CONGENITAL COAGULOPATHIES - HEMA 2 MTAP 2 Flashcards
VWD was first described by who?
Finnish professor Erik von Willebrand
When was the VWD first described?
1926
the most prevalent inherited mucocutaneous bleeding disorder
Von Willebrand Disease
Any one of dozens of germline mutations may cause VWD as these mutations produce what?
quantitative (type 1) or qualitative (functional, type 2)
Type 1 VWD is qualitative or quantitative?
Quantitative
Type 2 VWD is qualitative or quantitative?
Qualitative
What are the types of VWF abnormalities?
quantitative (type 1) or qualitative (functional, type 2)
Both quantitative and functional abnormalities lead to what?
decreased platelet adhesion
decreased platelet adhesion to injured vessel walls impairs what?
impairs primary hemostasis
When solely defined by laboratory assays as VWF deficiency, VWD is reputed to afflict approximately how many percent of the global population?
1%
when defined by the number of patients who experience bleeds serious enough to seek medical assistance, prevalence is how many?
1 in 20,000
when defined by the number of patients who experience bleeds serious enough to seek medical assistance, prevalence is how many in percent?
0.05%
The prevalence of VWD in women who report menorrhagia is how many percent of women?
24%
What genetic trait or condition is VWD?
autosomal dominant
VWD affects what sex?
affects both sexes
This is a multimeric glycoprotein
VWF
VWF is what type of glycoprotein?
multimeric glycoprotein
Molecular mass of VWF?
500,000 to 20,000,000 Daltons
This is the largest molecule in human plasma
VWF
plasma concentration of VWF
0.5 to 1.0 mg/dL
a great deal more of VWF is readily available on demand from where?
storage organelles
VWF is synthesized TWO locations
endoplasmic reticulum of
endothelial cells & megakaryocytes
VWF is synthesized in the endoplasmic reticulum of endothelial cells and stored where?
in their cytoplasmic Weibel-Palade bodies
VWF is synthesized in megakaryocytes and stored where?
the a-granules of platelets
Weibel-Palade bodies and a-granules release what?
VWF
Weibel-Palade bodies and a-granules release VWF in response to a variety of what?
hemostatic and inflammatory stimuli
The VWF gene consists of how many exons?
52 exons
The VWF gene consists of 52 exons spanning a kilobase of how much?
178 kilobase pairs
Where is the VWF gene located?
located on the p arm of chromosome 12
The translated protein is a monomer of how many amino acids?
2813 amino acids
The translated protein is a monomer of 2813 amino acids composed of how many domains?
four structural domains, A through D
It is a monomer of 2813 amino acids composed of four structural domains, A through D.
translated protein
The monomers of the translated proteins become glycosylated, then form what?
dimers and oligomers
The monomers become glycosylated, then form dimers and oligomers that migrate to the aforementioned storage organelles, where they polymerize to form what?
Ultralarge VWF (UL-VWF) multimers
At the time of storage, a propeptide, known as ????? becomes cleaved from the end of domain D
VWF antigen II
VWF antigen II becomes cleaved from the end of what domain?
domain D
when mature monomers are polymerized, how many amino acids does it consist?
2050 amino acids
This may occur anywhere on the VWF gene
VWD mutations
Where do VWD mutations occur?
may occur anywhere on the VWF gene
They bind platelets
VWF multimers bind platelets
It cleaves the now linear UL-VWF multimers, yielding multimers of various masses
ADAMTS13
This results in the retention of circulating UL-VWF multimers
ADAMTS13 deficiency
ADAMTS13 deficiency is the basis for what devastating disorder?
thrombotic thrombocytopenic purpura
It is the basis for the devastating disorder thrombotic thrombocytopenic purpura
ADAMTS13
What does the ADAMTS13 cleavage function appear to modulate?
(1) acute inflammation (2) stroke (3) myocardial infarction
This part of the VWF monomer supports its various functions
Epitopes of the structural domains
This domain supports a receptor site for collagen
Domain A
What is domain A?
