von Willebrand Disease: Clinical Guidelines

List of Abbreviations

aPTT — activated partial thromboplastin time

ADP — adenosine diphosphate

VWD — von Willebrand disease

HRT — hormone replacement therapy

IU — International Unit

PT — prothrombin time

FFP — fresh frozen plasma

CRP — C-reactive protein

PFA — platelet function activity

FVIII — blood coagulation factor VIII

FVIII:C — factor VIII procoagulant activity

vWF — von Willebrand factor

FVIII + vWF — blood coagulation factor VIII + von Willebrand factor

vWF:RCo — von Willebrand factor ristocetin cofactor activity

vWF:ag — von Willebrand factor antigen

vWF:agII — von Willebrand factor antigen II

vWF:CB — von Willebrand factor collagen-binding activity

vWF:FVIIIB — von Willebrand factor factor VIII binding assay

RIPA — ristocetin-induced platelet aggregation

GPIbα — platelet membrane receptor

ADAMTS-13 — metalloproteinase

EACA — ε-aminocaproic acid

vWF:GPIb — von Willebrand factor GPIb-binding activity

Terms and Definitions

Von Willebrand factor antigen — a laboratory parameter representing the concentration of von Willebrand factor.

Von Willebrand factor activity — a laboratory parameter reflecting the functional activity of von Willebrand factor.

Von Willebrand factor multimer analysis — an investigation of von Willebrand factor structure using electrophoresis.

Von Willebrand disease — an inherited deficiency or functional impairment of von Willebrand factor.

Hemarthrosis — bleeding into a joint cavity.

Hematoma — a localized accumulation of blood resulting from closed and/or open injuries to organs and tissues with vascular rupture, forming a cavity containing liquid or clotted blood.

Hematuria — the presence of blood in the urine exceeding physiological limits.

Hemophilia A — an inherited deficiency of blood coagulation factor VIII.

Hemostatic therapy — therapy aimed at stopping bleeding.

Coagulogram — an investigation of the blood coagulation system.

Blood coagulation factor — a protein that ensures coagulation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Von Willebrand disease (VWD) — the most common inherited hemorrhagic coagulopathy caused by a decrease in the level or impaired function of von Willebrand factor (vWF).

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

VWD is a phenotypically heterogeneous coagulopathy with an autosomal recessive or autosomal dominant inheritance pattern. High variability, not only in clinical manifestations with a significant number of mild and mildly symptomatic forms, but also in laboratory parameters (FVIII, RIPA, vWF, vWF:CB, vWF:Ag) in VWD, is caused by mutations in the vWF gene. Due to the diverse nature of genetic defects, the disease is characterized by broad clinical polymorphism.

There are several factors influencing the course of VWD, among which are:

• Non-modifiable — mutations in the vWF gene, blood type;

• Modifiable — stress, physical exertion, pregnancy, inflammation.

1.3 Epidemiology of the Disease or Condition

Various genetic variants of VWF occur in 0.5–1% of the population, the prevalence of clinically significant forms of VWD is 1–2 per 10,000 individuals; type 3 VWD occurs at a frequency of 1:500,000 individuals. Approximately 70% of patients with VWD have a mild form of the disease, while the rest have moderate or severe forms [1–3].

1.4 Features of Coding the Disease or Condition

D68.0 — Von Willebrand disease

1.5 Classification of the disease or condition

In 2012, the Scientific and Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis (ISTH) revised and approved the international classification of VWD (Table 1) [4, 5].

Table 1. Classification of von Willebrand disease

VWD types 1 and 3

Type 1 VWD is the most common, accounting for 55 to 70% of all diagnosed cases. In type 1 VWD, the amount of vWF is reduced to a certain extent, but the function of each molecule is preserved. Type 3 VWD is the most severe form of the disease, as vWF is almost completely absent. Since one of the functions of vWF is to bind to FVIII and protect it from premature proteolysis, patients with type 3 VWD exhibit not only a lack of vWF but also very low FVIII:C. Type 3 VWD is rare, occurring in 1–3% of VWD patients [1, 2, 6]. 

Type 2 VWD

Patients with type 2 VWD exhibit qualitative defects of vWF, which in the majority of patients manifest as a disproportionate decrease in vWF:RCo (vWF:CB) or vWF:FVIII relative to the vWF level determined by its antigen (vWF:Ag). To diagnose and classify type 2 VWD subtypes, the ratio of vWF activity to antigen and the analysis of vWF multimer structure (using agarose gel electrophoresis, which allows visualization of multimers) are used. Classification of type 2 VWD subtypes is the most challenging task due to the heterogeneity of functional and structural defects [7–9, 20, 37, 38, 39]. 

