von Willebrand disease
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von Willebrand disease | |
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autosomal dominant pattern. | |
Pronunciation | |
Specialty | Hematology |
Von Willebrand disease (VWD) is the most common hereditary blood-clotting disorder in humans. An acquired form can sometimes result from other medical conditions.[1] It arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. It is known to affect several breeds of dogs as well as humans. The three forms of VWD are hereditary, acquired, and pseudo or platelet type. The three types of hereditary VWD are VWD type 1, VWD type 2, and VWD type 3. Type 2 contains various subtypes.[2] Platelet type VWD is also an inherited condition.[3]
In 2008 a new diagnostic category of "Low VWF" was proposed to include those individuals whose von Willebrand factor levels were below the normal reference range but not low enough to be von Willebrand disease (levels in the 30-50 IU/dL range).[4] Patients with low VWF can experience bleeding, despite mild reductions in VWF levels.[5]
VWD type 1 is the most common type of the disorder, with mild bleeding symptoms such as
VWD type 2 is the second most common type of the disorder and has mild to moderate symptoms.
The factor is named after the Finnish physician Erik Adolf von Willebrand who first described the condition in 1926. Guidelines for the diagnosis and management of VWD were updated in 2021.[7][8]
Signs and symptoms
The various types of VWD present with varying degrees of
Severe internal bleeding and bleeding into joints are uncommon in all but the most severe type, VWD type 3.
Genetics
The VWF gene is located on the
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.
Pathophysiology
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]
Diagnosis
Basic tests performed in any patient with bleeding problems are a
When VWD is suspected,
ADP | Epinephrine | Collagen | Ristocetin | |
---|---|---|---|---|
P2Y receptor inhibitor or defect[15] | Decreased | Normal | Normal | Normal |
Adrenergic receptor defect[15] | Normal | Decreased | Normal | Normal |
Collagen receptor defect[15] | Normal | Normal | Decreased or absent | Normal |
Normal | Normal | Normal | Decreased or absent | |
Decreased | Decreased | Decreased | Normal or decreased |
A
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
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]
Type 1
Type 1 VWD (40
Many patients are asymptomatic or may have mild symptoms and not have clearly impaired
Trouble may, however, arise in some patients in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or
Type 2
Type 2 VWD (15[11]-50%[20] of cases) is a qualitative defect and the bleeding tendency can vary between individuals. Four subtypes exist: 2A, 2B, 2M, and 2N. These subtypes depend on the presence and behavior of the underlying multimers.[11]
Type 2A
VWD Type 2A results from a
Type 2B
This is a "gain of function" defect. The ability of the qualitatively defective VWF to bind to glycoprotein Ib (GPIb) receptor on the platelet membrane is abnormally enhanced, leading to its spontaneous binding to platelets and subsequent rapid clearance of the bound platelets and of the large VWF multimers. Thrombocytopenia may occur. Large VWF multimers are reduced or absent from the circulation.
The ristocetin cofactor activity 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 subtype are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation and aggravation of thrombocytopenia.
Type 2M
VWD Type 2M results from a
Type 2N (Normandy)
Type 2N VWD results from a
Type 3
VWD type 3 is a rare but the most severe form of VWD. It occurs in individuals who are
Comparison
Mechanism | Autosomal inheritance | vWF activity | RIPA | Multimer quantity | ||
---|---|---|---|---|---|---|
Type 1 | Decreased VWF quantity | Dominant | Decreased | Normal[12] or decreased[22] | Similar decrease among multimer types | |
Type 2 | A | Inability to form large multimers | Dominant or recessive | Decreased | Often decreased at high ristocetin concentrations[12] | Decreased large multimers |
B | Enhanced binding to GPIb receptor | Dominant | Decreased | Increased | Decreased large multimers | |
M | Decreased binding to GPIb receptor | Dominant or recessive | Decreased | Decreased at high ristocetin concentrations[12] | Similar decrease among multimer types | |
N | Decreased binding to factor VIII | Recessive | Normal | Normal | Normal | |
Type 3 | Absent VWF | Recessive | Absent or markedly decreased | Absent or markedly decreased | Usually undetectable |
Platelet-type
Platelet-type VWD (also known as pseudo-VWD) is an autosomal dominant genetic defect of the platelets. The VWF is qualitatively normal and genetic testing of the von Willebrand gene and VWF protein reveals no mutational alteration. The defect lies in the qualitatively altered GPIb receptor on the platelet membrane which increases its affinity to bind to the VWF. Large platelet aggregates and high molecular weight VWF multimers are removed from the circulation resulting in thrombocytopenia and diminished or absent large VWF multimers. The ristocetin cofactor activity and loss of large VWF multimers are similar to VWD type 2B.