(1) supports a receptor site for collagen (2) binding site (ligand) for PLT receptor GP Ib/IX/V (3) Heparin
This domain is a binding site (ligand) for platelet receptor glycoprotein (GP) Ib/IX/V
Domain A
This domain is a binding site (ligand) for heparin
Domain A
This domain provides a site that binds platelet receptor GPIIb/IIIa
Domain C
Domain C provides a site that binds what PLT receptor?
GPIIb/IIIa
Domain A provides a binding site for what PLT receptor?
GP Ib/IX/V
This domain provides the carrier site for factor VIII
Domain D
Domain D provides the carrier site for what factor?
FVIII
On release from intracellular stores, a percentage of VWF multimers complex with what?
factor VIII
This protects factor VIII from proteolysis
VWF
VWF protects what factor?
FVIII
VWF protects FVIII from what?
proteolysis
This prolongs plasma half-life of FVIII
VWF
VWF prolonging FVIII plasma half-life from a few minutes to how long?
8-12 hrs
FVIII has a half-life of a few minutes under what condition?
when free
FVIII has a half-life of 8-12 hrs under what condition?
When bound to VWF
This is the carrier molecule of FVIII
VWF
What is the primary function of VWF?
to mediate platelet adhesion to subendothelial colagen in areas of high flow rate and high shear force (capillaries, arterioles)
After being released from the Weibel-Palade bodies, this first unfolds and binds fibrillar intimal collagen exposed during the desquamation of endothelial cells or in a blood vessel injury
VWF
VWF first unfolds and binds fibrillar intimal collagen exposed during what?
during the desquamation of endothelial cells or in a blood vessel injury
platelets adhere through their GPIb/IX/V site to the what?
VWF “carpet.”
These are best equipped to serve the adhesion function
high-molecular-weight (HMW-VWF) multimers
What is the function of HMW-VWF multimers?
adhesion function
When VWF binds GPIb/IX/V, platelets become activated and express a second VWF binding site known as the
GPIIb/IIIa
This receptor binds arginine-glycine-aspartic acid (arginyl-glycylaspartic acid, RGD)
GPIIb/IIIa
GPIIb/IIIa receptos binds what sequence?
arginine-glycine-aspartic acid (arginyl-glycylaspartic acid, RGD)
arginine-glycine-aspartic acid (arginyl-glycylaspartic acid, RGD) are richly distributed to where?
VWF and fibrinogen molecules
This mediates irreversible platelet-to-platelet aggregation
arginine-glycine-aspartic acid (arginyl-glycylaspartic acid, RGD)
Is platelet aggregation an irreversible or reversible process?
Irreversible
These processes are essential to normal primary and secondary hemostasis.
adhesion and aggregation
What type of VWF abnormality is qualitative type 1?
Structural
What type of VWF abnormality is quantitative type 2?
Functional
These reduce platelet adhesion
VWF abnormalities
This leads to mucocutaneous hemorrhage of varying severity
Structural (qualitative) or quantitative VWF abnormalities
Structural (qualitative) or quantitative VWF abnormalities lead to what kind of hemorrhage?
mucocutaneous hemorrhage
Six kinds of mucocutaneous hemorrhages?
(1) Epistaxis (2) Ecchymosis (3) menorrhagia (4) hematemesis (5) gastrointestinal bleeding (6) surgical bleeding
severe quantitative VWF deficiency creates what?
FVIII deficiency
This is created as a result of the inability to protect unbound factor VIII from proteolysis
FVIII deficiency
FVIII deficiency is a result of what?
a result of the inability to protect unbound factor VIII from proteolysis
FVIII deficiency is created as a result of the inability to protect unbound factor VIII from what?
proteolysis
Many “low VWF” people have VWF levels in the intermediate range of what?
30% to 50% of normal
People termed as this maintain a factor VIII level sufficient for competent coagulation
“Low VWF”
People termed as this have VWF levels in the intermediate range of 30% to 50% of normal
“Low VWF”
What are the TWO criteria for a person to have “Low VWF”?
