Constitutional disease of hemostasis due to a mutation of the vWF gene (12p13.3).

It is the most common hemostasis anomaly: estimated prevalence of 0.5 to 1 % in Europa. The von Willebrand factor (vWF) is a multimeric protein (glycoprotein IbA and IbB, erythrocytic platelet glycoproteins 5 and 9) involved in the interactions between the blood platelets with the sub-endothelial zone, in the platelet aggregation process during the formation of a thrombus, and it is a carrier of FVIII. It is present in plasma (the high molecular weight multimers have the highest activity) and in the α granules of the blood platelets.

Three main types:

• type I (75-80 % of cases) [MIM 193 400]: moderate quantitative deficiency in vWF (< 30 IU/dL), often accompanied by a  moderate deficiency in factor VIII; it is the least severe form of the disease. It is often asymptomatic or is discovered after excessive bleeding during surgery (tonsils) or heavy periods. Patients with a low vWF level (30 - 50 IU/dL) have an hemorrhagic risk similar to type I and must benefit from the same prophylactic treatment in case of surgery.
• type II [MIM 613 554]: qualitative structurally abnormal vWF factor deficiency; 

There are 4 subgroups:

o         type IIa (10-15 % of all cases): autosomal dominant or recessive transmission; platelet aggregation is reduced; deficiency  in high and intermediate molecular weight vWF multimers

o Type IIb (5 % of cases): autosomal dominant transmission; platelet aggregation is increased; high molecular weight vWF multimers deficiency

o Type IIm (very rare): autosomal dominant or recessive transmission; the distribution of the sizes of vWF multimers is normal but the vWF-dependent functions of platelets are altered

o Type IIn (rare): complex transmission; the half-life of factor VIII is reduced because the affinity of VWF to FVIII is decreased

• type III (< 5 % of cases) [MIM 277 480]:  the most severe form of the disease: total absence of vWF (< 5 IU/dL) and low level of factor VIII often < 10 %; the clinical picture is similar to severe hemophilia A
• pseudo-Willebrand or blood platelet von Willebrand disease: clinical picture of type IIa von Willebrand disease but the anomaly is located at the level of platelets and not of the factor vWF itself
• acquired VWD: rare, usually associated with other illnesses such as 

1)        a malignant disease (lymphoma, Wilms tumour); in case of nephroblastoma, the association is rare (8 %), usually benign and  it responds to chemotherapy. However two cases have been described of persistent clinical signs of hemorrhagic diathesis that did not respond to substitutive treatments until the tumor vessels were clamped.

2)        an immune problem

3)        a cardiovascular disease that causes blood platelets shear stress (severe aortic stenosis, pulmonary stenosis, ventricular assistance especially if it is non-pulsatile, more rarely: VSD, ASD).

In the acquired forms, the vWF is either blocked by autoantibodies, or adsorbed by tumor cells or consumed at the platelet level. The treatment is complex because desmopressin is ineffective and vWF administration is less effective than in congenital cases. Sometimes it is necessary to use gammaglobulins or recombinant activated factor VII .

NB: 

-        blood group O patients have a vWF level 25 % lower than other blood groups but without hemorrhagic symptoms. This inferior level could be due to an higher clearance of vWF

-        in the normal patient, vWF level is high at birth, at its nadir between 6 and 12 months of age and reaches adult levels between 1 and 5 years of age.

-        in case of type I, vWF level increases of about 1 to 2 % per year of age, but also in case of stress, exercise, pregnancy, use of oral contraceptives or inflammatory syndrome, which can make the diagnosis more difficult to establish

Anesthetic implications: 

this disease may never manifest itself clinically and its evolution can be capricious, not only in its clinical expression but also the patient's laboratory results. It should suspected in case of prolonged ACT and the advice of a hematologist should be asked for the perioperative therapeutic management. The goal of the treatment is either to increase the circulating level or activity of vWF (types I, IIa; contraindicated in case of type IIb) or to replace it (IIb, IIm, IIn and III types), to co-administer factor VIII if neded and to decrease fibrinolysis.

The management includes the measurement of FVIII:C (a predictive factor for bleeding) and vWF (particularly for mucous bleeding). It must be done under the guidance of an hemostasis specialist.

