Management of inherited von Willebrand disease in 2007

Figures & data

Figure 1. Schematic representation of the von Willebrand factor(VWF) gene located in chromosome 12: the main exons are indicated with the number of base pairs from 5′ to 3′ (upper panel). The structure of VWF functional domains: the pre‐pro‐VWF is indicated with amino acids numbered from the amino‐ (aa 1) to carboxy‐terminal portions (aa 2813) of VWF. Note the important CK and D3 domains for formation of VWF dimers and multimers. The native mature subunit of VWF, after the cleaving of the pre‐pro‐VWF, is described with its functional domains: the VWF binding sites for factor VIII (D′ and D3), GPIb, botrocetin, heparin, sulfatide, collagen (A1), collagen (A3) and the arginine, glycine, aspartic acid (RGD) sequence for binding to αIIbβ3 (middle panel). Distribution of VWF mutations in patients with VWD types 2: the positions of mutations causing VWD types 2A, 2B, 2M, 2N are indicated with black bars throughout the VWF domains (lower panel).

Table I. Prevalence (%) of bleeding symptoms in patients with VWD from different cohorts and in normal individuals (adapted from Federici 12, Silwer 17, Lak et al. 18).

	Iranians	Italians ^a			Scandinavians
Ethnicity VWD Symptoms	Type 3 (n = 348)	Type 1 (n = 671)	Type 2 (n = 497)	Type 3 (n = 66)	VWD (n = 264)	Normals (n = 500)
Epistaxis	77	61	63	66	62	5
Menorrhagia	69	32	32	56	60	25
Postextraction bleeding	70	31	39	53	51	5
Hematomas	NR	13	14	33	49	12
Bleeding from minor wounds	NR	36	40	50	36	0.2
Gum bleeding	NR	31	35	56	35	7
Postsurgical bleeding	41	20	23	41	28	1
Postpartum bleeding	15	17	18	26	23	19
Gastrointestinal bleeding	20	5	8	20	14	1
Joint bleeding	37	3	4	45	8	0
Hematuria	1	2	5	12	7	1
Central nervous system bleeding	NR	1	2	9	NR	0

NR = not reported;

^a Bleeding symptoms in Italian patients have been recently recalculated according to the updated results of the Italian Registry of VWD and therefore are different from those previously reported 12,13.

Table II. Bleeding score used to evaluate the bleeding history (see Tosetto et al. 20).

	Score
Symptom	−1	0	1	2	3	4
Epistaxis	–	No or trivial (less than 5)	>5 or more than 10′	Consultation only	Packing or cauterization or antifibrinolytics	Blood transfusion or replacement therapy or desmopressin
Cutaneous	–	No or trivial (<1 cm)	>1 cm and no trauma	Consultation only
Bleeding from minor wounds	–	No or trivial (less than 5)	>5 or more than 5′	Consultation only	Surgical hemostasis	Blood transfusion or replacement therapy or desmopressin
Oral cavity	–	No	Referred at least 1	Consultation only	Surgical hemostasis or antifibrinolytics	Blood transfusion or replacement therapy or desmopressin
Gastrointestinal bleeding	–	No	Associated with ulcer, portal hypertension, hemorrhoids, angiodysplasia	Spontaneous	Surgical hemostasis, blood transfusion, replacement therapy, desmopressin, antifibrinolytics
Tooth extraction	No bleeding in at least 2 extractions	None done or no bleeding in 1 extraction	Referred in <25% of all procedures	Referred in >25% of all procedures, no intervention	Resuturing or packing	Blood transfusion or replacement therapy or desmopressin
Surgery	No bleeding in at least 2 surgeries	None done or no bleeding in 1 surgery	Referred in <25% of all surgeries	Referred in >25% of all procedures, no intervention	Surgical hemostasis or antifibrinolytics	Blood transfusion or replacement therapy or desmopressin
Menorrhagia	–	No	Consultation only	Antifibrinolytics, pill use	Dilatation and curettage, iron therapy	Blood transfusion or replacement therapy or desmopressin or hysterectomy
Postpartum hemorrhage	No bleeding in at least 2 deliveries	No deliveries or no bleeding in 1 delivery	Consultation only	Dilatation and curettage, iron therapy, antifibrinolytics	Blood transfusion or replacement therapy or desmopressin	Hysterectomy
Muscle hematomas	–	Never	Post trauma no therapy	Spontaneous, no therapy	Spontaneous or traumatic, requiring desmopressin or replacement therapy	Spontaneous or traumatic, requiring surgical intervention or blood transfusion
Hemarthrosis	–	Never	Post trauma no therapy	Spontaneous, no therapy	Spontaneous or traumatic, requiring desmopressin or replacement therapy	Spontaneous or traumatic, requiring surgical intervention or blood transfusion
Central nervous system bleeding	–	Never	–	–	Subdural, any intervention	Intracerebral, any intervention

Table III. Clinical and laboratory parameters used for VWD diagnosis.

Patients at risk for VWD:

• Clinical history: lifelong mucocutaneous and postoperative bleeding, to be collected with appropriate questionnaires to calculate the Bleeding Severity Score (BSS)

• Screening tests: prolonged bleeding time (maybe normal); normal platelet count; prolonged Partial Thromboplastin Time (PTT) (may be normal).

