Knee replacement surgery in a patient with acquired von Willebrand disease: a case study with recommendations for patient management

Introduction and importance: Acquired von Willebrand disease (AvWD) is a rare underdiagnosed bleeding disorder caused by alterations in the levels of the major blood-clotting protein von Willebrand factor (vWF). The clinical and laboratory parameters of AvWD are similar to congenital vWD, but it is found in individuals with no positive family history with no underlying genetic basis. The disease remains multifactorial and incompletely understood. Proposed mechanisms include the development of autoantibodies to vWF, absorption of high molecular weight vWF multimers that impair normal function, shear stress induced vWF cleavage and increased proteolysis. The aetiology of the disease is variable, the most common being hematoproliferation, lymophoproliferation, myeloproliferation and autoimmune and cardiovascular disorders. Consensus and protocols for AvWD patients that require major surgery are currently lacking. Patients with AvWD can experience thrombotic events during surgery as a result of therapeutic interactions with pro-thrombotic risk factors. Case presentation: Here, the authors report a patient with AvWD requiring a knee prosthesis implantation due to chronic pain, limited range of motion and functional impairment. The patient had a high risk of bleeding during surgery and was at risk of thrombosis due to age and obesity. Clinical discussion: Perioperative care required a collaborative approach and the management of bleeding. The patient was administered vWF concentrate Willfact lacking Factor VIII to prevent haemorrhage and to minimize the risk of thrombosis. Conclusion: The treatment was effective and well-tolerated. The authors use this information to provide recommendations for AvWD patients for whom major surgery is indicated.


Introduction
von Willebrand factor (vWF) is a multimeric glycoprotein that plays a key role during haemostasis following vascular injury [1] .vWF promotes coagulation by acting as a carrier for the essential blood-clotting protein factor VIII (FVIII), preventing its degradation by activated protein C [2] .vWF is released from injured endothelial cells and is an important biomarker of endothelial dysfunction [3] vWF promotes platelet adhesion at the sites of vascular damage, mediating thrombus formation through interactions with collagen and platelet receptors Ib, IX and V [4] .Deficiencies of vWF ( ≤ 50 IU/dl) result in the bleeding disorder Von Willebrand disease (vWD) [5] .
vWD can be inherited (autosomal dominant) or acquired [6] .Acquired deficiency or dysfunction of vWF (AvWD) is similar to congenital vWD regarding clinical and laboratory parameters, but is found in individuals with no positive family history.AvWD is less common than genetic vWD and diagnosis is often not suspected in a bleeding patient [7] .

HIGHLIGHTS
• Acquired von Willebrand disease is a rare disease.
• Information about the management of these patients is essential.• The clinical case presented here is important because it is a patient with a high risk of bleeding and high thrombotic risk due to surgery and pre-existing comorbidities.• The use of pure VWF concentrates that do not increase the thrombotic risk in these patients is essential.• Experience in this pathology is scarce, as is the management of orthopaedic surgery in a patient with comorbidities and treated with a pure VWF such as Wilfactin.
The development of AvWD is multifactorial.Common causes include the presence of autoantibodies that increase the plasma clearance of vWF and the absorption of high molecular weight and functionally impaired vWF multimers [8] .Waldenstrom macroglobulinemia promotes selective vWF immuno-adsorption due to lymphocyte dysfunction [9] .A similar mechanism was reported in a patient with multiple myeloma [10] .Increased proteolytic cleavage of vWF can occur as a result of intravascular shear stress during aortic stenosis, leukaemia and pancreatitis [11][12][13] .Impaired vWF production due to hypothyroidism and drugs that influence haemostatic parameters are also associated with AvWD development [14,15] .Individuals with AvWD manifest excessive mucocutaneous bleeding, bruising, epistaxis and menorrhagia.
A major challenge during the management of AvWD patients is the high risk of bleeding during major surgery.Consensus on the best practice for treatment aims and postoperative tests are lacking [16][17][18][19] .Recent guidelines on inherited vWD recommend the use of Willfact (human VWF) for the prevention of haemorrhages or surgical bleeding when desmopressin is ineffective or contraindicated [20] .Whilst Willfact is commonly used to support clotting in AvWD patients, its use during surgery has not been documented.
Here, we report the treatment of an elderly female patient with AvWD undergoing major knee surgery.We provide evidencebased guidelines for the management of AvWD during surgery and the use of vWF concentrates in this patient cohort.

