inherited coagulation disorders
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Inherited Coagulation Disorders
Dr Galila ZaherConsultant Hematologist
KAUH
BLOOD CLOTTINGBlood clotting interactions
Plasma protein clotting factors
Platelets Vascular endothelium
HemostasisSubendothelial matrixSubendothelial matrix
PlateletsPlatelets
Hemostatic plugHemostatic plug
FibrinFibrin
Endothelial cellEndothelial cell
RBCRBCWBCWBC
WBCWBC
HemostasisSubendothelial matrixSubendothelial matrix
PlateletsPlatelets
Hemostatic plugHemostatic plug
FibrinFibrin
Endothelial cellEndothelial cell
RBCRBCWBCWBC
WBCWBC
COAGULOPATHIES
Bleeding Thrombosis
Clotting factors Natural anticoagulant
platelets
Clot formation
Platelet activation Primary hemostasis
No &count (immediate)Fibrin generation plasma clotting Secondary
hemostasisfactors (delayed)
Adhesion
GpIIb/IIIa
Platelet Activation Pathways (1)
GpIIb/IIIaGpIIb/IIIa Aggregation
ADP
Adrenaline Platelet GpIb
Exposed Collagen
Endothelium
vWF
COLLAGEN
GpIIb/IIIaGpIIb/IIIa AggregationGpIIb/IIIaGpIIb/IIIa Aggregation
AdhesionAdhesion
ADP
Adrenaline
THROMBINTHROMBIN
Clotting factor productionLiver: source of plasma clotting factors
except VWF
Factor VIII: produced by liver & endothelium
VWF: endothelial cells & megakaryocytes
Vitamin K dependent clotting factors are: II, VII, IX, X
COAGULATION PATHWAYS
Intrinsic & extrinsic pathways “conclude” in the common pathway
Intrinsic pathway clotting factors
Extrinsic pathway clotting factors
Common pathway clotting factors
NORMAL COAGULATION PATHWAYS
Intrinsic pathway clotting factorsFactor XII Factor IXFactor VIII Factor XI
Extrinsic pathway clotting factorsTissue factor (TF)*Factor VII
Common pathway clotting factorsFactor XFactor VFactor II Prothrombin Factor I Fibrinogen
Intrinsic pathway XII ---> XIIa
v XI---------XIa
v IX --------> IXa
+ VIIIv
X----------------------> Xa [Common pathway] v Xa + V
prothrombin -------------> thrombin
vfibrinogen--------------> fibrin
Extrinsic pathwayVII + TF ----->VIIa/TF
vIXase (“crossover”)Xase (minor)
Fibrin
XIIIa
Cross-linked
fibrin
Defect Time ClinicalPlatelet disorders function or number
“immediate” (mins):
Mucosal bruising,petechia, epistaxis, childhoodmenorrhagia, post-op
Coagulation factor
“delayed” (hrs - days):
joint (hemarthrosis), muscle, skin (soft tissue hematomas)
fibrinolytic disorders
Deficiencies of:
Factor XII High molecular weight kininogen Prekallikrein
- Do NOT produce bleeding diatheses
COAGULATION TESTS Platelet tests <150,000 thrombocytopenia>400,000 thrombocytosis Tests of clotting factors
Platelet testsTest CommentPlatelet count Part of routine CBC,
normal count: 150,000 - 400,000/uL
Mean platelet volume MPV Some analyzers provide MPV measurement; in healthy individuals, MPV varies inversely with platelet count
Platelet aggregation Not routine tests, and secretion tests used only in special
circumstances
Tests of clotting factorsTest Abbreviation Comment
Prothrombin time PT extrinsic & common pathways
Functional test VIIX, V, II, I
Partial thromboplastin
PTT intrinsic &common pathways
Functional test prekallikrein, HMWK XII, XI, IX, VIIIX, V, II, I
Thrombin time TT Fibrinogen concentration
Quantitative test
Hemophilia
A = Factor VIII deficiency B = Factor IX deficiency Affects one in 6000 males A is 5 X > B Mild > 5 % normal amount of factor Moderate 2 - 5 %, severe < 2 % Levels remain stable throughout life
Inheritance
Both HA & HB are X linked
Only men can have the disease
Women are carriers
Clinical presentation
< 2 years: joint bleeds Rare Only bruising or mouth bleeds are seenHead injuries are a major concern
> 2 yearsjoint and muscle bleeds become more
common
Clotting factor deficiencies
Laboratory Diagnosis Isolated prolongation of APTT Microcytic hypochromic anemia Normal platelets count Mixing studies :corrected.
When to treat
All joint bleeds: Pain, swelling ,warmth or loss of movement .
