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===Laboratory Findings===
===Laboratory Findings===
==Overview==
The diagnosis of [[von Willebrand’s disease]] [[(VWD)]] begins with a relevant personal or family history of [[mucocutaneous bleeding]]. When [[VWD]] is suspected, several levels of testing are needed in order to make diagnosis<ref name="pmid25858564">{{cite journal |vauthors=Bodó I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di Paola J |title=Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH |journal=J. Thromb. Haemost. |volume=13 |issue=7 |pages=1345–50 |year=2015 |pmid=25858564 |doi=10.1111/jth.12964 |url=}}</ref><ref name="pmid21148813">{{cite journal |vauthors=Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, Haberichter SL, Hoffmann RG, Montgomery RR |title=Gain-of-function GPIb ELISA assay for VWF activity in the Zimmerman Program for the Molecular and Clinical Biology of VWD |journal=Blood |volume=117 |issue=6 |pages=e67–74 |year=2011 |pmid=21148813 |pmc=3056647 |doi=10.1182/blood-2010-08-299016 |url=}}</ref><ref name="pmid25673639">{{cite journal |vauthors=Sanders YV, Groeneveld D, Meijer K, Fijnvandraat K, Cnossen MH, van der Bom JG, Coppens M, de Meris J, Laros-van Gorkom BA, Mauser-Bunschoten EP, Leebeek FW, Eikenboom J |title=von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease |journal=Blood |volume=125 |issue=19 |pages=3006–13 |year=2015 |pmid=25673639 |doi=10.1182/blood-2014-09-603241 |url=}}</ref><ref>{{Cite journal
| author = [[F. Stufano]], [[A. S. Lawrie]], [[S. La Marca]], [[C. Berbenni]], [[L. Baronciani]] & [[F. Peyvandi]]
| title = A two-centre comparative evaluation of new automated assays for von Willebrand factor ristocetin cofactor activity and antigen
| journal = [[Haemophilia : the official journal of the World Federation of Hemophilia]]
| volume = 20
| issue = 1
| pages = 147–153
| year = 2014
| month = January
| doi = 10.1111/hae.12264
| pmid = 24028703
}}</ref>
Initail tests involve measurement of [[VWF]] antigen (VWF:Ag) level, [[Factor VIII]] activity (FVIII:C) and VWF–ristocetin cofactor activity [VWF:RCo].
When the results of all first-level tests are normal, VWD is ruled out; because of biologic variability, however, the tests should be repeated if values are at the low end of the normal range or if VWD is strongly suspected.<ref name="pmid25673639" />
Persons with a bleeding tendency who have VWF levels between 30 and 50 IU per deciliter (the lower limit of the normal range) are classified as having “low VWF” or “possible type 1 disease” but are not classified as having definitive VWD.<ref name="pmid25673639">{{cite journal |vauthors=Sanders YV, Groeneveld D, Meijer K, Fijnvandraat K, Cnossen MH, van der Bom JG, Coppens M, de Meris J, Laros-van Gorkom BA, Mauser-Bunschoten EP, Leebeek FW, Eikenboom J |title=von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease |journal=Blood |volume=125 |issue=19 |pages=3006–13 |year=2015 |pmid=25673639 |doi=10.1182/blood-2014-09-603241 |url=}}</ref>
When von Willebrand factor antigen is undetectable (or the level is <5 IU per deciliter, according to the latest disease classification), type 3 von Willebrand’s disease is diagnosed<ref name="pmid16889557">{{cite journal |vauthors=Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB |title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor |journal=J. Thromb. Haemost. |volume=4 |issue=10 |pages=2103–14 |year=2006 |pmid=16889557 |doi=10.1111/j.1538-7836.2006.02146.x |url=}}</ref><ref name="pmid25673639">{{cite journal |vauthors=Sanders YV, Groeneveld D, Meijer K, Fijnvandraat K, Cnossen MH, van der Bom JG, Coppens M, de Meris J, Laros-van Gorkom BA, Mauser-Bunschoten EP, Leebeek FW, Eikenboom J |title=von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease |journal=Blood |volume=125 |issue=19 |pages=3006–13 |year=2015 |pmid=25673639 |doi=10.1182/blood-2014-09-603241 |url=}}</ref>
If these first-level tests reveal definitive abnormalities, a diagnosis of [[VWD]] can be made; if the results are not conclusive, second-level tests are required.
Second level testing involves repeating the initial tests and then measurement of VWF multimer distribution using gel electrophoresis and ristocetin-induced platelet aggregation (RIPA).
Other tests performed in any patient with bleeding problems include: [[complete blood count]] (especially [[platelet]] counts), [[APTT]] (activated partial thromboplastin time), [[prothrombin time]],
[[thrombin]] time, [[fibrinogen]] level, testing for [[factor IX]] if [[hemophilia B]] is suspected and 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.


