14 - CONGENITAL HEMORRHAGIC DISORDERS

von Willebrand Disease

Hemophilia (A, B, C)

Other Congenital Single-Factor Deficiencies

Congenital Coagulopathies (3)

von Willebrand Disease

Most prevalent congenital bleeding disorder

quantitative

qualitative

vWF

von Willebrand Disease

Resulted from _ and _ abnormalities of _

vWF

von Willebrand Disease

plays an important role in primary hemostasis; acts as a bridge between the platelet and collagen (platelet adhesion)

mucocutaneous

soft tissue bleeding

von Willebrand Disease

Can cause both _ and _ _ _

adhesion

von Willebrand Disease

Reduces platelet _

von Willebrand Disease

Blood product for transfusion

1

Partial quantitative

CLASSIFICATION OF vWD
Type	Description
_	_ _ deficiency of vWF

2

Qualitative

CLASSIFICATION OF vWD
Type	Description
_	_ deficiency of vWF

2A

selective deficiency

CLASSIFICATION OF vWD
Type	Description
_	Decreased platelet-dependent vWF function with _ _ of high-molecular-weight multimers

2B

glycoprotein Ib

CLASSIFICATION OF vWD
Type	Description
_	Increased affinity for platelet _ _

2M

Decreased, high-molecular-weight

CLASSIFICATION OF vWD
Type	Description
_	_ platelet-dependent vWF function with _-_-_ multimers present

2N

factor VIII to vWF

CLASSIFICATION OF vWD
Type	Description
_	Markedly decreased binding of _ _ to _

3

Complete deficiency

CLASSIFICATION OF vWD
Type	Description
_	_ _ of vWF

von Willebrand Factor

von Willebrand Disease

Multimeric glycoprotein

Chromosome 12

von Willebrand Disease

von Willebrand Factor

vWF gene

Endoplasmic reticulum

Megakaryocytes

von Willebrand Disease

von Willebrand Factor

Synthesized in the:

_ _ of endothelial cells

_

Weibel-Palade bodies

Alpha granules

von Willebrand Disease

von Willebrand Factor

Stored in the:

_-_ _ of endothelial cells

_ _ of platelets

Domains A to D

von Willebrand Disease

von Willebrand Factor

Protein structure 4 domains

Domain A

von Willebrand Disease

von Willebrand Factor

Protein structure 4 domains

Supports a receptor site for collagen and a binding site (ligand) for platelet receptor GPIb/IX/V and heparin

Domain C

von Willebrand Disease

von Willebrand Factor

Protein structure 4 domains

Provides a site that binds platelet receptor GPIIb/IIIa

Domain D

von Willebrand Disease

von Willebrand Factor

Protein structure 4 domains

Provides the carrier site for factor VIII

vWF

von Willebrand Disease

von Willebrand Factor

protects FVIII (labile factor) from proteolysis, prolonging their half-life

adhesion, aggregation

VIII

von Willebrand Disease

von Willebrand Factor

Function

Mediate platelet _ and _

Carries Factor _

ADAMTS-13

von Willebrand Disease

von Willebrand Factor

enzyme that regulates vWF

ADAMTS-13

von Willebrand Disease

von Willebrand Factor

Regulates the big and smaller units of vWF

Thrombotic Thrombocytopenic Purpura (TTP)

von Willebrand Disease

von Willebrand Factor

ADAMTS-13

_ _ _: Antibodies attack ADAMTS-13 → no regulator for vWF → induces thrombosis → consumes platelets → thrombocytopenia

Type 1

von Willebrand Disease

Types of vWD

Partial quantitative decrease of normal vWF and FVIII

Type 1

von Willebrand Disease

Types of vWD

Most common and mildest form of vWD

Small, intermediate, large

von Willebrand Disease

Types of vWD

Type 1

SDS polyacrylamide gel: _, _, and _ multimers are present (but in decreased concentrations)

