Novel insights into the clinical phenotype and pathophysiology underlying low VWF levels

Abstract

Critical clinical questions remain unanswered regarding diagnosis and management of patients with low von Willebrand factor (VWF) levels (30-50 IU/dL). To address these questions, the Low VWF Ireland Cohort (LoVIC) study investigated 126 patients registered with low VWF levels. Despite marginally reduced plasma VWF levels, International Society of Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH BAT) confirmed significant bleeding phenotypes in the majority of LoVIC patients. Importantly, bleeding tendency did not correlate with plasma VWF levels within the 30 to 50 IU/dL range. Furthermore, bleeding phenotypes could not be explained by concurrent hemostatic defects. Plasma factor VIII to VWF antigen (VWF:Ag) ratios were significantly increased in LoVIC patients compared with controls (P < .0001). In contrast, VWF propeptide to VWF:Ag ratios >3 were observed in only 6% of the LoVIC cohort. Furthermore, platelet-VWF collagen binding activity levels were both significantly reduced compared with controls (P < .05). In response to 1-desamino-8-D-arginine vasopressin (DDAVP), peak VWF:Ag levels exceeded 100 IU/dL in 88% of patients and was sustained >100 IU/dL after 4 hours in 72% of subjects. In conclusion, our novel data suggest that low VWF levels can be associated with significant bleeding and are predominantly due to reductions in VWF synthesis and/or constitutive secretion. Although enhanced VWF clearance may contribute to the pathophysiology in some individuals, the absolute reduction in VWF plasma half-life is usually mild and not sufficient to significantly impact upon the duration of DDAVP-induced VWF response. This trial was registered at www.clinicaltrials.gov as #NCT03167320.

Conflict of interest statement

Conflict-of-interest disclosure: M.L. has received research funding from Baxalta and has served on advisory boards for Baxalta. P.J. receives research funding from CSL Behring, Octapharma, and Shire and has served on advisory boards for CSL Behring and Shire. J.S.O’D. has served on the speaker’s bureau for Baxter, Bayer, Novo Nordisk, Boehringer Ingelheim, Leo Pharma, and Octapharma and has also served on the advisory boards of Baxter, Bayer, Octapharma CSL Behring, Daiichi Sankyo, Boehringer Ingelheim, and Pfizer. J.S.O’D. has received research grant funding awards from Baxter, Bayer, Pfizer, and Novo Nordisk. The remaining authors declare no competing financial interests.

© 2017 by The American Society of Hematology.

Figures

Figure 1.

Patients with low VWF have significant bleeding phenotypes. (A) ISTH BAT scores by sex, females, n = 112 (triangles, median = 8), and males, n = 14 (circles, median = 3). (B) Condensed MCMDM-1 VWD bleeding scores by sex. Black lines indicate median scores in females, n = 112 (triangles, median 5), and males, n = 14 (circles, median 0.5). (C) ISTH BAT scores studied in LoVIC subgroups with lowest plasma VWF levels in the range 30 to 39 IU/dL (females, triangles; males, circles) compared with patients with lowest VWF levels in the range 40 to 49 IU/dL (females, diamonds; males, squares). No significant difference was seen for either females (median 9 vs 7, P = .09, ns = not significant) or males (median 3 vs 3, P = .7). The upper limit of bleeding scores considered normal for each score is indicated by the green dotted line; median is shown by the black line.

Figure 2.

Bleeding in low VWF is not explained by concomitant bleeding disorders. (A) Comparison of ISTH BAT scores (red bars) and condensed MCMDM-1 VWD scores (blue bars) for all patients (n = 126) according to individual bleeding subdomains. Data are represented as mean ± standard error of the mean of bleeding scores. (B) ISTH BAT scores were not significantly different for LoVIC patients with concomitant coagulation disorders (circles, n = 10) compared with those without (triangles, n = 81) (median scores 10.5 vs 9.0; P = .15). CNS, central nervous system.

Figure 3.

Plasma VWF levels normalize with age in some patients with low VWF. (A) In a subgroup of 64 LoVIC patients followed in the NCC for >5 years, plasma VWF:Ag levels were significantly higher at last follow-up compared with baseline levels (mean VWF:Ag at baseline = 47.8 IU/dL vs 60.6 IU/dL at last follow-up; ****P < .0001). (B) Similarly, plasma VWF:RCo levels were also significantly higher at last follow-up compared with baseline levels (mean VWF:RCo at baseline = 39.4 IU/dL vs 49.0 IU/dL at last follow-up; ****P < .0001). (C) Age at original registration of patients with a diagnosis with low VWF levels (n = 126).

Figure 4.

Reduced plasma VWF levels in patients with low VWF are due to both decreased VWF synthesis/secretion and subtly enhanced VWF clearance. (A) Plasma FVIII:C levels were significantly reduced in patients with low VWF (n = 126, triangles) compared with normal controls (n = 40, circles) (mean FVIII:C levels 76 IU/dL vs 105 IU/dL; ****P < .0001). (B) FVIII:C/VWF:Ag ratios were significantly increased in LoVIC patients compared with controls (mean ratio 1.3 vs 1.07; ****P < .0001). (C) Plasma VWF:pp levels in LoVIC patients were not significantly different from those in normal controls (mean VWF:pp levels 91.6 U/dL vs 85.4 U/dL; P = .58). (D) VWF:pp/VWF:Ag ratios were significantly increased in LoVIC patients compared with controls (mean ratio 1.42 vs 0.95; **P < .01). Elevated VWF:pp/VWF:Ag ratios >3 (green dotted line) were identified in only 8 patients. Mean values for each group are indicated by a black line. In a subgroup of 40 LoVIC patients, plasma VWF:Ag (E) and VWF:RCo (F) levels were measured at baseline and subsequently repeated at 1 hour and 4 hours following intravenous DDAVP administration.

Figure 5.

Platelet VWF levels are significantly reduced in patients with low VWF. Following platelet lysis, platelet VWF:Ag (A) and platelet VWF:CB levels (B) were determined in 54 patients with low VWF levels. (A) Platelet VWF:Ag was significantly reduced in LoVIC patients (n = 54, triangles) compared with controls (n = 22, circles) (mean values 0.16 vs 0.21 IU/109 platelets; *P < .05). (B) Platelet VWF:CB levels were also significantly reduced in LoVIC patients (triangles) compared with controls (circles) (mean values 0.19 vs 0.34 IU/109 platelets; P < .0001). (C) On the basis of platelet VWF:Ag and platelet VWF:CB levels, patients with low VWF levels were subdivided into 3 distinct groups of “platelet-low” (green box), “platelet-normal” (red box), and “platelet-discordant” (blue box). LoVIC patients are indicated as filled circles and healthy controls as open circles.