(1) VWF levels in the intermediate range of 30% to 50% of normal (2) maintain a factor VIII level sufficient for competent coagution
anatomic bleeding into joints and body cavities accompanies the typical mucocutaneous bleeding pattern of VWD when FVIII levels decrease to what value?
less than 30 units/dL
What happens when factor VIII levels decrease to less than 30 units/dL?
anatomic bleeding into joints and body cavities accompanies the typical mucocutaneous bleeding pattern of VWD
This is the Customary designation for the combination of factor VIII and VWF
FVIII/VWF
Factor VIII binds activated factor IX to form the complex of
VIIIa-IXa
This complex digests and activates factor X.
VIIIa-IXa
Factor VIII deficiency is called
hemophilia A
This binds activated factor IX to form the complex of VIIIa-IXa
FVIII
Epitope that is the antigenic target for the VWF immunoassay
VWF:Ag
This is measured in a clot-based factor assay
Factor VIII coagulant activity (FVIII:C)
This is also called VWF activity
Quantitative ristocetin cofactor activity (VWF:RCo)
Quantitative ristocetin cofactor activity (VWF:RCo) is also called
VWF activity
This is a second VWF activity assay
Collagen binding assay (VWF:CB)
Large VWF multimers bind immobilized target collagen, predominantly what?
collagen III
Automated nephelometric activity assay that employs latex microparticles and monoclonal anti-glycoprotein I–VWF receptor
VWF:Immunoactivity
This is a third method for assaying VWF activity
VWF:Immunoactivity
Activity assay that employs ristocetin-triggered bindng of recombinant glycoprotein Ib (GPIb)
VWF:GPIbR
This reaction is detected by LIA or CLIA
VWF:GPIbR
Activity assay that employs recombinant gain-of-function GPIb that binds the VWF A1 domain without the need for ristocetin
VWF:GPIbM
This Reaction is detected using LIA
VWF:GPIbM
VWF:GPIbM is detected using what?
LIA (latex immunoassay)
VWF:GPIbR is detected using what?
LIA or CLIA (Chemiluminescence immunoassay)
This is a quantitative VWF deficiency
Type 1 VWD
This is caused by one of several autosomal dominant frameshifts, nonsense mutations, or deletions that may occur anywhere in the VWF gene
Type 1 VWD
Type 1 comprises of what percent of VWD cases?
40-70%
True or False: The plasma concentrations of all VWF multimers and factor VIII are variably, albeit proportionally, reduced.
TRUE
In this VWD, there is mild to moderate systemic bleeding, usually after a hemostatic challenge such as dental extraction or surgery
Type 1 VWD
This is a common complaint that leads to the diagnosis of VWD
menorrhagia, which predicts postpartum hemorrhage
This encompasses four qualitative VWF abnormalities
Type 2 VWD
In this type of VWD, VWF levels may be normal or moderately decreased, but VWF function is consistently reduced.
Type 2 VWD
In type 2 VWD, what are its characteristics?
VWF = normal or moderately decreased; VWF function = consistently reduced
Approximately how many percent of all VWD patients suffer from subtype 2A?
10 - 20%
This type of VWD comprises 40-70% of VWD cases
Type 1 VWD
This type of VWD comprises 10-20% of VWD cases
Subtype 2A VWD
This type of VWD arises from well-characterized autosomal dominant point mutations in the A2 and D1 structural domains of the VWF molecule
Subtype 2A VWD
Subtype 2A VWD arises from well-characterized autosomal dominant point mutations in what structural domains of the VWF molecule?
A2 and D1 structural domains of the VWF molecule
These mutations render VWF susceptible to increased proteolysis by ADAMTS13
Subtype 2A VWD
subtype 2A VWD is caused by mutations that render VWF susceptible to what?
increased proteolysis
What leads to a predominance of small molecular-weight plasma multimers
increased proteolysis by ADAMTS13
True or False: The smaller multimers support more platelet adhesion activity than the normal high- or intermediate-molecular weight multimers.
False: The smaller multimers support less platelet adhesion activity than the normal high- or intermediate-molecular weight multimers.
These support less platelet adhesion activity than the normal high- or intermediate-molecular weight multimers.
Smaller multimers
Patients with this type of VWD have normal or slightly reduced VWF antigen levels as measured by immunoassay
subtype 2A VWD
This is a result of the loss of the high-molecular-weight and intermediate-molecular-weight multimers essential for platelet adhesion
VWF antigen levels: normal or slightly reduced, VWF activity: moderate to markedly reduced
What are the characteristics of patients with Subtype 2A VWD?