VWD type 2A

Patients with type 2A VWD exhibit an isolated deficiency of high-molecular-weight vWF multimers and reduced vWF-dependent platelet adhesion. This is due to increased susceptibility to the metalloproteinase ADAMTS-13, which cleaves ultra-high-molecular-weight vWF multimers, as well as defects in vWF multimer assembly caused by impaired dimerization (type 2A, phenotype IID) or multimerization (type 2A, phenotypes IIC, IIC Miami, and IIE). In phenotypes IIC and IIC Miami of type 2A VWD, the relative proportion of protomers increases. Furthermore, the proportion of large vWF multimers decreases, so that electrophoresis lacks bands corresponding to proteolytic fragments (e.g., triplets). In phenotype IIE of type 2A VWD, the triplet structure of vWF multimers is impaired, which is manifested by the absence of outer bands and the formation of pronounced inner bands upon electrophoresis [8]. 

VWD type 2B

Type 2B VWD includes various variants of qualitative vWF defects manifested by its increased affinity for the platelet GPIb receptor. Due to the increased affinity of vWF for GPIb, the binding of large high-molecular-weight vWF multimers to platelets occurs more efficiently, leading to their more rapid cleavage by the metalloproteinase ADAMTS-13. This results in a decreased number of large vWF multimers, and thrombocytopenia of varying severity is frequently observed, which may be exacerbated by stress or desmopressin administration. In rare cases, the increased affinity of vWF for GPIb is not accompanied by the loss of high-molecular-weight vWF multimers, and a normal triplet structure of vWF multimers is detected [10]. Type 2B VWD is characterized by increased ristocetin-induced platelet aggregation (RIPA) at low concentrations of ristocetin. 

VWD type 2M

Type 2M VWD includes various variants of qualitative vWF defects manifested by a decrease in vWF-dependent platelet adhesion. Meanwhile, the multimer profile or the amount of von Willebrand factor remains unchanged. The functional defect is caused by mutations that result in impaired binding of vWF to platelets or subendothelium. Decreased binding to platelets reduces the accessibility of vWF multimers for cleavage by the metalloproteinase ADAMTS-13; therefore, the molecular weight distribution of vWF multimers remains unchanged following secretion by endothelial cells. In the majority of patients with type 2M VWD, a disproportionately low vWF:RCo relative to vWF:Ag is observed. 

VWD type 2N

Type 2N VWD (Normandy) was first described in 1990. Patients with type 2N VWD have a vWF defect at the FVIII binding site. As a result, the vWF–FVIII complex cannot form. This variant of VWD is determined using the vWF-FVIII binding assay [11]. Many patients with this VWD variant were previously diagnosed with mild or moderate hemophilia A (FVIII:C — 5–22%) [1]. When highly purified FVIII concentrates lacking or containing very small amounts of vWF began to be used to treat hemophilia A, the need for differential diagnosis arose. In patients with type 2N VWD, administration of highly purified FVIII concentrates results in a nearly normal increase in FVIII activity, but the half-life of FVIII is very short. To treat bleeding in patients with Normandy-type VWD, concentrates containing both vWF and FVIII are required [8, 12, 13].

1.6 Clinical presentation of the disease or condition

The main manifestation of VWD is a bleeding diathesis of the microcirculatory/mixed type of spontaneous and post-traumatic character.

In types 1 and 2 VWD, the microcirculatory type of bleeding predominates: ecchymoses, mucosal bleeding (gingival, epistaxis, alveolar), menorrhagia, and bleeding during surgical interventions and invasive diagnostic procedures.

In severe VWD, a mixed (microcirculatory-hematoma) type of hemorrhagic syndrome is observed. In this case, the clinical picture may include musculoskeletal disorders resulting from recurrent joint hemorrhages (hemarthroses), spontaneous soft tissue hematomas of various localizations, retroperitoneal hematomas, and mucosal bleeding [14].

Life-threatening bleeding can be observed in all types of VWD, but is more characteristic of type 3 VWD. These include:

• bleeding/hemorrhage into the central nervous system (CNS);

• bleeding/hemorrhage into the gastrointestinal tract (GI);

• bleeding/hemorrhage into the neck/throat; retroperitoneal hematoma.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Differential diagnosis of VWD in adults is carried out with the following conditions:

▪ inherited thrombocytopathies;

▪ hemophilias;

▪ Osler-Weber-Rendu disease;

▪ hemorrhagic mesenchymal dysplasias;

▪ thrombocytopenias;

▪ deficiency of other blood coagulation factors;

▪ acquired coagulopathies.