===Imaging Findings===
===Imaging Findings===

Revision as of 16:11, 28 December 2016

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

Overview

Von Willebrand’s disease is an genetic coagulation disorder with resultant abnormality in platelet adhesion and aggregation. Von Willebrand disease (vWD) is the most common genetic coagulation disorder described in humans.[1] It affects up to 1% of the population, although most cases are mild. Symptomatic vWD is much rare, ~1 in 10000. Von Willebrand disease arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a large glycoprotein protein that is required for platelets to bind to collagen. vWF is therefore important in primary hemostasis. When the disease comes to medical attention, it usually presents in the typical manner for platelet disorders: mucosal bleeding and easy bruising. The disease is usually inherited in an autosomal dominant manner, although there are recessive forms as well, and it can also be acquired secondary to another disease. [2][3][4]

Historical Perspective

  • In the mid 1950s it was recognized that Von Willebrand's disease was usually accompanied by the following:[7]
    • A decreased level of coagulation factor VIII (FVIII) activity
    • Bleeding phenotype could be corrected by the infusion of normal plasma.
  • In the early 1970s the immunologic distinction between FVIII and von Willebrand factor was made.[7]
  • In the 1980s, cloning of the VWF gene was investigated which has facilitated investigation into the genetic basis of VWD.[7][8][9][10][11]

Classification

There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type.[12] 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 Hemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects.[13][12] The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD.[14]

Pathophysiology

In healthy individuals, VWF circulates as high-molecular-weight multimers carrying factor VIII. Some persons have mildly reduced VWF levels, which may contribute to a bleeding phenotype but are not necessarily caused by defects in the VWF gene. Persons with low VWF levels and a bleeding tendency are classified as having low VWF, rather than von Willebrand’s disease (VWD). There is a partial deficiency of functionally normal VWF in type 1 VWD and a complete deficiency in type 3 disease. This deficiency can result from a reduction in protein synthesis, which is often caused by null alleles (large gene deletions, stop codons, frame-shift mutations, or splice-site mutations) but may also be due to mutations in the promotor regions. Homozygosity or compound heterozygosity for these defects results in type 3 VWD. Some heterozygous carriers have mild symptoms and receive a diagnosis of type 1 disease. However, most cases of type 1 VWD are caused by heterozygous missense mutations that exert a dominant-negative effect because the mutant subunits are incorporated into the multimer together with the normal subunits, resulting in a abnormality of the entire multimer. Almost all cases of type 2 VWD are caused by missense mutations, which are usually restricted to specific functional domains. Inheritance of subtypes of type 2 disease is autosomal dominant, with the exception of type 2N,[15] which has a recessive pattern of inheritance. Patients may be either homozygous for two type 2N mutations or compound heterozygous for a type 1 defect and a type 2N defect. 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. Deficiency of vWF shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract and the uterus. 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.[16] 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.[17]

Von Willebrand's Disease is usually inherited in an autosomal dominant manner, although there are recessive forms as well, and it can also be acquired secondary to another disease.[18][19][20][21][22][23][24][25] Acquired VWD is associated with other diseases resulting from different pathological processes example, impaired vWF function, enhanced proteolysis, decreased synthesis and antibody formation resulting in increased clearance of VWF.[26][27]

