Flowchart proposed for the correct diagnosis and classification of different VWD types. After bleeding history of suspected patients with VWD is collected and family history of bleeding investigated (Table 1), a reduced level of VWF activity should be measured using VWF:RCo. First level of diagnosis: VWD3 can be diagnosed in case of undetectable VWF:Ag. FVIII:C is always reduced in VWD3 and in VWD2N; it can be reduced or normal in all the other VWD types. VWD2B can be identified in cases of heightened RIPA (<0.8 mg/mL), whereas VWD1, VWD2A, and VWD2M cause low ristocetin-induced platelet agglutination (>1.2 mg/mL). A proportionate reduction of both VWF:Ag and VWF:RCo with a VWF:RCo/Ag ratio >0.6 suggests VWD1. If the VWF:RCo/Ag ratio is <0.6, VWD2A, VWD2B, or VWD2M should be suspected. VWD2N can be suspected if FVIII:C/VWF:Ag ratio <1, whereas a FVIII:C/VWF:Ag ratio >1 can be associated with VWD1. Second level of diagnosis: Multimeric analysis in plasma is necessary to distinguish between VWD2A (lack of the largest and intermediate-sized multimers) and VWD2M (all multimers present). Patients with VWD2B can sometimes show all multimers. VWFpp/VWF:Ag is increased in VWD1 with a short half-life of VWF. A DDAVP challenge test can identify patients with no biological response, short biological response, or adequate response to this drug. VWF:FVIIIB should be performed to confirm VWD2N. After phenotypic diagnosis is performed, mutations should be sought to confirm VWF defects within the family of VWD patients. More detailed information is provided in Federici and Canciani.3 *Ristocetin-induced platelet agglutination is the specific assay used to identify VWD2B because aggregation always occurs with low concentrations (<0.8) of ristocetin. Similar findings can be found in PT-VWD. Additional testing, for example, with a binding assay of patient VWF to normal platelets in the presence of various doses of ristocetin, is needed to distinguish the 2 disorders. **FVIII:C/VWF:Ag ratio <1 is suggestive of VWD2N. ***To distinguish VWD2N from mild hemophilia A, the specific VWF:FVIII:B assay should be always performed.
