J. Heijdra1, R. Dirven2, M. Kruip3, F. Leebeek3, J. Eikenboom2, M. Cnossen1

1Erasmus University Medical Center – Sophia Children’s Hospital, Department of Pediatric Hematology, Rotterdam; 2Leiden University Medical Center, Department of Internal Medicine (Thrombosis and Hemostasis), Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden; 3Erasmus University Medical Center, Department of Hematology, Rotterdam

Background

Von Willebrand factor (VWF) levels represent a balance between synthesis, secretion and clearance of VWF*

  • VWF propeptide (VWFpp) is a marker of VWF synthesis
  • Increased VWFpp/VWF:Ag ratio reflects increased VWF clearance

Adding VWFpp to population pharmacokinetic (PK) models for therapy in VWD may allow for a more precise estimation of the endogenous VWF fraction released after DDAVP or trauma or during surgery.

Aim

To measure VWFpp concentrations before and after desmopressin infusion in von Willebrand disease (VWD) and “low VWF” patients, with hemophilia A patients as controls.

Conclusions

VWFpp and the VWFpp/VWF:Ag ratio can help to distinguish between synthesis/secretion defects and enhanced clearance in VWD (especially type 1). Incorporation of VWFpp concentrations may help in optimization of PK-models for VWD.

Patients and Methods

60 patients (38 “low VWF” (VWF 0.30-0.50 IU/mL), 15 VWD type 1, 6 type 2, and 17 controls (hemophilia A)

  • Mean age: 30 (5-72) years
  • Mean weight: 71 (22-125) kg
  • Mean desmopressin dose: 0.30 (0.26-0.30) μg/kg

1 Pre-dose sample and 2-4 post dose samples (1-24h post dose) per patient
VWFpp was measured with an ELISA using antibodies from Sanquin

Results

N (%) Median VWF:Ag [IQR] Median VWFpp [IQR] Median VWFpp/VWF:Ag ratio [IQR] Median fold VWFpp increase at t=1 [IQR]
Hemophilia A 17 (22) 1.24 [0.96-1.53] 0.8 [0.74-1.02] 0.71 [0.54-0.89] 7.9 [5.5-10.3]
Low VWF 38 (50) 0.52 [0.42-0.63] 0.64 [0.54-0.74] 1.20[0.96-1.45] 6.4 [4.7-8.1]
VWD type 1 15 (20) 0.35 [0.22-0.48] 0.66 [0.54-0.78] 1.78 [1.29-2.27] 6.8 [5.2-8.4]
VWD type 2 6 (8) 0.65 [0.49-0.82] 0.78 [0.68-0.88] 1.22 [0.90-1.547] 5.7 [4.3-7.2]

VWF = von Willebrand factor; Ag = antigen; pp = propeptide; VWF = von Willebrand disease

Figure 1. Baseline VWFpp/VWF:Ag ratio (before desmopressin)

Figure 2. Fold VWFpp increase over baseline at t = 1 hour

Figure 3. VWFpp half-life

*Sanders YV, Groeneveld D, Meijer K, et al. von Willebrand factor propeptide and the phenotypic classification of von Willebrand disease. Blood 2015:125(19):3006-3013