Willebrand disease is a congenital pathology of hemostasis, manifested by quantitative and qualitative deficiency of Willebrand plasma factor and increased bleeding. Willebrand disease is characterized by spontaneous formation of subcutaneous petechiae, ecchymoses; recurrent bleeding from the nose, gastrointestinal tract, uterine cavity; excessive blood loss after injuries and operations, hemarthrosis. The diagnosis is established according to the family history, clinical picture and laboratory screening of the hemostasis system. In Willebrand disease, transfusion of antihemophilic plasma, local and general hemostatic agents, antifibrinolytics are used.
D68.0 Willebrand’s disease
Willebrand disease (angiohemophilia) is a type of hereditary hemorrhagic diathesis caused by a lack or reduced activity of the plasma component of the VIII-th blood clotting factor – Willebrand factor (VWF). Willebrand disease is a common pathology of blood clotting, occurring with a frequency of 1-2 cases per 10,000 people, and among hereditary hemorrhagic diathesis is in 3rd place after thrombocytopathies and hemophilia A. Willebrand disease is equally diagnosed in both sexes, but due to a more severe course it is more often detected in women. The disease can be combined with connective tissue dysplasia, ligament weakness and joint hypermobility, increased skin extensibility, heart valve prolapse (Ehlers-Danlos syndrome).
Causes of Willebrand disease
Willebrand disease is a genetically determined pathology caused by mutations of the VWF factor gene localized in chromosome 12. The inheritance of Willebrand disease types I and II is autosomal dominant with incomplete penetrance (patients are heterozygotes), type III is autosomal recessive (patients are homozygotes). In type III Willebrand disease, there are deletions of large sections of the VWF gene, mutations or a combination of these defects. At the same time, both parents usually have a mild course of type I disease.
Acquired forms of Willebrand disease can occur as a complication after multiple hemotransfusions, against the background of systemic (SLE, rheumatoid arthritis), cardiac (aortic valve stenosis), oncological (nephroblastomas, Wilms tumors, macroglobulinemia) diseases. These forms of Willebrand disease are associated with the formation of autoantibodies to VWF, selective absorption of oligomers by tumor cells or defects in platelet membranes.
Willebrand disease is based on quantitative (types I and III) and qualitative (type II) violation of the synthesis of Willebrand factor – a complex plasma glycoprotein, which is a complex of oligomers (from dimers to multimers). Willebrand factor is secreted by vascular endothelial cells and megakaryocytes in the form of a proprotein, enters the blood and subendothelial matrix, where it is deposited in platelet a-granules and Weible-Pallas corpuscles.
Willebrand factor is involved in vascular-platelet (primary) and coagulation (secondary) hemostasis. VWF is a subunit of antihemophilic globulin (blood clotting factor VIII), providing its stability and protection against premature inactivation. Due to the presence of specific receptors, the Willebrand factor mediates the strong adhesion of blood platelets (platelets) to subendothelial structures and aggregation among themselves at the sites of damage to blood vessels.
The level of VWF in blood plasma is normally 10 mg / l, temporarily increases with physical activity, pregnancy, stress, inflammatory and infectious processes, taking estrogens; constitutionally reduced in persons with blood group I. The activity of the Willebrand factor depends on its molecular weight, the largest thrombogenic potential is observed in the largest multimers.
There are several clinical types of Willebrand disease – classic (type I); variant forms (type II); severe form (type III) and platelet type.
- With the most common (70-80% of cases) In type I of the disease, there is a slight or moderate decrease in the level of Willebrand factor in plasma (sometimes slightly less than the lower limit of the norm). The spectrum of oligomers has not been changed, but the constant presence of superheavy VWF multimers is noted in the form of a Winche.
- In type II (20-30% of cases), there are qualitative defects and a decrease in the activity of the Willebrand factor, the level of which is within the normal limits. The reason for this may be the absence or deficiency of high- and medium-molecular oligomers; excessive affinity (affinity) to platelet receptors, decreased ristomycin-cofactor activity, impaired binding and inactivation of factor VIII.
- In type III, the Willebrand factor is almost completely absent in plasma, the activity of factor VIII is low. Platelet type (pseudo-Willebrand disease) is observed with normal VWF content, but increased binding of it to the corresponding altered platelet receptor.
