von Willebrand disease

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.[9][10]

Severe internal bleeding and bleeding into joints are uncommon in all but the most severe type, VWD type 3.

The VWF gene is located on the short arm p of chromosome 12 (12p13.2). It has 52 exons spanning 178kbp. Types 1 and 2 are inherited as autosomal dominant traits. Occasionally, type 2 also inherits recessively. Type 3 is inherited as autosomal recessive. However, some individuals heterozygous for type 3 may be diagnosed with VWD type 1, indicating an intermediate inheritance in those cases. VWD occurs in approximately 1% of the population and affects men and women equally. [11]

Genetic testing is typically not part of the initial workup for von Willebrand disease, and is not needed for people diagnosed with type 1 VWD based on clinical history and laboratory tests.[12] It is mainly useful for:[12]

• Evaluating family members of individuals who have known variants.
• Differentiating between type 2B and platelet-type VWD, as well as between type 2N VWD and hemophilia A.

Von Willebrand factor 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 skin, gastrointestinal tract, and 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, a complex spectrum of molecular pathology may exist in addition to polymorphisms of the VWF gene alone.[13]

The individual's ABO 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.[14]

Basic tests performed in any patient with bleeding problems are a complete blood count-CBC (especially platelet counts), activated partial thromboplastin time-APTT, prothrombin time with International Normalized Ratio-PTINR, thrombin time-TT, and fibrinogen level. Patients with abnormal tests typically undergo further testing for hemophilias. Other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

When VWD is suspected, blood plasma of a patient must 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 collagen binding 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 then lead to a reduction in factor VIII levels, which explains the elevation in PTT. 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, 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 may give an abnormal collagen/epinephrine closure time, and in most cases, a normal collagen/ADP time. Type 2N may be considered if factor VIII levels are disproportionately low, but confirmation requires a "factor VIII binding" assay. Additional laboratory tests that help classify sub-types of VWD include von Willebrand multimer analysis, modified ristocetin induced platelet aggregation assay and VWF propeptide to VWF propeptide antigen ratio. In cases of suspected acquired von Willebrand syndrome, a mixing study (analysis of patient plasma along with pooled normal plasma/PNP and a mixture of the two tested immediately, at one hour, and at two hours) should be performed.[16] Detection of VWD is complicated by VWF being an acute-phase reactant with levels rising in infection, pregnancy, and stress.

The testing for VWD can be influenced by laboratory procedures. Numerous variables exist in the testing procedure that may affect the validity of the test results and may result in a missed or erroneous diagnosis. The chance of procedural errors are typically greatest during the preanalytical phase (during collecting storage and transportation of the specimen) especially when the testing is contracted to an outside facility and the specimen is frozen and transported long distances.[17] Diagnostic errors are not uncommon, and the rate of testing proficiency varies amongst laboratories, with error rates ranging from 7 to 22% in some studies to as high as 60% in cases of misclassification of VWD subtype. To increase the probability of a proper diagnosis, testing should be done at a facility with immediate on-site processing in a specialized coagulation laboratory.[18][19]

Types

Pie chart of relative incidences of von Willebrand disease types in South Africa. Platelet-type was <0.5% of cases.[20]

The four hereditary types of VWD described are type 1, type 2, type 3, and pseudo- or platelet-type. Most cases are hereditary, but acquired forms of VWD have been described. The International Society on Thrombosis and Haemostasis's classification depends on the definition of qualitative and quantitative defects.[21]

von Willebrand disease type III (and sometimes II) is inherited in an autosomal recessive pattern.

For patients with VWD type 1 and VWD type 2A, desmopressin is available as different preparations, recommended for use in cases of minor trauma, or in preparation for dental or minor surgical procedures. Desmopressin stimulates the release of VWF from the Weibel–Palade bodies of endothelial cells, thereby increasing the levels of VWF (as well as coagulant factor VIII) three- to five-fold. Desmopressin is also available as a preparation for intranasal administration (Stimate) and as a preparation for intravenous administration. Desmopressin is contraindicated in VWD type 2b because of the risk of aggravated thrombocytopenia and thrombotic complications. Desmopressin is probably not effective in VWD type 2M and is rarely effective in VWD type 2N. It is totally ineffective in VWD type 3.

For women with heavy menstrual bleeding, estrogen-containing oral contraceptive medications are effective in reducing the frequency and duration of the menstrual periods. Estrogen and progesterone compounds available for use in the correction of menorrhagia are ethinylestradiol and levonorgestrel (Levona, Nordette, Lutera, Trivora). Administration of ethinylestradiol diminishes the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary, leading to stabilization of the endometrial surface of the uterus.

Desmopressin is a synthetic analog of the natural antidiuretic hormone vasopressin. Its overuse can lead to water retention and dilutional hyponatremia with consequent convulsion.

For patients with VWD scheduled for surgery and cases of VWD disease complicated by clinically significant hemorrhage, human-derived medium purity factor VIII concentrates, which also contain von Willebrand factors, are available for prophylaxis and treatment. Humate P, Alphanate, Wilate and Koate HP are commercially available for prophylaxis and treatment of VWD. Monoclonally purified factor VIII concentrates and recombinant factor VIII concentrates contain insignificant quantity of VWF, so are not clinically useful.

Development of alloantibodies occurs in 10-15% of patients receiving human-derived medium-purity factor VIII concentrates and the risk of allergic reactions including anaphylaxis must be considered when administering these preparations. Administration of the latter is also associated with increased risk of venous thromboembolic complications.