The criteria for establishing a VWD diagnosis are the following indicators [4, 5, 15–17]:

1. History of the disease, which must include 2 bleeding episodes requiring therapy or 3 bleeding episodes of the same localization.

2. burdened family history — increased bleeding tendencies in first-degree relatives.

3. Laboratory data (Appendix A3.1).

The diagnosis is established in the presence of at least two criteria: the mandatory third criterion and one (or both) of the first two. In the presence of the first two criteria, but the absence of the third, the diagnosis of VWD is highly probable, and dynamic laboratory monitoring at intervals of 3–6 months is required.

An indication for patient examination may be a single life-threatening bleeding episode or abnormal coagulation screening performed for another reason. The diagnosis can also be established based on laboratory changes, without prior hemorrhagic manifestations or a history of a bleeding disorder in the family [20, 38].

2.1 Complaints and Anamnesis

Comments: hemorrhagic manifestations in VWD are nonspecific and similar to those in other hemostatic disorders. VWD can be suspected in the presence of the following clinical signs:

– bleeding from minor cuts or wounds that lasts for more than 15 minutes and/or occurs delayed within 7 days after trauma;

– episodes of prolonged or recurrent bleeding after surgery or tooth extraction, including delayed bleeding within the first 7–10 days;

– spontaneous or post-traumatic soft tissue hematomas that are disproportionate to the extent of trauma;

– epistaxis lasting more than 10 minutes despite physical compression, or requiring medical intervention;

– presence of blood in the stool without an apparent cause;

– gastrointestinal bleeding not explained by ulcers or portal hypertension;

– any heavy uterine bleeding lasting longer than 7–10 days;

– signs of angiodysplasia;

– history of retroperitoneal hematomas or hemarthrosis;

– family history of von Willebrand disease (VWD).

Taking the medical history and anamnesis will help determine the scope of the patient's examination.

When taking the anamnesis in patients with suspected VWD, it is advisable to assess bleeding symptoms using bleeding assessment tools, taking into account their age and sex specificity (Appendix G1, G2) [12,18]. In patients with severe hemorrhagic manifestations, an examination is indicated without using bleeding assessment tools [20].

Normal values: men – 0–3, women 0–5, children 0–2.

When assessing bleeding during surgical interventions, the percentage of surgeries/tooth extractions accompanied by hemorrhagic manifestations is evaluated. For example, 3 surgeries/tooth extractions, in 1 of which hemorrhagic syndrome developed = 33%, score = 2. The absence of a pathological bleeding score, especially in children, cannot serve as a basis for refusing further laboratory investigation.

2.2 Physical Examination

Comments: attention should be paid to the presence of cutaneous hemorrhagic syndrome of varying severity in the form of ecchymoses and soft tissue hematomas in various locations. Bleeding from mucous membranes (epistaxis, gingival, tooth socket) may be detected. Signs of joint involvement may be identified in the form of deformity, edema, and local skin temperature elevation (acute hemarthrosis) and/or signs of impaired mobility, range of motion, limb muscle hypotrophy on the affected joint side, and gait disturbance (deforming arthropathy) in type 3 VWD. The examination allows assessing the severity of the patient's condition and the need for specific replacement and/or hemostatic therapy [5,6].

2.3 Laboratory Diagnostics

Laboratory tests are the basis for diagnosis and treatment monitoring in patients with VWD. An important aspect of laboratory research is the participation of laboratories in quality control systems. Obtaining the maximum amount of data facilitates diagnosis verification and the exclusion of acquired coagulopathies (Appendix A3.1) [19–22].

Comment: isolated prolongation of PT / decrease in Quick's percentage / increase in INR, isolated prolongation of TT or APTT, isolated decrease in fibrinogen, as well as their combination, requires the exclusion of other coagulopathies or preanalytical errors.

Comment: if the above laboratory tests cannot be performed, the patient must be referred to a medical facility with the necessary diagnostic capabilities. All patients with clinical manifestations of von Willebrand disease and normal platelet-binding vWF activity (greater than 40% but less than 100%) should undergo a collagen-binding assay and vWF antigen determination [20,40]. The collagen-binding assay may be more sensitive in type 2 and decrease while the platelet-binding activity test remains normal [40].

