Pseudohemophilia of Erik von Willebrand caused by homozygous one nucleotide deletion in exon 18 of the VW-factor gene

Table 1 FVIII: C and von Willebrand factor levels in family S together with finding of heterozygous non-sense mutation, deletion exon 18, consistent with mild von Willebrand disease type 1

Family S, Number	Mutation	FVIII: CIU/dL	VWF: AgIU/dL	VWF: RCoIU/dL	RCo/AgRatio
5		0.93
6		0.51
12	del 18	0.81	0.80	0.73	0.91
13	del 18	0.53	0.56	0.46	0.82
14	del 18	0.35	0.35	0.32	0.91
18	negative	0.96	0.86	0.65	0.76
19	del 18	1.10	0.67	0.81	1.20
22	unknown	0.50	0.38	0.25	0.66
23	unknown	0.73	0.39	0.39	1.00
24	P1266L	0.39	0.34	0.42	1.23
25	del 18/P1266L	0.69	0.20	0.30	1.5

VWF: von Willebrand factor; VWD: von Willebrand disease; FVIII: Factor VIII.

Table 2 Reports of autosomal recessive severe type 1 von Willebrand disease caused by homozygous missense or double heterozygous missense/null mutations in the D1 or D2 domain

Mutation	F/M(yr)	BT(min)	VIII: C(U/dL)	VWF: Ag(U/dL)	VWF: RCo(U/dL)	Domain/VWF	VWD type
D141Y/null[19]	F/63	> 30	0.03	< 1	< 1	D1	Severe 1
C275S/null[19]	F/26	> 30	0.03	< 1	< 1	D1	Severe 1
R273W/R273W[20]	Boy	15	0.20	0.06	0.06	D1	Severe 1
R273W/R273W	Boy	15	0.33	0.09	0.04	D1	Severe 1
R273W/R273W	Boy	> 20	0.09	< 0.01	< 0.01	D1	Severe 1
W377C/W377C[12]	Child	> 20	0.02	0.03	0.03	D1	No data
C570S/C570S[21]	Boy	↑↑	0.12	0.05	0.05	D2	Severe 1
Q77X/splice site Intron[24]		> 30	0.20-0.31	0.04-0.06	0.03-0.06	D1/D2	Severe 1

VWF: von Willebrand factor; VWD: von Willebrand disease.

Table 3 Laboratory features of recessive severe type 1 due to a double heterozygous missense mutation in the CK domain of the von Willebrand factor gene

Mutation	Age (yr)	Gender	BT	FVIII: C	VWF: Ag	VWF: RCo	VWF: RCo/Ag	RIPA	VWD type
C2754W/C2754W[31]	13	F	> 20	0.12	< 0.05	< 0.05	-	nt	3
Father C2754W[31]	-	M	5	0.54	0.33	0.38	1.15	nt	Mild 1
Mother C2754W[31]	-	F	5	0.55	0.38	0.43	1.13	nt	Mild 1

VWF: von Willebrand factor; VWD: von Willebrand disease; M: Male; F: Female; FVIII: Factor VIII; RIPA: Ristocetin induced platelet aggregation.

Table 4 Laboratory phenotype and clinical symptoms in 69 patients with true von Willebrand factor deficiency type 1 heterozygous for the von Willebrand factor null allele (parents of type III von Willebrand disease)

Author		Zhang et al[13]		Eikenboom et al[15]
Number of patients		25	17	14		6
Blood Group		A	O	A		O
FVIII: C (%)	Mean	81	74	93		81
	Range	37-121	11-128	69-138	58-93
VWF: Ag	Mean	45	32	61
	Range	13-94	12-70	37-98	40-66	52
VWF: RCo	Mean	-	-	56		53
	Range	-	-	30-92	39-68
Mild bleedings1		13	11	1		1
		52%	65%	7%		17%

¹Mild bleeding was defined by one or two bleeding symptoms mainly epistaxis, bruises and/or prolonged menstruations without abnormal bleeding after both extraction or surgy, hemarthros or muscle bleeding. VWF: von Willebrand factor.

Table 5 Von Willebrand factor antigen (VWF: Ag) levels in heterozygous carriers for a null allele related to pseudohemophilia A-von Willebrand disease type 3 and for the mutation C2364F related to severe recessive type 1 von Willebrand disease

Carriers	Number ofpatients	VWF: Ag mean ± SD(IU/dL)	VWF: Ag range(IU/dL)
Null allele:
Blood group O	15	43.2 ± 10.8	30-66
Blood group non-O	15	61.3 ± 23.6	25-98
C2364F:
Blood group O	8	35.2 ± 16.2	25-55
Blood group non-O	15	61.5 ± 26.6	30-140

VWF: von Willebrand factor; VWD: von Willebrand disease.

Table 6 The 2006 Antwerp Classification of recessive von Willebrand disease type 3, recessive severe on Willebrand disease type 1 and obligatory carriers of a null or missense allele with asymptomatic or mild on Willebrand disease type 1 and variable penetrance of bleeding tendency

Category VWD	BT	FVIII: C (%)	VWF (%) Ag	RCo	RIPA	Bleeding type	VWF gene mutation
Severe type 3	↑↑↑	1-9	zero	zero	zero	Severe	Double
Recessive						Hemophilia	Nonsense
Severe type 1	↑↑↑	9-40	1-10	0-6	zero	Moderate	Double
Recessive VWD						Severe	Missense
Blood group O (30-32)	N	35-150	35-150	35-150	N	Asymp	None
(Pseude-VWD)						Very mild
Carrier type 3	N↑	30-140	15-90	15-90	N	Asymp	Single
Minor influence (-10%)						Very mild	Non-sense
of bloodgroup O							(null allele)
Carrier type 1	N	N	N	N	N	Asymp	Single
(polymorphism)							Missense
Mild type 1	N↑	20-80	20-50	20-50	N	Mild	Mis/Non-sense
Recessive or							or Y1584C/
variable penetrance and multigenetic backgroud							Bloodgroup O[19
Dominant type 1	N↑	20-80	10-40	0-30	N	Mild	Single
Secretion defect	↑/↑↑	5-20	5-20	5-20		Moderate	Missense
Dominant type 1
Vicenza	N/↑	< 15	< 15	< 15		Moderate	SingleR120SH
							Missense

VWF: von Willebrand factor; VWD: von Willebrand disease; RIPA: Ristocetin induced platelet aggregation.

Table 7 Response of FVIII: C and von Willebrand factor parameters to DDAVP (0.3 ug/kg) in an obligatory carriers of a null allele heterozygous for the nonsense splice site mutation IV7 + 1G > A in intron 7. (0874 + 1G > A) in intron 7

DDAVP	Before	1	2	4	6	H post-DDAVP
FVIII: C	0.84	5	5.4	5.3	4.9	IU/mL
VWF: Ag	0.64	1.3	1.7	1.5	1.4	IU/mL
VWF: RCo	0.67	1.8	2	1.35	1.2	IU/mL
FVIII: C/VWF: Ag ratio	1.3	3.8	3.1	3.5	3.5	Carrier of null allele
VWF: RCo/Ag ratio	1.05	1.38	1.17	0.9	0.86	Mild type 1 VWD

VWF: von Willebrand factor; VWD: von Willebrand disease; DDAVP: Desmopressin acetate.