Diagnosis and definition of VWD type:

• VWF antigen (a)

• VWF:Ristocetin cofactor activity (b)

• Factor VIII (c)

• VWF multimeric structure on low resolution gels (e)

Characterization of VWD type:

• Ristocetin‐induced platelet agglutination (RIPA) (d)

• VWF multimeric structure on high resolution gels (e)

• Platelet VWF content (f)

• Factor VIII‐binding assay (g)

For the use of these tests see the diagnostic flowchart reported in Figure 2, and also Federici et al. 12.

Figure 2. Flowchart proposed for the diagnosis of different von Willebrand disease(VWD) types. Type 3 VWD can be diagnosed in case of unmeasurable VWF:Ag (a). A proportionate reduction of both VWF:Ag and VWF:RCo with a RCo/Ag ratio >0.7 suggests type 1 VWD (b). If the VWF:RCo/Ag ratio is <0.7 type 2 is diagnosed. Type 2B VWD (d) can be identified in case of heightened ristocetin‐induced platelet aggregation (RIPA) (<0.8 mg/mL), whereas types 2A and 2M cause low RIPA (>1.2 mg/mL). Multimeric analysis in plasma (e) is necessary to distinguish between type 2A VWD (lack of the largest and intermediate multimers) and type 2M VWD (all the multimers present). Type 2N VWD can be suspected in case of discrepant values for FVIII (c) and VWF:Ag (ratio <0.5), and diagnosis should be confirmed by the specific test (g) of VWF:factor VIII binding capacity (VWF:FVIIIB). In type 1 VWD the ratio between Factor VIII and VWF:Ag is always ⩾1 and the severity of the type 1 VWD phenotype can usually be evaluated from platelet VWF (f) measurements. (This figure was derived from that originally reported previously 12.)

Table IV. List of the most frequent mutations in type 2A, 2B, 2M, and 2N according to VWF domains and exons of VWF gene.

Localization of VWF defects	VWD types	VWF mutations associated with specific types
D2 domain (exons 11–15)	Type 2A (formerly IIC)	F404insNP, R436del6, N528S, G550R, C623W, A625insG
D′–D3 domains (exons 18–28a)	Type 2N	R782W, G785E, E787K, C788R, C788Y, T791M, Y795C, M800V, R816W, R816Q, H817Q, R854Q, R854W, C858F, D879N, Q1053H, C1060R, C1225G
D3 domain (exons 26–28a)	Type 2M (formerly 1 Vicenza)	R1205H, Y1146C
	Type 2A (formerly IIE)	C1143Y, C1173R
A1 domain (exon 28)	Type 2B (formerly IIB)	P1266L, H1268D, C1272G, C1272R, M1304insM, R1306Q, R1306L, R1306W, R1308C, R1308P, I1309V, S1310F, W1313C, V1314F, V1314L, V1316M, P1337L, R1341L, R1341Q, R1341W, L1460V, A1461V
	Type 2M	G1324S, G1324A, E1359K, F1369I, I1425F, Q1191del1, K1408delK
	Type 2M/2A	L1276P, R1374C, R1374H, C1458Y, R1374R
A2 domain (exon 28)	Type 2A (formerly IIA)	G1505E, G1505R, S1506L, F1514C, K1518E, L1540P, S1543F, Q1556R, L1562P, R1597G, R1597Q, R1597W, V1604F, V1607D, V1609R, P1627H, I1628T, G1629R, V1630F, E1638K, L1639P, P1648S, L1657I, V1665E, G1672R
CK domain (exon 52)	Type 2A (formerly IID)	C2773R

For an updated list of VWF mutations according to VWD types 1, 2, and 3 the website www.shef.ac.uk/vwf can be checked; for the location of VWF domains in VWD types 2 see also Figure 1.

Table V. Recommendations for the infusion test with DDAVP

Infusion protocol:	Administer in 30 minutes 0.3 μg/kg of desmopressin in 50 mL of saline. The same dosage can be administered also subcutaneously
Clinical and laboratory parameters:	Factor VIII/VWF activities must be measured before and 0.5, 1, 2, and 4 hours after the administration of desmopressin; check platelet count before and at least 2 hours after infusion
Definition of responsiveness:	VWD patients should be considered responsive to Desmopressin if after 2 hours they show increases of baseline levels of FVIII:C and VWF:RCo by at least three times, with levels of at least 30 U/dL

(See Federici et al. 12,37)

Table VI. Treatment of different types of VWD.

	Treatment of choice	Alternative and adjunctive therapy
Type 1	Desmopressin	Antifibrinolytics, estrogens
Type 2A	VWF/FVIII concentrates	Desmopressin for mild bleeding
Type 2B	VWF/FVIII concentrates
Type 2M	Desmopressin	VWF/FVIII concentrates
Type 2N	Desmopressin	VWF/FVIII concentrates
Type 3	VWF/FVIII concentrates	Desmopressin, platelet concentrates
Type 3 with alloantibodies	Recombinant factor VIII	Recombinant activated factor VII

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