von Willebrand factor propeptide: biology and clinical utility

Abstract

von Willebrand factor (VWF) is a large multimeric glycoprotein that mediates the attachment of platelets to damaged endothelium and also serves as the carrier protein for coagulation factor VIII (FVIII), protecting it from proteolytic degradation. Quantitative or qualitative defects in VWF result in von Willebrand disease (VWD), a common inherited bleeding disorder. VWF is synthesized with a very large propeptide (VWFpp) that is critical for intracellular processing of VWF. VWFpp actively participates in the process of VWF multimerization and is essential for trafficking of VWF to the regulated storage pathway. Mutations identified within VWFpp in VWD patients are associated with altered VWF structure and function. The assay of plasma VWFpp has clinical utility in assessing acute and chronic vascular perturbation associated with diseases such as thrombotic thrombocytopenic purpura, sepsis, and diabetes among others. VWFpp assay also has clear utility in the diagnosis of VWD subtypes, particularly in discriminating true type 3 subjects from type 1C (reduced plasma survival of VWF), which is clinically important and has implications for therapeutic treatment.

Idiopathic pulmonary arterial hypertension – a unrecognized cause of high‐shear high‐flow haemostatic defects (otherwise referred to as acquired von Willebrand syndrome) in children

“…The authors speculated that, as in other diseases characterized by endothelial dysfunction, increased secretion of VWF might overwhelm the natural proteolysis of VWF. Of note, chronic endothelial activation has also been linked to increased secretion of VWFpp and marginally increased VWFpp concentration (van Mourik et al , ); elevated VWFpp has been used as a biomarker of endothelial activation in several diseases including chronic renal failure, aortic stenosis, and sickle cell disease (Haberichter, ).…”

von Willebrand factor clearance – biological mechanisms and clinical significance

“…The observation that VWF circulatory half‐life was significantly reduced in selected patients with VWD originated from fall‐off studies performed following desmopressin (DDAVP) administration (Fig ). Subsequently, it was demonstrated that enhanced clearance in VWD patients could also be identified by measuring steady state plasma VWF propeptide (VWFpp) and VWF:Ag levels (Haberichter et al , , ; Haberichter, ). On the basis of DDAVP and/or VWFpp/VWF:Ag ratio studies, several large cohort studies have demonstrated that enhanced VWF clearance is prevalent in patients with type 1 VWD.…”

Patients with aortic stenosis have von Willebrand factor abnormalities and increased proliferation of endothelial colony forming cells

“…Elevated thrombin generation and platelet activation have been reported in patients with a higher pressure gradient across the stenotic valve . Acute release of VWF from activated platelets during phlebotomy could contribute to the increase in VWF:Ag and VWFpp . However, because VWF:Ag and VWFpp are significantly elevated in our patient cohort and well above the normal reference range, the contribution of platelet activation during phlebotomy is most likely minimal.…”