Von Willebrand's disease: case report and review of literature

Von Willebrand Disease (VWD) is the most common human inherited bleeding disorder due to a defect of Von Willebrand Factor (VWF), which a glycoprotein crucial for platelet adhesion to the subendothelium after vascular injury. VWD include quantitative defects of VWF, either partial (type 1 with VWF levels < 50 IU/dL) or virtually total (type 3 with undetectable VWF levels) and also qualitative defects of VWF (type 2 variants with discrepant antigenic and functional VWF levels). The most bleeding forms of VWD usually do not concern type 1 patients with the mildest VWF defects (VWF levels between 30 and 50IU/dL). Von willebrand factor is a complex multimeric protein with two functions: it forms a bridge between the platelets and areas of vascular damage and it binds to and stabilizes factor VIII, which is necessary for the clotting cascade. By taking a clinical history of bleeding (mucocutaneous bleeding symptoms suggestive of a primary haemostatic disorder, a quantitative or qualitative abnormality of VWF is possible) it is important to think about VWD and to make the appropriate diagnosis. If the VWD is suspected diagnostic tests should include an activated partial thromboplastin time, bleeding time, factor VIII: C Ristocetin cofactor and vWF antigen. Additional testing of ristocetin induced plattlet adhesion (RIPA) the multimeric structure and collagen binding test and genanalysis allow diagnosing the different types of von. Willebrand Disease. The treatment of choice in mild forms is the synthetic agent desmopressin. In patients with severe type 1, type 2B, 2N and type 3 or in people who do not response to desmopressin, the appropriate treatment is a factor VIII concentrate that is rich of VWF. We report a case of infant in 27-month-old boy who had been referred due to haemorrhagic shock. His birth histories, his familie's social history and developmental milestones were unremarkable. He was born at full term with no antenatal or perinatal complications. Prior to the symptoms, the child was on a normal diet and was thriving appropriately. The child presented one days before his admission trauma to the inner face of the lower lip that caused an external acute bleeding loss. The laboratory data showed unfortunately, the most severe form of Von Willebrand's Disease; Type 3. The management was based on erythrocyte and fresh-frozen plasma (FFP) transfusions with administration of factor VII with good evolution.


Introduction
Von Willebrand disease (VWD) is usually reported to be "the most common human inherited bleeding disorder." Actually found in approximately 1% of the general population [1]. Originally described by the Finish physician Erik von Willebrand in 1926. VWD is due to quantitative deficiencies and/or qualitative defects in von Willebrand factor (VWF), a complex plasma protein with multiple functions, which overall contribute to the formation of a platelet thrombus at sites of injury to help prevent blood loss [2]. VWF accomplishes this major haemostasis function by anchoring platelets to sites of vascular injury (primary haemostasis function), as well binding to factor VIII (FVIII), thus protecting FVIII from degradation and delivering it to sites of vascular injury (thereby facilitating secondary haemostasis). VWF binds to platelets via several receptors, most notably glycoprotein Ib(GPIb), but also GPIIb/IIIa. VWF also binds to subendothelial matrix components, most notably collagen and in this way facilitates anchoring of platelets to damaged endothelium by forming an adhesive bridge.
The peculiar structure of VWF, in terms of its size and formation of multimers has particular relevance here, as the larger VWF molecules facilitate better anchoring of platelets and thus thrombus formation and prevention of bleeds. This a heterogeneous quantitative or qualitative deficiency in the von Willebrand factor (vWF) may also be associated with a concomitant decrease in factor VIII levels (FVIII), since vWF serves as the carrier protein for FVIII [3]. It is well recognized that deficiency of VWF results in a bleeding disorder that varies in severity according to the degree of deficiency and the specific characteristics of the molecule and which may have features of both primary and secondary haemostatic defects. Clinical expression of VWD is usually mild in type 1, with increasing severity in type 2 and type 3. In general, the severity of bleeding correlates with the degree of the reduction of FVIII. Mucocutaneous bleeding (epistaxis especially during childhood, easy bruising) is a typical, prominent manifestation of the disease and may affect the quality of life. However, the rate of spontaneous bleeding may be low even in patients with severe VWF deficiency [4]. We report the observation of a child admitted to the emergency department for a state of haemorrhagic shock, revealing a severe defect in von villebrand factor.

Patient and observation
We report the 27-month-old man who had been referred due to haemorrhagic shock. Pregnancy and birth history were unremarkable. The boy had been born full-term (39 weeks) with a birth weight (3200g). No parental consanguinity was observed. He was on exclusively breast-fed, there were no incidents during vaccinations, food diversification was started at 6 months old, his weight, length and psychomotor development were within the normal range. He was until yet not circumcised. Prior to the symptoms, the child was described as a good eater, was on a normal diet and was thriving appropriately. The boy was admitted in our department for hemorrhagic shock, he was lethargic, very pale with profound hypotonia, tachycardic, tachypnea and Oliguria at the presentation, the capillary refill time (CRT) was > 3s. Blood was oozing from a wound at the inner surface of the lower lip, the gums propeptide (VWFpp)) and functional assays (VWF binding to platelet GPIb, to collagen (VWF:CB) and to FVIII (VWF:FVIIIB)) [8,9]. The algorithm diagnosis of von Willebrand disease is summarizes in Figure 1 [6]. The diagnosis of VWD type and subtype is crucial for many purposes: to make a differential diagnosis between VWD 2N and hemophilia A or between VWD 2B and a platelet disorder named "pseudo VWD or platelet type VWD," [10] to predict the response to desmopressin [11] or the kinetic of VWF during pregnancy, to anticipate the risk of allo-immunization in patients with type 3 VWD [12] and to help for genetic counseling [13]. When and low VWF as a risk factor ("low VWF").
In type 2B a transient thrombocytopenia frequently follows desmopressin administration [16]. This has been regarded as a reason for contraindication and although no harmful effects have been reported, the therapeutic response is usually poor and Page number not for citation purposes 4 desmopressin is not recommended for type 2B VWD [17].
Desmopressin is relatively contraindicated in children < 2 years old.
If after careful consideration, it is to be used in this age group then fluid restriction, avoidance of hyponatraemic solutions and close monitoring of serum electrolytes and urine output for at least 24 hr after administration is advised. Tranexamic acid administered topically, as a mouthwash, orally or parenterally remains a useful therapy for minor bleeding or surgery (beginning prior to the procedure) either on its own or as an adjunctive therapy to desmopressin or concentrates [18].

Competing interests
The authors declare no competing interest.