Comments: used for further diagnosis in certain patients to determine the subtype of von Willebrand disease. For differential diagnosis, certain cases require the study of biological material (platelets) using flow cytometry, thromboelastography/thromboelastometry, determination of coagulation factor II, V, VII, X, IX, XI, XII activity in blood serum, factor XIII activity in blood plasma, alpha-2-antiplasmin level in blood, as well as expanded genetic testing and platelet aggregation studies with ADP, adrenaline, collagen, thrombin (TRAP), arachidonic acid, and lupus anticoagulant testing. If type 2B VWD is suspected, ristocetin-induced aggregation is performed at two concentrations. Laboratory test abnormalities characteristic of specific types of von Willebrand disease are presented in Appendix A3.1.

Comments: acquired deficiency or dysfunction of vWF (acquired von Willebrand syndrome) may occur in patients with concomitant conditions (heart defects, lymphoproliferative disorders, myeloproliferative disorders, systemic connective tissue diseases).

2.4 Instrumental Diagnostics

Comment: instrumental diagnostics allow visualization of bleeding/hemorrhages in various locations, as well as the identification of complications resulting from hemorrhagic manifestations. The choice of a specific instrumental diagnostic method will depend on the suspected source of bleeding and the clinical presentation, and may include:

o Esophagogastroduodenoscopy;

o Endoscopic endonasal examination of the nasal cavity and nasopharynx, fiberlaryngoscopy;

o Bronchoscopy;

o Ureteroscopy, cystoscopy;

o Joint ultrasound;

o Comprehensive abdominal ultrasound and retroperitoneal ultrasound;

o Renal ultrasound and urinary tract ultrasound;

o Soft tissue ultrasound;

o Transabdominal ultrasound of the uterus and appendages;

o Magnetic resonance imaging of the joint, magnetic resonance imaging of soft tissues;

o Magnetic resonance imaging of the brain and other organs;

o Joint radiography;

o Computed tomography of the chest organs;

o Computed tomography of the abdominal cavity and retroperitoneal space;

o Computed tomography of the brain;

o Rhinoscopy;

o Otoscopy;

o Colposcopy;

o Proctosigmoidoscopy;

o Colonoscopy;

o Hysteroscopy.

2.5 Other Procedures

Comments: medical consultations help identify impairments in various organs and systems resulting from past or recent bleeding/hemorrhage. Depending on the suspected site of bleeding, one or more specialists should be involved:

o obstetriciangynecologist;

o orthopedic trauma surgeon;

o surgeon;

o urologist;

o neurologist;

o otorhinolaryngologist;

o dermatovenerologist;

o oncologist;

o gastroenterologist;

o coloproctologist;

o dentist;

o psychiatrist.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

The goal of VWD treatment is the prevention and cessation of bleeding, as well as the prevention of VWD complications. This goal can be achieved through specific replacement therapy with products containing von Willebrand factor or via non-specific methods. Specific replacement therapy can be prophylactic or on-demand in the event of bleeding. Regular prophylactic treatment is prescribed to patients with VWD less frequently than to patients with hemophilia. However, in cases of recurrent joint hemorrhages, gastrointestinal and uterine bleeding, as well as any other bleeding leading to acute or chronic posthemorrhagic anemia or iron deficiency, and/or requiring patient hospitalization, prophylactic replacement therapy may be rational [41].

Not all patients with VWD require treatment. The criteria for initiating treatment in patients with a verified VWD diagnosis include the following indicators:

- occurrence of moderate/severe, spontaneous/post-traumatic bleeding;

- surgical intervention;

- any recurrent bleeding that impairs quality of life.

Since VWD is a complex disease resulting from various genetic defects and varying in severity, a wide range of medications may be used in therapy in addition to replacement therapy with plasma-derived coagulation factor VIII + von Willebrand factor concentrates. Such methods include the use of systemic hormonal contraceptives and antifibrinolytic agents [41].

3.1 Conservative Treatment

3.1.1 Replacement therapy

Modern VWD therapy is based on the "home treatment" principle: self-administration of medications by the patient at home, provided mandatory training and follow-up are conducted at a specialized medical center. The decision to use a hemostatic agent is made by the patient or their relatives in accordance with the hematologist's recommendations.

Comments: the use of FVIII + vWF concentrates^** is possible for therapy in the following regimens: on-demand (for bleeding cessation), prophylactically (to prevent hemorrhagic syndrome).

The dose of coagulation factor VIII + von Willebrand factor** intended for VWD treatment must be calculated based on the activity of the von Willebrand factor contained in the medicinal product (FVIII:C or vWF:RCo). The recovery of vWF:RCo in adults should be approximately 1.5–2% per 1 IU of vWF:RCo/kg administered. With an infusion dose of 50 IU/kg, an increase in vWF:RCo within the range of 75–100% should be expected. Thus, a dose of 40–50 IU of vWF:RCo/kg is recommended for patients with low baseline vWF:RCo activity. In children, recovery levels may be lower due to physiological characteristics, which may require higher single doses and more frequent administrations.

