Hereditary Coagulation Disorders Flashcards
where is vWF synthesied?
- both endothelial cells (Weibel-Palade bodies)and megs (PLTs will store this in alpha granules)
- large glycoprotein of variable sizes
inheritance for vwF
- autosomal
- chromosome 12
when is vWF released?
- in response to hemostatic stimuli
- damaged endothelial cells
- exposure of subendothelial collagen = vWF unrolls and exposes functional sites
vWF stored as…
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
vWF unctional or binding domains
- 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
vWF functinos
- carrier protein for FVIII
- protects FVIII
- concentrations FVIII at injury sites
- enhances FVIII synthesis
- PLT adhesion
factor VIII portion of comlex with vWF
- 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
von Willebrand disease
- gene mutation leads to abnormal or deficient vWF (6 possible subtypes)
- autosomal dom
- most common hemostatic disorder; about 1% of poln
deficiency in vWF
- 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
clinical preentation of vW disease
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
treatment of vW disease
- 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
hemophilias
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)
Hemophilia A
- factor VIII def (mutation = quantitative disorder)
- factor VIII gene on X chromosome
> male hemizygote = symptomatic; bleeding disorder
> female heterozygote = carrier; usually no bleeding symptoms
two types of treatment for Hemophilia A
- 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
excessive bleeding that requires medical or physical intervention
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)
mucocutaneous bleeding
skin or body orifices: gums, uncontrolled nosebleeds, menorrhagia
> typically primary hemostasis defects; thrombocytopenia, qualitative disorders, or vascular disorders
anatomic bleeding
soft tissues, joints, muscles, deep tissues
- recurrent or excessive bleeding after minor trauma, dental extraction, or surgery
> defects in secondary hemostasis
congenital hemorrhagic disorders
- young age diagnosis
- may have relatives w similar symptoms
- recurrent bleeds, spontaneous/following minor injury, in unexpected locations
- vWD, Hemophilia A, Hemophilia B
acquired hemorrhagic disorders
- bleeding symptoms usually occur after childhood
- may be associated with a disease or physical trauma
- family members typically without bleeding issues
diagnosis of vWD
- 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)
clinical presentation hemophilia A
- 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!)
hemophilia A diagnosis
- often detected in childhood; family history
- presents w easy bruising and bleeding
factor VIII assay
- 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