Acquired
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.[medical citation needed]
A form of VWD occurs in patients with
Treatment
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.[medical citation needed]
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.[medical citation needed]
Desmopressin is a synthetic analog of the natural antidiuretic hormone vasopressin. Its overuse can lead to water retention and dilutional hyponatremia with consequent convulsion.[medical citation needed]
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.[medical citation needed]
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.[medical citation needed]
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.[medical citation needed]
Epidemiology
The prevalence of VWD is about one in 100 individuals.[27] However, the majority of these people do not have symptoms. The prevalence of clinically significant cases is one per 10,000.[27] 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.[28]
History
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.[29] He published another article on the disorder in 1931, in the German language, which attracted international attention in the disease.[30] The eponymous name was assigned to the disease between the late 1930s and the early 1940s, in recognition of von Willebrand's extensive research.[31]
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.
Other animals
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
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.[34]
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.[35]
In animals of other species affected by VWD, the causal mutations have not yet been identified.
Oral manifestations
In the case of severe deficiency, there may be spontaneous gingival bleeding,
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.[37]
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%.[37]
Dental considerations
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.[38]
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.[38]
See also
- Bernard–Soulier syndrome, caused by a deficiency in the VWF receptor, GPIb
- List of hematologic conditions
- Purpura
References
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- ^ "Von Willebrand Disease". hemophilia.org. 4 March 2014. Retrieved 4 April 2018.
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- ^ a b c d e National Hemophilia Federation (2014-03-05). "Von Willebrand Disease". National Hemophilia Federation. Retrieved 3 December 2017.
- ^ a b c d e Karen A. Moser; George M. Rodgers III; Kristi J. Smock. "Von Willebrand Disease - VWD". ARUP laboratories. Last Update: July 2020. Content Review: June 2020
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- ^ S2CID 260318180.
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- ^ a b Unless otherwise specified in boxes, reference is: Margaret E Rick. "Clinical presentation and diagnosis of von Willebrand disease". UpToDate. Literature review current through: Jan 2021. This topic last updated: Feb 05, 2021. In turn adapted from The National Heart, Lung and Blood Institute. The Diagnosis, Evaluation, and management of Von Willebrand Disease. National Institutes of Health Publication 08-5832, December 2007
- PMID 12878741.
- PMID 20598466.
- ^ "Vonvendi (von willebrand factor- recombinant kit". DailyMed. 13 February 2019. Retrieved 27 March 2020.
- ^ "Veyvondi EPAR". European Medicines Agency (EMA). 20 September 2018. Retrieved 27 March 2020.
- ^ PMID 15377463. Archived from the originalon 2011-10-02. Retrieved 2009-01-30.
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- S2CID 221750622.
- ISBN 978-1447114154.
- S2CID 11256355. Archived from the original(PDF) on 2018-06-20.
- ^ "Canine von Willebrand Disease - Breed Summaries". ahdc.vet.cornell.edu. 2019-02-08.
- ^ "Canine von Willebrand Disease". vetgen.com.
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- ^ "Hemophilia A" (PDF). College of Dental Hygienists of Ontario. September 2, 2015.
- ^ ISBN 978-1-60795-188-9.
- ^ a b Andrew Brewer, Maria Elvira Correa (May 2006). "Guildelines for Dental Treatment of Patients with Inherited Bleeding Disorders" (PDF). Treatment of Hemophilia. 40: 9 – via World Federation of Hemophilia (WFH).
Further reading
- Harrison's textbook of Internal Medicine, Chapter 177.
- Sadler JE (1998). "Biochemistry and genetics of von Willebrand factor". Annual Review of Biochemistry. 67: 395–424. PMID 9759493.
- Mannucci PM (August 2004). "Treatment of von Willebrand's Disease". The New England Journal of Medicine. 351 (7): 683–94. PMID 15306670.
- Laffan M, Brown SA, Collins PW, Cumming AM, Hill FG, Keeling D, Peake IR, Pasi KJ (May 2004). "The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization". Haemophilia. 10 (3): 199–217. S2CID 731315.
- Williams Hematology, 7th edition, Grune and Stratton, chapters 112 (p. 1806) and 118 (p. 1937)
External links
- 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).