VWF antigen levels: normal or slightly reduced, VWF activity: moderate to markedly reduced
Patients with this type of VWD are identified in LESS THAN 5% of all VWD patients
Subtype 2B VWD
Patients with subtype 2B VWD are identified in what percent of VWD cases?
LESS THAN 5%
Patients with subtype 2B VWD have mutations in what domain of the VWF?
A1 domain
In this type of VWD, this VWD raise the affinity of VWF for platelet GPIb/IX/V, its customary binding site
subtype 2B VWD
Patients with subtype 2B VWD raise the affinity of VWF for what platelet glycoprotein?
GPIb/IX/V
GPIb/IX/V is the customary binding site of what VWD?
subtype 2B VWD
This VWD are these are hence “gain-of-function” mutations
subtype 2B VWD
What type of mutation is the subtype 2B VWD?
“gain-of-function” mutations
These multimers spontaneously bind resting platelets
HMW-VWF multimers
HMW-VWF multimers spontaneously bind what?
resting platelets
Why are abnormal HMW-VWF multimers consequently unavailable for normal platelet adhesion?
as they are cleared with the bound platelets
This is characterized by lack of HMW-VWF multimers, but intermediate-molecular-weight multimers may still be present
electrophoretic multimer pattern
The electrophoretic multimer pattern is characterized by what?
lack of HMW-VWF multimers, but intermediate-molecular-weight multimers may still be present
Subtype 2B VWD may be confirmed using a specially designed reduced-concentration called
ristocetin-induced (RIPA) platelet agglutination assay
Patients with Subtype 2B VWD may also express this disease
moderate thrombocytopenia
This is caused by chronic platelet activation because multimer-coated platelets indiscriminately bind the endothelium and become cleared
moderate thrombocytopenia
moderate thrombocytopenia caused by what?
chronic platelet activation
Why is moderate thrombocytopenia caused by chronic platelet activation?
because multimer-coated platelets indiscriminately bind the endothelium and become cleared
This platelet mutation creates a clinically similar disorder called platelet-type VWD (PT-VWD) or pseudo-VWD
platelet mutation that raises GPIb affinity for normal HMW-VWF multimers
A platelet mutation that raises GPIb affinity for normal HMW-VWF multimers creates a clinically similar disorder called
platelet-type VWD (PT-VWD) or pseudo-VWD
platelet-type VWD (PT-VWD) is also called
pseudo-VWD
platelet-type VWD (PT-VWD) or pseudo-VWD is caused by what?
A platelet mutation that raises GPIb affinity for normal HMW-VWF multimers
In platelet-type VWD (PT-VWD) or pseudo-VWD, these are lost from the plasma
large multimers
In this type of VWD, the large multimers also are lost from the plasma, and platelets become adhesive
platelet-type VWD (PT-VWD) or pseudo-VWD
this is not a true form of VWD
Pseudo-VWD
PT-VWD’s prevalence is approximately what percent of subtype 2B VWD sufferers?
10%
This is often mistaken for immune thrombocytopenia
platelet-type VWD
This describes a qualitative VWF variant that possesses poor platelet receptor binding
Subtype 2M VWD
What are the characteristics of patients with Subtype 2M VWD?
(1) Poor PLT receptor binding (2) Normal multimeric distribution pattern in electrophoresis
What is the the distinguishing feature of subtype 2M that separates it from type 1?
(1) a discrepancy between the concentration of VWF:Ag (2) its activity as measured using the VWF ristocetin cofactor assay
type 1 or subtype 2A is often incorrectly identified as
Subtype 2M VWD
Subtype 2N VWD is also called
Normandy variant
This is the autosomal hemophilia
Subtype 2N VWD
An autosomal VWF gene missense mutation in the D9 domain impairs the protein’s factor VIII binding site function
Subtype 2N VWD
Subtype 2N VWD is an autosomal VWF gene missense mutation in what domain?
Domain 9
What type of mutation is the Subtype 2N VWD?
VWF gene missense mutation
What is impaired in Subtype 2N VWD?
impairs the protein’s factor VIII binding site function
Subtype 2N VWD is present in what percent of VWD patients?