Muscle bleeds that cause severe pain or are in a dangerous location
Bruises usually don’t need treatment When in doubt .
Treatment
Keep weight off of joint Ice pack Factor replacement - the sooner the
better Amicar or tranexamic acid : mouth bleed CVL s :Frequent bleeds or factor given
on a regular basis Port-a-catheters
Dose & Duration
1 IU/kg of factor VIII increases the level by 2%
1 IU/kg of factor IX increases the level by 1%
Every 12 hours the level decreases by half
Prophylaxis
To prevent bleeds Started after developing a target joint Usually it is administered 3/week Stepwise approach: Initially 1/week,
increasing to 2-3/week if needed Goal is to prevent long-term joint
damage
Team Approach
We all work togetherChild and parentsDoctor and nursesPhysiotherapySocial work
Everyone has an essential role The aim is to get life to be as normal
as possible
Factor VIII Replacement
Mechanism of action : activate FX Mode of administration : IV Monitoring : no predict the
effectiveness of treatment Indications :HA & HB
Severe surgical bleeding Factor VII deficiency
Factor VIII
Derived from pooled human plasma Derived from pig (porcine) plasma Recombinate products
Porcine factor VIII
Hyate:C Apparently no pig viruses present Can replace human Factor VIII in
clotting cascade Minimal cross reactivity with AHF
antibodies Minimal von Willebrand factor present
von Willebrand Factor (V W F)
VWF bridges platelets to collagen exposure from blood vessel injury
VWF contributes to primary hemostasis
Factor VIII circulates bound to VWF .
VWD: clinically similar to platelet disorders
Most common inherited bleeding disorder
VWD Inherited as a dominant or recessive . Most common congenital bleeding disorder Affecting 1-3% of the population. Personal and family bleeding history. Highly heterogeneous Ranging from asymptomatic to a life
threatening bleeding. The most common bleeding symptoms ever
were epistaxis, bruising Menorrhagia is one of the most important and
frequent complications in women
Platelet disorders
DIAGNOSIS The condition is caused by a quantitative
or qualitative deficiency of vWF. Prolonged bleeding time (BT) & activated
partial thromboplastin time (APTT) iron deficiency anemia . type 1 vWD
Managment The aim of treatment is to correct the dual
defect of hemostasis ( low VIII:C & prolonged bleeding time).
DDAVP is the treatment of choice for the mild forms of type 1 and 2 VWD
Unresponsive to DDAVP, plasma virally inactivated concentrates of factor VIII
Tranexamic acid
Increased PTDeficient, function or inhibition :Liver disease production/ vit K
malabsorptionvit. K antagonistswarfarin (blocks
carboxylation)Heparin the PTT is a more
sensitive testFDPs inhibits coagulationlupus anticoagulant PTT is a better test(LA)
Increased PTT
Heparin unfractionated heparin inhibits Xa and IIa
vit K antagonists PT is a more sensitive
fibrin/fibrinogen inhibits coagulation
degradation productslupus anticoagulant PTT is a better
than PT
TT increased Congenital disorders afibrinogenemia homozygous def. hypofibrinogenemia heterozygous def.
dysfibrinogenemia dysfunctional fibrinogen
Acquired disorders hypofibrinogenemia liver disease, (disseminated intravascular coagulation), thrombolytic therapy dysfibrinogenemia liver disease, hepatic malignancy Fibrin degradation inhibits coagulation products
Heparin inactivates IIa
Fibrinogen level hypofibrinogenemia)
Liver disease decreased production
Consumption disseminated intravascular
coagulation (DIC)Thrombolytic therapy Congenital def. afibrinogenemia: homo.
def.hypofibrinogenemia:
hetero.
Fibrinogen assayquantitative immunoassay:
Functional
“immunologic” or “antigenic” fibrinogen
Increased: Estrogen PregnancyAcute phase response
Estrogen PregnancyAcute phase response
decreased hypofibrinogenemia)
hypofibrinogenemia) also - dysfunctional fibrinogen (dysfibrinogenemia
Problem solvingPT PTT TTIncr. NL NL _____________
NL Incr. NL _____________
Incr. Incr. NL _____________
Incr. Incr. Incr. _____________
Intrinsic pathway XII ---> XIIa
v XI---------XIa
v IX --------> IXa
+ VIIIv
X----------------------> Xa [Common pathway] v Xa + V
prothrombin -------------> thrombin v
fibrinogen--------------> fibrin
Extrinsic pathwayVII + TF ----->VIIa/TF
vIXase (“crossover”)Xase (minor)
vXIII ---> XIIIa vcross-linked fibrin
---> VIIIa
---> Va
Actions of thrombin
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