Type 2 (flawed vWF)

von Willebrand Disease

Types of vWD

Primary qualitative defects of vWF

Type 2 (flawed vWF)

von Willebrand Disease

Types of vWD

Seen in 15-20% of patients with vWD

Can be either autosomal dominant or recessive

Type 2A

von Willebrand Disease

Types of vWD

Inherited as autosomal dominant

A2

von Willebrand Disease

Types of vWD

Type 2A

Autosomal mutations in _ domain of vWF

ADAMTS13

von Willebrand Disease

Types of vWD

Type 2A

More susceptible to _

small

von Willebrand Disease

Types of vWD

Type 2A

Increase in _ molecular-weight multimers (small units are less functional)

Results to less platelet adhesion

normal/slightly reduced

reduced

von Willebrand Disease

Types of vWD

Type 2A

Laboratory result:

vWF:Ag = _/_ _

vWF activity = _

Type 2B

von Willebrand Disease

Types of vWD

Inherited as an autosomal dominant trait

Type 2B

von Willebrand Disease

Types of vWD

<5% of vWD patients

A1

“gain-of-function” mutation

von Willebrand Disease

Types of vWD

Type 2B

Mutations in the _ domain which increases the affinity of vWF to GPIb/IX/V = ?

spontaneous

von Willebrand Disease

Types of vWD

Type 2B

Leads to _ binding to resting platelets

high

von Willebrand Disease

Types of vWD

Type 2B

Decrease of _ molecular-weight vWF and platelets

Small, intermediate

von Willebrand Disease

Types of vWD

Type 2B

SDS polyacrylamide gel: _ and _ multimers are present (large units are consumed)

Platelet-type vWD/pseudo-vWD

von Willebrand Disease

Types of vWD

Type 2B

Same mechanism, but the mutation is with GPIb of platelets

Type 2M

von Willebrand Disease

Types of vWD

Characterized by poor platelet receptor binding

Small, intermediate, large

von Willebrand Disease

Types of vWD

Type 2M

SDS polyacrylamide gel: _, _, and _ multimers are present (unusable due to poor platelet receptor binding)

1

2A

von Willebrand Disease

Types of vWD

Type 2M

Often incorrectly identified as type _ or subtype _

Type 2N

von Willebrand Disease

Types of vWD

Mode of inheritance: Autosomal recessive

Normandy variant or autosomal hemophilia

von Willebrand Disease

Types of vWD

Type 2N other name

vWF

5

von Willebrand Disease

Types of vWD

Type 2N

Markedly decreased affinity of _ for FVIII, resulting in FVIII levels reduced to usually around _% of the reference range

vWF antigen

ristocetin

von Willebrand Disease

Types of vWD

Type 2N

_ _ concentration and _ cofactor activity are usually normal

decreased

von Willebrand Disease

Types of vWD

Type 2N

Problem is with the vWF but the FVIII levels are _

Type 3

von Willebrand Disease

Types of vWD

Complete lack of von Willebrand factor (more severe)

Null allele

von Willebrand Disease

Types of vWD

Type 3

“_ _” vWF gene translation or deletion mutation

desmopressin acetate

von Willebrand Disease

Types of vWD

Type 3

Absence of vWF from both platelets and endothelial cells, and a lack of response to _ _

VIII

von Willebrand Disease

Types of vWD

Type 3

Factor _ is also absent/diminished

rare

von Willebrand Disease

Types of vWD

Type 3

Most _ form of vWD

mucocutaneous

anatomic hemorrhage

von Willebrand Disease

Types of vWD

Type 3

Produces severe _ and _ _

<1%

2-8%

>15 minutes

von Willebrand Disease

Types of vWD

Type 3

Laboratory:

vWF level: ?

Factor VIII clotting activity: ?

Bleeding time: ?

Decreased

Normal

vWD VS HEMOPHILIA A
vWD	Hemophilia A
vWF: _	vWF: _

decreases

Diminished

vWD VS HEMOPHILIA A
vWD	Hemophilia A
FVIII gradually _	_ FVIII

Prolonged

Prolonged

vWD VS HEMOPHILIA A
vWD	Hemophilia A
Laboratory Result
APTT: _	APTT: _

Prolonged

Normal

vWD VS HEMOPHILIA A
vWD	Hemophilia A
Laboratory Result
Bleeding Time: _	Bleeding Time: _

Prolonged

Normal

vWD VS HEMOPHILIA A
vWD	Hemophilia A
Laboratory Result
Platelet Adhesion Tests: _	Platelet Adhesion Tests: _

