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

phase 1: -rapid loss of via

diffusion phase 2: -biological half life -determines

frequency and dose

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

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 .

PURIFIED CONC. COAGULATION FACTORS:

RECOMBINANT FACTORS

PORCINE FACTORS

PROTHROMBIN COMPLEX CONCENTRATES:

- contains factor 2,7,9,10,protein c,s, - high thrombogenic potential

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.

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.

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

----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

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.

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

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

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

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

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

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

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.

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.

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

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

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

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

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

EHLER-DANLOS SYNDROME MARFAN SYNDROME OSTEOGENESIS IMPERFECTA PSEUDOXANTHOMA ELASTICUM

----To avoid contact sports,isometric exercises,antiplatelets

----to undergo regular screening

pt can present with purpura,hematuria,hemoptysis etc

options : - steroids - plasmapheresis - immunosuppresants

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.

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

----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

-- 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.