BAB 81 : Von Willebrand Disease

Review

Von Willebrand disease (VWD) adalah gangguan perdarahan herediter yang paling
umum pada anjing dan manusia, dan sifat ini telah dilaporkan pada banyak spesies lain.

Mekanisme Penyakit

The bleeding tendency of VWD is caused by quantitative and functional deficiencies of

VWF, a large plasma glycoprotein required for platelet adhesion at sites of vessel injury.
Endothelial cells are the major site of VWF synthesis and storage. Platelets provide a secondary
pool of VWF in some species. Mature VWF circulates as linear strings of subunits (multimers)
assembled within the endoplasmic reticulum and Golgi apparatus. VWF also mediates
intraplatelet bridging via platelet glycoprotein IIb IIIa. High MW VWF multimers are most
effective in supporting platelet adhesion. Deficiency of VWF, or loss of high MW forms, results
in failure of platelet plug assembly, especially under high shear in the microvasculature.

DISEASE CLASSIFICATION

VWD Subtypes

Von Willebrand disease in people is classifi ed into one of three categories based on
plasma VWF concentration, function, and multimer structure. Type 1 VWD is a partial
quantitative defi ciency. Type 2 VWD refers to a group of VWF functional variants. Although
four distinct subtypes are found in people, type 2A VWD is the only subtype described in
animals to date. Type 3 VWD refers to a complete absence of plasma VWF. Dogs affected with
type 3 VWD have at most mild reduction in FVIII, presumably due to species - differences in
FVIII stability.

Affected Species and Breeds

 Clinical expression of VWD is best characterized in dogs. Type 1 VWD is the most
common form in dogs, with cases identifi ed in many purebreds and in mixed breed dogs. Type 2
VWD represents 10 – 20% of human cases; however, this subtype has been found only in two
related canine breeds (German wirehaired and shorthaired pointers) in addition to horses and
cattle. The most severe form, type 3 VWD, has been described as a familial trait in several
breeds (Kooiker, Scottish terrier, Shetland sheepdog), and there are many sporadic cases in other
breeds and species. Selection may eliminate the trait within a certain family, in spite of relatively
high overall breed prevalence.

INHERITANCE AND EXPRESSION PATTERNS

Molecular characterization of VWD reveals a variety of mutation - types and numerous

distinct mutations throughout the VWF gene ( VWF ). In general,mutations causative for type 2
VWD are clustered in VWF regions required for multimer assembly and stability, or VWF -
platelet interactions. Type 3 patients include frameshift, nonsense, and large deletions that disrupt
VWF synthesis.