Blood transfusions are given as needed to correct anemia and hypotension secondary to hypovolemia. Infusion of platelet concentrates is recommended for correction of hemorrhage associated with platelet-type VWD.

Vonicog alfa is a recombinant von Willebrand factor that was approved for use in the United States in December 2015, and for use in the European Union in August 2018.[26][27]

The prevalence of VWD is about one in 100 individuals.[28] However, the majority of these people do not have symptoms. The prevalence of clinically significant cases is one per 10,000.[28] 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.[29]

In 1924, a 5-year-old girl from Föglö, Åland, Finland, was brought to the Deaconess Hospital in Helsinki, where she was seen by Finnish physician Erik Adolf von Willebrand. He ultimately assessed 66 members of her family and reported in a 1926 Swedish-language article that this was a previously undescribed bleeding disorder that differed from hemophilia.[30] He published another article on the disorder in 1931, in the German language, which attracted international attention in the disease.[31] The eponymous name was assigned to the disease between the late 1930s and the early 1940s, in recognition of von Willebrand's extensive research.[32]

In the 1950s, it became clear that a "plasma factor", factor VIII, was decreased in these persons and that Cohn fraction I-0 could correct both the plasma deficiency of FVIII and the prolonged bleeding time. Since this time, the factor causing the long bleeding time was called the "von Willebrand factor" in honor of Erik Adolf von Willebrand.

Variant forms of VWF were recognized in the 1970s, and these variations are now recognized as the result of synthesis of an abnormal protein. During the 1980s, molecular and cellular studies distinguished hemophilia A and VWD more precisely. Persons who had VWD had a normal FVIII gene on the X chromosome, and some had an abnormal VWF gene on chromosome 12. Gene sequencing identified many of these persons as having a VWF gene mutation. The genetic causes of milder forms of low VWF are still under investigation, and these forms may not always be caused by an abnormal VWF gene.

VWD can also affect dogs, pigs, and mice. Furthermore, cases have been reported in cats, horses, cattle, and rabbits.

The causal mutation for VWD type 1 was identified in dogs of the breeds Doberman Pinscher, German Pinscher, Bernese Mountain Dog, Manchester Terrier, Kerry Blue Terrier, Cardigan Welsh Corgi, Poodle, Coton de Tulear, Drentse Patrijshond, Papillon, and Stabyhoun. Causal mutations for type 2 were identified in dogs of the breeds German Wirehaired Pointer, German Shorthaired Pointer, and Chinese Crested; and for type 3 in dogs of the breeds Kooikerhondje, Scottish Terrier and Shetland Sheepdog. In dogs affected by type 1 VWD, the causal mutation was the same across all breeds and the same mutation was also detected in some human VWD type 1 patients. In contrast, the mutations causing VWD type 3 in dogs are specific to each breed. Genetic screening is offered for known breeds.[33][34]

In pigs, the causal mutation for VWD type 3 has also been identified. It is a large duplication within the VWF gene and causes serious damage to the gene function, so that virtually no VWF protein is produced. The clinical picture in pigs is most similar to that in humans with VWD type 3. Therefore, those pigs are valuable models for clinical and pharmacological research.[35]

Mice affected by VWD type 3 were produced by genetic engineering to obtain a small sized model for the human disease. In these strains, the VWF gene has been knocked out.[36]

In animals of other species affected by VWD, the causal mutations have not yet been identified.

In the case of severe deficiency, there may be spontaneous gingival bleeding, ecchymosis, and epistaxis. Symptoms of VWD include postoperative bleeding, bleeding after dental extraction, gingival bleeding, epistaxis and easy bruising. The intake of oral contraceptives as the first-line treatment for menorrhagia may lead to gingival enlargement and bleeding in women.[37]

Platelet or coagulation disorders with severely altered hemostasis can cause spontaneous gingival bleeding, as seen in conjunction with hyperplastic hyperemic gingival enlargements in leukemic patients. Deposition of hemosiderin and other blood degradation products on the tooth surfaces turning them brown can occur with continuous oral bleeding over long periods.[38]

The location of oral bleeds was as follows: labial frenum, 60%; tongue, 23%; buccal mucosa, 17% and gingiva and palate, 0.5%. Severe hemophilia will have most frequent bleeding occurrences, followed by moderate and then mild hemophilia. They mostly come from traumatic injuries. Bleeding will also be induced by iatrogenic factors and poor oral hygiene practices. The frequency of oral hemorrhage by location in people with deficiency of F VIII and F IX is: gingiva, 64%; dental pulp, 13%; tongue, 7.5%; lip, 7%; palate, 2% and buccal mucosa, 1%.[38]

The protocols suggest the use of factor concentrate along with the use of local hemostatic techniques, such as suturing, and local measures, such as the use of oxidized cellulose, for example, Surgicel or fibrin glue in conjunction with post-operatively administered antifibrinolytic agents where appropriate.[39]

The use of any non-steroidal anti-inflammatory drug (NSAID) must be discussed beforehand with the patient's hematologist because of their effect on platelet aggregation. There are no restrictions regarding the type of local anaesthetic agent used although those with vasoconstrictors may provide additional local hemostasis.[39]

• Bernard–Soulier syndrome, caused by a deficiency in the VWF receptor, GPIb
• List of hematologic conditions
• Purpura

• GeneReviews/NCBI/NIH/UW entry on von Willebrand Disease
• NHLBI von Willebrand Disease Expert Panel (January 2008). The Diagnosis, Evaluation and Management of von Willebrand Disease. National Heart, Lung, and Blood Institute (Report).