Causes

VWD is caused by a quantitative or qualitative defect in vWF. Von Willebrand Factor binds platelets to collagen and is important in primary hemostasis. It also serves as a carrier for Factor VIII and prevents it form being degraded. Most cases of vWD are due to inherited mutations that affect production of vWF. There are also acquired forms of vWD where vWF is impaired due to other pathological processes. Acquired defects in vWF can be caused by a number of conditions example mitral valve prolapse, ventricular assist device, ventricular septal defect, aortic stenosis, monoclonal gammopathy of undetermined significance, leukemia example chronic myeloid leukemia and chronic lymphocytic leukemia, wilms tumor, waldenström macroglobulinemia,essential thrombocythemia, multiple myeloma, non-Hodgkin lymphoma, polycythemia vera, valproic acid, ciprofloxacin, griseofulvin, systemic lupus erythematosus,hypothyroidism, uremia, hemoglobinopathies and angiodysplasia.[28][29][18][19][20][21][22]

Epidemiology and Demographics

The prevalence of von Willebrand’s disease is 0.6 to 1.3%.[14][1] It is estimated that the referral prevalence of von Willebrand’s disease is approximately 1 case per 10,000 persons.[30] The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population. The symptoms of VWD is disproportionately more common in women of child-bearing age.[14] Although autosomal inheritance pattern of disease lead to an equal distribution of male patients and female patients, the disease has female predominance whose bleeding tendency shows during menstruation.[31][32] There is no racial predilection to vWD however, it may be more severe or apparent in people with blood type O.[33]

Risk Factors

There are no established risk factors for Von Willebrand disease however, 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.[34] Interestingly the risks of cardiovascular disease and ischemic stroke are reduced among patients with von Willebrand’s disease.[35][36]

Screening

There is no established screening modality for Von Willebrand disease. However, several questionnaires and laboratory investigations have been developed to help in the screening process. Von Willebrand factor antigen and activity have been tried in the screening for von Willebrand disease.[37] The use of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia is not sufficiently sensitive to detect Von Willebrand Ristocetin cofactor activity (RCoF) values <50 IU/dl with normal multimer patterns.[38]

Natural History, Complications, and Prognosis

  • Patients with von willebrand disease have a lower health-related quality of life compared to the general population especially with the bleeding phenotype.[39]
  • There is physiologic rise in von Willebrand factor levels throughout life. As a result of this, patients with type 1 von Willebrand’s disease may have normal levels of vWF at older age.[40] However, bleeding symptoms occur at similar frequency in patients older than 65 years as well as in those who are 18 to 65 years of age[41]
  • Menorrhagia is a major complication, which also impairs the quality of life.[42]
  • Angiodysplasia is serious, and possibly life-threatening complication.[43]
  • Intraarticular bleeding (although rare) may be a presenting symptom in those with type 2N or type 3 disease.[44]
  • Primary and secondary postpartum bleeding is a commmon complication.[45][46][47]

Diagnosis

History and Symptoms

The symptoms of von Willebrand’s disease vary among patients, depending on the level of residual von Willebrand factor activity, the disease subtype, and to some extent, age and sex.[14] Children with von Willebrand’s disease most frequently present with symptoms of bruising and epistaxis.[48]

Adults patients with vWD mainly present with bleeding after surgery (example bleeding after dental extraction/surgery), mucosa-associated bleeding, Heavy menstrual periods and postpartum hemorrhage. Severe internal or joint bleeding is rare (which only occurs in type 3 vWD). [49]

Physical Examination

Laboratory Findings

Overview

The diagnosis of von Willebrand’s disease (VWD) begins with a relevant personal or family history of mucocutaneous bleeding. When VWD is suspected, several levels of testing are needed in order to make diagnosis[50][51][52][53]

Initail tests involve measurement of VWF antigen (VWF:Ag) level, Factor VIII activity (FVIII:C) and VWF–ristocetin cofactor activity [VWF:RCo].

