Von Willebrand's disease: case report and review of literature
Hanae Echahdi, Brahim El Hasbaoui, Mohamed El Khorassani, Aoma Agadr, Mohamed Khattab
Received: 13 Mar 2017 - Accepted: 16 Jun 2017 - Published: 29 Jun 2017
Domain: Pediatric hematology
Keywords: Von Willebrand disease, Von Willebrand factor, factor VIII, platelets, hemorrhage
©Hanae Echahdi et al. Pan African Medical Journal (ISSN: 1937-8688). This is an Open Access article distributed under the terms of the Creative Commons Attribution International 4.0 License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Cite this article: Hanae Echahdi et al. Von Willebrand's disease: case report and review of literature. Pan African Medical Journal. 2017;27:147. [doi: 10.11604/pamj.2017.27.147.12248]
Available online at: https://www.panafrican-med-journal.com/content/article/27/147/full
Von Willebrand's disease: case report and review of literature
Hanae Echahdi1, Brahim El Hasbaoui2,&, Mohamed El Khorassani1, Aomar Agadr2, Mohamed Khattab1
1Center of Hematology and Oncology Paediatrics, Children's Hospital, Faculty of Medicine and Pharmacy, University Mohammed V Rabat, Morocco, 2Department of Pediatrics, Military Teaching Hospital Mohammed V, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco
Brahim El Hasbaoui, Department of Pediatrics, Military Teaching Hospital Mohammed V, Faculty of Medicine and Pharmacy, University Mohammed V, Rabat, Morocco
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.
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 . 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 . 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 . 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 . 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.
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 appeared otherwise healthy. No other abnormal findings were evident on physical examination (there were no organomegaly and no joint disease (Hemarthrosis). The child had one days before his admission a trauma to the inner face of the lower lip that caused an external acute bleeding loss. The initial step of resuscitation was; immediately tried to stop the source of hemorrhage by manual compression, to restore circulating blood volume by administration of hypertonic salt solutions through large intravenous access calibre with providing an adequate oxygenation. Blood count pronounced: hemoglobin (Hb) level at 3 g/dL; leukocyte and platelet count were normal. Blood chemistry showed: Prothrombin Time (PT) and fibrinogen level were normal while activated partial thromboplastin time (PTT or APTT) was elongated. On the basis of the clinical presentation of hemorrhage, a tentative diagnosis of vWD had been made. This diagnosis was supported by the normal platelet count and the results of the coagulation panel. Following erythrocyte and fresh-frozen plasma (FFP) transfusions, administration of factor VII (Novoseven) was initiated at the admission. Less than 2 hr after transfusion began, the child appeared pinker and the oral bleeding had stopped. Three hours after transfusion, vital signs were within normal limits; the heart rate had decreased to 75 bpm and the respiratory rate was 26 bpm. The rest of biologic data was reported on day 4 and showed normal factor IX level but factor VIII level was low at 16.6%. The result of Factor Von Willebrand: Ag assay was very low at 1.8% that confirmed a severe form of Von Willebrand disease (type 3). The child was discharged with recommendation of relatif sedentary lifestyle in combination with prophylactic therapy in minor surgery including dental work.
Von Willebrand factor (VWF) is a large multimeric glycoprotein crucial for primary hemostasis and for coagulation. It is synthesized as a monomeric protein, secreted into plasma and their size is regulated by a specific cleaving-protease named ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13) . VWF is synthesized by endothelial cells and megakaryocytes. The gene coding for VWF (VWF) has been cloned and located at chromosome 12p13.2. It is a large gene of approximately 178 kilobases and containing 52 exons. VWD is a complex genetic disorder in which three subtypes have been described. The simplified classification of VWD proposed Sadler is still in common use. Despite the potential for reclassification based on molecular defects, there has been a reluctance to move to a more complex taxonomy; only minor qualifications were introduced when last reviewed. Table 1 summarizes how the classification is currently applied . These include both quantitative and qualitative defects. Type 1 accounts for 70% of cases and is the mildest form of the disease. Type 1 cases are caused bya partial deficiency of VWF. Type 2 cases are more difficult to diagnose due to the qualitative nature of the defect. These defects range from absence of certain protein multimers for binding during hemostasis to improper binding and decreased affinity. This Type 2 sub-group accounts for approximately 20-30% of cases. Qualitative VWD type 2 is further divided into four variants: 2A, 2B, 2N and 2M, based on the characteristics of the dysfunctional vWF. The type of mutation affecting the vWF locus forms the basis for classification of most type 2 VWD variants. Fortunately, the most severe form, Type 3, is rare. It accounts for 5% of cases overall. However, in some Swedish communities with prevalent disease, 1/ 200,000 people may have the severe form . The diagnosis of VWD is based on clinical and biological information. When patients present with mucocutaneous bleeding symptoms suggestive of a primary haemostatic disorder, a quantitative or qualitative abnormality of VWF is a possible cause or contributory factor. During the initial assessment it is important to remember that bleeding histories can be subjective and the disease characteristics can take time to evolve. A medical health history is important to help determine if other relatives have been diagnosed with a bleeding disorder or have experienced symptoms.