Therapy requires laboratory monitoring, including testing for von Willebrand factor antigen levels, von Willebrand factor activity and properties in the blood, determining serum factor VIII activity, and evaluating the pharmacokinetic curve of their parameters (in case of unsatisfactory treatment efficacy).

For a preliminary assessment of the efficacy of hemostatic therapy, thromboelastography/thromboelastometry or an aPTT test can be performed (obtaining normal or subnormal values is necessary). When interpreting the results of these tests, it must be taken into account that changes in them are primarily associated with changes in factor VIII activity and can assess the qualitative and quantitative characteristics of von Willebrand factor only indirectly [17].

Comments: the concentration of vWF in fresh frozen plasma is relatively low. Its use for replacement therapy will not be sufficiently effective [44,45,46].

3.1.2 Prophylactic therapy

Comments: such bleeding can significantly interfere with daily activities and lead to impairment of organ and joint function (arthropathy). Arthropathy is also observed in patients with type 2N VWD, especially when FVIII:C is less than 10%, and in patients with severe type 1 VWD, in whom vWF quantity and FVIII:C activity are significantly reduced. In such cases, it is recommended to prescribe prophylactic treatment with coagulation factor VIII+ von Willebrand factor**. Depending on age, pharmacokinetic characteristics, and/or individual efficacy, children may receive higher single doses of medications as well as shorter intervals between administrations.

3.2.2 Management of bleeding

Comments: the use of non-specific hemostatic agents without replacement therapy is often insufficiently effective in patients with a severe VWD phenotype [20].

Comments: the duration of treatment is determined by the localization and severity of bleeding, as well as the risk of rebleeding, and may be 14 days or more. In some cases of bleeding cessation (e.g., refractory bleeding, bleeding into vital organs), after an initial loading dose, prolonged infusion of coagulation factor VIII + von Willebrand factor** may be used [50].

Depending on age, pharmacokinetic characteristics, and/or individual efficacy, children may receive higher single doses of concentrates as well as shorter intervals between administrations.

Comments. In each case, it is necessary to establish the exact localization of bleeding. For this purpose, the involvement of specialists and the performance of procedures specified in sections 2.4 and 2.5 may be required.

3.3 Surgical interventions

In patients with von Willebrand disease (VWD), surgical intervention may be required to treat both manifestations of the disease and VWD-unrelated conditions.

Comments: the hematologist must determine the need for and scope of replacement and other hemostatic therapy. In an emergency situation, surgical treatment may be performed without a prior evaluation (examination, consultation) by a hematologist. When performing invasive manipulations (procedures), the need for replacement therapy and the use of antifibrinolytic agents must be decided on an individual basis, taking into account the severity of VWD and the nature of the manipulation (procedure) (Appendix A3.4.

Comments: depending on age, pharmacokinetic features, and/or individual efficacy, higher single doses of concentrates and shorter intervals between administrations may be used in children. In some cases, during perioperative prophylaxis, a prolonged infusion of coagulation factor VIII + von Willebrand factor** may be used after the initial loading dose [50].

Comments: #tranexamic acid** is contraindicated in renal bleeding.

3.4 Thrombosis prophylaxis

Comments: the decision to use antithrombotic prophylaxis should be made on an individual basis, taking into account the specifics of the surgical intervention, the severity of hemorrhagic manifestations at the time of surgery, the volume of replacement therapy, and the presence of risk factors for thrombotic complications in the patient. It may be prescribed due to the increased risk of thrombosis in patients receiving high doses of coagulation factor VIII + von Willebrand factor**, taking comorbidities into account.

3.5 Other treatments

Comments: estrogen administration increases FVIII:C and vWF:RCo, and the use of systemic hormonal contraceptives containing progestogens (G03AC) and synthetic estrogens (G03CB), vaginal rings, or intrauterine devices releasing these hormones may be sufficient to control moderate menorrhagia. Systemic hormonal contraceptives can be prescribed long-term to reduce menstrual blood loss. Despite the need for further study of this issue, clinical data indicate that estrogen administration can be used to stop heavy uterine bleeding. Systemic hormonal contraceptives (progestogens (G03AC) and synthetic estrogens (G03CB)) can be prescribed long-term to reduce the duration and heaviness of menstrual bleeding.

In perimenopause, in the presence of endometrial pathology and uterine bleeding, endometrial ablation may be performed.

