Maladie de Willebrand / Von Willebrand disease

Maladie de Willebrand

La maladie de Willebrand ou plutôt la maladie de von Willebrand ou syndrome de Willebrand, est la plus fréquente des maladies hémorragiques constitutionnelles (prévalence mondiale : 1 %). Elle touche les deux sexes. Il n’existe pas une maladie de Willebrand mais un ensemble de maladies de Willebrand qui ont comme point commun une anomalie quantitative ou qualitative du facteur Willebrand.

Erik Adolf von Willebrand, médecin finlandais, a été le premier à décrire la maladie en 1925.

Chez de nombreux patients atteints de la maladie de von Willebrand, un autre facteur de coagulation, le facteur VIII, est également touché ce qui fait que cette maladie a souvent été confondue avec l’hémophilie A.

Elle se manifeste beaucoup plus souvent chez la femme que chez l’homme en raison de la grossesse ou des règles. Le sous diagnostic chez l’homme est fréquent.

L’importance des manifestations varie beaucoup même dans une famille.

Le traitement dépend du type et de l’importance des hémorragies.

Les manifestations hémorragiques ne s'améliorent généralement pas avec l'âge.

Sommaire

Autres noms

Pseudo hémophilie A

Étiologie

  • Mutation du gène VWF localisé sur le locus p13.3 du chromosome 12. Le facteur Willebrand FW joue un rôle dans l'agrégation plaquettaire. En effet le FW joue un rôle d'interaction entre les plaquettes et les cellules endothéliales (cellules de la paroi des capillaires sanguins).

Manifestations cliniques

Elle se manifeste par des hémorragies muqueuses (épistaxisgingivorragiesménorragies ..) et cutanées, spontanées ou provoquées par un traumatisme. Dans les formes sévères (type 3), on retrouve même parfois des hématomes, des hémorragies intra-abdominales et rétro-péritonéales.

Types

Maladie de Willebrand Type I

La plus fréquente, 75 % des Willebrand, correspond à un déficit quantitatif partiel (Le facteur Von Willebrand fonctionne normalement, mais se trouve en quantité insuffisante)

Maladie de Willebrand Type II

20 % des Willebrand, correspond à un déficit qualitatif (la quantité dans le sang des personnes atteintes est souvent normale. Le problème est que le facteur Von Willebrand ne fonctionne pas normalement).

Il existe plusieurs sous types dont la distinction est importante entraînant des traitements différents. Le type 2 est divisé en :

  • IIA

10 à 15% des Willebrand et 75% des maladies de Willebrand de type 2.

Le facteur von Willebrand ne possède pas une structure normale lui permettant d’interagir normalement avec les plaquettes sanguines et les vaisseaux sanguins.

  • IIB

Le facteur von Willebrand se fixe avec trop d’affinité aux plaquettes sanguines. Le taux de plaquettes sanguines peut être abaissé.

  • IIC
  • IIM

Le facteur von Willebrand présente une affinité réduite pour les plaquettes.

  • IIN

Le facteur von Willebrand ne se lie pas normalement au facteur VIII de la coagulation sanguine. La concentration de ce facteur est sévèrement abaissée.

Maladie de Willebrand Type III

La maladie de Von Willebrand de type 3 est très rare. Elle affecte environ une personne sur 500 000. Elle correspond à un déficit quantitatif complet: il n'y a pas de synthèse de facteur Willebrand.

Diagnostic

Le diagnostic se fait lors de l'examen médical.

Test de dépistage

Évalue de façon globale l’hémostase primaire (mesure le temps qu’il faut à une simple coupure pour cesser de saigner). Les méthodes habituelles de Duke et d’Ivy ne sont pas standardisées. Il faut faire un temps de saignement avec des dispositifs type Simplate II ou Surgicutt.

Mais un résultat normal n’exclut pas le diagnostic de maladie de Willebrand et n’est pas prédictif des complications hémorragiques

Non spécifique de la maladie.

Un temps de céphaline activé normal n’exclut pas le diagnostic de la maladie de Willebrand car dépend du type de Willebrand. Utile pour le diagnostic différentiel des autres maladies hémorragiques

  • Taux de plaquettes

Normal dans la maladie de Willebrand

  • Dosage du facteur VIII

Constamment diminué dans le type 3.