When the results of all first-level tests are normal, VWD is ruled out; because of biologic variability, however, the tests should be repeated if values are at the low end of the normal range or if VWD is strongly suspected.[52]

Persons with a bleeding tendency who have VWF levels between 30 and 50 IU per deciliter (the lower limit of the normal range) are classified as having “low VWF” or “possible type 1 disease” but are not classified as having definitive VWD.[52]

When von Willebrand factor antigen is undetectable (or the level is <5 IU per deciliter, according to the latest disease classification), type 3 von Willebrand’s disease is diagnosed[12][52] If these first-level tests reveal definitive abnormalities, a diagnosis of VWD can be made; if the results are not conclusive, second-level tests are required. Second level testing involves repeating the initial tests and then measurement of VWF multimer distribution using gel electrophoresis and ristocetin-induced platelet aggregation (RIPA).

Other tests performed in any patient with bleeding problems include: complete blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time, thrombin time, fibrinogen level, testing for factor IX if hemophilia B is suspected and 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.

Imaging Findings

There are no imaging findings associated with Von Willebrand disease.

Other Diagnostic Studies

There are no other diagnostic findings associated with Von Willebrand disease.

Treatment

Medical Therapy

Prevention

  • There are no known preventive measures for von Willebrand disease.
  • In families with type 3 disease, genetic analysis may be useful for counseling.[54]

