Table 2.
Evolution of vWD classification scheme with distinguishing features and representative mechanisms and mutations
| 2006 | 1994 | 1987 | Multimers on Gel |
DDAVP Response |
Rcof:Ag Ratio |
Inheritance | Mechanism | Bleeding Risk | Representative Mutations |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 1 | IA, I Platelet normal, l–2 | All present but↓ | Good | Normal | Autosomal dominant | Mild to moderate | Upstream regulatory region, D1,D2,D′/D3,A1,A2,A3,D4, B2,B3,C1,C2,CK | |
| l–3 | All present | Good | Normal | Autosomal dominant | Normal plasma vWF-Ag, low in platelets | ||||
| I Platelet low, I-1 | All present but↓ | Poor | Normal | Autosomal dominant | Impaired intracell transport, heterodimers | D′/D3-C1149R | |||
| 1 | 2M | Unclassified, I Vincenza | Large↑ (Variable)/large mildly↓ with satellite ↓(C1130) | Pronounced immediate but shortened half-life | Usually low (normal on some studies) | Autosomal dominant | Increased clearance, ↓RIPA | Moderate | D′/D3-R1205H or C1130F/G/R, W1144G |
| 2A | 2A | IB, I Platelet discordant | Large, mildly↓ | Poor–variable | Low | Autosomal dominant | Same as severe type 2M? | A1-R1374C/H? | |
| IIA (IIA-1, IIA-2, IIA-3) | Large and intermediate↓/satellite bands↑↑ | Poor–variable | Low | Autosomal dominant | Increased ADAMTS13 susceptibility | Mild to moderate | A2/A3 - C1272S, G1505R, S1506L, M1528V, R1569dl, R1597W, V1607DM G1609R, I1628T, G1629E, G1631D, E1638K, P1648S | ||
| IIC | Larger↓↓/satellite↓↓ | Poor | Low | Recessive–rare | Propeptide mutations impair Golgi multimer assembly and make resistant to ADAMTS13 | D2 | |||
| IID | Larger↓↓/abnormal satellite ↓↓/old numbered multimers | Poor | Low | Autosomal dominant–rare | Impaired dimerization in ER → Monomers become chain terminators | Hetero, moderate; homozyogous, severe | CK-C2010R | ||
| IIE | Larger↓/satellite↓ (Smeary) | Poor | Low | Autosomal dominant–rare | Impaired assembly at disulfide bonds | Mild to moderate | D3-Y1146C, C1153Y, T1107C | ||
| IIF, IIG, IIH, II-I | Larger↓/satellite ↓ abnormalities | Poor | Low | Rare | Case reports | ||||
| 2B | 2B | IIB | Large ± intermediate/satellite bands↑↑ | Contraindicated but increase in response | Often low (Ag normal, borderline RCof) | Autosomal dominant | ↑GPIb binding leads to platelet aggregation and clearance = ↑RIPA, periodic ↓plts | Variable, correlates with thrombocytopenia | A1/A2-C1272G/R, M1304Insm, R1306W/Q/L, I1309V, S1310F, W1313C, V1314F/L/P, V1316M, H1268D, P1337L, R1306W, R1341Q/W/L, R1308C/P, L1460V, A1461V |
| I New York, Malmö | Near normal | Good | Usually normal | Autosomal dominant | Increased RIPA but apparently normal function in vivo | Low to none - usually no thrombocytopenia | A1-P1266L/Q, R1308L | ||
| 2M | 2M | Type B | All present but↓ | Poor–variable | Low | Autosomal dominant | Impaired binding to GPIb | Variable-R1374C/H more severe | A1-Y1321D, G1324A/S, E1359K, K1362T, F1369I, R1374C/H, R1394I, K148deI, I1425F, I1526T |
| IC | Smaller/Satellite bands↓ | Hetero–good | Normal | Recessive | Decreased proteolysis | Heter, mild; homozygous, severe | B2-C2362F | ||
| ID | All↓/satellite bands↓ | Good | Low | Autosomal dominant? | Decreased RIPAMay be a Vincenza analog | ||||
| 2N | 2N | Normandy | Normal | Not indicated | Normal | Recessive | Impaired binding to factor VIII cause increased FVIII degradation | Severity depends on mutation. Mimicks mild hemophilia A | D′/D3-R854G=milder disease. Others include P812, R816W, R854Q, R1035 |
| 3 | 3 | III | Absent or nearly absent | None | Unmeasurable | Recessive | High | Nonsense, frameshift, deletions, unique | |
| Differences | Mutation Locus | Type 1 Criteria | |||||||
| 1994 | Only vWF gene | Decreased vWF:Ag but no multimer abnormalities | |||||||
| 2006 | Not restricted | Decreased vWF:Ag normal multimer distribution, may have satellite band abnormalities, normal activity-to-antigen ratio | |||||||
Data are compiled from multiple references as listed in the text.