Coagulation course

( 5 lectures)

1: Haemostasis & role of platelets

2: Haemostasis, role of coagulation proteins
3: Bleeding disorders/ role of platelets & blood
vessels
4: Bleeding disorders due to coagulation defects
5: Thrombophilia
 Summary:

Bleeding
Abnormalities in

Coag. Platelets Blood

proteins vessels

inherited acquired Number Function

 Summary
Inherited Coagulation Disorders
Hemophilia A
Hemophilia B
VWD, FIX def,..
Acquired Coagulation Disorders
Vit K def
Liver dis, DIC,
Massive transfusion
 Hereditary Coagulation
Disorders
 Inherited Diseases

Hemophilia A FVIII deficiency

Hemophilia B FIX deficiency
(Christmas disease)
von Willebrand disease VWF deficiency
FXIII def, FVII, …. rare
[inherited]
 Hemophilia A

Hemophilia A is 5 times more common

than B

Prevalence:
1:10,000

(hemophilia B : 1:50,000)
Hemophilia A (deficiency of factor VIII)

An inherited disease X- linked

affects males only (females are carriers)

Hemophilia A – mode of inheritance
Nicholas
 Hemophilia A
 FVIII gene:
Located on the long arm of X chromosome
(a big gene = 26 exons)

The disease occurs due to deletion or

mutation in the gene
[in 33% of cases no family hx found (spontaneous mutation)]
Factor VIII in the Coagulation Cascade
Hemophilia – Clinical manifestations
 Joint& soft tissue bleeds
 Excessive bruising
 Bleeding following tooth extraction
 Haemarthrosis ( bleeding into the joints)
 Muscle hematomas

 Ifpoorly treated, progressive joint deformity

 Social, psychological, economical problems
Hemophilia

Intra-cerebral hemorrhage:
* rare
* major cause of death in hemophiliacs
- Hemophilia

The clinical severity of the disease correlates

with the extent of factor VIII deficiency
(level of factor VIII)
 Hemophilia-disease severity

< 1% severe disease

spontaneous bleeding episodes from

early life
joint deformity & crippling
1-5% moderate disease
post-traumatic bleeding
occasional spontaneous episodes
5-20% mild disease
post- traumatic bleeding
Hemophilia
Lab findings
1: prolonged APTT
2: normal PT & TT
3: normal bleeding time

Hemophilia A decreased FVIII

Hemophilia B decreased FIX
 Treatment of Hemophilia
Ideally done in a
specialized hemophilia
center where
collaboration between
hematologists, dentists,
orthopedicians and
social workers
-Treatment of Hemophilia

Treatment of bleeding episodes:

Replacement therapy

FVIII concentrate (or F IX in

hemophilia B)

For Rx of a joint or muscle

bleed FVIII up to 20%
For operative or post-operative
bleed = = 100%
-Treatment of Hemophilia

Concept of “ Home
treatment”

Prophylactic
treatment

Gene therapy
Complications of Hemophilia Treatment

HIV
Hepatitis
Antibodies (inhibitors) to factor VIII
Hemophilia B
Christmas disease (FIX def)

Identical to hemophilia A
Can only be distinguished by factor assay

Rx Replacement FIX concentrate

 von Willebrand Disease
von Willebrand Factor (VWF)
• a large complex multimeric protein made up of several
subunits

• it is synthesized by endothelial cells and megakaryocytes

• it is stored in “ Weibel-Palade” bodies in endothelial cells

and in α granules in platelets
 Role of von Willebrand Factor
(VWF)

• Involved in platelet adhesion to the vessel

wall
• involved in platelet aggregation
• A carrier for Factor VIII c
 von Willebrand disease
Reduced level or abnormal function of VWF

? Most common inherited bleeding disorder

Inherited as autosomal dominant

 von Willebrand Disease
 Lab findings:
prolonged bleeding time
FVIII level is often low
APTT may be prolonged
Defective platelet aggregation with Ristocetin
(in platelet function / aggregation testing)
 Treatment of VWD
Local measures to stop
bleeding
DDAVP ( ADH analogue)
Intermediate purity FVIII
concentrate
Cryoprecipitate
Factor XI deficiency:
Autosomal recessive,
Heterozygotes 8% in Ashkenazi Jews,
variable bleeding tendency; but 1:100,000,000 in
general population.
Dx: prolonged PTT, normal PT
Rx: fresh frozen plasma (FFP).
Contact Factors: XII –deficiency
rare (patients do not bleed)
paradoxical increased incidence of thrombosis;
Prekallikrein and HMWK deficiencies –
no bleeding; autosomal recessive.
Prolonged APTT
Congenital Factors II, V, X and fibrinogen
Deficiencies –

prolonged PT and/ or APTT (common pathway)

rare; autosomal recessive; bleeding tendency

proportionate to severity of biochemical lesion.

Rx: FFP and specific concentrates (e.g. for

fibrinogen = cryoprecipitate).
Congenital Factor VII Deficiency –
prolonged PT and normal PTT

variable bleeding tendency

incidence 1:500,000

autosomal recessive

Rx: FFP and factor VII concentrate.

Factor XIII deficiency

Factor XIII - fibrin stabilizing factor with abnormal

urea solubility test.

Not tested in usual screening tests.

Severe cases have delayed bleeding and form

keloid scars.
Rare; autosomal recessive

Rx: cryoprecipitate.
 Vitamin K deficiency
 Some coagulation factors are vit K dependent (II,
VII, IX, X, Pr C & S)
Causes of vit K def:
Neonatal/ fetal immaturity
Dietary, drugs(warfarin / antibiotics)
Hemorrhagic dis of newborn
bleeding due to vit K def
Diag: prolonged PT, APTT
Bleeding tendency due to Liver
disease

 With severe liver disease:

Reduced synthesis of coag. Factors

Reduced thrombopoietin production

Chronic DIC
 Massive Transfusion Syndrome

 With serious blood loss, loss of platelets &

coag. Factors
 Replaced stored blood lacks viable platelets
and factors V &VIII
Rx
FFP + plts with massive blood transfusion
 THE CLINICAL DISTINCTION BETWEEN DISORDERS OF
PLATELETS AND DISORDERS OF BLOOD COAGULATION
Disorders of Coagulation Disorders of Platelets

Petechiae are Rare Petechiae are Common

Deep Dissecting Hematomas are
Characteristic
•Superficial Ecchymoses are
Common; usually Large and
Solitary
Deep Dissecting Hematomas
are Rare
•Superficial Ecchymoses are
Characteristic; usually Small
and Multiple

•Hemarthrosis is Common Hemarthrosis is Rare

•Positive Family History is •Positive Family History is Rare
Common except for VWD
•80% to 90% of Inherited Forms •Relatively more Common in
are in Males Females