Symptoms of Willebrand disease
Willebrand disease is manifested by hemorrhagic syndrome of varying intensity – mainly petechial-bruising, bruising-hematomic, less often – hematomic types, which is determined by the severity and variant of the disease.
Mild forms of Willebrand disease of types I and II are characterized by spontaneous occurrence of nosebleeds, small and moderate intradermal and subcutaneous hemorrhages (petechiae, ecchymoses), prolonged bleeding after injuries (cuts) and surgical manipulations (tooth extraction, tonsillectomy, etc.). Girls have menorrhagia, uterine bleeding, and women in labor have excessive blood loss during childbirth.
In type III and severe cases of types I and II of Willebrand disease, the clinical picture may resemble the symptoms of hemophilia. There are frequent subcutaneous hemorrhages, painful soft tissue hematomas, bleeding from injection sites. Hemorrhages occur in large joints (hemarthrosis), prolonged uncupable bleeding during operations, injuries, profuse bleeding from the nose, gums, gastrointestinal tract and urinary tract. The formation of rough post-traumatic scars is typical.
With a severe course of Willebrand’s disease, hemorrhagic syndrome manifests itself already in the first months of a child’s life. Hemosyndrome in Willebrand’s disease proceeds with alternating exacerbation and almost complete (or complete) disappearance of manifestations, but with a pronounced severity can lead to severe posthemorrhagic anemia.
Family history, clinical picture and laboratory screening data of vascular platelet and plasma hemostasis play an important role in the recognition of Willebrand’s disease. A general and biochemical blood test is prescribed, a coagulogram with determination of platelet and fibrinogen levels, clotting time; PTI and APTT, a pinch test and a tourniquet test are carried out. From general examinations, it is recommended to determine the blood group, a study of a general urine analysis, a stool analysis for hidden blood, an ultrasound of the abdominal cavity.
To confirm the fact of Willebrand’s disease, the level of VWF in the blood serum and its activity, ristocetin-cofactor activity are determined using immunoelectrophoresis and ELISA methods. In Willebrand’s disease type II, with normal levels of VWF and VIII factors, the study of platelet activation factor (PAF), activity of coagulation factor VIII, platelet aggregation is informative. Patients with Willebrand’s disease are characterized by a combination of reduced levels and activity of VWF in the blood serum, prolonged bleeding time and APTT, impaired adhesive and aggregation function of platelets.
Willebrand’s disease requires differential diagnosis with hemophilia, hereditary thrombocytopathies. In addition to consulting a hematologist and a geneticist, additional examinations are carried out by an otolaryngologist, dentist, gynecologist, gastroenterologist.
Treatment of Willebrand disease
Regular treatment of Willebrand’s disease with low-symptomatic and moderate hemosyndrome is not carried out, but patients still have an increased risk of bleeding. Treatment is prescribed in case of their occurrence during childbirth, with injuries, menorrhagia, hemarthrosis, prophylactically – before surgical and dental intervention. The purpose of such therapy is to provide the minimum necessary level of deficient blood clotting factors.
Transfusion of antihemophilic plasma and cryoprecipitate (with a high VWF content) at doses lower than in hemophilia is indicated as replacement therapy. In Willebrand’s disease type I, desmopressin is effective for stopping bleeding. For mild and moderate forms of hemorrhages, aminocaproic acid, tranexamic acid can be used. To stop bleeding from the wound, a hemostatic sponge, fibrin glue is used. With recurrent uterine bleeding, COCs are used, in the absence of a positive result, a hysterectomy is performed – surgical removal of the uterus.
Prognosis and prevention
In the case of adequate hemostatic treatment, Willebrand’s disease usually proceeds relatively favorably. The severe course of Willebrand’s disease can lead to severe posthemorrhagic anemia, fatal bleeding after childbirth, serious injuries and operations, sometimes subarachnoid hemorrhages and hemorrhagic stroke. In order to prevent Willebrand’s disease, it is necessary to exclude marriages between patients (including relatives), in the presence of a diagnosis – exclude the use of NSAIDs, antiplatelet drugs, avoid injuries, accurately follow the doctor’s recommendations.