Hemostasis and Coagulation Disorders.pdf

This note describes the haemostatic process and disorders associated with impaired blood coagulation process

1. COAGULATION DISORDERS Norasidi Raffie

2. Learning objectives
Introduction to coagulation disorders
Hemophilia A
Hemophilia B
Disseminated Intravascular Coagulation

3. Hemostatic
Process
•Three main steps:
1.Primary
hemostasis: local
vasoconstriction
& platelet plug
formation
2.Coagulation
cascade
3.Fibrinolysis

4. Hemostatic
Process
Platelet
Plug
Formation
Vascular injury
Release and binding of vWF to exposed
blood vessel collagen
Glycoprotein IB on platelet surface
membrane binds to vWF
TxA
2 → vasoconstriction & platelet
adhesion
Platelet factor 3 (PF3) phospholipid
layer (procoagulant)

5. 5

6. Platelet Activation
& Aggregation
Exposedendothelialsurface
Plateletsexposedto collagen
“activated”
Releasecontents of cytoplasmic granules
Adenosine diphosphate (ADP)
Thromboxane (Tx A
2)
Vasoconstriction
accelerates platelet
aggregation/activation
↑ ADP release from platelets

7. Hemostatic Process:
Coagulation Cascade
To stabilize and reinforce the weak platelet plug
Fibrinogen → fibrin
•Formation of prothrombin activator
•Conversion of prothrombin into thrombin
•Conversion of fibrinogen to fibrin
3 main steps:

8. 8

9. Coagulation Cascade
•Involves different factors in two pathways (I – XIII)
•Separate but interacting pathways
•Anything that interferes blocks final outcome
•Calcium (Factor IV) required for most steps
•Several factors are made in liver (II, VII, IX, X)

10. Coagulation Factors
•I – Fibrinogen
•II – Prothrombin
•III – Thromboplastin
•IV – Ca++
•V – Proaccelerin / labile factor
•VII – Proconvertin / Stable factor
•VIII – AHF
•IX – AHF B/Christmas factor
•X – Stuart-Prower factor
•XI – Plasma thromboplastin antecedant
•XII – Hageman factor / Glass factor
•XIII – Fibrin stabilizing factor/ Laki Lorand factor
•HMWK – Fitzgerald factor

11. Clot Formation (Coagulation)
IntrinsicPathway
ExtrinsicPathway
Final CommonPathway
ProthrombinActivatorSubstance(PAS)
Prothrombin
Thrombin
FibrinogenFibrinmonoom ers
Polymers, threads

12. Final Common Pathway
ProthrombinActivatorSubstance(PAS )
Prothrombin
Thrombin
Fibrinogen
Fibrinmonoom ers
Polymers, threads
Fibrin
Stabilizing
Factor

13. Coagulation
Cascade

14. Coagulation Mechanism
activation of clotting factors
Requires a phospholipid
surface
Tissue factor (TF) extrinsic to the blood
Activated platelet (platelet factor 3
phospholipid) intrinsicto blood
vitamin-K dependent factors (II, VII, IX, X)
Formation of reaction
complex
Labile factors : factors V and VIII

15. Coagulation
Disorders

16. Common presentation
Comm onlymanifestsin theformoflarge
ecchymosisandhematomas–delayed
bleeding
Bleedingfromthenose,gums,GIT,GUT
Jointbleeds,musclebleeds
Excessive
bleeding
Postvaccination
Postdentalextraction
Postsurgical trauma

17. InvestigationsofCoagulation
disorders
Screeningtests
APTT
PT
TT
Specialtests
Coagulationfactor
assays

18. Laboratory Monitoring
Activated Partial Prothrombin Time (aPTT)
Test for Intrinsic and Common pathways
Dependent on activity of all coagulation factors, except
VII and XIII
Normal values: 30 - 40 seconds
Monitors heparin treatment & screen for haemophilia

19. Laboratory Monitoring
Prothrombin Time (PT)
Test Of Extrinsic Pathway
Activity And Common
Pathway.
Measures Vitamin K -
Dependent Factors Activity
(Factors II, VII, IX, X)
Thromboplastin + Ca
2+
To Plasma
= Clotting Time
Normal Values: 10 - 14 Seconds