Hereditary VWD

Hereditary VWD is an autosomal trait. In this form of inheritance, males and females
transmit and express the trait with equal frequency. Most type 2 VWD kindreds and all type 3
VWD families demonstrate recessive expression patterns. Two distinct mutations have been
described in canine breed - variants of type 3 VWD. A deletion mutation within exon 4 and a
splice site mutation at the boundary of exon 16 are causative for type 3 VWD in Scottish terriers
and Dutch Kooikers, respectively. Type 1 VWD is typically a dominant trait, or dominant with
incomplete penetrance. The causative mutations underlying this phenotype in people are often
classifi ed as “ dominant - negative, ” where an abnormal gene product affects VWF processing
or clearance.
Acquired VWD
Acquired von Willebrand syndrome (AVWS) refers to VWF quantitative and functional
defects that develop as a consequence of other primary disease conditions. The pathogenesis of
AVWS in people includes antibody - mediated clearance secondary to immune disorders, shear -
induced proteolysis due to cardiac disease, and increased VWF - platelet binding in thrombotic
and neoplastic syndromes. In addition to these defi ned mechanisms, AVWS has been described
in people (and animals) in association with hypothyroidism and treatment with plasma expanders
(e.g. hydroxyethyl starch, dextran).
VON WILLEBRAND FACTOR ASSAYS
Definitive diagnosis of VWD is based on specifi c assay of plasma VWF. 6 Species
differences in VWF antigenic structure and function require species - specifi c assays, or
validation of human assays, for veterinary applications.
Quantitative VWF Assays
VWF antigen (VWF : Ag) refers to the immunologic quantitation of VWF concentration.
Determination of VWF : Ag is the initial step in characterizing VWD. The most sensitive and
accurate assay methods in current use are enzyme - linked immunosorbant assay (ELISA) and
automated latex immunoassay (LIA). In general, plasma VWF : Ag below 50% ( 50 U/dL)
indicates VWF deficiency.
Functional and Structural VWF Assays
Functional VWF assays measure various aspects of VWF interaction with platelets,
collagen, or FVIII. The ristocetin cofactor assay (VWF : RCo) is a traditional test that measures
VWF - dependent platelet agglutination. This property of VWF depends on the presence of high
MW multimers and that VWF : RCo values are disproportionately decreased compared to VWF :
Ag in people with type 2A, 2B, and 2M VWD. VWF multimers are visualized using protein
electrophoresis for size separation, followed by direct hybridization with anti - VWF probes, or
transfer to a membrane (western blot) before antibody labeling.
Point - of - Care Analyses
Bleeding time tests are in vivo measures of primary hemostasis performed by making a
superfi cial incision in a capillary bed and monitoring the time to cessation of blood flow. In
addition to nonspecifi city, bleeding time tests have fallen out of use in human medicine because
of high inter – operator variability, patient discomfort, and poor predictive values. The Platelet
Function Analyzer (PFA - 100 ® , Dade Behring) is a table - top instrument that measures
platelet plug formation in whole blood under high shear flow. The test endpoint (closure time)
refers to occlusion of an aperture coated with collagen and ADP or epinephrine.
CLINICAL MANAGEMENT OF VWD
Clinical Diagnosis
Clinical Signs
Clinical signs of VWD in all species include mucosal hemorrhage, cutaneous bruising,
and prolonged bleeding after surgery or trauma. Specifi c sites of mucosal hemorrhage in VWD
case series include epistaxis, hematuria, gastrointestinal hemorrhage, prolonge destral bleeding,
and gingival bleeding at deciduous teeth. The bleeding tendency of type 1 VWD ranges from
mild to severe. Mildly affected patients infrequently develop spontaneous hemorrhage. Types 2
and 3 VWD are invariably severe bleeding disorders. Neonatal deaths caused by hemorrhage
may occur, but many animals survive to adulthood, albeit with transfusion support. Oronasal and
urinary tract tissues are rich in fi brinolysins, and injuries to these tissues often cause more
prolonged bleeding than superfi cial wounds.

Diagnostic Evaluation
Thrombocytopenia and coagulation factor defi ciencies are common causes of
hemorrhage. Bleeding scores derived from standardized questionnaires have been proposed to
improve the diagnostic utility of VWD screening in people. A brief hemostasis questionnaire is
also useful as a screening tool to identify veterinary patients with hereditary or drug – induced
bleeding disorders. Prolongation of in vivo bleeding time (beyond 4 – 6 minutes) and PFA - 100
® collagen/ADP closure time (beyond 2 minutes) is compatible with VWD, and the finding of
low plasma VWF (VWF : Ag < 50%) confirms VWF defi ciency. Diagnosis of type 2 VWD is
based on quantitative defi ciency, combined with additional structural and functional
abnormalities. The current management strategy for type 1 VWD in people considers VWF defi
ciency as a biomarker for hemostatic risk.
Treatment of VWD

Management of VWD is directed at controlling hemorrhage in patients with active bleeds

and preventing hemorrhagic complications in case of surgery or trauma.
Transfusion Therapy
 Transfusion is the mainstay of emergency treatment and prophylaxis of VWD. The most
successful strategy is early, high - dose transfusion to rapidly increase plasma VWF to levels
capable of supporting platelet adhesion. Patients with types 2 and 3 VWD almost invariably
require transfusion to undergo invasive procedures or stop an active bleed. Transfusion for type 1
VWD can be assessed based on clinical history, severity of VWF deficiency, any underlying
disease, and the nature of the hemostatic stress. Plasma cryoprecipitate is the most specifi c
component for rapid VWF replacement therapy, with fresh frozen plasma an acceptable
alternative.
Non - transfusion Therapy
Hereditary VWD causes a life - long bleeding tendency; therefore invasive procedures
are best avoided. In case of injury or non - elective surgery, local wound care may help reduce
transfusion requirements. Signs of VWD can be exacerbated by concurrent thrombocytopenia
and other disease conditions that affect hemostasis. Desmopressin acetate (deamino 8 - d -
arginine vasopressin [DDAVP]) is a synthetic vasopressin analog used as a specific
pharmacologic agent for type 1 VWD in people. The drug is believed to act by stimulating
endothelial V2 vasopressin receptors, resulting in release of VWF intracellular stores.