Permet le diagnostic différentiel avec l’hémophilie de type A

  • Analyse des fonctions plaquettaires

Test de diagnostic

  • Dosage immunologique du facteur vW

Son interprétation dépend du groupe sanguin.

Variation du taux en cas d’inflammation, de l’âge, de la grossesse et de la prise de contraception.

Détecte la plupart des types 1,une partie des types 2 et tous les types 3

  • Dosage de l’activité cofacteur de la ristocétine

C’est le test diagnostique.Il s'agit d'un test biologique qui apprécie l'activité fonctionnelle du facteur Willebrand.

Presque toujours diminué (excepté le type 2 N ) donc très spécifique

  • Etude de la distribution des multimères

Ne se pratique que dans des laboratoires de références de l’exploration de l’hémostase

  • Etude de l’agrégation à faible doses de ristocétine

Permet de diagnostiquer certains types de maladie de Willebrand

Diagnostic différentiel

La maladie de Willebrand a souvent été confondue avec l’hémophilie surtout de type A d’où son nom de pseudo hémophilie.

Traitement

Moyens

  • Desmopressine
  • Concentré de facteur VIII avec facteur de Von Willebrand
  • Acide tranexamique
  • Acide aminocaproïque

Indications

Type I

Type II et III

  • Le traitement fait appel aux concentrés de facteur VIII avec facteur de Von Willebrand

Mode de transmission

Sources

http://fr.wikipedia.org/wiki/Maladie_de_Willebrand

Von Willebrand disease

von Willebrand disease
Classification and external resources
ICD-10D68.0
ICD-9286.4
OMIM193400
DiseasesDB14007
eMedicineped/2419
MeSHD014842

von Willebrand disease (vWD) is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion. It is known to affect humans and dogs (notably Doberman Pinschers), and rarely in swine, cattle, horses, and cats. There are four types of hereditary vWD. Other factors including ABO blood groups may also play a part in the severity of the condition.

Contents

Signs and symptoms

The various types of vWD present with varying degrees of bleeding tendency, usually in the form of easy bruising, nosebleeds and bleeding gums. Women may experience heavy menstrual periods and blood loss during childbirth.

Severe internal or joint bleeding is rare (which only occurs in type 3 vWD).

Diagnosis

When suspected, blood plasma of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF. This is achieved by measuring the amount of vWF in a vWF antigen assay and the functionality of vWF with a glycoprotein (GP)Ib binding assay, a collagenbinding assay or, a ristocetin cofactor activity (RiCof) or ristocetin induced platelet agglutination (RIPA) assays. Factor VIII levels are also performed because factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels. Normal levels do not exclude all forms of vWD: particularly type 2 which may only be revealed by investigating platelet interaction with subendothelium under flow (PAF), a highly specialized coagulation study not routinely performed in most medical laboratories. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used. A platelet function assay (PFA) will give an abnormal collagen/adrenaline closure time and in most cases (but not all) a normal collagen/ADP time. Type 2N can only be diagnosed by performing a "factor VIII binding" assay. Detection of vWD is complicated by vWF being an acute phase reactant with levels rising in infectionpregnancy and stress.

Other tests performed in any patient with bleeding problems are a complete blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin timethrombin time and fibrinogen level. Testing for factor IX may also be performed if hemophilia Bis suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease will typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

Classification and types

Classification

There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type. There are inherited and acquired forms of vWD. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and Haemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects.[1]

Type 1

Type 1 vWD (60-80% of all vWD cases) is a quantitative defect (heterozygous for the defective gene) but may not have clearly impaired clotting, most patients usually end up leading a nearly normal life. Trouble may arise in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or menorrhagia (heavy periods). Decreased levels of vWF are detected (10-45% of normal, i.e. 10-45 IU).

Type 2

Type 2 vWD (20-30%) is a qualitative defect and the bleeding tendency can vary between individuals. There are normal levels of vWF, but the multimers are structurally abnormal, or subgroups of large or small multimers are absent. Four subtypes exist: 2A, 2B, 2M and 2N.

Type 2A

This is an abnormality of the synthesis or proteolysis of the vWF multimers resulting in the presence of small multimer units in circulation. Factor VIII binding is normal. It has a disproportionately low ristocetin co-factor activity compared to the von Willebrand's antigen.