Less than 5%
This results in factor VIII deficiency despite a normal VWF antigen concentration assay result, normal VWF activity, and a normal multimeric pattern
Normandy variant
What are the characteristics of the Subtype 2N VWD?
(1) FVIII deficiency (2) normal VWF antigen conc assay (3) Normal VWF activity (4) Normal multimeric pattern
The disorder is also known as autosomal hemophilia
Normandy variant
Subtype 2N VWD is also known as
autosomal hemophilia
Why is subtype 2N VWD also known as autosomal hemophilia?
because its clinical symptoms are indistinguishable from the symptoms of hemophilia except that it affects both men and women
Subtype 2N is suspected when a girl or woman is diagnosed with hemophilia subsequent to what?
subsequent to anatomic bleeding symptoms
In boys or men, subtype 2N is suspected when a male patient misdiagnosed as a hemophilia A sufferer fails to respond to what?
fails to respond to factor VIII concentrate therapy
This occurs because free factor VIII has a plasma half-life of mere minutes
poor therapeutic response
Why does poor therapeutic response in Subtype 2N VWD occurs?
because free factor VIII has a plasma half-life of mere minutes.
The diagnosis of VWD subtype 2N is confirmed using what?
using a molecular assay that detects the specific mutation responsible for the abnormal FVIII binding function.
What type of genetic mutation occurs in Type 3 VWD?
“Null allele” VWF gene translation or deletion mutations
This VWF abnormality has “Null allele” VWF gene translation or deletion mutations
Type 3 VWD
This may occur anywhere on the gene produce severe mucocutaneous and anatomic hemorrhage in compound heterozygotes or, in consanguinity, homozygotes
Type 3 VWD
The “Null allele” VWF gene translation or deletion mutationsthat may occur anywhere on the gene produce what?
severe mucocutaneous and anatomic hemorrhage
In type 3 VWD, severe mucocutaneous and anatomic hemorrhage happen in what?
compound heterozygotes or, in consanguinity, homozygotes.
This is the most rare form of VWD
Type 3 VWD
In type 3 VWD, VWF concentration is measured by WHAT?
measured by immunoassay or by activity assay is less than 10%
In type 3 VWD, VWF concentration is measured by measured by immunoassay or by activity assay is less than what percent?
less than 10%
In this type of VWD, FVIII is proportionally diminished or absent
Type 3 VWD
In type 3 VWD, this is proportionally diminished or absent
FVIII
Definitive diagnosis of VWD depends on the combination what?
(1) personal history (2) family history of mucocutaneous bleeding (3) laboratory demonstration of decreased VWF concentration or activity (function)
What are the fundamental tests that a physician orders for the laboratory detection and classification of VWD?
(1) CBC (2) PT (3) PTT
This laboratory test is ordered by the physician to rule out thrombocytopenia as the cause of mucocutaneous bleeding?
CBC
These tests are ordered to assess the coagulation cascade to rule out a coagulation factor deficiency other than VWF
PT and PTT
according to the 2009 National Heart Lung and Blood Institute (NHLBI) VWD guidelines, these tests are obsolete/no longer recommended
bleeding time test and the PFA-100 or other automated functional platelet assays
What are the 3 primary assays to be incorporated in a standard VWD test panel?
(1) VWF:Ag (2) VWF activity by ristocetin cofactor assay (VWF:RCo) (3) coagulation factor VIII activity
It is the most prominent member of the primary VWD laboratory profile
quantitative VWF:Ag assay
This is the traditional reference method for detection and classification of VWD
enzyme immunoassay (EIA) methodology
For the detection and classification of VWD, this method possesses the best sensitivity to VWF concentrations less than 10% and the best precision.
chemiluminescence immunoassay (CLIA)
The CLIA method possesses the best sensitivity to VWF concentrations less than what percent?
less than 10%
This method possesses the best precision for detection of VWD
CLIA method
This primary assay’s results generally parallel VWF:Ag and VWF:RCo results in VWD types 1 and 3, and may parallel VWF:Ag in subtypes 2A, 2B, and 2M, but are markedly reduced in VWD subtype 2N.