References

  1. ↑ 1.0 1.1 Rodeghiero F, Castaman G, Dini E (1987). "Epidemiological investigation of the prevalence of von Willebrand's disease". Blood. 69 (2): 454–9. PMID 3492222.
  2. ↑ Ng et al. Diagnostic Approach to von Willebrand Disease. Blood 2015; 125(13): 2029-2037.
  3. ↑ Blomback et al. Von Willebrand Disease Biology Hemophilia 2012; 18: 141-147.
  4. ↑ Favarolo et al. Von Willebrand Disease and Platelet Disorders. Hemophilia 2014; 20: 59-64.
  5. ↑ Template:WhoNamedIt
  6. ↑ 6.0 6.1 6.2 Lenting PJ, Casari C, Christophe OD, Denis CV (2012). "von Willebrand factor: the old, the new and the unknown". J Thromb Haemost. 10 (12): 2428–37. doi:10.1111/jth.12008. PMID 23020315.
  7. ↑ 7.0 7.1 7.2 James PD, Goodeve AC (2011). "von Willebrand disease". Genet Med. 13 (5): 365–76. doi:10.1097/GIM.0b013e3182035931. PMC 3832952. PMID 21289515.
  8. ↑ Lynch DC, Zimmerman TS, Collins CJ, Brown M, Morin MJ, Ling EH; et al. (1985). "Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method". Cell. 41 (1): 49–56. PMID 3873280.
  9. ↑ Sadler JE, Shelton-Inloes BB, Sorace JM, Harlan JM, Titani K, Davie EW (1985). "Cloning and characterization of two cDNAs coding for human von Willebrand factor". Proc Natl Acad Sci U S A. 82 (19): 6394–8. PMC 390722. PMID 2864688.
  10. ↑ Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GA, Latt SA; et al. (1985). "Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization". Science. 228 (4706): 1401–6. PMID 3874428.
  11. ↑ Verweij CL, Diergaarde PJ, Hart M, Pannekoek H (1986). "Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit". EMBO J. 5 (8): 1839–47. PMC 1167049. PMID 3019665.
  12. ↑ 12.0 12.1 12.2 Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L; et al. (2006). "Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor". J Thromb Haemost. 4 (10): 2103–14. doi:10.1111/j.1538-7836.2006.02146.x. PMID 16889557.
  13. ↑ Sadler JE (1994). "A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis". Thromb. Haemost. 71 (4): 520–5. PMID 8052974.
  14. ↑ 14.0 14.1 14.2 14.3 Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL; et al. (2008). "von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)". Haemophilia. 14 (2): 171–232. doi:10.1111/j.1365-2516.2007.01643.x. PMID 18315614.
  15. ↑ Hampshire DJ, Goodeve AC (2011). "The international society on thrombosis and haematosis von Willebrand disease database: an update". Semin Thromb Hemost. 37 (5): 470–9. doi:10.1055/s-0031-1281031. PMID 22102189.
  16. ↑ James P, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, Brown C, Andrews C, Labelle A, Chirinian Y, O'Brien L, Othman M, Rivard G, Rapson D, Hough C, Lillicrap D (2007). "The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study". Blood. 109 (1): 145–54. doi:10.1182/blood-2006-05-021105. PMID 17190853.
  17. ↑ Gill, JC (1987). "The effect of ABO blood group on the diagnosis of von Willebrand disease". Blood. 69 (6): 1691–5. PMID 3495304. Unknown parameter |coauthors= ignored (help)
  18. ↑ 18.0 18.1 Franchini M, Lippi G (2007). "Acquired von Willebrand syndrome: an update". Am J Hematol. 82 (5): 368–75. doi:10.1002/ajh.20830. PMID 17133419.
  19. ↑ 19.0 19.1 Tiede A, Rand JH, Budde U, Ganser A, Federici AB (2011). "How I treat the acquired von Willebrand syndrome". Blood. 117 (25): 6777–85. doi:10.1182/blood-2010-11-297580. PMID 21540459.
  20. ↑ 20.0 20.1 Kumar S, Pruthi RK, Nichols WL (2002). "Acquired von Willebrand disease". Mayo Clin Proc. 77 (2): 181–7. doi:10.4065/77.2.181. PMID 11838652.
  21. ↑ 21.0 21.1 Veyradier A, Jenkins CS, Fressinaud E, Meyer D (2000). "Acquired von Willebrand syndrome: from pathophysiology to management". Thromb Haemost. 84 (2): 175–82. PMID 10959686.
  22. ↑ 22.0 22.1 Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H; et al. (2000). "Acquired von Willebrand syndrome: data from an international registry". Thromb Haemost. 84 (2): 345–9. PMID 10959711.
  23. ↑ Ng et al. Diagnostic Approach to von Willebrand Disease. Blood 2015; 125(13): 2029-2037.