- type I (vWF level < 50 IU/dL): usually of minor severity. It responds well, if necessary, to treatment with DDAVP (or desmopressin), IV (0.3 µg/kg in 30 min) or nasal (150 µg) 1 to 1.5 hour before the surgical incision. The effect of a dose lasts from 6 to 8 hours on average. It is useful to perform a therapeutic test in the hemostasis laboratory a few weeks before a scheduled procedure to evaluate the patient's response to this treatment. Desmopressin acts on the V2 receptors of the endothelial cells and thus releases the vWF contained in the Weibel-Palade's bodies.  Warning: risk of hyponatremia. Desmopressin is contraindicated in the IIb form as it may aggravate thrombopenia.

- severe or non-desmopressin-responsive forms: (including patients with type III form): they require pre-, per- and postoperative treatment including the administration of vWF:

-        of plasma origin (Humate P®, Wilate®, Wilfactin®) which contains vWF and factor VIII) at the dose of 40-60 IU/kg for major surgery (but also delivery, cesarean section) and 40 IU/kg in case of minor surgery (1 dose). Maintenance doses are given every 8 to 24 hours so that vWF and FVIII levels exceed IU/100ml

-        of plasma origin but depleted in FVIII (Koate®): 40-60 IU/kg 12 to 24 hours before the operation (or 1 hour before with FVIII), then 2 to 3x/day with FVIII in order to maintain a vWF and FVIII levels of 50UI/100 ml

-        recombinant (Vonvendi®): 40-60 IU/kg 12 to 24 hours before the intervention and pre- and post-operative monitoring of vWF and FVIII levels.

→   in the presence of anti-vWF antibodies, recombinant FVIII should be used.

In all forms of the disease, it is useful to administer an antifibrinolytic as tranexamic acid (10-15 mg/kg every 8 hours) or ε-aminocaproic acid (50 - 60 mg/kg every 4 hours) intravenously or orally.

Elective surgery is undertaken only after verifying that hemostasis is normal on the day of the procedure and, in these circumstances, there is no reason to deprive the child of the benefits of locoregional anesthesia, especially in the type I forms. Conversely, in severe forms (and in particular type III forms), it is necessary to balance carefully the indications of all invasive techniques, not only regional anesthesia  (a priori contraindication of central blocks), but also the insertion of vascular lines (arterial and central venous catheters). 

References : 

-        Montgomery RR, Kroner PA.
von Willebrand disease: a common pediatric disorder.
Pediatr Ann 2001;30:534-40.

-        Mannucci PM .
Treatment of von Willebrand’s disease.
N Engl J Med 2004 ; 351 : 683-94.

-        Maquoi I, Bonhomme V, Born JD, Dresse MF, Ronge-Colard E, Minon JM, Hans P.
Perioperative management of a child with von Willebrand disease undergoing surgical repair of craniosynostosis: looking at unusual targets.
Anesth Analg 2009; 109: 720-4.

-        Lison S, Dietrich W, Spannagi M.
Unexpected bleeding in the operating room : the role of acquired von Willebrand disease.
Anesth Analg 2012 ; 114 : 73-81.

-        Coppes MJ, Zandvoort SW, Sparling CR et al.
Acquired von Willebrand in Wilms‘ tumor patients.
J Clin Oncol 1992; 10:422-7.

-        Baxter PA, Nuchtern JG, Guillerman RP, Mahoney DH et al.
Acquired von Willebrand syndrome and Wilms tumor: not always benign.
Pediatr Blood Cancer 2009; 52: 392-3.

-        Carpenter SL, Abshire TC, Anderst JD,et al.
Evaluating for suspected child abuse : conditions that predispose to bleeding.
Pediatrics 2013; 131: e1357-73.

-        Bonhomme F, Schved J-F, Giansily-Blaizot M, Samama C-M, de Moerloose P.
Déficits rares de la coagulation et gestes invasifs.
Ann Fr Anesth Réanim 2013 ; 32 : 198-205.

-         Costello JP, Yaser AD, Michael P-A, Jones MB et al.
Acquired von Willebrand syndrome in a child folllowing Berlin Heart EXCOR pediatric ventricular assist device implantation: case report and concise literature review.
World J Pediatr Cong Heart Surg 2014; 4: 592-8.

-         Parker JW, James PD, Haley SL.
Spinal anesthesia in 2 consecutive caesarean deliveries in a parturient with type 3 von Willebrand disease: a case report.
A&A Practice 2019; 12: 79-81

-        Miesbach W.
Perioperative management for patients with von Willebrand disease: defining the optimal approach.
Eur J Haematol 2020; 105:365-77.

-        Srivaths L, Kouides P.
Low von Willebrand Factor in children and adolescents : a review.
JAMA Pediatr  2021;175:1060-7.

Updated: October 2021