Hereditary Coagulation Disorders

Question 1

where is vWF synthesied?

Answer 1

• both endothelial cells (Weibel-Palade bodies)and megs (PLTs will store this in alpha granules)
• large glycoprotein of variable sizes

Question 2

inheritance for vwF

Answer 2

• autosomal

- chromosome 12

Question 3

when is vWF released?

Answer 3

• in response to hemostatic stimuli
• damaged endothelial cells
• exposure of subendothelial collagen = vWF unrolls and exposes functional sites

Question 4

vWF stored as…

Answer 4

ultra-large multimers

• cleaved into smaller multimers by ADAMTS-13 (vWF cleaving protease) when released
• ADAMTS-13 def leads to increased PLT aggregation and thrombosis
• TTP

Question 5

vWF unctional or binding domains

Answer 5

• collagen binding sites for damaged subendothelial tissues
• PLT-binding site = GP Ib/IX/V
• VIII (carried into circulation bc quite labile; helps protect it from breakdown)
• VWF:Ag epitope

Question 6

vWF functinos

Answer 6

• carrier protein for FVIII
• protects FVIII
• concentrations FVIII at injury sites
• enhances FVIII synthesis
• PLT adhesion

Question 7

factor VIII portion of comlex with vWF

Answer 7

• coagulation protein needed for secondary hemostasis (smaller portion of complex w vWF)
• main production source = liver
• X-linked recessive inheritance
• deficient or nonfunctional in Hemophilia A and severe vWF disease

Question 8

von Willebrand disease

Answer 8

• gene mutation leads to abnormal or deficient vWF (6 possible subtypes)
• autosomal dom
• most common hemostatic disorder; about 1% of poln

Question 9

deficiency in vWF

Answer 9

• decreased PLT adhesion = mucocutaneous bleeding
• vWF protects FVIII from degradation = half-life of VIII is minutes then and severe vWF deficiency leads to decrease in FVIII

Question 10

clinical preentation of vW disease

Answer 10

0 variable
 > asymptomatic to mucocutaneous bleeding = gums, GI tract, easy bruising, severe nosebleeds, menorrhagia, post-surgical bleeds
- vWF activity level varies according to
 > ABO blood group
 > hormones
 > age
 > inflammation
 > physical stress

Question 11

treatment of vW disease

Answer 11

• mild = protection, rest, ice, compression, elevation (PRICE)
• moderate= desmopressin to release vWF from storage; most useful for type 1 vWD; anti-diuretic hormone analogue; also estrogen or anti-fibrinolytic drugs
• severe = blood bank = concentrated form of FVIII/vWF

Question 12

hemophilias

Answer 12

congenital single factor deficiencies

• soft tissue bleeding, bleeding into joints
• rarer than vwD
• most frequent = A (lack of VIII), then B (IX) and then XI (hemophilia C)

Question 13

Hemophilia A

Answer 13

• factor VIII def (mutation = quantitative disorder)
• factor VIII gene on X chromosome
  > male hemizygote = symptomatic; bleeding disorder
  > female heterozygote = carrier; usually no bleeding symptoms

Question 14

two types of treatment for Hemophilia A

Answer 14

• on-demand = for bleeding or pe-surgery
• prophylaxis to maintain FVIII levels

> recombinant and human-derived FVIII concentrates (risk of developing anti-FVIII Abs which is a pathological inhibitor)
Desmopressin (temporarily increases VIII and vWF levels; only useful dor mild hemophilia

Question 15

excessive bleeding that requires medical or physical intervention

Answer 15

hemorrhage

• localize: injury,i nfection, tumor, or blood vessel defect
• systemic: multiple sites, spontaneous, recurrent (must be disorders, 1 or 2 hemostasis, or uncontrolled fibrinolysis)

Question 16

mucocutaneous bleeding

Answer 16

skin or body orifices: gums, uncontrolled nosebleeds, menorrhagia
> typically primary hemostasis defects; thrombocytopenia, qualitative disorders, or vascular disorders

Question 17

anatomic bleeding

Answer 17

soft tissues, joints, muscles, deep tissues
- recurrent or excessive bleeding after minor trauma, dental extraction, or surgery
> defects in secondary hemostasis

Question 18

congenital hemorrhagic disorders

Answer 18

• young age diagnosis
• may have relatives w similar symptoms
• recurrent bleeds, spontaneous/following minor injury, in unexpected locations
• vWD, Hemophilia A, Hemophilia B

Question 19

acquired hemorrhagic disorders

Answer 19

• bleeding symptoms usually occur after childhood
• may be associated with a disease or physical trauma
• family members typically without bleeding issues

Question 20

diagnosis of vWD

Answer 20

• patient and or family history of mucocutaneous bleeding
• normal PT, variable PTT and normal PLT count
• PLT aggregation
  > w ADP, collagen, epinephrine, and arachidonic acid (N)
• w ristocetin = abnormal (relies on GPIb and vWF)
• ristocetin cofactor assay
• vWF assay (quantitative and qualitative)
• factor VIII activity ( decreased in types 1 and 3)
• multimer analysis (electrophoresis)

Question 21

clinical presentation hemophilia A

Answer 21

• male with variable bleeding problems
• bleeding correlated with factor VIII activity levels
  > severe = FVIII <1% of normal
  > moderate = FVIII 1-5% of normal
  > mild = FVIII 5-30% of normal
• anatomic bleeds (deep muscle, joint hemorrhages, deep tissue bleeds = hematomas; wound oozing, CNS bleeds = fatal!)

Question 22

hemophilia A diagnosis

Answer 22

• often detected in childhood; family history

- presents w easy bruising and bleeding

Question 23

factor VIII assay

Answer 23

• tests ability of patient plasma to correct FVIII deficient plasma (substrate)
  > standards: dilutions of normal plasma + substrate
  > test samples: dilution of patient plasma/control + substrate
• aPTT run for each of standards and test samples; standard graph to interpret results