Case presentation
A 71-year-old woman with suspected AvWD was referred to our clinic for the first time in February, 2010 and treated from 2010 to 2022.Her past medical history included a normal pregnancy at 24 years of age, mastectomy, radiotherapy and chemotherapy for carcinoma of the left breast at 38 years, lacrimal duct agenesis surgery at 51 years, and meniscus tear surgery at 67 years of age.No complications or bleeding were associated with any of these treatments.The patient was in complete remission from the carcinoma.The patient was diagnosed with advanced arthrosis in the right knee and hip aged 60.Cardiovascular risk factors including dyslipidaemia, hypertension, hyperglycaemia and obesity were recorded.A family history of bleeding was noted.
Significant history included the development of frequent epistaxis and bleeding following a dental extraction at the age of 60 years.The patient was treated at our clinic over a period of 12 years (2010-2022) for retinal haemorrhage; recurrent hemarthrosis; and advanced gonarthrosis.The patient had poorly controlled pain and required treatment with oxycodone hydrochloride, paracetamol, metamizole, and infiltrations with triamcinolone 40 mg and ropivacaine (0.1% at a total dose of 8 ml) every 6-8 months.This case report follows the guidance of SCARE (Surgical Case Report) criteria [21] .

Diagnosis
In 2012, the patient was diagnosed with AvWD associated with Monoclonal Gammopathy of Undetermined Significance (MGUS) (Fig. 1).The diagnosis of AvWD was made based on a negative family history of bleeding, recent onset bleeding, elongated aTTP, and the frequent association of AvWD with MGUS [22][23][24] .In 2022, the patient was evaluated for chronic pain in the knees with functional impairment and limited mobility (range of motion: 0-90 o ).Imaging studies revealed arthropathy that led to varus deformities of both knees (Fig. 2).The patient had a body mass index of 30 and did not perform physical activity.A right knee prosthesis implantation was recommended.The patient was considered at a high risk of bleeding and thrombosis.The patient had a partial response to DDAVP which was deemed not suitable for the implantation of a knee prosthesis as haemostatic levels must be maintained for extended time periods and tachyphylaxis can occur after 48 h.Patient management was planned by a team of orthopaedic, haematology,
The preoperative levels of both VWF and FVIII were less than or equal to 10% of normal values.Preoperative factor tests were performed and the patient was administered a single dose of human recombinant FVIII (rFVIII) (20 IU/Kg) and Willfact (50 IU/Kg) in combination.Willfact was not administered alone as the half-life of the infused concentrates are shorter in AVWD patients.Pure Willfact was selected to reduce FVIII accumulation and thus the thrombotic risk.Single dose tests showed high recovery of FVIII and VWF, albeit with a shorter half-life than normal (Table 1).
Table 2 shows the FVIII/ vWF: RCo levels during surgery and postoperatively.On the day of surgery, a single dose of rFVIII 20 UI/kg was administered with Willfact (50 IU/Kg).Maintenance doses of Willfact (50 IU/Kg) were administered every 8 h for the first 4 days and every 12 h from days 5 to 8. Due to difficulties in maintaining adequate levels of FVIII and VWF, no anticoagulant treatments were used during surgery.

Surgical procedure
Following successful implantation (Fig. 3), coagulation was managed through blood loss through the drains, blood haemoglobin and FVIII levels (Table 2).The patient showed no signs of a coagulation, thrombotic events or FVIII accumulation.The patient did not meet the criteria for corticosteroid therapy.

Post-surgical management
Anticoagulants were administered early after surgery to reduce the risk of thrombosis.In patients with AvWD, the VWF concentrate is rapidly eliminated and does not protect from the risk of bleeding.The patient began mobilization and movement exercises within 24 h of surgery.

Postoperative outcome
The day after surgery, the patient was in good condition, was afebrile, had well-controlled pain and no bleeding or deep vein thrombosis.Six days post-surgery, the patient developed knee pain, which was particularly intense in the popliteal fossa, both at rest and when walking.The extremities showed significant swelling and intense pain on examination (Fig. 4).Knee swelling, pitting oedema, skin erythema and a subcutaneous haematoma occurred.A Homan's sign test could not be performed.Laboratory tests included Cmax FVIII: C: 43.4% and VWF: RCo 56.4%.A musculoskeletal ultrasound was performed, showing patent popliteal vessels and minimal joint fluid.The episode resolved spontaneously with the patient reporting improved mobility, increased physical activity and decreased pain.