Screening assays include classically activated partial thromboplastin time (aPTT), platelet count and closure time (PFA-100 analyzer). Second-level-specific VWF assays are crucial to diagnose VWF deficiency and they include the measurement of FVIII activity (FVIII:C), VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo) allowing the calculation of ratios (VWF:RCo/VWF:Ag and FVIII:C/VWF:Ag) and the measurement of ristocetin-induced platelet aggregation (RIPA). Third-level VWF assays are devoted to a better characterization of VWD types and they include structural assays (VWF multimers analysis, VWF 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 . 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,"  to predict the response to desmopressin  or the kinetic of VWF during pregnancy, to anticipate the risk of allo-immunization in patients with type 3 VWD  and to help for genetic counseling . When a diagnosis of VWD is made it is appropriate to test first degree relatives with or without a positive bleeding history. In this circumstance, a presumptive diagnosis of VWD may be made on the basis of laboratory findings alone. For patients with "low VWF" (0.3-0.5 iu/ml), family testing may be justifiable depending on bleeding and family history. The severity of the bleeding tendency is usually proportional to the degree of the primary deficiency of VWF and to that of the secondary deficiency of FVIII, as VWF is the carrier of FVIII in circulating plasma [14, 15]. Thus, in VWD the aim of therapy is to correct the dual defect of hemostasis, i.e the abnormal platelet adhesion-aggregation and the abnormal intrinsic coagulation due to low FVIII levels. In management of VWD there are available therapies to correct haemostasis comprise the non-concentrate therapies tranexamic acid and desmopressin or concentrates containing either high purity VWF alone or intermediate purity concentrates containing FVIII-VWF; the pharmacology and clinical use of desmopressin to temporarily elevate FVIII and VWF levels by releasing endothelial stores have been extensively, because of its clinical utility and the wide variation in response, a trial of desmopressin should be considered in all patients with type 1, type 2A, 2M and 2N VWD who do not have a contraindication to its use. It is also useful in patients with bleeding and low VWF as a risk factor ("low VWF").
In type 2B a transient thrombocytopenia frequently follows desmopressin administration . This has been regarded as a reason for contraindication and although no harmful effects have been reported, the therapeutic response is usually poor and desmopressin is not recommended for type 2B VWD . 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 . VWF-containing concentrates a number of plasma-derived concentrates containing VWF are available for replacement therapy in patients whose desmopressin response is inadequate for the relevant bleeding episode or surgical procedure . For haemostatic activity, the relevant characteristics of these concentrates are the multimeric composition of the VWF and the amount of FVIII contained per unit of VWF. A VWF:RCo/VWF: Ag ratio close to 1 is desirable because it indicates the VWF has normal multimeric structure and adhesive function, but the appropriate amount of FVIII is debatable and will vary according to the circumstance. It's recommended for treatment of acute bleeding or emergency surgery, a VWF-FVIII concentrate or a combination of high purity FVIII and high purity VWF concentrates should be used. Treatment of acute bleeding episodes in VWD such as epistaxes, gum bleeding and menorrhagia. Post-traumatic bleeding can also occur and type 3 patients can develop spontaneous joint or muscle bleeding. When any of these are frequent, self-administration of desmopressin and tranexamic acid can be helpful . If the patient is non-desmopressin responsive, then acute treatment transfusion and secondary prophylaxis using concentrates should be considered. When bleeding persists despite apparently normal plasma levels of VWF activity, platelet transfusion may be helpful. Platelet transfusion is also the treatment of choice in platelet-type VWD pseudo (PT-VWD) and may be supplemented by FVIII-VWF concentrate. Because most cases of VWD are relatively mild and patients do not suffer from serious spontaneous bleeding, prophylaxis is rarely indicated. Exceptions include patients with type 3 disease plus haemarthroses, severe epistaxis, women with menorrhagia and those with VWD in conjunction with an on-going risk factor for bleeding, such as angiodysplasia.
Von Willebrand disease (VWD) is the commonest inherited bleeding disorder. However, despite an increasing understanding of the pathophysiology of VWD, the diagnosis of VWD is frequently difficult because of uncertainty regarding the relationship between laboratory assays and function in vivo. The aim of this work is to show that von willebrand disease can be the cause of serious life-threatening hemorrhage and given its prevalence and presenting symptoms, VWD should always be considered in the assessment of children suspectedof non-accidental injury, the risk for increased bleeding should be kept in mind when elective and medical procedures are undertaken in this hemostasis disorder..
The authors declare no competing interest.
Brahim El Hasbaoui: editing, bibliographic search, design, reviews; Hanae Echahdi has participated in the drafting, bibliographic research, design, revisions; Mohamed El Khorassani; corrections, critical reviews, appraisals, bibliographic search, approval final version; Aomar Agadr; corrections, critical reviews, appraisals, bibliographic search, approval final version; Mohamed Khattab; corrections, critical reviews, appraisals, bibliographic search, approval final version. All the authors contributed to the conduct of this work. All authors also state that they have read and approved the final version of the manuscript.
- Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood. 1987; 69(2): 454-9. PubMed | Google Scholar
- Yee A, Kretz CA. Von Willebrand factor: form for function. Semin Thromb Haemost. 2014; 40(1): 17-27. PubMed | Google Scholar
- Annucci M. Treatment of von Willebrand's disease. N EnglJ Med. 2004; 351(7): 683-94. PubMed | Google Scholar
- Castaman G, Tosetto A, Federici AB, Rodeghiero F. Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance. Thromb Haemost. 2011; 105(4): 647-54. PubMed | Google Scholar
- Lenting PJ, Christophe OD, Denis CV. Von Willebrand factor biosynthesis, secretion and clearance: connecting the far ends. Blood. 2015 Mar 26; 125(13): 2019-28. PubMed | Google Scholar
- Laffan MA1, Lester W, O'Donnell JS, Will A, Tait RC, Goodeve A, Millar CM, Keeling DM. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014 Nov; 167(4): 453-465. PubMed | Google Scholar
- Rodeghiero F, Castaman G. Textbook of Hemophilia. Oxford, UK: Blackwell Publishing; von Willebrand disease: epidemiology.2005; pp. 265-71. Google Scholar
- Eikenboom J, Federici AB, Dirven RJ, Castaman G, Rodeghiero F, Budde U, Schneppenheim R, Batlle J, Canciani MT, Goudemand J, Peake I, Goodeve A, MCMDM-1VWD Study Group. VWF propeptide and ratios between VWF, VWF propeptide, and FVIII in the characterization of type 1 von Willebrand disease. Blood. 2013 Mar 21; 121(12): 2336-9. PubMed | Google Scholar
- Flood VH, Lederman CA, Wren JS, Christopherson PA, Friedman KD, Hoffmann RG, Montgomery RRJ. Absent collagen binding in a VWF A3 domain mutant: utility of the VWF:CB in diagnosis of VWD. Thromb Haemost. 2010 Jun; 8(6): 1431-3. PubMed | Google Scholar
- Othman M, Emsley J. Platelet-type von Willebrand disease: toward an improved understanding of the "sticky situation". Semin Thromb Hemost. 2014 Mar; 40(2): 146-50. PubMed | Google Scholar
- Castaman G, Lethagen S, Federici AB, Tosetto A, Goodeve A, Budde U, Batlle J, Meyer D, Mazurier C, Fressinaud E, Goudemand J, Eikenboom J, Schneppenheim R, Ingerslev J, Vorlova Z, Habart D, Holmberg L, Pasi J, Hill F, Peake I, Rodeghiero F. Response to desmopressin is influenced by the genotype and phenotype in type 1 von Willebrand disease (VWD): results from the European Study MCMDM-1VWD. Blood. 2008 Apr 1; 111(7): 3531-9. PubMed | Google Scholar
- Ames PD, Lillicrap D, Mannucci PM. Alloantibodies in von Willebrand disease. Blood. 2013 Aug 1; 122(5): 636-40. PubMed | Google Scholar
- Ames PD, Goodeve AC. von Willebrand disease. Genet Med. 2011 May; 13(5): 365-76. PubMed | Google Scholar
- De Meyer SF, Deckmyn H, Vanhoorelbeke K. Von Willebrand factor to the rescue. Blood. 2009; 113(21): 5049-57. PubMed | Google Scholar
- Casonato A, Steffan A, Pontara E, Zucchetto A, Rossi C, De Marco L, Girolami A. Post-DDAVP thrombocytopenia in type 2B von Willebrand disease is not associated with platelet consumption: failure to demonstrate glycocalicin increase or platelet activation. Thromb Haemost. 1999 Feb; 81(2): 224-8. PubMed | Google Scholar
- Mannucci PM. Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood. 1988 Nov; 72(5): 1449-55. PubMed | Google Scholar
- Pasi KJ, Collins PW, Keeling DM, Brown SA, Cumming AM, Dolan GC, Hay CR, Hill FG, Laffan M, Peake IR. Management of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organization. Haemophilia. 2004 May; 10(3): 218-31. PubMed | Google Scholar
- Batlle J, López-Fernández MF, Fraga EL, Trillo AR, Pérez-Rodríguez MA. Diagnosis and management of von Willebrand disease in Spain. Semin Thromb Hemost. 2011 Jul; 37(5): 503-10. PubMed | Google Scholar
- Batlle J1, López-Fernández MF, Fraga EL, Trillo AR, Pérez-Rodríguez MA. Von Willebrand factor/factor VIII concentrates in the treatment of von Willebrand disease. Blood Coagul Fibrinolysis. 2009 Mar; 20(2): 89-100. PubMed | Google Scholar
- Leissinger C, Becton D, Cornell C Jr, Cox Gill J. High-dose DDAVP intranasal spray (Stimate) for the prevention and treatment of bleeding in patients with mild haemophilia A, mild or moderate type 1 von Willebrand disease and symptomatic carriers of haemophilia A. Haemophilia. 2001 May; 7(3): 258-66. PubMed | Google Scholar