Congenital Coagulopathies

Question 1

Congenital Coagulopathies

Answer 1

1. Von Willebrand Disease
2. Hemophilia A
3. Hemophilia B
4. Hemophilia C
5. Other Congenital Single-Factor Deficiencies

Question 2

First described by Finnish professor Erik von Willebrand

Answer 2

von Willebrand Disease

Question 3

The most prevalent inherited mucocutaneous bleeding disorder. Either quantitative (type 1) or qualitative (type 2)

Answer 3

von Willebrand Disease

Question 4

von Willebrand Disease type 1

Answer 4

quantitative

Question 5

von Willebrand Disease type 2

Answer 5

qualitative

Question 6

Leads to decreased platelet adhesion to injured vessel walls

Answer 6

von Willebrand Disease

Question 7

1. The largest molecule in human plasma
2. Is synthesized in the ER of ECs and stored in
   Weibel-Palade bodies
3. Is also synthesized in megakaryocytes and stored in the alpha granules of platelets

Answer 7

VWF

Question 8

VWF gene: Consists of __exons spanning __kilobase pairs on
chromosome __

Answer 8

52
178
12

Question 9

VWF gene is a monomer of ___amino acids composed of __ structural domains (A to D)

Answer 9

2813, four

Question 10

supports the receptor site for collagen and GP
Ib/IX/V

Answer 10

vwf Domain A

Question 11

provides a site that binds GP IIb/IIIA

Answer 11

vwf Domain C

Question 12

provides the carrier site for factor VIII
VWF protects factor VIII from proteolysis

Answer 12

Domain D

Question 13

mediate platelet adhesion to subendothelial collagen in areas of high flow rate and high
shear force

Answer 13

von Willebrand Disease

Question 14

○ VWF deficiency creates factor VIII deficiency
○ Leads to mucocutaneous hemorrhage

Answer 14

von Willebrand Disease

Question 15

When factor VIII levels (<30 units/dL) decrease, anatomic bleeding accompanies mucocutaneous bleeding

Answer 15

von Willebrand Disease

Question 16

von Willebrand Disease Types and Subtypes

Answer 16

1. Type 1 vWD
2. Type 2 vWD (2A, 2B, 2M, 2N)
3. Type 3 vWD

Question 17

Caused by autosomal dominant frameshifts, nonsense mutations, or deletions

Answer 17

Type 1 von Willebrand Disease

Question 18

Comprises 40-70% of vWD cases

Answer 18

Type 1 von Willebrand Disease

Question 19

Quantitative vWF deficiency

Answer 19

Type 1 von Willebrand Disease

Question 20

Encompasses four qualitative vWF
abnormalities:
o Subtype 2A
o Subtype 2B
o Subtype 2M
o Subtype 2N

Answer 20

Type 2 von Willebrand Disease

Question 21

Arises from an autosomal dominant point mutations in A2 and D1 structural domains of the vWF molecule

Answer 21

Type 2 von Willebrand Disease: Subtype 2A

Question 22

VWF is susceptible to ADAMTS-13

Answer 22

Type 2 von Willebrand Disease: Subtype 2A

Question 23

Predominance of small molecular weight plasma multimers

Answer 23

Type 2 von Willebrand Disease: Subtype 2A

Question 24

● Mutations within the A1 domain
● Raised affinity to GP Ib/IX/V
● “gain-of-function” mutation

Answer 24

Type 2 von Willebrand Disease:
Subtype 2B

Question 25

HMW-VWF multimers spontaneously bind to resting platelets

Answer 25

Type 2 von Willebrand Disease: Subtype 2B

Question 26

A platelet mutation that raises GP Ib affinity for normal HMW-VWF multimers

Answer 26

Platelet-type vWD (PT-VWD) or pseudo-VWD

Question 27

Possesses poor platelet receptor binding despite generating a normal multimeric distribution pattern in electrophoresis

Answer 27

Type 2 von Willebrand Disease: Subtype 2M

Question 28

Missense mutation in the D9 domain impairs the protein's factor VIII binding site

Answer 28

Type 2 von Willebrand Disease: Subtype 2N

Question 29

Also known as Autosomal Hemophilia. It affects both men and women

Answer 29

Type 2 von Willebrand Disease: Subtype 2N

Question 30

"Null allele" VWF gene translation or deletion mutations. Is the most rare form of vWD

