Frequency spectrum of 321 patients diagnosed with VWD type 2 in the Milan cohort study. Type 2M was the most common type (35%), followed by 2A (31%), 2B (26%), and 2N (8%). In type 2M, 41% of patients had variants at the VWF A1 domain, with a platelet-binding defect (classical 2M), whereas 26% had variants at the A3 domain, with a collagen-binding defect (2MCB). Almost one third of type 2M patients (33%), with variants in the A1 domain, shared a similar phenotype between type 2M and 2A, and they were classified as 2M/2A. In type 2A, 65% of patients had variants located at the A2 domain, with an enhanced susceptibility for ADAMTS-13, and were classified as 2A(IIA), with an exceptional case in the A1 domain. The remaining 33% were located at the D3 domain, with multimerization defects, and were classified as 2A(IIE). Patients with a diagnosis of type 2A(IIC) or 2A(IIH) made up only 2% of the type 2A cohorts. Most patients with 2B (75%) had variants at the A1 domain, with a platelet-binding defect (classical 2B), and the rest (25%) had variants at the D3-A1 junction, classified as 2B NY. Patients with 2N were mainly compound heterozygotes for 2N/type 1 or 3 (46%), and only 16% were homozygotes for the 2N variant. Type 2N carriers accounted for 38% of the 2N population.