Discussion
The perioperative management of AvWD is challenging due to unpredictable coagulation pharmacokinetics and an increased risk of bleeding and thrombosis [16,17] .Patients with AVWD show defective VWF production but normal FVIII levels [25][26][27][28][29] .The administration of commercially available FVIII concentrates are required following major orthopaedic surgery which can increase the risk of thrombosis [30] .This risk is further increased by age, obesity and cardiovascular disease.Desmopressin and pdFVIII/vWF concentrates form the cornerstone of VWD management.Desmopressin is effective in individuals with mild to moderately severe vWD with FVIII and vWF levels above 10% (type 1 and type 2A).pdvWF/FVIII concentrates can control and prevent bleeding in patients with more severe vWF and FVIII deficiency (type 3) [24] .
In this study, perioperative care required a collaborative approach and the management of bleeding parameters.VWF concentrate Willfact lacking Factor VIII was used to prevent haemorrhage and surgical bleeding and to minimize the risk of thrombosis.The treatment was effective and well-tolerated.
A single dose of vWF requires 6-12 h to increase FVIII: C concentrations to therapeutic levels.When haemostasis requires immediate correction during haemorrhage, severe trauma or emergency surgery, FVIII products must be administered with the initial vWF injection to ensure basal plasma levels.Table 2 illustrates how FVIII/ vWF: RCo levels were effectively main-tained in the absence of FVIII accumulation in our patient (normal range: 50-200 IU/dl).
The replacement therapy of choice during the perioperative period is dependent on baseline FVIII activity, the Von Willebrand Ristocetin Cofactor range, the pattern of reaction to desmopressin dosage and the type of operation [31] .The use of desmopressin alone with prolonged periods of replacement therapy is limited by the increased incidence of tachyphylaxis after 48 h [32] .Replacement therapy containing FVIII and vWF can increase the risk of thrombosis.When baseline levels of FVIII are low, dual vWF/ FVIII products are effective.In patients with normal FVIII levels, dual administration can induce thromboembolism [33] .To avoid rapid increases in FVIII levels, high-purity vWF concentrates have been developed which are of low Factor VIII content (Willfact, LFB-Biomedicaments).
Willfact therapy should be initiated at 12-24 h prior to surgery and 1 h prior to elective surgery.Co-administration of FVIII was not necessary in our patient as endogenous FVIII achieved threshold levels of 0.4 IU/ml (40%).This should however be monitored on a patient-by-patient basis [21] .Surprisingly, the multimeric pattern was type 3. Genetic studies showed no pathogenic variants.
Close monitoring of bleeding parameters during and after surgery are necessary.The use of a concentrate that does enhance the accumulation of FVIII is also essential.Pure VWF concentrates such as Willfact, contain minimal FVIII, which minimizes the risk of thrombosis [34] .
Recommendations for AvWD patients undergoing surgery vWF, hepatic status and renal function should be characterized prior to surgery.Surgery should be performed in centres experienced in the management of haemorrhagic coagulopathies with freely available laboratory assays for Factor VIII vWF, Ag, and Von Willebrand Ristocetin Cofactor [vWF: RCo]).
Close monitoring of bleeding parameters during surgery is necessary.The vWF concentrate Willfact contains low levels of FVIII and data from this case report supports its efficacy and safety during major surgery.
We recommend that joint consultations are regularly performed amongst the departments of Orthopaedic Surgery,  Haematology, Rehabilitation, Pharmacy and Nursing for patients with bleeding disorders requiring major surgery.The orthopaedic surgeon should present the surgical technique and allow the haematologist to design the haemostatic support.Rehabilitation physicians should ensure that the patient arrives at the surgery in the best possible condition.An individualized postsurgical rehabilitation program should be designed to address pain control, joint function recovery and gait retraining.The physiotherapist should initiate rehabilitation within 24 h of surgery.

Figure 2 .
Figure 2. Plain films revealing varus deformities and osteoarthritis in both knees.
pharmacy and rehabilitation medicine specialists.The patient was diagnosed with the IgG MGUS shortly after diagnosis due to elevated serum proteins.Imunofixation analyses detected monoclonal IgG k.

Figure 3 .
Figure 3. Post-surgical films showing successful implantation of the knee replacement.

Figure 4 .
Figure 4. Knee swelling after the operation.