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Chapter 138 Structure, Biology, and Genetics of von Willebrand Factor 2063

Castaman G, Tosetto A, Rodeghiero F: Pregnancy and delivery in women
Assessment of a Neonate
with von Willebrand’s disease and different von Willebrand factor muta-
tions. Haematologica 95:963, 2010.
A baby boy was born to a mother with known type 2B VWD. On the day
of birth, investigations demonstrated the following: VWF : Ag 78 IU/dL, Cumming A, Grundy P, Keeney S, et al: An investigation of the von Wil-
VWF : RCo 61 IU/dL, and FVIII : C 0.69 IU/dL (unclear whether these lebrand factor genotype in UK patients diagnosed to have type I von
were done on mom or the baby). The mother was informed that the Willebrand disease. Thromb Haemost 96:630, 2006.
results were all within normal range and that her newborn infant was Eikenboom J, Van Marion V, Putter H, et al: Linkage analysis in families
not affected by type 2B VWD. When he was approximately 18 months diagnosed with type 1 von Willebrand disease in the European study,
of age, the mother noted excessive mucocutaneous bleeding. Blood molecular and clinical markers for the diagnosis and management of type
work at that time demonstrated: VWF : Ag 50 IU/dL, VWF : RCo 20 IU/ 1 VWD. J Thromb Haemost 4:774, 2006.
dL, and FVIII : C 51 IU/dL. Multimer analysis revealed a lack of HMW Federici AB: The use of desmopressin in von Willebrand disease: the experi-
multimers. Finally, genotyping revealed that the boy was heterozygous
for the same mutation, R1306W that his mother carried. ence of the first 30 years (1977-2007). Haemophilia 14(5):2008.
This case illustrates several important points. Neonatal levels of Federici AB, Bucciarelli P, Castaman G, et al: The bleeding score predicts
VWF are increased over baseline; if investigations are performed, they clinical outcomes and replacement therapy in adults with von Willebrand
should be interpreted using appropriate reference ranges. Alternatively, disease. Blood 123:4037, 2014.
if a phenotypic diagnosis is being sought, it is preferable to postpone Federici AB, Rand JH, Bucciarelli P, et al: Acquired von Willebrand syndrome:
investigations, decreasing the likelihood of pretest analytical variables, data from an international registry. Thromb Haemost 84:345, 2000.
such as difficulty in collecting an appropriate blood sample from a Giannini S, Cecchetti L, Mezzasoma AM, et al: Diagnosis of platelet-type
neonate, and the difficulties with interpretation of the results. Finally, von Willebrand disease by flow cytometry. Haematologica 95:1021, 2010.
in cases in which the mutation is known, genotyping is diagnostic and Goodeve AC: The genetic basis of von Willebrand disease. Blood Rev 24:123,
also the most straightforward.
2010.
Haberichter SL, Castaman G, Budde U, et al: Identification of type 1 von
Willebrand disease patients with reduced von Willebrand factor survival
The diagnosis and care of infants and children with VWD require by assay of the VWF propeptide in the European study: molecular and
special consideration. An accurate assessment of hemorrhagic symp- clinical markers for the diagnosis and management of type 1 VWD
toms is a key component in the diagnosis of VWD, but it often (MCMDM-1VWD). Blood 111:4979, 2008.
presents a significant challenge in the pediatric population. Because Halimeh S, Krümpel A, Rott H, et al: Long-term secondary prophylaxis
young children may have been exposed to few hemostatic challenges in children, adolescents and young adults with von Willebrand disease.
and may be prepubertal, the bleeding history may be unimpressive. Results of a cohort study. Thromb Haemost 105:597, 2011.