Comments: recurrent gastrointestinal bleeding without a history of ulcer may be due to Heyde syndrome, which features a combination of pathologies: aortic stenosis, angiodysplasia, and gastrointestinal bleeding. The cause of bleeding is the deposition of high-molecular-weight vWF multimers on damaged aortic valves in the area of altered blood flow and constant elevated stress.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Comments: in type 3 VWD, musculoskeletal disorders may occur, significantly limiting the social adaptation of patients. Patients with musculoskeletal involvement require rehabilitation. The development of rehabilitation measures should be carried out jointly by rehabilitation specialists, balneologists, and hematologists.

Treatment can be carried out in sanatorium-resort organizations within the patient's climatic zone of residence, as well as at balneological resorts.

Methods of therapeutic physical training and physical rehabilitation may be used: therapeutic exercise for joint diseases and injuries, mechanotherapy for joint diseases and injuries. In addition, hardware physiotherapy methods may be used, including: drug electrophoresis for joint diseases, pulsed current electrophoresis, ultraphonophoresis, general magnetotherapy, and ultrasound therapy.

Comments: psychological adaptation programs for patients with VWD are an important and validated approach in comprehensive treatment aimed at helping the patient adapt to a chronic disease.

5. Prevention and Dispensary Observation

Comments: it is advisable to conduct follow-up monitoring of patients once a year to assess the efficacy of ongoing therapy, evaluate the presence of adverse events during replacement therapy, and perform laboratory monitoring (if necessary).

6. Organization of Medical Care

Indications for planned hospitalization in a medical organization:

1) elective surgical treatment.

Indications for emergency hospitalization to a medical organization:

1) life-threatening bleeding;

2) emergency surgical intervention.

Indications for patient discharge from a medical organization:

1) complete cessation of bleeding.

7. Additional Information

7.1 Dental care

Comments: routine dental examinations and teeth cleaning can be performed without replacement therapy with coagulation factor VIII + von Willebrand factor**. However, other hemostatic agents (#tranexamic acid**) must be available. Good oral hygiene is important for patients with VWD as it helps prevent periodontal disease and caries. A soft toothbrush should be used for teeth cleaning.

Comments: tooth extraction or other dental surgical procedures must be performed after consultation with a hematologist. For extensive dental procedures (suturing, extraction of multi-rooted teeth), hospitalization may be required.

7.2 Management of patients with VWD during pregnancy and childbirth

Comments: the mode of delivery is determined by obstetric indications. To determine the management of therapy during labor in patients with von Willebrand disease (VWD), it is advisable to perform activated partial thromboplastin time testing, testing of von Willebrand factor activity and properties in the blood, testing of von Willebrand factor antigen levels, and determination of factor VIII activity. Inpatient monitoring of patients with VWD is required for 7 days after delivery.

7.3 VWD in neonates

Comments: since VWD is inherited in an autosomal dominant manner in the majority of cases, children of both sexes can inherit the disorder. Nevertheless, prenatal diagnosis of VWD is usually not performed, as the risk of bleeding complications in newborns is generally low.

Severe VWD (type 3) can be diagnosed immediately after birth using a cord blood sample; however, milder forms of VWD are practically impossible to diagnose in a newborn because vWF concentrations increase significantly after birth. A normal test result may mask a mild form of VWD. Therefore, evaluation of the child should be postponed for several months.

7.4 Vaccination

Comments: subcutaneous administration of vaccines is preferred over intramuscular or intradermal routes. Vaccination must not be performed during active bleeding [35].

7.5 Contraindicated pharmacotherapy

7.6 Patient and family education

Patient and family education is an essential prerequisite for ensuring adequate care for individuals with VWD. Education begins immediately after diagnosis and is conducted on an ongoing basis by physicians and nurses at the specialized center where the patient is followed. Education is provided individually during center visits and within the framework of a patient school.

Main directions of patient and family education: what VWD is, specific features of children with VWD, skills in assessing the child's condition, skills in recognizing symptoms, nature and severity of bleeding, storage and administration of coagulation factor concentrates, indications and doses of replacement therapy, home infusion skills, vein care, use of other hemostatic agents, physical activity, psychological and social adaptation, vocational guidance, and legal aspects.

In addition to physicians and nurses, psychologists, legal experts, and representatives of patient advocacy organizations for bleeding disorders should be involved in educating patients and their families.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Nadezhda I. Zozulya, MD, DSc, National Hematology Society, Moscow.