20. Reference Values

21. Disorders ofCoagulation
Hereditary
(
Eitherquantitativeor
qualitative defectin
single coagulation
factor)
1.HaemophiliaA
2.HaemophiliaB
3.vWD
Acquired
(Deficienciesof Multiple
coagulation factors)
1.Vit K Def
2.Liver Disorders
3.Fibrinolytic
defects
4.DIC

22. Hereditary Factor Deficiencies
Hemophilia A
x-linkedrecessivedisorderthatisduetodefective
and/ordeficientfactorVIIImolecule s
Incidence–1in10,000live births.
Thegeneforhemophilia iscarriedontheX
chromosomeandthegene isrecessive(Xlinked
recessivedisorder).

23. History'smostfamouscarrierof thegeneforhemophilia
was Victoria (1819-1901),Queenof England
andgrandmothertomostof the royaltyinEurope
Also knownas
“TheRoyal
Disease”

24. Czar NicholasII ofRussiaandhis family,photographedc.1916,showinghis
wifeAlexandra (whowasacarrierofhemophilia),
his four daughters,and(intheforeground)his sonAlexis,
perhapsthemostfamousEuropeanroyal withhemophilia.

25. Inheritance pattern in hemophilia

26. Father
with
Hemophilia
xx
Normal
Moth er
r
xx
r
XY XX XY
Camier
Daughter
Nolimal
Son
1Carii\ier
Daughter
Norimal
Son
Inheritance pattern in hemophilia

27. Hemophilia A
Severitylinkedtolevelof Factor VIIIactivity
1%Severe
1% - 5%Moderate
6 - 30%mild(littleriskofspontaneousbleeding)

28. Hemophilia A
Bleedingcan occuranywhere
Deepmuscles
Joints
UrinaryTract
Intracranial
Recurrenthemarthrosisandprogressivejoindestructionare
majorcauseofmorbidity
Intracranialbleedismajorcauseofdeathinall
hemophiliacs

32. Hemophilia Progression

33. Mucosal bleedingis rareunless associated
with vonWillebrands or plateletinhibition.
Anytrauma can initiatesbleeding.
Bleedingcan occurusuallyby8 hoursbutas
late as 1 to3 days afte rtrauma.

34. Management:
Generalmeasures–avoidance ofaspirin
Home therapyisincreasinglycommonand mostreport
to ER only withcomplicatedproblemsorTrauma
Hospitals should have filesof knownhemophiliacsin the
area
AcceptedtherapyiswithFactorVIII replacement
NewerpreparationcarrylowerriskforHep Band HepC
transmission

35. Hemophilia B (Christmas Disease)
Clinically indistinguishablefromhemophilia A
DeficiencyoffactorIX
Incidence –1 in 25,000 to30,000 livebirths
Specificassaysare theonly waytodistinguish
hemophilia A & B
Factor IXpreparationusedintreatment
Gene manipulationinanimals showspromising
resultsforthefuture

36. Hereditary Platelet Disorder
von Willebrand Disease (vWD)
Mostcommoncongenitalbleeding disorder.
Quantitativeorqualitativ eabnormalityofvWF.
vWFplaysroleinbothformationofplatelet plug
aswell asfibrin clot.
By mediating
adhesion of platelets
tothe injured
endothelium
By functioningasa
Protectivecarrier
of FactorVIII

37. Clinical features
Bleedingsymptomsresemble thoseof
platelet functiondefect, sinceplatelet
adhesionis impaired.
Most commonsymptomsare easybruising,
epistaxis, menorr hagiaetc.
Hemart hrosisoccursonlyinseverelyaffected
patients, unlikehemophilia whooftenhave
joint bleeds.

38. Type1:mostcommonform
Partialquantitativedeficienc yofvWF
Autosomaldominant
Mucocutaneousbleeding
Hematologyconsultpriortosurgery
Prolongedbleeding time,normalplatelet
TYPES

39. Type 2:qualitativealterationsinthe vWFstructure &
function
Type 3: leastcommonand mostsevere
Completeabsen
ceof vWF in plasm aor storageorganelle
Autosomalrecessive
AcquiredvWD
Lymphoproliferativedisease▪cardiac/valvulardisease
Tumors ▪medications(valproicacid)
Autoimmune
disease ▪hypothyroidism

40. Lab Findings
Increased bleeding timewithnormal
platelet count.
DecreasedvWF concentrationinplasma.
Decreased factorVIIIactivity.