Type 2B

This is a "gain of function" defect leading to spontaneous binding to platelets and subsequent rapid clearance of the platelets and the large vWF multimers. A mild thrombocytopenia may occur. The large vWF multimers are absent in the circulation and the factor VIII binding is normal. Like type 2A, the RiCof:vWF antigen assay is low when the patient's platelet-poor plasma is assayed against formalin-fixed, normal donor platelets. However, when the assay is performed with the patient's own platelets ("platelet-rich plasma"), a lower-than-normal amount of ristocetin causes aggregation to occur. This is due to the large vWF multimers remaining bound to the patient's platelets. Patients with this sub-type are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation.

Type 2M

Patients with type 2M von Willebrand disease have similar lab results to those who have type 2A von Willebrand disease. It is characterized by a platelet function deficiency and can be acquired by a gene mutation. This is caused by a decrease of high–molecular weight multimers. Decreased von Willebrand activity was observed in lab findings. However, the von Willebrand factor antigen, factor VIII, was found to be within the reference range.

Type 2N (Normandy)

This is a deficiency of the binding of vWF to factor VIII. This type gives a normal vWF antigen level and normal functional test results but has a low factor VIII. This has probably led to some 2N patients being misdiagnosed in the past as having hemophilia A, and should be suspected if the patient has the clinical findings of hemophilia A but a pedigree suggesting autosomal, rather than X-linked, inheritance.

Type 3

Type 3 is the most severe form of vWD (homozygous for the defective gene) and may have severe mucosal bleeding, no detectable vWF antigen, and may have sufficiently low factor VIII that they have occasional hemarthroses (joint bleeding), as in cases of mild hemophilia.

Platelet-type(also known as pseudo-vWD or platelet-type (pseudo) vWD) Platelet-type vWD is an autosomal dominant type of vWD caused by gain of function mutations of the vWF receptor on platelets; specifically, the alpha chain of the glycoprotein Ib receptor (GPIb). This protein is part of the larger complex (GPIb/V/IX) which forms the full vWF receptor on platelets. The ristocetin activity and loss of large vWF multimers is similar to type 2B, but genetic testing of VWF will reveal no mutations.

Acquired von Willebrand disease

Acquired vWD can occur in patients with autoantibodies. In this case the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.

A form of vWD occurs in patients with aortic valve stenosis, leading to gastrointestinal bleeding (Heyde's syndrome). This form of acquired vWD may be more prevalent than is presently thought.

Acquired vWD has also been described in the following disorders: Wilms' tumourhypothyroidism and mesenchymal dysplasias.

Pathophysiology

vWF is mainly active in conditions of high blood flow and shear stress. Deficiency of vWF therefore shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract and the uterus. In angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly.

In more severe cases of type 1 vWD, genetic changes are common within the vWF gene and are highly penetrant. In milder cases of type 1 vWD there may be a complex spectrum of molecular pathology in addition to polymorphisms of the vWF gene alone.[2] The individual'sABO blood group can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.[3]

Genetics

von Willebrand disease types I and II are inherited in an autosomal dominant pattern.
von Willebrand disease type III (and sometimes II) is inherited in anautosomal recessive pattern.

The vWF gene is located on chromosome twelve (12p13.2). It has 52 exons spanning 178kbp. Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally type 2 also inherits recessively.

Epidemiology

The prevalence of vWD is about 1 in 100 individuals.[4] However the majority of these people do not have symptoms. The prevalence of clinically significant cases is 100 per million.[4] Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation. It may be more severe or apparent in people with blood type O.

Therapy

Patients with vWD normally require no regular treatment, although they are always at increased risk for bleeding. For women with heavy menstrual bleeding, the combined oral contraceptive pill may be effective in reducing bleeding or in reducing the length or frequency of periods. Prophylactic treatment is sometimes given for patients with vWD who are scheduled for surgery. They can be treated with human derived medium purity factor VIII concentrates complexed to vWF (antihemophilic factor, more commonly known as Humate-P) Mild cases of vWD can be trialled on desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) (desmopressin acetate, Stimate), which works by raising the patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies in the endothelial cells.

History

vWD is named after Erik Adolf von Willebrand, a Finnish pediatrician (1870–1949).[5] He first described the disease in 1926.

Sources

See also

External links

http://en.wikipedia.org/wiki/Von_Willebrand_disease
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