Factor VIII assay
Factor VIII assay results generally parallel VWF:Ag and VWF:RCo results in what VWD types?
VWD types 1 and 3
Factor VIII assay results may be parallel in VWF:Ag in what VWD types?
subtypes 2A, 2B, and 2M
Factor VIII assay results are markedly reduced in what VWD type?
VWD subtype 2N
Factor VIII assay results may be parallel in what other primary assays?
Parallel in (1) VWF:Ag results (2) VWF:RCo results
in VWD types 1 and 3, FVIII assay results are parallel with what assay?
VWF:Ag and VWF:RCo
True or False: FVIII assay results are parallel with VWF:Ag and VWF:RCo results in VWD types 1, 2A, 2B, 2M, and 3
TRUE
The traditional VWF:RCo assay employs what?
ristocetin
This traditional assay employs ristocetin
VWF:RCo assay
When was ristocetin introduced as an unsuccessful antibiotic?
1956
This is added to in vitro patient plasma where it unfolds the VWF molecule and reduces repelling negative charges, enabling HMW-VWF multimers to bind reagent platelet membrane GPIb/IX/V re
Ristocetin
The VWF:RCo assay is typically performed using a what?
platelet aggregometer
This primary assay employs preserved reagent platelets and measures platelet agglutination, yielding a quantitative measure of VWF function
VWF:RCo assay
This has been successfully automated but has been partially replaced by automated ristocetin-triggered nonplatelet recombinant GPIbbased LIA and CLIA methods
VWF:RCo assay
VWF:RCo has been partially replaced by what?
automated ristocetin-triggered nonplatelet recombinant GPIb-based LIA and CLIA methods
A promising alternative to VWF:RCo and VWF:GPIbR is an assay that incorporates what?
incorporates a gain-of-function high-affinity recombinant GPIb protein that resembles the GPIb of PT-VWD platelets.
This binds the A1 domain of native VWF without the need for ristocetin
GPIb
The GPIb binds what domain of the native VWF?
A1 domain
This assay has been commercialized as a LIA (Innovance VWF Ac, Siemens), and it appears to improve on ristocetin-based assays as it offers smaller VWF detection limits and less variability
VWF:GPIbM
All VWF activity assays rely on this
GPIb binding avidity
This is a surrogate for VWF activity
GPIb binding avidity
the laboratory professional infers qualitative or type 2 VWD, when the ratio of the VWF:RCo, VWF:GPIbR, or
VWF:GPIbM assay value to the VWF:Ag concentration is less than what values?
less than 0.5, 0.6, or 0.7
when the ratio of the VWF:RCo, VWF:GPIbR, or VWF:GPIbM assay value to the VWF:Ag concentration is less than 0.5, 0.6, or 0.7, the laboratory professional infers what VWF abnormality?
qualitative or type 2 VWD
Low-dose RIPA is also called
ristocetin response curve
ristocetin response curve is also called
Low-dose RIPA
This test identifies subtype 2B
ristocetin response curve
ristocetin response curve identifies what VWD?
subtype 2B
The low-dose RIPA test is performed on what blood component?
Platelet Rich Plasma (PRP)
What blood component is VWF:RCo assay performed on?
preserved platelet suspension
A preserved platelet suspension is used to perform what assay?
VWF:RCo assay
In subtype 2B the patient’s platelets agglutinate in response to how much ristocetin?
less than 0.5 mg/mL ristocetin / 0.1 mg/mL (sometimes)
normal platelets agglutinate only at ristocetin concentrations of??
greater than 0.5 mg/mL
platelets from a patient with this VWD may not agglutinate to ristocetin at all
subtype 2A
VWF multimer analysis with this gel electrophoresis is a complex secondary confirmatory procedure that helps establish VWD type 2 and differentiates between VWD subtypes 2A, 2B, and perhaps 2M.
VWF multimer analysis by sodium dodecyl sulfate–polyacrylamide gel electrophoresis
sodium dodecyl sulfate– polyacrylamide gel electrophoresis is a complex secondary confirmatory procedure that helps establish what VWD?