41. Treatment
vWF replacementtherapy.
“ To summarise,patientswithvWD have a
compounddefectinvolvingplatelet
function andthe coagulationpathway.”

43. Hemostatic Balance

44. DISSEMINATED INTRAVASCULAR
COAGULATION
Defibrinationsyndrome / consumptive
coagulopathy
“ an acute, subacute/chronic
THROMBOHEMORR HAGIC disorder occuring
as a secondarycomplicationof some diseases
or conditions.”
“NOTAPRIMARYDISEASE”!!

45. Anacquiredsyndrome
characterizedby
systemicintravascular
coagulation
Coagulationisalways
the initialevent
SYSTEMIC
ACTIVATIONOF
COAGULATION
Intravascular
deposition of
fibrin
Depletionof
platelets and
coagulation
factors
Thrombosis of
small and
midsiz evessels
Bleeding
Organfailure

46. Pathophysiology ofDIC
Activationof Blood Coagulation
SuppressionofPhysiologic
Anticoagulant Pathways
ImpairedFibrinolysis
Cytokines activation

47. Diagnosis ofDIC
1. Presenceofdisease associatedwith DIC
2. Appropriate clinicalsetting
Clinical evidenceof thrombosis,hemorrhageor
both.
3. Laboratorystudies
Nosingletestisaccurate
Serialtestaremorehelpfulthan singletest

48. Conditions Associated With DIC
Infectious/Septicemia
Bacterial
Gm-/ Gm+
Viral
CMV
Varicella
Hepatitis
Fungal
Intravascularhemolysis
AcuteLiverDisease
TissueInjury
trauma
extensivesurgery
tissue necrosis
headtrauma
Obstetric
Amnioticfluid
emboli
Placentalabruption
Eclampsia
Missedabortion

49. Conditions Associated With DIC
Malignancy
Leukemia
Metastaticdisease
Cardiovascular
Postcardiac arrest
AcuteMI
Prosthetic devices
Hypothermia/Hyperthermia
Pulmonary
ARDS/RDS
Pulmonary
embolism
Severeacidosis
Severe anoxia
Collagen
vascular disease
Anaphylaxis

50. ClinicalManifestations ofDIC
ORGAN
Skin
ISCHEMIC
Pur.Fulminans
Gangrene
HEMOR
RHAGE
Petechiae Echymosis
Acralcyanosis
Delirium/Coma
Infarcts
Oliguria/Azotemia
CorticalNecrosis
MyocardialDysfxn
Dyspnea/Hypoxia
Infarct
Ulcers,Infarcts
Adrenalinfarcts
Oozing
Intracranial
bleedin g
Hematuria
CNS
Renal
Cardiovascular
Pulmonary
GI
Endocrine
Hemorrhagic
lung
Massive
hemorrhage
Ischemic
Findings are
earliest!
Bleedingisthe
most obvious
clinicalfinding

51. Clinical Manifestations of DIC

52. Microscopicfindings in DIC
Fragments
Schistocytes
Paucityofplatelets

53. Laboratory diagnosis
Thrombocytopenia
platletcount<100,000orrapidly declining
Prolongedclottingtimes(PT,APTT)
Presence of Fibrindegradation productsor
positiveD-dimer
Lowlevelsof coagulationinhibitors
ATIII,proteinC
Lowlevelsof coagulationfactors
FactorsV, VIII, X, XIII
Fibrinogenlevelsnot useful diagnostically

54. Treatment of DIC
Stopthe triggeringprocess
Theonlyproventreatment!
Supportivetherapy
No specifictreatments
Plasmaandplateletsubstitut ion
therapy
Anticoagulants
Physiologiccoagulationinhibitors

55. Summary
DICisasyndromecharacterizedsystemic
intravascular coagulation.
Coagulationistheinitialeventand theextentof
intravascular thrombosishas thegreatestimpacton
morbidityandmortality.
Important linkbetweeninflammation and
coagulation.
Morbidityand mortalityremain high.
Theonlyproventreatmentisreversalorcontrol
oftheunderlyingcause.