Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single‐centre cohort study

Abstract

Summary. Background: Diagnosis of acquired von Willebrand syndrome (AVWS) remains challenging. Diagnostic algorithms suggest the use of factor VIII (FVIII:C), von Willebrand factor antigen (VWF:Ag), ristocetin cofactor (VWF:RCo), and collagen‐binding capacity (VWF:CB), but the sensitivity of these and other laboratory tests for the diagnosis of AVWS is unknown. Objectives: To analyze the capacity of laboratory tests, including point‐of‐care testing (POCT), for the identification of patients with AVWS. Patients/methods: Thirty‐five consecutive patients were enrolled with AVWS diagnosed because of a history of recent onset of bleeding, a negative family history of von Willebrand disease, and abnormal plasma VWF multimers. Results: According to our inclusion criteria, all patients had bleeding symptoms, and the VWF high molecular weight multimers were either decreased or absent. Regarding POCT, PFA‐100 was inconclusive, due to anemia or thrombocytopenia, in 29%; the sensitivity was 80% in the remaining patients. The sensitivity of VWF:Ag (23%), VWF:RCo/Ag ratio < 0.7 (26%), VWF:CB/Ag ratio < 0.7 (46%), anti‐VWF antibodies (15%) and VWF propeptide/Ag ratio (22%) was too low to rule out the disease. A combination of VWF:Ag < 50 IU dL−1, VWF:RCo/Ag ratio < 0.7 and VWF:CB/Ag ratio < 0.8 yielded a sensitivity of 86%. Patients diagnosed only because of abnormal VWF multimers showed similar clinical characteristics as other patients. Conclusions: Early diagnosis of AVWS is difficult, due to lack of sensitivity of the tests used. A substantial number of patients present with normal or increased test results, emphasizing the importance of multimer analysis in all patients with suspected AVWS.

Acquired von Willebrand Syndrome

“…Although autoantibodies play a role in the pathogenesis of AvWS in only some patients, especially those with concomitant lymphoproliferative neoplasms [35], their presence is associated with worse prognosis, namely with a tendency to cause severe bleeding [18,39]. Anti-vWF autoantibodies can be detected during a mixing study.…”

“…Presence of non-neutralizing antibodies that do not block the activity of vWF but enhance its clearance cannot be detected during a mixing study [44]. However, these antibodies can be determined with an enzyme-linked immunosorbent assay (ELISA) [11,39].…”

“…Usually, AvWS is associated with complete loss of HMW vWF or decreased level thereof [19]. Owing that HMW vWF deficiency may be also observed in some patients with normal levels of vWF:RCo, vWF:Ag and vWF:CB, as well as in persons with normal vWF:RCo/ vWF:Ag and vWF:CB/vWF:Ag ratios, all subjects with suspected AvWS should be subjected to multimer analysis [9,35,39]. Although most patients with AvWS present with type 2 vWD [19], type 1 or type 3 vWD can be also detected in individuals in whom AvWS is associated with abnormal synthesis of vWF (e.g.…”

“…Also, vWF:RCo/vWF:Ag and vWF:RCo/vWF:CB ratios should be determined, as these parameters are typically decreased during the course of AvWS [38]. In a retrospective study conducted by Tiede et al [39], all patients with cardiovascular diseases and most individuals with lymphoproliferative neoplasms presented with normal or elevated values of vWF:Ag, vWF:RCo and vWF:CB, and frequently showed abnormal vWF:RCo/vWF:CB and vWF:RCo/vWF:Ag ratios. These findings confirm the usefulness of collagen binding assay, which should be routinely used in the evaluation of patients with suspected AvWS.…”

Differences in von Willebrand factor function in type 2A von Willebrand disease and left ventricular assist device‐induced acquired von Willebrand syndrome

“…Indeed, we and others8, 12 show that VWF:CB/VWF:Ag and VWF:RCo/VWF:Ag ratios are not always below 0.7 in LVAD patients. As a consequence, VWF multimer analysis is the gold standard to detect aVWS in these patients 5, 19. Comparable findings were obtained for aortic stenosis patients, in which aVWS has also been frequently detected 20, 21.…”