The effect this negative history may have on perceived risk for bleed- James AH, Jamison MG: Bleeding events and other complications during
ing is highlighted in two of the previously published bleeding scores, pregnancy and childbirth in women with von Willebrand disease. J
which assign a negative value to lack of bleeding symptoms and are Thromb Haemost 5:1165, 2007.
based on the accumulation of bleeding symptoms or complications. James AH, Kouides PA, Abdul-Kadir R, et al: von Willebrand disease and
Finally, the initial diagnostic assessment of an infant is complicated other bleeding disorders in women: consensus on diagnosis and manage-
by the fact that VWF levels are higher in the neonatal period. Con- ment from an international expert panel. Am J Obstet Gynecol 201:12.
sequently, phenotypic testing of VWD should be delayed until later e1, 2009.
in childhood (see Fig. 138.6). James PD, Notley C, Hegadorn C, et al: The mutational spectrum of type
DDAVP should be avoided in children younger than the age of 1 von Willebrand disease: results from a Canadian cohort study. Blood
2 because of the potential difficulty in restricting fluids. Infant males 109:145, 2007.
should be circumcised only after consultation with a pediatric hemo- Keeney S, Bowen D, Cumming A, et al: The molecular analysis of von
stasis specialist. Typically, only patients with type 3 VWD experience Willebrand disease: a guideline from the UK haemophilia centre doctors’
spontaneous musculoskeletal bleeding, such as that seen in patients organisation haemophilia genetics laboratory network. Haemophilia
with severe hemophilia, and should be considered for long-term 14:1099, 2008.
prophylaxis with VWF/FVIII concentrates, as discussed in the pre- Mannucci PM, Kempton C, Millar C, et al: Pharmacokinetics and safety
ceding section (see box on Assessment of a Neonate). of a novel recombinant human von Willebrand factor manufactured
with a plasma-free method: a prospective clinical trial. Blood 122:648,
2013.
SUGGESTED READINGS McGrath RT, van den Biggelarr M, Byrne B, et al: Altered glycosyaltion of
platelet-derived von Willebrand factor confers resistance to ADAMTS13
Abshire TC, Federici AB, Alvarez MT, et al: Prophylaxis in severe forms proteolysis. Blood 122:4107, 2013.
of von Willebrand’s disease: results from the von Willebrand Disease Millar CM, Brown SA: Oligosaccharide structures of von Willebrand factor
Prophylaxis Network (PN). Haemophilia 19:76, 2013. and their potential role in von Willebrand disease. Blood Rev 20:83,
Berntorp E: Haemate P/Humate-P: a systematic review. Thromb Res 124:S11, 2006.
2009. Nichols WL, Hultin MB, James AH, et al: von Willebrand disease (VWD):
Bowen D: An influence of ABO blood group on the rate of proteolysis of von evidence-based diagnosis and management guidelines, the national
Willebrand factor ADAMTS13. J Thromb Haemost 1:33, 2003. heart, lung, and blood institute (NHLBI) expert panel report (USA).
Bowman M, Mundell G, Grabell J, et al: Generation and validation of the Haemophilia 14:171, 2008.
condensed MCMDM-1VWD bleeding questionnaire for von Willebrand Sadler JE, Budde U, Eikenboom JCJ, et al: Update on the pathophysiology
disease. J Thromb Haemost 6:2062, 2008. and classification of von Willebrand disease: a report of the subcommittee
Bowman M, Tuttle A, Notley C, et al: The genetics of Canadian type von on von Willebrand factor. J Thromb Haemost 4:2103, 2006.
Willebrand disease: further evidence for co-dominant inheritance of Sanders Y, Giezenaar M, Laros-van Gorkom B, et al: von Willebrand disease
mutant alleles. J Thromb Haemost 11:512, 2013. and aging: an evolving phenotype. J Thromb Haemost 12:1066, 2014.
Casari C, Lenting PJ, Wohner N, et al: Clearance of von Willebrand factor. Springer TA: Biology and physics of von Willebrand factor concatamers. J
J Thromb Haemost 11(Suppl 1):202, 2013. Thromb Haemost 9:130, 2011.
Castaman G, Lethagen S, Federici AB, et al: Response to desmopressin is Tiede A, Rand JH, Budde U, et al: How I treat the acquired von Willebrand
influenced by the genotype and phenotype in type 1 von Willebrand syndrome. Blood 117:6777, 2011.
disease (VWD): results from the European study MCMDM-1VWD. Zhou YF, Eng TE, Zhe J, et al: Sequence and structure relationships within
Blood 111:3531, 2008. von Willebrand factor. Blood 120:449, 2012.