Prolonged

Normal

vWD VS HEMOPHILIA A
vWD	Hemophilia A
Laboratory Result
vWF Tests: _	vWF Tests: _

FVIII

von Willebrand Disease

vWF protects _ → so both are decreased

Hemophilia A

von Willebrand Disease

_ _: Only FVIII is dysfunctional; vWF is normal

Ristocetin

von Willebrand Disease

Used for assaying vWF

ristocetin

von Willebrand Disease

vWF activity is measured by the ability of _ to cause agglutination of reagent platelets by the patient’s vWF

Hemophilia

“The Royal Disease”

X-linked

Hemophilia

_-_ recessive pattern of inheritance

males

Hemophilia

Most people with hemophilia A or B are _

Carriers

Hemophilia

Women: _

Congenital

Hemophilia

_ single-factor deficiencies

anatomic soft tissue bleeding

Hemophilia

Characterized by _ _ _ _

vWD

Hemophilia

Second to _ in prevalence

Factor VIII deficiency

Hemophilia

Hemophilia A

Factor IX deficiency

Hemophilia

Hemophilia B

Factor XI deficiency

Hemophilia

Hemophilia C

Rosenthal Syndrome

Hemophilia

Hemophilia C is also known as?

50

50

Hemophilia

Mother with Hemophilia + father with Hemophilia

_% chance of an affected female

_% chance of an affected male

Rare occurrence

50

100

Hemophilia

Mother with Hemophilia + normal father

_% chance of a carrier female

_% chance of an affected male

Rare occurrence

intrinsic

Hemophilia

Affects the _ pathway

Hemophilia A

Hemophilia

Classic Hemophilia: Lack of blood clotting factor VIII

Hemophilia B

Hemophilia

AKA Christmas Disease

Named after Stephen Christmas, the first patient described

Hereditary deficiency of Factor IX

50-70

10

30-40

CLASSIFICATION OF HEMOPHILIA A AND B
	Classification
	Severe	Moderate	Mild
Percentage of patients	?	?	?

<1

1-5

6-30

CLASSIFICATION OF HEMOPHILIA A AND B
	Classification
	Severe	Moderate	Mild
Factor VIII or factor IX activity, %	?	?	?

≈2-4 per month approximately

≈4-6 per year approximately

Uncommon

CLASSIFICATION OF HEMOPHILIA A AND B
	Classification
	Severe	Moderate	Mild
Pattern of bleeding episodes	?	?	?

Spontaneous

Minor trauma

Major trauma surgery

CLASSIFICATION OF HEMOPHILIA A AND B
	Classification
	Severe	Moderate	Mild
Cause of bleeding	?	?	?

bruises

Joint

Hemophilia

Signs and Symptoms

Many large or deep _

_ pain and swelling caused by internal bleeding

muscles

urine, stool

Prolonged bleeding

Hemophilia

Signs and Symptoms

Bleeding within _

Blood in _ or _ – hematuria or melena

_ _ from cuts or injuries, or after surgery or tooth extraction

Factor VIII/IX concentrates

Hemophilia

Treatment

_ _ _ (may be human plasma derived or recombinant)

Cryoprecipitate

Hemophilia

Treatment

rich in FVIII and FIX

desmopressin acetate

Hemophilia

Treatment

Mild hemophilia may be treated with _ _ (DDAVP, 1-deamino 8-D-arginine vasopressin)

desmopressin acetate

Hemophilia

Treatment

Helps the body release factor VIII that is stored within the lining of blood vessels

Hemophilia C

Hemophilia

Factor XI deficiency

Rosenthal Syndrome

Hemophilia

Hemophilia C

Other name

dominant

Mild to moderate

Hemophilia

Hemophilia C

Autosomal _ trait

_ to _ bleeding symptoms

Ashkenazi

Hemophilia

Hemophilia C

Predominantly occurs in Jews of _ descent

joints, muscle

either sex

Hemophilia

Hemophilia C

To differentiate Hemophilia C from Hemophilia A:

Absence of bleeding into _ and _

Occurrence in individuals of _ _ (equal chances for M and F to develop condition)