VWD type 2
sodium dodecyl sulfate– polyacrylamide gel electrophoresis is a complex secondary confirmatory procedure that helps differentiate between what VWDs?
VWD subtypes 2A, 2B, and perhaps 2M.
These VWDs lack high-molecular-weight multimers
both 2A and 2B
intermediate multimers are presumed to be present in the electrophoretic pattern of what VWDs?
subtype 2B VWD
What is presumed to be present in the electrophoretic pattern subtype 2B VWD but are absent from the pattern of a patient with subtype 2A VWD?
intermediate multimers
In this type of VWD, the multimeric pattern appears to be normal despite the reduced function to concentration ratio.
type 2M
This is available from specialized reference laboratories for differentiation of VWD type 2 subtypes.
Multimer analysis
These influence VWF activity
(1) Varying genetic penetrance (2) ABO blood group (3) inflammation (4) hormones (5) age (6) physical stress
Raised estrogen levels during what stages of pregnancy nearly normalize plasma VWF activity even in women with moderate VWF deficiency?
second and third trimesters
This factor during the second and third trimesters of pregnancy nearly normalize plasma VWF activity even in women with moderate VWF deficiency
Raised estrogen levels
These decrease rapidly after delivery
VWF concentration and function
these medications raise VWF activity
Oral contraceptives and hormone replacement therapy
VWF activity waxes and wanes with what?
with the menstrual cycle
VWF activity decreases/rises substantially in acute inflammation such as occurs postoperatively, subsequent to trauma, or during an infection
Rises
Physical stress such as cold, exertion, or a child’s crying or struggling during venipuncture causes VWF activity to rise/decrease
Rises
What happens to the VWF activity when the phlebotomist allows the tourniquet to remain tied for more than 1 minute before venipuncture?
VWF activity rises
What happens when the specimen is stored in the refrigerator before testing?
VWF descends
What influences the RISE OF VWF ACTIVITY?
(1) Oral contraceptives (2) hormone replacement therapy (3) Acute inflammation (4) trauma (5) infection (6) Physical stress (7) cold (8) exertion (9) child’s crying (10) struggling during venipuncture (11) tied tourniquet for more than 1 minute
In the United States proficiency surveys consistently reveal VWF:RCo assays to have an unimpressive interlaboratory coefficient of variation of what? and a least detectable activity range of what?
30%; 6% to 12%
results of the VWF:RCo assay has led to development of what?
VWF collagen-binding (VWF:CB) assay
VWF:CB employs what type of collagen as its solid-phase target antigen?
type III collagen
What is the role of type III collagen in the VWF:CB?
It is its solid-phase target antigen
When was VWF:CB assay developed?
1990
VWF:CB assay produces results that more closely match those of what assay?
VWF:RCo assay
Why does the VWF:CB assay produces results that more closely match those of VWF:RCo assay?
because collagen type III binds predominantly HMW-VWF multimers
This requires standardization before VWF:CB assay achieves routine assay status
target collagen composition
When collagen is standardized, this assay provides better precision than the VWF:RCo assay
VWF:CB assay
This assay detects abnormalities of VWF collagen binding
VWF:CB assay
This assay detects only abnormalities of VWF platelet GPIb binding
VWF:RCo, VWF:GPIbR, and VWF:GPIbM
may improve assay sensitivity and precision when approved for clinical deployment
CLIA-based VWF:CB
To reduce false-positive type 1 VWD diagnoses, the 2009 NHLBI VWD guidelines have coined the non-disease description of what?
“low VWF”
This term is to describe the condition in which VWF activity and antigen concentrations are between 30% and 50% of normal
“low VWF”
“low VWF” term is to describe the condition in which VWF activity and antigen concentrations between what?
30% and 50% of normal
“Low VWF” in the ratio of VWF:RCo to VWF:Ag is greater than what?
greater than 0.5
The FVIII activity of VWF:RCo to VWF:Ag with “Low VWF” patients is measured at…
greater than 50 units/dL
What is the criteria to make a definite type 1 VWD diagnosis?
30% of normal VWF activity is used as the limit.
These associate consistently with VWF levels less than 30%
VWF gene mutations
linkages to a VWD appear in only half of instances when the VWF:Ag levels are what range?