Answer 30

Type 3 von Willebrand Disease

Question 31

To rule out thrombocytopenia as the cause of mucocutaneous bleeding

Answer 31

CBC

Question 32

Assess the coagulation cascade to rule out coagulation factor deficiency other than VWF

Answer 32

PT and PTT

Question 33

Most prominent member of the primary VWD laboratory profile

Answer 33

VWF:Ag (quantitative)

Question 34

Ristocetin (an unsuccessful antibiotic) unfolds the VWF molecule and reduces repelling negative charges, enabling HMW-VWF multimers to bind reagent platelet membrane GP Ib/IX/V receptors

Answer 34

VWF:RCo assay

Question 35

Standard VWD test pane

Answer 35

A. VWF:Ag (quantitative) B. VWF:RCo assay C. Factor VIII assay

Question 36

von Willebrand Disease Treatment

Answer 36

PRICE ○ protection, ○ rest, ○ ice, ○ compression, ○ elevation

Question 37

are congenital single-factor deficiencies marked by anatomic soft tissue bleeding

Answer 37

Hemophilias

Question 38

85% are factor VIII deficient 14% are factor IX deficient 1% are factor XI deficient

Answer 38

take note

Question 39

translated from the X chromosome. Most mutations result in quantitative disorders. Rarely qualitative

Answer 39

Hemophilia A (Factor VIII Deficiency)

Question 40

Male homozygotes, whose sole X chromosome contains FVIII gene mutation, experience anatomic bleeding, but female heterozygotes, who are carriers, do not

Answer 40

Hemophilia A (Factor VIII Deficiency)

Question 41

Hemophilia A (Factor VIII Deficiency) Causes anatomic bleeds with deep muscle and joint hemorrhages

Answer 41

true

Question 42

The severity of hemophilia A symptoms is ___ to FVIII activity

Answer 42

inversely proportional

Question 43

Hemophilia A (Factor VIII Deficiency) < 1 unit/dL

Answer 43

severe

Question 44

1-5 units/dL Hemophilia A (Factor VIII Deficiency)

Answer 44

moderate

Question 45

5-40 units/dL: Hemophilia A (Factor VIII Deficiency)

Answer 45

mild

Question 46

Debilitating and progressive musculoskeletal lesions and deformities and neurologic deficiencies subsequent to intracranial hemorrhage

Answer 46

Hemophilia A (Factor VIII Deficiency)

Question 47

70% of hemophilics treated before 1984 are HIV positive or have died from AIDS

Answer 47

true

Question 48

Hemophilia A (Factor VIII Deficiency) Laboratory Diagnosis

Answer 48

○ Normal PT, TT, Fibrinogen ○ Prolonged PTT

Question 49

used to detect female carriers of hemophilia A

Answer 49

Ratio of FVIII activity to VWF:Ag concentration

Question 50

Hemophilia A (Factor VIII Deficiency) Therapy:

Answer 50

○ Human plasma-derived FVIII (pdFVIII) concentrates ■ Undergoes viral inactivation ■ None has transmitted lipid-envelope viruses ■ May transmit non—lipid envelope viruses

Question 51

● Also called Christmas disease ● Sex-linked

Answer 51

Hemophilia B

Question 52

Hemophilia B Laboratory Diagnosis:

Answer 52

○ Normal PT, Fibrinogen, TT ○ Prolonged PTT

Question 53

Also called Rosenthal syndrome, Factor XI deficiency

Answer 53

Hemophilia C

Question 54

More than half of the cases have been described in Ashkenazi Jews

Answer 54

Hemophilia C

Question 55

The frequency and severity of bleeding episodes do not correlate with factor XI levels

Answer 55

true

Question 56

Other Congenital Single-Factor Deficiencies: Factor V Deficiency

Answer 56

● Prolonged bleeding time ● Prolonged PT and PTT

Question 57

Factor V Deficiency effective form of therapy

Answer 57

Platelet concentrate

Question 58

Due to deficiency of factor XIII, patients form weak (non-crosslinked) clots that dissolve within 2 hours when suspended in __ (traditional factor XIII assay)

Answer 58

5M Urea solution

Question 59

To be confirmed by chromogenic substrate assay

Answer 59

5M Urea solution