  24. ↑ Blomback et al. Von Willebrand Disease Biology Hemophilia 2012; 18: 141-147.
  25. ↑ Favarolo et al. Von Willebrand Disease and Platelet Disorders. Hemophilia 2014; 20: 59-64.
  26. ↑ van Genderen PJ, Vink T, Michiels JJ, van 't Veer MB, Sixma JJ, van Vliet HH (1994). "Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen". Blood. 84 (10): 3378–84. PMID 7949092.
  27. ↑ Handin RI, Martin V, Moloney WC (1976). "Antibody-induced von Willebrand's disease: a newly defined inhibitor syndrome". Blood. 48 (3): 393–405. PMID 1085186.
  28. ↑ Simone JV, Cornet JA, Abildgaard CF (1968). "Acquired von Willebrand's syndrome in systemic lupus erythematosus". Blood. 31 (6): 806–12. PMID 4172730.
  29. ↑ Wautier JL, Levy-Toledano S, Caen JP (1976). "Acquired von Willebrand's syndrome and thrombopathy in a patient with chronic lymphocytic leukaemia". Scand J Haematol. 16 (2): 128–34. PMID 1083062.
  30. ↑ Sadler JE, Mannucci PM, Berntorp E, Bochkov N, Boulyjenkov V, Ginsburg D; et al. (2000). "Impact, diagnosis and treatment of von Willebrand disease". Thromb Haemost. 84 (2): 160–74. PMID 10959685.
  31. ↑ Lee CA (1999). "Women and inherited bleeding disorders: menstrual issues". Semin Hematol. 36 (3 Suppl 4): 21–7. PMID 10513768.
  32. ↑ Miller CH, Philipp CS, Stein SF, Kouides PA, Lukes AS, Heit JA; et al. (2011). "The spectrum of haemostatic characteristics of women with unexplained menorrhagia". Haemophilia. 17 (1): e223–9. doi:10.1111/j.1365-2516.2010.02382.x. PMID 21040234.
  33. ↑ Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR (1987). "The effect of ABO blood group on the diagnosis of von Willebrand disease". Blood. 69 (6): 1691–5. PMID 3495304.
  34. ↑ Gill, JC (1987). "The effect of ABO blood group on the diagnosis of von Willebrand disease". Blood. 69 (6): 1691–5. PMID 3495304. Unknown parameter |coauthors= ignored (help)
  35. ↑ Sanders YV, Eikenboom J, de Wee EM, van der Bom JG, Cnossen MH, Degenaar-Dujardin ME; et al. (2013). "Reduced prevalence of arterial thrombosis in von Willebrand disease". J Thromb Haemost. 11 (5): 845–54. doi:10.1111/jth.12194. PMID 23506463.
  36. ↑ Seaman CD, Yabes J, Comer DM, Ragni MV (2015). "Does deficiency of von Willebrand factor protect against cardiovascular disease? Analysis of a national discharge register". J Thromb Haemost. 13 (11): 1999–2003. doi:10.1111/jth.13142. PMID 26368360.
  37. ↑ Verfaillie CJ, De Witte E, Devreese KM (2013). "Validation of a new panel of automated chemiluminescence assays for von Willebrand factor antigen and activity in the screening for von Willebrand disease". Int J Lab Hematol. 35 (5): 555–65. doi:10.1111/ijlh.12087. PMID 23551532.
  38. ↑ Naik S, Teruya J, Dietrich JE, Jariwala P, Soundar E, Venkateswaran L (2013). "Utility of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia". Pediatr Blood Cancer. 60 (7): 1184–7. doi:10.1002/pbc.24456. PMID 23335259.
  39. ↑ de Wee EM, Mauser-Bunschoten EP, Van Der Bom JG, Degenaar-Dujardin ME, Eikenboom HC, Fijnvandraat K, de Goede-Bolder A, Laros-van Gorkom BA, Meijer K, Raat H, Leebeek FW (2010). "Health-related quality of life among adult patients with moderate and severe von Willebrand disease". J. Thromb. Haemost. 8 (7): 1492–9. doi:10.1111/j.1538-7836.2010.03864.x. PMID 20345712.
  40. ↑ Rydz N, Grabell J, Lillicrap D, James PD (2015). "Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease". Haemophilia. 21 (5): 636–41. doi:10.1111/hae.12664. PMC 4678413. PMID 25756206.
  41. ↑ Sanders YV, Giezenaar MA, Laros-van Gorkom BA, Meijer K, van der Bom JG, Cnossen MH, Nijziel MR, Ypma PF, Fijnvandraat K, Eikenboom J, Mauser-Bunschoten EP, Leebeek FW (2014). "von Willebrand disease and aging: an evolving phenotype". J. Thromb. Haemost. 12 (7): 1066–75. doi:10.1111/jth.12586. PMID 24750783.
  42. ↑ Kadir RA, Edlund M, Von Mackensen S (2010). "The impact of menstrual disorders on quality of life in women with inherited bleeding disorders". Haemophilia. 16 (5): 832–9. doi:10.1111/j.1365-2516.2010.02269.x. PMID 20584085.