30% to 50%
VWD Interferences that cause false positives
Rheumatoid factor and heterophile antibodies
Specimen mishandling such as prolonged tourniquet application, plasma refrigeration, filtration, or ultracentrifugation lead to what outcome?
false positives, false negatives, or false phenotypes
the major determinant of bleeding risk is what?
low VWF
VWF test result reference intervals are now based on what?
population based rather than ABO stratified
What is The internationally generalized cutoff for LOW VWF?
50%
What is The internationally generalized cutoff for VWD?
30%
What is the reference interval of VWF by ABO of Type O?
36-157%
What is the reference interval of VWF by ABO of Type A?
48-234%
What is the reference interval of VWF by ABO of Type B?
57-241%
What is the reference interval of VWF by ABO of Type AB?
64-238%
Reference interval of Population based: “Low VWF”
<50%
Reference interval of Population based: von Willebrand disease
<30%
What is the athlete’s acronym for Mild bleeding?
Protection Rest Ice Compression Elevation (PRICE)
Moderate bleeding may respond to what substances to trigger release of VWF from storage organelles?
estrogen and desmopressin acetate
For VWD treatment, therapeutic dosages are monitored using what?
serial VWF:Ag assays
this is an antidiuretic hormone analog used to control incontinence in diabetes mellitus and bedwetting
Desmopressin acetate
What is the chemical component of Desmopressin acetate ?
1-desamino-8-D arginine vasopressin
Desmopressin acetate is an antidiuretic hormone analog used to control what?
incontinence in diabetes mellitus and bedwetting
What is a side effect of desmopressin acetate?
release of VWF from storage organelles
What is Desmopressin acetate called in its ORAL FORM?
DDAVP, or oral spray form, Stimate
What is the oral spay from of desmopressin acetate called?
Stimate
This medication is consistently effective for type 1 and subtype 2M VWD and generally useful for subtype 2A.
Desmopressin acetate
Desmopressin acetate is consistently effective for what types of VWD?
effective for type 1 and subtype 2M VWD and generally useful for subtype 2A.
Desmopressin acetate is contraindicative of what VWD type?
subtype 2B
Because of its THIS, repeated doses may lead to hyponatremia (low serum sodium)
antidiuretic property
These inhibit fibrinolysis and may help control bleeding when used alone or in conjunction with desmopressin acetate.
e-aminocaproic acid (EACA) and tranexamic acid (TXA)
Therapy using THIS preparation is preferred over human plasma-derived biologic therapy because nonbiologics eliminate the risk of viral disease transmission and circumvent religious objections to receipt of human blood products.
nonbiologic preparations
For treatment of severe VWD (type 3) and subtype 2B, three commercially prepared human plasma-derived high purity preparations are available that provide a mixture of
VWF and coagulation FVIII:
Humate-P, Alphanate, and Wilate
Humate-P, Alphanate, and Wilate are three three commercially prepared human plasma-derived high-purity preparations that are available for what VWD types?
Type 3 and Subtype 2B
This is a recombinant VWF that provides no accompanying factor VIII.
Vonvendi
The initial Vonvendi dose is HOW MUCH for HOW MANY HOURS?
40 to 80 IU/kg body weight every 8 to 24 hours
Vonvendi is adjusted to the extent of what?
Vonvendi is adjusted to the extent of continued bleeding or the target VWF:Ag concentration.
If the baseline factor VIII concentration is less than 40 IU/dL, physicians give recombinant VWF-free factor VIII within how many minutes?
within 10 minutes
If the baseline factor VIII cocentration is less than 40 IU/dL, physicians give recombinant VWF-free factor VIII within 10 minutes of completing Vonvendi infusion at a ratio of WHAT?
1.3:1
These concentrates contain no VWF and cannot be used to treat VWD.
Recombinant and affinity-purified factor VIII concentrates
These blood components are less desirable alternatives because of the risk of virus transmission, and the necessary plasma volume per dose may cause TACO.
Cryoprecipitate and plasma
Cryoprecipitate and plasma are less desirable alternatives because of the risk of virus transmission, and the necessary plasma volume per dose may cause WHAT?
TACO (Transfusion-associated circulatory overload)
