Von Willebrand Disease

What is Von Willebrand Disease?

The disease was first studied in 1926 by the scientist Willebrand, who on the Aland Islands described a family with a kind of autosomal dominantly inherited hemorrhagic diathesis, similar to thrombocytomatopathy and hemophilia. It was noted that members of this family suffer from the classic form of the disease belonging to type I. Confirmed dominant inheritance with different manifestations of the pathological gene. This makes Willebrand disease different from hemophilia, which is severely inherited and in which all sick family members in different generations have the same severity of factor VIII deficiency.

According to the prevalence among all hereditary hemorrhagic diathesis, Willebrand disease ranks 3rd after thrombocytopathy and hemophilia A.

The basis of the pathogenetic mechanisms of von Willebrand disease is a violation of the synthesis of the main large-molecular component of factor VIII, also called von Willebrand factor.

According to the above characteristics, there is a “classic” type of von Willebrand disease (type I), in which there is a more or less pronounced paresis of the synthesis of the considered factor with a concordant decrease in plasma of all its components and a corresponding absence or decrease in the vascular endothelium.

Variant forms of the disease (type II) differ from this type, in which there are qualitative anomalies of the multimeric structure and properties of the components of factor VIII.

The disease by the dominance of the deficiency of the components of factor VIII is attributed to plasma defects of hemostasis. With more in-depth examination with no less right, it can be attributed to primary vascular diseases, since the basis of the disease is the weakening or distortion of the synthesis of von Willebrand factor in the endothelium of blood vessels – the only place of its formation in the body.

The old name of the disease “angiohemophilia” is very close to the correct understanding of its essence, although it is rarely used nowadays.

Symptoms of Von Willebrand Disease

The severity of hemorrhagic syndrome in Willebrand disease varies from very mild forms with rarely observed nasal bleeding and small hemorrhages into the skin to extremely severe variants with very frequent, prolonged and abundant bleeding of various localization, the formation of hematomas and large hemorrhages in the soft tissues and in the internal organs. Sometimes there are hemorrhages in the joints.

Hemorrhagic syndrome in type I is much harder than in types IIA and IIB of the disease.

It should be noted that the intensity of bleeding of the most varied localization (gastrointestinal, uterine, nasal) often does not correspond to the violation of coagulative and vascular-platelet hemostasis.

In particular, against the background of moderate violations in these links of hemostasis, catastrophic bleeding of any one localization persists. In such cases, you should think about some additional local vascular or stromal dysplasia, provoking bleeding. To identify them, a thorough additional study of the mucous membranes of the nose, throat and pharynx, oral cavity, stomach and intestines (rhinoscopy, laryngoscopy, fibroduodenogastroscopy, colonoscopy) is necessary. On the mucous membranes are often found vascular formations in the form of superficially located dilated and tortuous vessels with a diameter of 1-2 mm, easily giving abundant, difficult to stop bleeding.

It is known that such vascular formations, more often – arteriovenous fistula, cause recurrent gastrointestinal bleeding. These fistulas are most dangerous for von Willebrand disease, when the basic mechanisms for the relief of bleeding are violated.

It should be noted that the combination of von Willebrand disease with angiodysplasia and other connective tissue defects cannot be considered accidental. In patients with this disease, prolapse of mitral and other valves of the heart is often detected, mistakenly diagnosed without echocardiography as rheumatic mitral heart disease.

In the same light, combination of von Willebrand disease with hyperelastosis of the skin, weakness of the ligamentous apparatus (frequent and habitual dislocations, loose joints, less often – Marfan syndrome) should be considered.

The intensity of bleeding is directly dependent on the level of factor VIII in the plasma, which should be taken into account both in injuries and in surgical interventions.

When making a diagnosis of von Willebrand disease, they are based on a combination of the following signs: autosomal dominant inheritance of the disease, bleeding, significant lengthening of the bleeding time.

A number of important functional characteristics are added to the main diagnostic features that facilitate the recognition of reduced variants of von Willebrand disease.

In Willebrand disease, a gradual rather than an immediate increase in the activity of factor VIII in the plasma of patients after the transfusion of antihemophilic plasma is detected.

The corrective effect of transfusion far exceeds the amount of factor VIII administered.

Noteworthy is a significantly longer than with hemophilia, the duration of a single transfusion effect is about 36 hours, which is characterized by a longer lifespan in the circulation of the recipient of factor VIII.

The most informative quantitative determination of von Willebrand factor in the patient’s plasma.

These diagnostic signs make it possible in most cases to clearly argue the diagnosis of von Willebrand disease, to determine its severity and shape.

Capillaroscopic changes (irregularity and twisted capillary loops, their club-shaped extensions) are not used in the diagnosis of von Willebrand disease, because they are detected in less than half of patients and are far from pathognomonic, but at the same time they are very demonstrative and contribute to proper diagnosis.

The autosomal recessive form of von Willebrand disease is an independent disease. In heterozygotes, the disease is completely or almost asymptomatic, whereas homozygotes show extremely heavy bleeding in the almost complete absence of factor VIII in the plasma. However, damage to the joints and other parts of the musculoskeletal system, despite such a significant deficit of factor VIII, is still much easier than with hemophilia.

Willebrand Disease Treatment

The most important pathogenetic point in therapy, contributing to the normalization (often only temporarily) of all impaired hemostatic functions, is transfusion therapy – the administration of hemograms containing factor VIII complex, including von Willebrand factor.

For this purpose, antihemophilic plasma and cryoprecipitate are most often used.

In addition, under the influence of Willebrand factor introduced from the outside, the own production of factor VIII increases, therefore, Willebrand disease replacement therapy requires much more rare transfusions and smaller doses of hemografts than the treatment of hemophilia A. Single transfusions of antihemophilic plasma or cryoprecipitate raise the level of factor VIII by the end of the first day up to 100%, after which its concentration above 50% is maintained independently for 36 hours. However, the concentration of the von Willebrand factor itself decreases earlier, in strength which platelet-vascular hemostasis again disrupted at still higher level VIIIk plasma. This explains the fact that in von Willebrand disease transfusion therapy more steadily and reliably maintains the level of factor VIII and prevents postoperative bleeding than it suppresses microcirculatory bleeding (uterine and nasal). In this regard, the most appropriate introduction of hemopreparations (antihemophilic plasma, cryoprecipitate) at least 1 time in 2 days and in a single dose of not less than 15 U / kg.

Correction develops gradually, therefore, before surgical interventions, transfusions begin 2-4 days before the operation, and during childbirth – at the very beginning of labor.

The indications for replacement therapy are abundant and prolonged bleeding of any localization, although such treatment is not always effective for uterine bleeding.

Platelet transfusions for von Willebrand disease are ineffective, since platelet dysfunction is secondary in this disease. For the same reason, in Willebrand disease, many pharmacological drugs used for thrombocytopathy, ATP, magnesium salts, serotonin, etc., proved to be ineffective.

Fundamentally new is the use of the arginine-terminal synthetic analogue of vasopressin in the treatment of Willebrand disease.

In light and moderate diseases, the effectiveness of aminocaproic acid in doses of up to 0.2 g / (kg / day) has been proven, which is used for all microcirculatory bleeding, including uterine bleeding from the first day of the menstrual cycle until the end of menstruation.

The joint use of aminocaproic acid, contraceptive drugs and cryoprecipitate should be avoided, since such treatment may be complicated by disseminated intravascular coagulation of blood or thrombosis. Nosebleeds are arrested in the same way as for hemophilia.

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