  43. ↑ Makris M, Federici AB, Mannucci PM, Bolton-Maggs PH, Yee TT, Abshire T, Berntorp E (2015). "The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease". Haemophilia. 21 (3): 338–42. doi:10.1111/hae.12571. PMID 25381842.
  44. ↑ van Galen KP, Mauser-Bunschoten EP, Leebeek FW (2012). "Hemophilic arthropathy in patients with von Willebrand disease". Blood Rev. 26 (6): 261–6. doi:10.1016/j.blre.2012.09.002. PMID 23010260.
  45. ↑ Kouides PA (2015). "An update on the management of bleeding disorders during pregnancy". Curr. Opin. Hematol. 22 (5): 397–405. doi:10.1097/MOH.0000000000000167. PMID 26164463.
  46. ↑ De Wee EM, Knol HM, Mauser-Bunschoten EP, van der Bom JG, Eikenboom JC, Fijnvandraat K, De Goede-Bolder A, Laros-van Gorkom B, Ypma PF, Zweegman S, Meijer K, Leebeek FW (2011). "Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease". Thromb. Haemost. 106 (5): 885–92. doi:10.1160/TH11-03-0180. PMID 21947221.
  47. ↑ Stoof SC, van Steenbergen HW, Zwagemaker A, Sanders YV, Cannegieter SC, Duvekot JJ, Leebeek FW, Peters M, Kruip MJ, Eikenboom J (2015). "Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey". Haemophilia. 21 (4): 505–12. doi:10.1111/hae.12635. PMID 25688733.
  48. ↑ Sanders YV, Fijnvandraat K, Boender J, Mauser-Bunschoten EP, van der Bom JG, de Meris J; et al. (2015). "Bleeding spectrum in children with moderate or severe von Willebrand disease: Relevance of pediatric-specific bleeding". Am J Hematol. 90 (12): 1142–8. doi:10.1002/ajh.24195. PMID 26375306.
  49. ↑ de Wee EM, Sanders YV, Mauser-Bunschoten EP, van der Bom JG, Degenaar-Dujardin ME, Eikenboom J; et al. (2012). "Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease". Thromb Haemost. 108 (4): 683–92. doi:10.1160/TH12-04-0244. PMID 22918553.
  50. ↑ Bodó I, Eikenboom J, Montgomery R, Patzke J, Schneppenheim R, Di Paola J (2015). "Platelet-dependent von Willebrand factor activity. Nomenclature and methodology: communication from the SSC of the ISTH". J. Thromb. Haemost. 13 (7): 1345–50. doi:10.1111/jth.12964. PMID 25858564.
  51. ↑ Flood VH, Gill JC, Morateck PA, Christopherson PA, Friedman KD, Haberichter SL, Hoffmann RG, Montgomery RR (2011). "Gain-of-function GPIb ELISA assay for VWF activity in the Zimmerman Program for the Molecular and Clinical Biology of VWD". Blood. 117 (6): e67–74. doi:10.1182/blood-2010-08-299016. PMC 3056647. PMID 21148813.
  52. ↑ 52.0 52.1 52.2 52.3 Sanders YV, Groeneveld D, Meijer K, Fijnvandraat K, Cnossen MH, van der Bom JG, Coppens M, de Meris J, Laros-van Gorkom BA, Mauser-Bunschoten EP, Leebeek FW, Eikenboom J (2015). "von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease". Blood. 125 (19): 3006–13. doi:10.1182/blood-2014-09-603241. PMID 25673639.
  53. ↑ F. Stufano, A. S. Lawrie, S. La Marca, C. Berbenni, L. Baronciani & F. Peyvandi (2014). "A two-centre comparative evaluation of new automated assays for von Willebrand factor ristocetin cofactor activity and antigen". Haemophilia : the official journal of the World Federation of Hemophilia. 20 (1): 147–153. doi:10.1111/hae.12264. PMID 24028703. Unknown parameter |month= ignored (help)
  54. ↑ Batlle J, Pérez-Rodríguez A, Corrales I, López-Fernández MF, Rodríguez-Trillo Á, Lourés E, Cid AR, Bonanad S, Cabrera N, Moret A, Parra R, Mingot-Castellano ME, Balda I, Altisent C, Pérez-Montes R, Fisac RM, Iruín G, Herrero S, Soto I, de Rueda B, Jiménez-Yuste V, Alonso N, Vilariño D, Arija O, Campos R, Paloma MJ, Bermejo N, Toll T, Mateo J, Arribalzaga K, Marco P, Palomo Á, Sarmiento L, Iñigo B, Nieto Mdel M, Vidal R, Martínez MP, Aguinaco R, César JM, Ferreiro M, García-Frade J, Rodríguez-Huerta AM, Cuesta J, Rodríguez-González R, García-Candel F, Cornudella R, Aguilar C, Borràs N, Vidal F (2016). "Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm". Thromb. Haemost. 115 (1): 40–50. doi:10.1160/TH15-04-0282. PMID 26245874.

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