2. Pavel V. Svirin, Hematologist, National Society of Pediatric Hematologists and Oncologists, Moscow.

3. Andrey N. Mamaev, MD, DSc, National Hematology Society, Barnaul.

4. Pavel A. Zharkov, MD, DSc, National Society of Pediatric Hematologists and Oncologists, Moscow.

5. Rodion V. Ponomarev, PhD, National Hematology Society, Moscow.

Expert Council:

Alexander G. Rumyantsev, Academician of the RAS, MD, DSc, National Society of Pediatric Hematologists and Oncologists.

Elena N. Parovichnikova, Corresponding Member of the RAS, MD, DSc, National Hematology Society.

Conflict of interest: the authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

• Hematologists

• Pediatricians

• Internists

• Surgeons

• Dentists

• Otolaryngologists

• Orthopedic traumatologists

Table 1. Scale for assessing levels of evidence (LE) for diagnostic methods (diagnostic interventions)

Table 2. Rating scale for levels of evidence (LE) for preventive, therapeutic, and rehabilitation methods (interventions)

Table 3. Rating scale for grades of recommendation (GR) for preventive, diagnostic, therapeutic, and rehabilitation methods (interventions)

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

Appendix A3.1 Laboratory criteria for von Willebrand disease types

Appendix A3.2 Replacement prophylactic therapy in VWD

Appendix A3.3 On-demand hemostatic therapy for various types of bleeding

Appendix A3.4 Classification of Invasive Procedures and Surgical Interventions According to Associated Bleeding Risk

Appendix A3.5 Perioperative replacement therapy with coagulation factor VIII + von Willebrand factor**

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

Patients with von Willebrand disease (vWD) experience internal and external bleeding. Multiple bleeds in the same joint can lead to joint damage and pain. Recurrent bleeding can cause other conditions, such as arthritis, which makes walking or performing other simple activities difficult.

Intraarticular and intramuscular bleeding occur most frequently in the specified areas.

How are patients with VWD treated?

Currently, the treatment of VWD is very effective. Missing blood clotting factors, factor VIII and von Willebrand factor, are administered via injection. When a sufficient volume of blood clotting factor reaches the injury site, the bleeding stops.

Treat bleeding promptly!

Immediate treatment helps reduce pain and damage to joints, muscles, and organs. Prompt treatment requires less clotting factor to stop the bleeding.

When in doubt, treat!

If you think you have started bleeding, treat it even if you are not sure. Never wait until a joint becomes inflamed, swollen, and painful. Do not think that the treatment might be "in vain".

There is no radical cure for VWD yet, but with treatment, patients can lead a healthy lifestyle.

Without treatment, patients with severe forms and type 3 VWD may find it difficult to regularly attend school or work. They may become physically disabled, experience problems walking or performing other simple activities, or die at an early age.

When should treatment be administered?

Treatment is required in the following cases:

• in case of intraarticular bleeding;

• in case of intramuscular bleeding, especially in the arms and legs;

• in case of injuries to the neck, mouth, tongue, face, or eyes;

• in case of severe head bruises and unusual headaches;

• in case of heavy or persistent bleeding anywhere;

• in case of severe pain or swelling anywhere;

• in case of any open wounds that require stitches;

• after any accident that could result in bleeding.

Treatment is required before:

• surgical operations, including dental procedures;

• activities that may cause bleeding.

When might treatment not be required?

Children with VWD often get minor scrapes, but they are usually harmless. However, head scrapes can have more serious consequences and should be examined by a nurse or doctor specializing in VWD.

Minor cuts and scratches will bleed for the same amount of time as in a healthy person. They are usually harmless.

Deep cuts often (but not always) bleed longer than usual. As a rule, bleeding can be stopped by applying pressure to the wound.

Nosebleeds can usually be stopped by pinching the nose for five minutes. In case of heavy, prolonged bleeding, a doctor should be consulted.

What to do if bleeding starts?

VWD is a lifelong disease, and currently there is no cure for it. However, with the development of a comprehensive care system for VWD patients and the availability of products containing the deficient blood clotting factors, VWD patients—even those with severe forms—can now control their bleeding tendency.

When is it necessary to seek immediate medical attention?

• After a blow to the head or other head injuries, or when the causes of persistent headaches, nausea, or vomiting are unclear.

• Heavy bleeding that cannot be stopped without special assistance or that recurs even after first aid has been provided.

• When blood appears in the urine or stool.

• When the cause of abdominal pain is unclear.

• When bleeding or pain occurs in the neck area.

What bleeding is serious or life-threatening?

The main cause of mortality in VWD, especially in children, is intracranial hemorrhage (usually resulting from trauma). These hemorrhages can cause headache, nausea, vomiting, lethargy, disorientation, loss of coordination, weakness, seizures, and loss of consciousness.

