Critical Importance Of VWF Propeptide (VWFpp) In The Diagnosis Of Type 1 Von Willebrand Disease (VWD)

Type 1 VWD is the most common form of VWD and is characterized by quantitative deficiency of VWF. Mechanisms causing type 1 VWD include decreased VWF synthesis due to promoter polymorphisms, decreased VWF secretion with intracellular retention/degradation, and increased clearance of VWF from plasma (type 1C VWD). VWF and its propeptide (VWFpp) are released into plasma in equimolar amounts but have very different half-lives (8 – 12 hours and 2-3 hours, respectively). The assay of VWFpp can be used to assess VWF synthesis, secretion, and clearance. Reduced VWFpp level indicates reduced VWF synthesis or secretion. An increased VWFpp/VWF:Ag ratio is expected when VWF is cleared rapidly from plasma (type 1C VWD), while decreased VWF secretion/intracellular retention results in a normal ratio. We enrolled 502 type 1 VWD index cases with a pre-existing diagnosis of type 1 VWD through the Zimmerman Program for the Molecular and Clinical Biology of VWD. We confirmed 262 index cases as type 1 VWD (VWF:Ag or VWF:RCo ≤ 40 IU/dL). Of the confirmed type 1 VWD cases, 58 met the criteria for type 1C VWD with VWFpp/VWF:Ag ≥ 3 and VWF:Ag ≤ 30 IU/dL, and 12 met the criteria for “Type 1 – Severe” with VWF:Ag of 1 – 5 IU/dL and VWFpp/VWF:Ag < 3. Type 1C VWD comprised 22% of all type 1 VWD cases. The type 1C cohort included several individuals previously diagnosed as type 2A (11), type 2M (2), and “Unclassified” (3). The most significant reclassification involved 7 cases previously diagnosed as type 3 VWD – these patient had detectable VWF:Ag (2 – 6 IU/dL) and VWFpp (14 – 66 IU/dL), and elevated VWFpp/VWF:Ag (4.2 – 33.0). Although plasma VWF:Ag is very low in these patients, they might be expected to have normal platelet stores of VWF:Ag, unlike type 3 VWD patients. Type 3 VWD patients in our study had undetectable (<1 IU/dL) VWFpp and VWF:Ag. In fact, type 1C VWD comprised the majority of severe type 1 VWD cases. At very low VWF:Ag levels (2 – 10 IU/dL), 76% of index cases had a type 1C phenotype, while the remainder had normal VWFpp/VWF:Ag consistent with a decreased secretion phenotype. In the VWF:Ag of 11 – 20 IU/dL group, 38% were type 1C. At still higher VWF:Ag levels (21 – 30 IU/dL), only 7% had a type 1C phenotype and the majority had a decreased secretion phenotype. Additionally, 43% of the type 1C cohort had VWFpp levels below the normal range, indicating reduced synthesis/secretion is also involved in the mechanism causing type 1C VWD. Mutations associated with type 1C were located in the VWF D3, A1, and D4 domains while decreased secretion variants were located primarily in the D1, D2, and D3 domains. Somewhat surprisingly, no difference in bleeding score was identified between type 1C and other type 1 patients. We can conclude that a reduced VWF survival phenotype (type 1C) is very frequent in severe type 1 VWD patients with VWF:Ag < 20 IU/dL. Identification of type 1C VWD is important because the rapid clearance of VWF in these patients may preclude the use of desmopressin, which is commonly given in type 1 VWD, but may be insufficient to achieve hemostasis in type 1C patients.