Transcript Inherited Coagulation Disorders Dr Galila Zaher Consultant Hematologist KAUH

Inherited Coagulation Disorders
Dr Galila Zaher
Consultant Hematologist
KAUH
BLOOD CLOTTING
Blood clotting interactions
Plasma protein clotting factors
Platelets
Vascular endothelium
Hemostasis
Subendothelial matrix
WBC
Hemostatic plug Endothelial cell
WBC
RBC
Platelets
Fibrin
COAGULOPATHIES
Bleeding
Clotting factors
platelets
Thrombosis
Natural anticoagulant
Clot formation
Platelet activation
No &count
Fibrin generation
plasma clotting
factors
Primary hemostasis
(immediate)
Secondary hemostasis
(delayed)
Platelet Activation Pathways
(1)
COLLAGEN
THROMBIN
ADP
Aggregation
Aggregatio
GpIIb/IIIa
GpIIb/IIIa
GpIIb/IIIa
Adrenaline
Platelet
Adhesion
vWF
Endothelium
Exposed Collagen
Clotting factor production
Liver: 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 factors
Factor XII
Factor VIII
Extrinsic pathway clotting factors
Tissue factor (TF)*
Factor VII
Common pathway clotting factors
Factor X
Factor V
Factor II
Prothrombin
Factor I
Fibrinogen
Factor IX
Factor XI
Intrinsic pathway
XII ---> XIIa
v
XI---------XIa
v
IX --------> IXa
Extrinsic pathway
VII + TF ----->VIIa/TF
v
IXase (“crossover”)
Xase (minor)
+ VIII
v
X----------------------> Xa
[Common pathway]
v
Xa + V
prothrombin -------------> thrombin
v
fibrinogen--------------> fibrin
Fibrin
XIIIa
Cross-linked
fibrin
Defect
Time
Clinical
Platelet disorders
function
or number
“immediate” (mins):
Mucosal
bruising,petechia,
epistaxis,
childhood
menorrhagia, 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 tests
Test
Platelet count
Comment
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
and secretion tests
Not routine tests,
used only in special
circumstances
Tests of clotting factors
Test
Abbreviation
Comment
Prothrombin time
PT
extrinsic &
common pathways
Functional test VII
X, V, II, I
Partial
thromboplastin
PTT
intrinsic &
common pathways
Functional test
prekallikrein, HMWK
XII, XI, IX, VIII
X, 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
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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 seen
Head injuries are a major concern
 > 2 years
joint and muscle bleeds become more common
Clotting factor deficiencies
Laboratory Diagnosis
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Isolated prolongation of APTT
Microcytic hypochromic anemia
Normal platelets count
Mixing studies :corrected.
When to treat
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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
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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
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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
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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
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We all work together
Child and parents
Doctor and nurses
Physiotherapy
Social work
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Everyone has an essential role
The aim is to get life to be as normal as
possible
Factor VIII Replacement
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Mechanism of action : activate FX
Mode of administration : IV
Monitoring : no predict the
effectiveness of treatment
Indications :HA & HB
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Severe surgical bleeding
Factor VII deficiency
Factor VIII
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Derived from pooled human plasma
Derived from pig (porcine) plasma
Recombinate products
Porcine factor VIII
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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
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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
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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
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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 PT
Deficient, function or inhibition :
Liver disease
production/ vit K malabsorption
vit. K antagonists warfarin (blocks carboxylation)
Heparin
the PTT is a more sensitive test
FDPs
inhibits coagulation
lupus 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 products
lupus anticoagulant PTT is a better than
PT
TT increased
 Congenital disorders
afibrinogenemia
homozygous def.
hypofibrinogenemia
heterozygous def.
dysfibrinogenemia
dysfunctional fibrinogen
 Acquired disorders
hypofibrinogenemia
dysfibrinogenemia
Fibrin degradation
products
Heparin
liver disease, (disseminated
intravascular coagulation),
thrombolytic therapy
liver disease, hepatic malignancy
inhibits coagulation
inactivates IIa
Fibrinogen level
hypofibrinogenemia)
Liver disease
decreased production
Consumption
disseminated intravascular
coagulation (DIC)
Thrombolytic therapy
Congenital def.
afibrinogenemia: homo. def.
hypofibrinogenemia: hetero.
Fibrinogen assay
quantitative
immunoassay:
Functional
“immunologic” or
“antigenic” fibrinogen
Increased:
Estrogen
Pregnancy
Acute phase
response
Estrogen
Pregnancy
Acute phase
response
decreased
hypofibrinogenemia)
hypofibrinogenemia)
also
- dysfunctional
fibrinogen
(dysfibrinogenemia
Problem solving
PT
Incr.
PTT
NL
TT
NL
_____________
NL
Incr.
NL
_____________
Incr.
Incr.
NL
_____________
Incr.
Incr.
Incr. _____________
Actions of thrombin
Intrinsic pathway
XII ---> XIIa
v
XI---------XIa
v
IX --------> IXa
Extrinsic pathway
VII + TF ----->VIIa/TF
v
IXase (“crossover”)
Xase (minor)
+ VIII ---> VIIIa
v
X----------------------> Xa
[Common pathway]
v
Xa + V ---> Va
prothrombin -------------> thrombin
v
fibrinogen--------------> fibrin
v
XIII ---> XIIIa v
cross-linked fibrin