Von Willebrand factor (VWF) is a large, multimeric plasma glycoprotein produced in endothelial cells and megakaryocytes. Following synthesis, VWF is transported and stored in the Weibel-Palade bodies and platelet α-granules. 1 VWF plays a crucial role in both primary and secondary hemostasis by supporting platelet adhesion/aggregation at sites of vascular injury and acting as plasma carrier and stabilizer for coagulation factor VIII (FVIII). 2 Defects in VWF, quantitative or qualitative, are responsible for the inherited bleeding disorder von Willebrand disease (VWD), which is classified into three main types. VWD types 1 and 3 are due to the quantitative deficiency of VWF, type 2 to functional abnormalities of this protein. 3 Type 2N VWD is an uncommon recessive disorder first described almost 30 years ago and caused by the defective capacity of VWF to bind FVIII, leading to the accelerated clearance of unbound FVIII, shortening of its half-life and thus to reduced FVIII levels in plasma. 4 Because patients with type 2N exhibit clinical and laboratory manifestations similar to those of male patients with mild/moderate hemophilia A or female carriers of hemophilia A, 2N VWD may be misdiagnosed, but a differential diagnosis is warranted because genetic counseling and treatment are different. 5,6 In this narrative review, we discuss the pathophysiologic mechanisms, diagnostic approach, molecular biology, clinical presentation and treatment of type 2N VWD.

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Von Willebrand disease, the most common inherited bleeding disorder that affects both males and females, is due to quantitative or qualitative defects of the multimeric glycoprotein von Willebrand factor, which cause mucous membrane bleeding but also soft tissue bleeding owing to the secondary deficiency of factor VIII. The aim of treatment is to correct this dual defect of hemostasis. In addition to the episodic management of bleeding episodes, therapy includes their short- or long-term prevention. Short-term prophylaxis is mainly warranted in order to provide effective hemostatic coverage to patients undergoing surgery or invasive procedures and to affected women at the time of delivery or during menstruations associated with excessive bleeding. The aim of long-term prophylaxis is to prevent bleeding in particular categories of patients at increased risk of frequent and spontaneous bleeding in the joints, nose, and gastrointestinal tract.

von Willebrand disease (VWD) type 2 is caused by qualitative abnormalities of von Willebrand factor (VWF). This study aimed to determine the genotype and phenotype characterization of a large VWD type 2 cohort from Milan. We included 321 patients (54% females) within 148 unrelated families from 1995-2021. Patients were fully characterized using laboratory phenotype tests and the genotype diagnosis was confirmed by target genetic analysis using Sanger sequencing. Patients were diagnosed with type 2A (n= 98, 48 families), 2B (n= 85, 38 families), 2M (n= 112, 50 families), and 2N (n= 26, 12 families). Eighty-two unique VWF variants including 8 novels were found. The potential pathogenic effect of novel variants was assessed by in silico analysis. Most patients were heterozygous for a single variant (n= 259, 81%), whereas 37 cases (11%) had 2 variants (4 homozygous, 9 in trans and 24 in cis). Twenty-five patients (8%) had 3 or more variants, mainly due to gene conversions. Among the 82 distinct variants identified, five different types including missense (n= 64), gene conversion (n= 10), synonymous (n= 1), deletion (n= 4) and splice (n= 3) were observed. The results of this large cohort showed that VWD type 2 is invariably due to variants that do not prevent the synthesis of the protein and the vast majority of patients (88%) had missense variants. Given the complexity of type 2 diagnosis and the necessity of performing several phenotypic tests, genetic analysis for patients suspected of type 2 is beneficial to establish the correct diagnosis.