Throat hemorrhages can be caused by infection, injury, dental injections, or surgery. Throat hemorrhages cause swelling, difficulty swallowing, and breathing difficulties.

Other hemorrhages—in the eyes, spine, and psoas muscle—can be very serious, but are usually not life-threatening.

What are inhibitors?

Inhibitors are antibodies (proteins) produced by the body to get rid of substances it perceives as "foreign".

The blood of a VWD patient may develop inhibitors that seek to destroy the foreign protein in the therapeutic product. If the inhibitors are stronger, standard-dose treatment may be less effective.

Inhibitors are quite rare. They are most commonly found in patients with severe VWD.

Check for inhibitors before any surgery, including dental procedures.

Advantages of home treatment

Home treatment is the transfusion of clotting factor concentrate outside the hospital. All treatment records should be kept—maintain a transfusion diary.

Home treatment involves not only a great responsibility for the transfusion, but also the skill to perform it yourself—since you are treating your own bleeding.

A VWD patient and their family share the responsibility for the patient's health with healthcare professionals. Talk to your hematologist before starting home treatment. The hematologist will explain the rules of home treatment and teach you how to properly determine the doses of factor VIII + von Willebrand factor** for adequate bleeding therapy; a nurse will help you master vascular access and explain the transfusion technique. It is advisable to have two people in the VWD patient's family who know the transfusion technique (you and a close relative).

Who is eligible for home treatment? These are individuals with severe von Willebrand disease. It should be noted that home treatment does not replace clinical care.

Benefits of home treatment:

• Bleeding treatment starts quickly, preserving the joints, which is the key to preventing disability.

• Fewer trips to the hospital.

• If bleeding in target joints is stopped quickly, there is no need to endure pain.

• No need for painkillers.

• No missed school or work.

• Increased physical and social activity.

• Becoming independent.

Basic rules for VWD patients:

1. To stop bleeding, effective doses of medications must be administered immediately. Inadequate dosing will fail to stop the bleeding, lead to wasted time, worsening hemorrhagic syndrome, and unjustified consumption of expensive drugs.

2. During home treatment, the patient's choice of medication should be based on the recommendations of the attending physician and be justified according to the clinical situation.

3. Hemostatic therapy with specific agents (blood coagulation factor concentrates) should be initiated as early as possible (as soon as practically possible, preferably within the first 2 hours after injury or the appearance of the first subjective or objective signs of hemorrhage/bleeding); therefore, the patient's subjective sensations or the fact of injury may serve as the basis for initiating therapy. The goal should be to stop bleeding or hemorrhage before significant clinical manifestations develop. In the event of injury, the patient must be examined by a hematologist or an orthopedic traumatologist.

4. Treatment of mild and moderate bleeding should be carried out at home by the patient or their relatives in accordance with the hematologist's recommendations. In the event of severe bleeding, therapy must be initiated as soon as possible (at home) and continued under the supervision of a hematologist in an inpatient or outpatient setting.

5. Patients must not use medications that impair platelet function and inhibit blood coagulation, especially acetylsalicylic acid** and other nonsteroidal anti-inflammatory drugs (NSAIDs, M01A), except when the benefits outweigh the risks of their use.

6. Intramuscular injections and arterial punctures should be avoided.

7. Regular exercise that promotes muscle development, joint protection, and physical fitness should be encouraged (e.g., therapeutic gymnastics, swimming, terrain cures).

8. Patients should avoid situations associated with a high risk of injuries, including contact combat sports, games with a heavy ball, exercising on sports apparatus, etc.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Bleeding assessment scale (based on the ISTH/SSC bleeding assessment tool)

Russian name: bleeding assessment scale.

Original name: ISTH-SSC Bleeding Assessment Tool.

Source: Rodeghiero F, Tosetto A, Abshire T, Arnold DM, Coller B, James P, Neunert C, Lillicrap D; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost. 2010 Sep;8(9):2063–5.

Type: rating scale.

Purpose: assessment of bleeding severity.

Content, key:

Key (interpretation):

Appendix G2. Bleeding Questionnaire for children under 18 years of age (based on the Pediatric Bleeding Questionnaire (PBQ))

Russian title: Bleeding questionnaire for children under 18 years of age.

Original title: The Pediatric Bleeding Questionnaire.

Source: Mittal N, Naridze R, et al. Utility of a Paediatric Bleeding Questionnaire as a screening tool for von Willebrand disease in apparently healthy children. Haemophilia. 2015; 21: 806–11.

Type (underline): questionnaire.

Purpose: assessment of bleeding symptoms in children under 18 years of age.

Content, key: