von Willebrand Disease

VWD type 1 is the most common form, followed by VWD type 2 and the least common type 3. Most studies and registries estimate the distribution of VWD types to be 60–70% type 1, 20–30% type 2, and 5–10% type 3 [9- 12].

A genetic epidemiological, population-based study of 141,456 individuals estimated the global prevalence at 74 per 1,000 people for type 1, 3 per 1,000 for type 2A, 3 per 1,000 for type 2B, 6 per 1,000 for type 2M, 0.31 per 1,000 for type 2N, and 0.7 per 1,000 for type 3 [19].

These results suggest that von Willebrand disease (VWD) is underdiagnosed or that the bleeding phenotype is attenuated by unknown factors [8].

Age of diagnosis: The age of onset varies, with earlier onset associated with more severe VWF deficiency [20].

The reported prevalence was higher in women than in men (p < 0.01), although the gender distribution between men and women should actually be approximately equal [21].

Joint bleeding (hemarthrosis) occurs particularly in severe forms of VWD, such as type 3. These bleeds are less common than in hemophilia but can also lead to hemophilic arthropathy. Hemarthrosis is very rarely observed in VWD types 1 and 2, but can occur post-traumatically [36, 37].

As with severe hemophilia, prophylactic treatment may be advisable in patients with a severe VWD who experience spontaneous bleeding events. One recommendation for prophylaxis is substitution with a VWF/VWF-VIII concentrate at a dosage of 40–60 IU 2–3 times per week intravenously [10].

Patients with VWD have an increased risk of angiodysplasia. The association between angiodysplasia and gastrointestinal (GI) bleeding in patients with VWD was first described in 1976 by Ramsey et al. [38].

One explanation for the occurrence of angiodysplasia may be the influence of VWF on angiogenesis. A deficiency of functional VWF can lead to dysregulation of angiogenesis with increased formation of large-lumen and thin-walled vessels, as vascular stabilization and maturation are reduced in favor of proliferation and migration [39- 42].

In the gastrointestinal tract, angiodysplasia occurs most frequently in the appendix and ascending colon, but has also been found throughout the gastrointestinal tract and is characterized by a fragile vascular network [43, 44].

The incidence of angiodysplasia varies depending on the VWE subtype. Angiodysplasia was found in 2% of patients with VWE type 2 and in 4.5% of patients with VWE type 3 [45].

Angiodysplasia may be associated with anemia and life-threatening gastrointestinal bleeding requiring transfusions [46- 49]. Although gastrointestinal bleeding caused by angiodysplasia also occurs in the general population, it is rare (prevalence 0.092–0.83%) and the lesions are usually small and have a low risk of bleeding [50, 51].

In a retrospective study of VWE patients with occult or angiodysplastic bleeding in the VWE prophylaxis network, angiodysplasia was confirmed as the cause of gastrointestinal bleeding in only one-third of the patients [52].

The management of angiodysplasia poses significant challenges due to the complexity of the condition and the absence of effective surgical or endoscopic treatment options. The high recurrence rate of this condition further complicates therapeutic efforts. In addition to endoscopic and surgical interventions, treatment encompasses the substitution of VWF and VWF/factor VIII concentrates, along with therapeutic trials involving statins, tamoxifen, thalidomide, and VEGF inhibitors, among others, in cases of acute severity. It is also recommended that patients receive prophylaxis [40, 53].

Recurrent bleeding events due to angiodysplasia can lead to a deterioration in quality of life in patients with VWE.

Iron deficiency anemia or iron deficiency can be an initial indication of VWE. General symptoms of anemia such as exhaustion, fatigue, dizziness, and even depressive disorders, which lead to an impairment of quality of life, may occur. In women and girls with VWE, iron deficiency (anemia) / may be caused by menorrhagia.

Regular hemoglobin checks are recommended for patients with VWE, and oral or intravenous iron treatment may be initiated as needed [54- 57].

The abortion rate in patients with VWE is reported to be 7% to 25% based on retrospective studies or databases.

A recently published study evaluated the frequency of miscarriage in women with VWE compared to women with a similar mucocutaneous bleeding phenotype ("bleeding disorder of unknown cause" – non-VWE) and control subjects without bleeding disorders.

No statistically significant difference was found between the two patient groups and the normal collective (odds ratio 0.94) in a total of 1,193 pregnancies examined. At least one live birth was documented in >90% of participants and in 95% of patients with VWE and non-VWE.

Finally, a comparative study showed that patients with VWE (with VWF-Ag and VWF-Act values < 50%) do not have an increased risk of miscarriage compared to the normal population. In addition, a German group was able to show that there were no differences in outcome between patients with and without VWE after reproductive medicine measures [58, 59].

The diagnosis of von Willebrand disease is a multifaceted process, characterized by a series of obstacles that must be overcome. Patients present with a broad spectrum of symptoms, ranging from mild to severe manifestations, which complicates the diagnostic process. A detailed medical history, including family history, is therefore important. A special feature of the diagnosis is the variability of von Willebrand factor levels due to acute phase reactions such as stress, physical exertion, infections, pregnancy, and acute illnesses, but also due to age and blood type. Nicotine abuse and air pollution also have an influence [61].

The diagnosis of VWE should be made when the patient is in a "basic state of health". Repeated measurements are therefore often useful.

In summary, the diagnosis includes [62, 63]:

1. Bleeding assessment tools (standardized questionnaires on

2. bleeding history),

3. Laboratory tests (including diagnosis-relevant threshold values)

4. special diagnostics for the diagnosis of subtypes

5. Genetic testing

VWF parameters may increase with age, leading to normalization of VWF levels [24]. In a study group (n=617) with a median age of 28 years and a mean observation period of 16 years, it was shown that VWF and factor VIII increased discreetly from the age of 20 and linearly from the age of 40. In type 2 vWE, only an increase in factor VIII was observed, while in type 1 vWE and patients with low vW levels, an increase in both vW activity and factor VIII was documented.

The authors observed an overall average increase in VWF of 22 IU/dl over a period of 10 years, accompanied by an increase in VWF propeptide (VWFpp), VWF:Ag of 6.9% over 10 years, and FVIII [64- 66].

VWF:Ag levels in individuals with blood group O are measured at 25-30% lower than in individuals with blood groups A, B, and AB. Individuals with blood group O are overrepresented among VWE patients (77% of all VWE patients), although they make up only 45% of the total European and American population. In addition to ABO, other modifying genes have been identified, including CLEC4M, STXBP5, and STAB2. Variants in the genes for the sinusoidal endothelial receptors "C-type lectin domain family 4 member M" (CLEC4M) and "Stabilin-2" are associated with plasma levels of VWF and/or FVIII in healthy individuals. The ability of these receptors to bind, internalize, and remove the VWF-FVIII complex from the bloodstream [67- 69]. Blood groups ABO-adjusted reference ranges are not considered necessary according to the 2021 guidelines for the diagnosis of VWE [70].

The existence of different VWD subtypes (e.g., type 1, type 2 with subtypes 2A, 2B, 2M, 2N, and type 3), which must be identified by different tests, also makes diagnosis complex, expensive, and time-consuming (e.g., multimer analyses or genetic testing).

Furthermore, the optimal approach for managing patients who exhibit a propensity for bleeding in their daily lives and who fall within the borderline range of 50–70% remains to be elucidated [71, 72]. See chapter 5.3 Diagnostics.

The diagnosis of von Willebrand disease requires a combination of detailed medical history, including family history, a combination and, if necessary, repetition of specialized laboratory tests, and a differentiated interpretation of the results. Prothrombin time (Quick, PT) and partial thromboplastin time (aPTT) have been determined to be unreliable screening tests for diagnosing VWD are not reliable tests for screening for the diagnosis of VWD. Although the aPTT may be prolonged in certain types of VWD, such as type 3 or type 2N (as a proxy for the degree of factor VIII activity), it is not traditionally used as a screening test for VWD because it is normal in most cases [73].

Figure 1 below shows a significantly simplified diagnostic scheme. Further explanations follow in chapter 5.2.

For the initial screening examination in cases of suspected VWE, the use of a validated bleeding assessment tool (ISTH-BAT) is recommended [30]. BATs can be helpful in documenting the severity of bleeding and can be used in combination with laboratory tests for initial diagnosis. A standardized medical history questionnaire has been shown to be more accurate than individual interviews conducted by individual practitioners. It should be noted that BAT is most effective in adult women. In patients with a high probability of VWD (e.g., those with affected first-degree relatives), the decision to perform specific tests should not be based on BAT alone [28].

There are practical suggestions for the use of BAT [74]:

A: Use of BAT in cases of moderate VWE probability: For patients with a moderate probability of VWE (approximately 20%, often with a history of bleeding or abnormal initial tests), BAT alone should not be used to decide whether further tests are necessary.

B: BAT in cases of high VWE probability: Target group: Patients with a high pre-test probability of VWE (approximately 50%), often due to a family history, regardless of their own bleeding symptoms or initial laboratory tests.

The following is a diagnostic decision tree with explanations (Figure 2), adapted from the WFH/ISTH guideline [62], as well as another proposal from 2021 [63].

If VWD is suspected, specific tests such as VWF antigen (VWF-Ag), platelet-dependent VWF activity (e.g., VWF:GPIb), and factor VIII activity (FVIIIc) should be performed, ideally in conjunction with aPTT and PFA measurements (see chapter 5.2.3). Various reagents from different companies are available for determining von Willebrand parameters.

After determining these parameters, most laboratories automatically determine the VWF:Act / VWF:Ag ratio.

If the VWF:Act / VWF:Ag ratio is < 0.7, this indicates type 2 VWD.

Multimer analysis is particularly useful for differentiating between the various types of VWD: type 2. This is important because a reliable diagnosis of patients with types 2A, 2B, or 2M is essential for the prognosis and counseling of patients and their families. The analysis is performed by electrophoresis [76, 77].

Other measurement methods include von Willebrand factor collagen-binding activity (VWF:CBA) and VWF:propeptide (VWF:pp).

Explanation: VWF: The functionality of von Willebrand factor (VWF) is assessed by the CBA, which involves testing the ability of VWF to bind to subendothelial collagen. The test is often performed using an enzyme-linked immunosorbent assay (ELISA) or chemiluminescence [78, 79].

The VWF:CBA test is helpful in distinguishing between different types of VWD. The ISTH guidelines recommend either VWF multimer analysis or the VWF:CBA/VWF:Ag ratio for the diagnosis of type 2 VWD in patients suspected of having type 2A, 2B, or 2M [62, 80].

Von Willebrand propeptide measurement (VWF: pp) was originally used to diagnose type 1C VWD. The propeptide is produced during the synthesis of von Willebrand factor (VWF) in the Weibel-Palade bodies and is released into the bloodstream in the same amount as VWF [81]. Due to its shorter half-life compared to VWF, the ratio of VWFpp to VWF:Ag (VWF:Ag) provides important insights into the synthesis, secretion, and degradation of VWF.

Increased degradation of VWF from the blood is reflected in a high VWF:pp/VWF:Ag ratio.

A normal VWF:pp/VWF:Ag ratio but low absolute values indicate reduced VWF synthesis [82]. This test is therefore useful for determining VWE type 1C. Unfortunately, the test is not yet widely available [83]. Alternatively, a DDAVP test can/should be performed if there are no contraindications. In the DDAVP test, the VWF levels that are elevated after one hour in VWE 1C already decrease again after 4 hours (see chapter 6.3.3) [62].

If the multimeric analysis cannot be performed, is unclear, or if further diagnostic confirmation is desired, additional detailed examinations can be performed. The focus is on the difficult diagnosis of VWE type 2 B and VWE type 2 N. The diagnosis of the subtypes VWE type 2 B (RIPA) and type 2 N (VWF:FVIIIB) is particularly difficult. The following are explanations and suggestions for step-by-step diagnosis (Figure 3).

Von Willebrand disease type 1C and von Willebrand type Vicenza are not the same, even though they have some similarities. They are both characterized by low von Willebrand factor (VWF) levels, but they differ in cause and mechanism.

VWE 1C is a subcategory of type 1 VWE characterized by increased clearance of VWF from the bloodstream. This means that VWF is produced normally but is unstable and therefore breaks down faster than usual. It is characterized by certain known mutations (see chapter 5.2.8). Patients typically have low VWF levels, a reduced half-life of VWF (can be detected by the DDAVP test (chapter 6.3.3) and due to the high VWF:pp/ag ratio), and a tendency to bleed.

Von Willebrand disease type Vicenza is characterized by very low VWF levels (<10 IU/dl) and an exceptionally short half-life of circulating VWF. It is typically associated with the R1205H mutation in the VWF gene. This mutation causes VWF to be removed from the blood unusually quickly. The bleeding tendency can vary greatly. The Vicenza type was first described in the Vicenza region of Italy but is not limited to this region. The multimeric pattern shows ultra-large multimers.

VWE Vicenza is often considered a special case within type 1 disorders, with overlaps with type 1C (increased clearance) [87- 89].

The PFA-100/200 simulates the conditions of an injured endothelium under flow conditions and thus records, among other things, the function of VWF. The closure time (CT) is measured. One advantage of this method is that it can be performed quickly. PFA alone is not an adequate diagnostic tool for VWE [90- 92].

Genetic analyses are becoming increasingly important in the diagnosis of VWD. In line with the British guidelines, genetic testing can be performed if patients have reduced VWF activity (as determined by any activity test) or VWF levels: antigen <30 IU/dL on two occasions and VWF levels between 30 and 50 IU/dL are detected, if no other causes for the bleeding phenotype have been identified [93].

In line with the WFH ISTH guidelines (James et al.), genetic testing should be preferred over RIPA for the diagnosis of VWE type 2B.

Genetic testing is also recommended for the determination of type 2N, if available. Alternatively, the FVIII binding test can be used.

Genetic testing can also be helpful in distinguishing between congenital and acquired forms [94]. Genetic testing is also helpful in the diagnosis of VWD type 3, type 1C, and type Vicenza [95].

Many mutations are already known. Most mutations that cause VWD type 1 are missense mutations (about 70%), followed by splice site mutations (about 9%), transcription mutations (8%), small deletions (6%), nonsense mutations (5%), and small insertion or duplication mutations (2%). Type 2 VWD can be explained genetically in a relatively simple manner, as mutations in specific areas of the VWF protein lead to defects in its function. Type 3 VWS is the most severe form: due to homozygosity or compound heterozygosity for zero alleles in the VWF gene, affected individuals produce virtually no von Willebrand factor (VWF). In addition, it has been demonstrated that copy number variants (CNVs) can cause all subtypes of VWE [96- 98].

In recent years, it has become increasingly evident that a more comprehensive genetic understanding of VWE also requires analysis outside the VWF gene. This is evident from the fact that not all patients with low VWF or type 1 VWS have characteristic mutations in the VWF gene, which highlights the genetic complexity of this disease. Specifically, no probable causative variant in the VWF gene has yet been identified in approximately 35% of patients with VWE type 1, and only 41% of families with VWE type 1 show linkage to the VWF locus [99].

The same applies to type 3 VWE: in one study, no null mutations in the VWF gene were detected in approximately 15% of type 3 patients, suggesting that other genes may also play a role in the disease. An increase in genetic testing is expected in the coming years [100- 104].

The authors believe that the recommendations will be adapted in the coming years. Next-generation sequencing (NGS) is a suitable method for this purpose.

This method enables more accurate and faster diagnosis, can identify variants that are not detected by the older test, and offers the possibility of updating or expanding the diagnosis at a later date when new findings become available [95, 105].

In general, before a person undergoes genetic testing, a declaration of consent must be obtained that also contains information about possible incidental findings. Not all physicians are allowed to order all genetic tests. The respective regulations of the federal states must be considered.

It is important to observe the preanalytical conditions; current recommendations are available.

Whole blood samples for coagulation tests should be stored at an ambient temperature of 18–25°C during transport and storage prior to processing. Refrigeration should be avoided.

The time between sample collection and testing (or freezing) of citrated plasma for VWE tests should not exceed twelve hours.

Before making a diagnosis of VWE, it is recommended that results that deviate from the normal values be confirmed at a specialised center with experience in performing the tests and interpreting the results. In addition, samples should be taken on site to check the preanalytics [93].

*see also chapter 5.1.4 Subtypes

• 0.3–0.50 IU/mL and 0.5–0.7 IU/mL are diagnostically challenging.

• According to WFH guidelines: In cases of clinically relevant bleeding, the threshold value is < 0.50 IU/mL; if the lower normal limit of the local laboratory is below this, its reference values should be used.

• Patients with 0.5–0.7 IU/mL are not currently classified as having VWD, but require a careful bleeding history and, if necessary, control measurements, especially in older patients [62].

In a German cohort of patients with suspected VWD, 47 patients with a slight reduction in VWF at the lower end of the normal range (50-70 IU/dL) were examined to gain more insight into this specific cohort, which does not meet the official diagnostic criteria for VWD. Remarkably, approximately 70% (33 of 47) of these patients carried VWF variants associated with VWD. Most of the VWF variants identified in this group were also present in patients with a confirmed diagnosis of VWD type 1 [106].

Once the diagnosis of von Willebrand disease has been confirmed, there are only a few differential diagnoses.

Thrombocytopenia in VWD type 2b can sometimes lead to a false diagnosis of isolated thrombocytopenia [12].

Type 2N can be difficult to distinguish from moderate hemophilia A. In this case, the FVIIIc binding test or genetic analysis are helpful and effective [107].

It is therefore most important to consider Von Willebrand disease in patients with a bleeding tendency and to investigate this possibility.

Local hemostatic agents are also available to support the daily lives of VWD patients.

Local hemostatic agents are applied directly to a wound to stop bleeding. Their principle is based on promoting blood clotting or mechanically sealing the wound. Here are the main principles with examples [110- 112]:

1. Activation of blood clotting by chemical substances or promotion of platelet aggregation, e.g., thrombin-based agents (e.g., Thrombin-JMI®, a fibrin glue)

2. There are also bioactive agents that promote cell activation. E.g. Chitosan-based products (e.g. Celox®): Promote platelet activation and have an antibacterial effect.

3. Kaolin-containing products (e.g., QuikClot®): activate the intrinsic coagulation pathway

4. Mechanical sealing of the wound:

   • Gauze or cellulose sponges (e.g., Surgicel®): These are placed in the wound, absorb blood, and promote hemostasis through swelling.

   • Gelatin sponges (e.g., Gelfoam®): These act as a physical barrier and absorb blood. TABOTAMP-Nu-Knit (absorbable cellulose) [113] is also commercially available.

It is important to note that these products for local hemostasis are also prescription-only.

Tranexamic acid (Cyklokapron®, a fibrinolysis inhibitor) can be used to support mucosal bleeding in all types of VWD. It is available as intravenous administration (not intramuscular), orals as well as a gel (nasal ointment) [114, 115].

The recommended dosage is:

• oral: 3 x 1-2 tablets of 500 mg per day.

• Ampoules of 500 or 1000 mg: 3 x 1 slow intravenous injection of one ampoule per day
  In other words, 3x25 mg/kg.

For tooth extractions, rinsing the mouth with tranexamic acid is recommended (1 ampoule in 1/2 glass of water, rinse mouth for 3 minutes and then spit out).

In children, tranexamic acid should only be used from the age of 1 year in a reduced dose of 20 mg/kg/day.

It should not be administered in cases of urogenital bleeding due to the possible formation of blood clots in the urinary tract [116, 117].

Furthermore, dose adjustments are advisable in cases of renal insufficiency.

Desmopressin (1-desamino-8-D-arginine vasopressin, or DDAVP for short) is a synthetically produced protein. It is very similar to the body's own hormone vasopressin (also known as antidiuretic hormone, or ADH for short). The administration of DDAVP releases VWF from the body's own endothelial stores.

In mild forms of VWE, especially VWE type 1, DDAVP can be used to increase the amount of von Willebrand factor (VWF) available in the blood. A 2–3-fold increase in VWF parameters is expected. This is mainly the case with VWE type 1 or some VWE type 2. A certain amount of residual activity must be present. However, since not all patients (e.g., VWE type 1C) respond to DDAVP, a DDAVP test should be performed once.

• The test must be performed in basic state of health.

• VWF antigen, VWF activity, and factor VIII levels are measured at baseline and 1 and 4 hours after administration.

• Response definition: At least a twofold increase in VWF antigen and activity levels and a VWF level (antigen or activity) and factor VIII level above 0.50 IU/mL.

• During this test, patients should also be informed about the restriction on fluid intake on that day to 1-1.5 liters.

It should be noted that desmopressin, due to its antidiuretic effect, can cause hyponatremia with all the associated complications such as flushing and seizures.

The contraindications and side effects result from the mode of action. It is particularly unsuitable for small children under 5 years of age and elderly people over 65. Other contraindications include coronary heart disease, arterial hypertension, kidney disease, known seizures, known allergy to ingredients, migraine, presence of TTP, and interactions with various medications.

Patients with VWE type 2B often have a contraindication to minirin administration due to the risk of thrombocytopenia.

Desmopressin (e.g., Minirin®, desmopressin acetate nasal spray, Octostim®) can be administered subcutaneously, intranasally, or intravenously, depending on availability and approval status. A common dosage is 0.3 μg/kg/bw in an infusion of 100 ml NaCl over 30 minutes. The maximum effect in terms of VWF increase occurs after 30 to 60 minutes and is detectable for approximately 6 hours. Octostim® is currently not commercially available, but desmopressin acetate nasal spray can be used instead. The dosage of the current nasal spray (desmopressin acetate spray) is 2x1 spray from 12 years of age = 300 µg, 1 x1 spray (ages 4-12) corresponds to 150 µg.

Subcutaneous administration is approved. The dose for subcutaneous administration is 0.3μg/kg/ body weight, and the maximum effect occurs after 60-90 minutes. It is reported to be better tolerated in terms of side effects such as facial flushing, increased heart rate, and decreased blood pressure.

The nasal spray can be confused with the spray for diabetes insipidus, which is approximately 10 times more concentrated.

Administration for a maximum of 3 days is recommended because tachyphylaxis may then occur. Sodium levels should be monitored during repetitive administration. For surgeries requiring prolonged bleeding control, factor concentrate administration should be planned. It should also be determined in advance whether fluid restriction and sodium control can be implemented.

There is little data on use during pregnancy. No randomized studies exist [118- 122].

Haemate® is approved for the treatment of von Willebrand disease and hemophilia A, both for the prophylaxis and treatment of bleeding or bleeding during surgery when treatment with desmopressin (DDAVP) alone is ineffective or contraindicated.It contains von Willebrand factor (VWF) and factor VIII (FVIII) from human plasma [123- 125]. It is approved for children and adults, although no data from clinical studies on the dosage of Haemate P® for prophylaxis in children are available.

It is administered intravenously at a recommended maximum rate of 4 mL/min.

In general, 1 IU/kg VWF:RCo raises the plasma level of VWF:RCo by 0.02 IU/mL (2%). VWF:RCo levels of >0.6 IU/mL (60%) and FVIII:C levels of >0.4 IU/mL (40%) should be targeted.

Usually, 40–80 IU/kg of von Willebrand factor (VWF:RCo) and 20–40 IU FVIII:C/kg body weight are recommended to achieve hemostasis. 100 IU/kg is also possible.

Voncento® is approved for the treatment of von Willebrand disease and hemophilia A, as well as for the prophylaxis and treatment of bleeding and bleeding during surgery in all age groups, and contains von Willebrand factor (VWF) and factor VIII (FVIII) from human plasma. For further information, see approval status.

It is administered intravenously at a recommended maximum rate of 4 mL/min.

In general, 1 IU/kg VWF:RCo raises the plasma level of VWF:RCo by 0.02 IU/ml (2%). VWF:RCo levels of >0.6 IU/mL (60%) and FVIII:C levels of >0.4 IU/mL (40%) should be targeted.

Usually, 40–80 IU/kg of von Willebrand factor (VWF:RCo) and 20–40 IU FVIII:C/kg body weight are recommended to achieve hemostasis. 100 IU/kg is also possible.

Wilate® is a human combination preparation of von Willebrand factor (VWF) and coagulation factor VIII (FVIII). It is used to treat von Willebrand disease and hemophilia A. Indications include acute control of bleeding, perioperative bleeding control, and prophylactic reduction of bleeding episodes. Wilate® is approved for use in children and adults. Wilate is indicated for the prevention and treatment of bleeding or the treatment of bleeding during surgical procedures in patients with von Willebrand disease (VWD) when treatment with desmopressin (DDAVP) alone is ineffective or contraindicated. There are insufficient data on the use of Wilate in children under 6 years of age.

The drug consists of VWF and FVIII in a 1:1 ratio. It is derived from human plasma and is available as a lyophilized powder for the preparation of an intravenous solution. The dosage form facilitates precise dosing, especially in prophylactic treatment regimens [54].

The drug may cause hypersensitivity reactions, including allergic reactions.

To prevent bleeding during surgery, Wilate® should be administered 1–2 hours before the procedure. VWF:RCo plasma levels of ≥ 60 IU/dl (≥ 60%) and FVIII:C plasma levels of ≥ 40 IU/dl (≥ 40%) should be achieved. Repeated doses may be given after 12 hours. The dosage can be calculated using the following formula.

Required units = body weight (kg) × desired factor VIII increase (%) (IU/dl) × 0.5 IU/kg

In general, one unit of VWF:RCo and FVIII:C/kg BW increases the activity by 1.5–2 IU/dl of the respective protein. Normally, approximately 20–50 IU Wilate®/kg BW are administered to achieve adequate hemostasis. This increases VWF:RCo and FVIII:C in the patient by approximately 30–100%. An initial dose of 50–80 IU Wilate®/kg BW may be necessary [54, 126].

Willfact® contains only human von Willebrand factor (pd-VWF). It is used for the treatment and prophylaxis of bleeding in patients with von Willebrand disease (vWD), including type 3, in which patients have a complete deficiency of VWF.

It is administered intravenously at a recommended maximum rate of 4 ml/min. It is approved for all age groups.

In general, 1 IU/kg of von Willebrand factor leads to an increase in the circulating level of VWF:RCo by 0.02 IU/ml (2%).

Levels of VWF:RCo > 0.6 IU/ml (60%) and FVIII:C > 0.4 IU/ml (40%) should be achieved. This means that, depending on the extent of the procedure and the individual's residual activity, a factor VIIIC preparation should be added. Alternatively, substitution can be started 12-24 hours before the procedure. The dosage here is 820 IU kg BW [127- 131].

This is a genetically engineered von Willebrand factor (rVWF) without FVIII [129].

It is used for the prophylaxis and treatment of bleeding, as well as bleeding during surgery in adults (aged 18 years and older) with von Willebrand disease (VWD) when treatment with desmopressin (DDAVP) alone is not effective or indicated. rVWF is a treatment option based on recombinant von Willebrand factor and was developed specifically for the treatment and prevention of VWD.

VEYVONDI must not be used to treat hemophilia A.

The on-demand dose, e.g., preoperatively, is 40 to 60 IU/kg VEYVONDI to ensure endogenous FVIII levels reach the target value of at least 0.4 IU/mL for minor procedures and 0.8 IU/mL for major procedures.

VEYVONDI should be administered together with recombinant factor VIII to control bleeding if FVIII:C levels are < 40% or unknown. The rFVIII dose should be calculated based on the difference between the patient's baseline FVIII:C level and the desired peak FVIII:C level in order to achieve an adequate plasma level of FVIII:C based on the approximate average recovery of 0.02 (IU/mL) /(IU/kg). The full dose of VEYVONDI should be administered, followed by rFVIII within 10 minutes.

The standard treatment for patients is with factor concentrates. When dosing these concentrates, the different content of VWF and FVIII should be taken into account..

Long-term prophylaxis, which has become standard for hemophilia, is not very common for VWE. However, recent data suggest that a significant number of VWE patients could benefit from prophylactic treatment with VWF-containing concentrates. For example, 35 Swedish VWE patients who required prophylaxis (mainly due to nose/mouth and joint bleeding) showed a significant overall reduction in bleeding episodes, and children who were treated with prophylaxis before the age of 5 did not develop arthropathies. Studies on VWE prophylaxis are urgently needed to develop evidence-based guidelines for this approach. The VWE Prophylaxis Network has therefore initiated the international VWS Prophylaxis Study [132].

All factor concentrates are subject to stringent documentation requirements ensuring traceability. Each batch must be documented in the patient's medical record. The Paul Ehrlich Institute, in collaboration with patient associations (Interessengemeinschaft Hämophiler e. V., or IGH for short, and the German Hemophilia Society, or DHG for short) and the medical association GTH (Gesellschaft für Thrombose- und Hämostaseforschung e. V.), has been maintaining the German Hemophilia Registry (DHR) since 2008. Patients who receive factor concentrates are to be recorded anonymously in an annual report, either individually or as a collective report, in accordance with § 21 (1a) TFG. It is advisable for patients to document their own substitutions and bleeding episodes. Both paper and electronic substitution calendars are available for this purpose.

Prophylaxis with von Willebrand factor (VWF) concentrates is indicated for patients with a history of severe and frequent bleeding. It is particularly suitable for patients with type 3 VWE or severe forms of type 1 and type 2A, who experience spontaneous bleeding or gastrointestinal bleeding. In addition to gastrointestinal bleeding, frequent reasons for prophylaxis include bleeding into the joints, severe epistaxis or heavy menstrual bleeding, and anticoagulation as concomitant medication. A distinction is made between long-term prophylaxis and short-term (intermittent prophylaxis). Both forms can significantly reduce the risk of bleeding and improve quality of life [129].

All factor concentrates are approved for prophylaxis.

One standard dosage is 20–40 IU/kg body weight and is administered intravenously two to three times a week. The exact dose and frequency can be adjusted individually based on the patient's bleeding profile.

Patients should be monitored regularly, as is the case with patients with hemophilia. Continuous communication with the treatment team ensures that the therapy is optimally adapted to the patient's changing needs.

A therapy diary (paper, app) documenting infusions and possible bleeding episodes facilitates the adjustment of therapy.

It is also advisable to check VWF levels and the effectiveness of prophylaxis at regular intervals of between 3 and 6 months.

As a concomitant measure, patient and family education regarding infusion administration techniques, promotion of a salubrious lifestyle, and the importance of optimal oral hygiene to mitigate oral hemorrhaging have demonstrated efficacy.

After receiving appropriate training, patients can administer their own infusions at home, which increases adherence to the prophylaxis regimen.

It should be noted that prior to surgical procedures or traumatic events, the dose should be temporarily adjusted to minimize the risk of bleeding [10, 54, 133].

In recent years, home care service for patients has become increasingly established.

Various providers (e.g., pharmacies) offer support for people with von Willebrand disease and other bleeding disorders. Reasons for using a home care service include problematic vein conditions, fear of needles, emotional coping with the disease, and the organization of factor preparations. The support program is aimed at people of all ages. The services team consists mainly of health care professionals and nurses who also educate patients on prophylaxis and offer telephone support. This significantly increases patient adherence. In most cases, the services are supplemented by reminder management or assistance with documentation. Collaboration with the treating physicians is a matter of course.

We would like to emphasize once again that multidisciplinary care with close cooperation between hemostasiologists, gynecologists, and other specialists is crucial to ensure comprehensive care [10, 34][133- 135].

Patients with VWD should be trained for emergencies and carry an emergency card.

Patients should also know whether they can receive DDAVP and which factor preparation has already been used. Patients should also be familiar with self-help methods such as cold and pressure bandages. In individual cases, it is certainly difficult to assess the timing of a medical consultation. In our opinion, it is important that patients are offered the opportunity to consult a doctor and are aware that medical consultation is possible.

Due to the complexity of von Willebrand disease, not all therapies are suitable for all patients. This once again underlines the importance of an individual emergency card.

There are various types of emergencies that occur at home and are not caused by trauma. There is certainly room for improvement in patient awareness here, as emergencies are usually associated with accidents and not with bleeding that is difficult to stop. The following is a (probably incomplete) practical overview.

Epistaxis emergency: First, patients should sit upright and tilt their head slightly forward, not backward, while breathing calmly through their mouth. The soft wings of the nose should be pressed for 5-10 minutes. In addition, a cool compress on the neck or forehead is helpful [136].

It is important that patients know when to take further action: (1) if the bleeding does not stop after 15–20 minutes of pressure, (2) if the bleeding is very heavy, or (3) if symptoms such as dizziness, weakness, or palpitations occur.

In these cases, the priority is to stop the bleeding with factor concentrates. Desmopressin takes too long, as do tranexamic acid and nasal spray, and ointment is not effective enough.

Substitution with a VWF factor concentrate is a possible treatment: The dosage of the various factor preparations depends on the approval (see chapter 6 Treatment).

Emergency heavy menstrual bleeding: Despite taking basic medication such as tranexamic acid or having already taken hormones, uncontrollable, Hb-relevant bleeding occurs repeatedly [57].

Emergency upper gastrointestinal bleeding: Furthermore, upper gastrointestinal bleeding due to angiodysplasia (see chapter 4.1.3), which can also manifest itself in abdominal pain or nonspecific symptoms, is an emergency, especially if the patient has not yet been diagnosed. Here, in addition, a switch to prophylaxis is advisable [137].

The special feature in children and adolescents is that DDAVP etc. must be viewed critically and not all medications are approved. The information is included in the respective chapters.

A survey of gynecologists showed that awareness of bleeding tendencies, including VWD, as a cause of heavy menstrual bleeding is low among gynecologists [138].

Where feasible, the utilization of multidisciplinary medical facilities that facilitate collaborative examinations by gynecologists and hematologists/hemostasiologists is recommended. These specialized settings are designed to optimize the treatment of heavy menstrual bleeding in patients with bleeding tendencies. [74].

Women with known bleeding disorders and heavy menstrual bleeding should undergo a standard gynecological examination, which is recommended for women with heavy menstrual bleeding in the general population, to rule out common pelvic disorders such as fibroids and polyps, especially those that do not respond to initial treatment [139].

Women with inherited bleeding tendencies such as VWD are still more likely to be referred for bleeding, have a longer diagnostic delay, and often require treatment for gender-specific bleeding [140].

It is important to mention that heavy menstrual bleeding in particular, with all its consequences (iron deficiency, dizziness, social withdrawal, etc.), is receiving greater awareness.

The basic treatment for heavy menstrual bleeding is tranexamic acid, which can be taken in doses of 3x500 mg to 3x1g for approximately 4-5 days.

It is important to our committee that inhibitors can also occur in patients with VWE.

Type 3 von Willebrand disease (VWD) is characterized by the complete absence of von Willebrand factor (VWF) and leads to a severe bleeding phenotype. The standard treatment is replacement therapy with VWF-containing products. A key problem with this therapy is that the immune system can produce anti-VWF antibodies against the administered VWF. These antibodies can either have a neutralizing effect by blocking the function of VWF, or they can be non-neutralizing, which can nevertheless impair the effectiveness of the therapy or even lead to severe allergic reactions such as anaphylaxis.

• 18% of the 49 patients with type 3 VWE tested had anti-VWF antibodies (inhibitors).

• Of these antibodies, 67% were neutralizing and 33% were non-neutralizing.

• The antibodies targeted various VWF binding partners such as factor VIII, collagen III, collagen IV, and platelet glycoprotein Ibα (GPIbα).

• 89% of the identified antibodies belonged to the IgG class, specifically the IgG1 and IgG4 subclasses.

These important findings were obtained as part of the Zimmerman Program and should be noted by clinicians. It is possible to detect the antibodies using ELISA [152].

A recent study also investigated the occurrence of anti-VWF antibodies. These were found in 8.4% of subjects with type 3 VWE, while neutralizing VWF inhibitors were found in 6%, mainly in subjects who were homozygous for VWF null alleles [153, 154].

A distinction is made between minor and major surgical procedures, i.e., those with a high and low risk of bleeding.

A review provides guidance on classification [155]:

While there is good data on the risk of bleeding in hemophilia, there is little data available for VWE. The table should therefore be used as a guide, based on the recommendations for patients with hemophilia.

For major surgery, both FVIII and VWF activity levels of ≥0.50 IU/ml should be targeted for at least 3 days postoperatively. The respective target values should be determined individually depending on the patient, the type of surgery, the bleeding history, and the availability of VWF and FVIII tests.

The duration of treatment may vary depending on the type of surgery. On the one hand, this gives practitioners freedom in their choice of therapy, but on the other hand, it underscores the significance of von Willebrand disease as a complex clinical picture.

There is an interesting meta-analysis on the question of optimal postoperative VWF:Ag/FVIIIc levels [156].

Here, too, given the limited evidence available as a basis for treatment decisions, a process of shared decision-making for individualized treatment plans is of great importance.

Another publication examined the target values for surgical procedures. It showed a mean FVIII activity of 1.344 IU/ml (134%) and a mean VWF activity of 0.924 IU/ml (92%). Below this, hemostatic efficacy was excellent in 92% of cases, good in 4% of cases, and poor in 4% of cases. There were no postoperative bleeding complications, therapy-related adverse events, or thrombotic events. Another study reported a mean FVIII level of 1.15 IU/mL (IQR, 0.97-1.34 IU/mL) and a mean VWF level of 0.85 IU/mL (IQR, 0.67-1.03 IU/ml) with 100% hemostatic efficacy and no thrombotic events. These case series probably reflect the practice of many clinicians to bring VWF:Ag and FVIIIC levels within the normal range [157, 158].

There is little data on the bleeding risks associated with vaccinations, especially in comparison to patients with hemophilia. In principle, all vaccinations can be administered, and standard vaccinations are highly recommended. The bleeding risk is not considered high, even with intramuscular administration. Prior to vaccination, prophylactic administration of von Willebrand factor/concentrate or desmopressin (for mild forms) or tranexamic acid can help reduce the risk of bleeding, especially in patients with a history of bleeding and/or residual activity below 10%.

It should also be noted that most vaccinations are also approved for subcutaneous administration (see German RKI website).

General measures such as a pressure bandage after the injection are advisable [159, 160].

An individual risk assessment should be carried out, taking into account the patient's diagnosis and medical history. Regular monitoring of VWF and FVIII levels is advisable but is strongly recommended in the third trimester.

VWE type 1: In many women, VWF activity levels rise to normal levels in the third trimester. Nevertheless, the risk of bleeding remains, especially in cases with low baseline values (<30%).

VWE type 2: VWF levels may appear normal, but the factor is dysfunctional. Therefore, factor administration is often necessary.

VWE type 3: Women with this subtype do not show an increase in VWF during pregnancy and have a particularly high risk of bleeding complications.

The care of women with VWE during pregnancy and childbirth requires interdisciplinary collaboration between obstetricians and hematologists. The goal is to prevent bleeding complications without risking unnecessary interventions. Factor therapy should be planned early to ensure the safety of both the mother and the child. Both the risk of postpartum hemorrhage (PPH) in the mother and potential bleeding in the newborn must be taken into account. Therapeutic measures include factor administration, antifibrinolytics (e.g., tranexamic acid), and platelet transfusions. Recommended for platelet counts <50 × 10⁹/L, especially in type 2B VWD [161].

Patients with VWE have a life expectancy similar to that of the normal population and therefore may have comorbidities that influence treatment decisions and bleeding risk [178].

In particular, the question arises as to whether patients with VWD and cardiovascular disease who require treatment with antiplatelet agents or anticoagulants should receive such treatment (see chapter 6.8.4).

It should be noted that VWE does not protect against the occurrence of thrombosis and endothelial dysfunction as risk factors for cardiovascular disease [179]. Additionally, bleeding tendencies change with age (see chapter 5.2 Diagnosis).

In principle, patients may have various comorbidities that affect therapy. The diseases listed below require evaluation to determine if prophylaxis is appropriate.

The main reason why patients with VWD start prophylaxis is joint bleeding (40%) [180].

Patients with phenotypically severe VWD have an increased risk of developing arthropathy, especially after joint bleeding. Joint bleeding is observed in approximately 50% of patients with VWD type 3 and in 5-10% of patients with moderate to severe forms of VWD type 1 and type 2. However, comprehensive data on the prevalence and severity of arthropathy are limited [181, 182].

Retrospective analyses suggest that joint bleeding has a negative impact on joint health and health-related quality of life [183]. A Dutch case-control study investigated the incidence and severity of arthropathy in VWD patients and social participation in VWD patients with and without clinically manifest joint bleeding.

The Hemophilia Joint Health Score (HJHS) was developed and validated to assess arthropathy in children [184].

It is also used in everyday clinical practice to assess joints in patients with von Willebrand disease.

It was found that 40% of VWE patients with a documented history of treated joint bleeding showed arthropathy (HJHS ≥10) on physical examination, while 25% exhibited radiological signs of arthropathy in the ankles, knees, or elbows (PS >3). In contrast, the prevalence of arthropathy in VWD patients without a history of joint bleeding was significantly lower—10% with HJHS ≥10 and 4% with PS >3.

Arthropathy was strongly associated with clinically significant joint pain, reduced social participation, and greater functional limitations. Predictors for the development of arthropathy ly in VWD patients were a factor VIII (FVIII) level of <10 IU/dl and the cumulative number of joint bleeds. Arthropathy in these patients correlates with significant functional limitations, reduced social participation, and frequent joint pain, underscoring the long-term effects of joint bleeding in VWD [185].

We therefore recommend routine screening (HJHS, ultrasound, or radiological) in patients with residual activity below 30 IU/dl regardless of severity, as well as in all patients with known joint pain of any kind [186, 187].

Prophylaxis should be considered in patients who have experienced joint bleeding (see chapter 4.1.1 and chapter 6.3.10).

Further studies are warranted.

No comparative studies have been conducted on the circumstances under which anticoagulants can be administered without significantly increasing the risk of bleeding. A review of the literature revealed two case series reported in three sources [188- 190].

Patients should be informed about the risks and benefits of antiplatelet agents or anticoagulants to enable shared decision-making.

In patients with a severe bleeding phenotype (e.g., severe VWD type 1, type 2, or type 3), prophylaxis with VWF concentrate may be necessary to prevent bleeding during antiplatelet or anticoagulant therapy.

DDAVP therapy is generally contraindicated in individuals with cardiovascular disease (e.g., coronary artery disease, cerebrovascular disease, and peripheral vascular disease) and/or an increased risk of thrombosis.

Among the 26 patients with VWE in the series (see above literature), there was 1 serious bleeding event. Serious adverse events, hospitalizations, transfusions, health-related quality of life, or heavy menstrual bleeding were not reported.

The ISTH/WFH guidelines committee reported on their experience with 65 patients with VWD who were recommended antiplatelet or anticoagulant therapy for cardiovascular disease. In the 56 patients who received this therapy and in the 9 patients who did not receive therapy despite it being recommended, the mean mortality, thrombotic events, serious adverse events, hospitalizations, and bleeding were low in both groups, and most patients had an acceptable health-related quality of life according to their physicians.

In summary, based on the evidence, both antiplatelet agents and anticoagulants reduce the risk of thromboembolic complications.

Due to the significant potential benefits of these therapies, which have been demonstrated in large cardiovascular disease studies involving patients without VTE, these therapies should not be withheld from patients with VTE.

In line with the WFH/ISTH guidelines, measures should be considered that limit the duration of the required antiplatelet or anticoagulant therapy (e.g., non-drug-coated stents). In patients with a severe bleeding phenotype, prophylaxis with VWF concentrate or the administration of tranexamic acid may be necessary to minimize bleeding. An individual treatment plan (e.g., administration of VWF concentrate for prophylaxis) should be developed.

However, second-generation drug-eluting stents are now available that are compatible with patients at risk of bleeding due to the short one-month dual antiplatelet therapy; they have therefore recently been proposed as the first choice for hemophilia patients. This approach also appears to be appropriate for patients with VWD [191].

An interdisciplinary discussion with cardiologists is important [192].

In addition to questions about long-term anticoagulation due to atrial fibrillation or similar conditions, treatment recommendations exist for coronary angiography and catheter ablation. These treatments appear safe and feasible after substitution with VW factor in patients with VWE and HA. The recommended dosage is similar to that used for minor surgical procedures. These recommendations are similar to those for patients with hemophilia [193, 194].

Emicizumab is a bispecific antibody developed for the treatment of hemophilia A with and without inhibitors. Emicizumab forms a bridge between activated factors IX and X, thereby replacing the function of FVIII. Emicizumab is not approved for VWE.

Off-label use of emicizumab has been successfully used in patients with VWD, particularly type 3 [204]. The drug is therefore a good alternative, especially for patients with inhibitors. Case reports show a significant improvement in hemostasis in patients who did not respond to other treatments. Subcutaneous administration also makes emicizumab more attractive for patients who prefer a less complex treatment for prophylaxis [205].

In contrast to intravenous prophylaxis, which involves several infusions of clotting factor concentrate per week, emicizumab is administered subcutaneously (SC) weekly, biweekly, or monthly, which significantly reduces the effort required [204][206- 208].

These case reports include the successful treatment of hemarthrosis in men and women and a significant improvement in hemoglobin monovolume concentration in an 11-year-old girl with VWE type 3, anemia, and hypovolemic shock. She had not responded to hormone therapy, cryoprecipitate, or tranexamic acid. After the addition of low-dose emicizumab (3 mg/kg sc, once a month), no further menorrhagia or bleeding occurred [208]. In addition, recent in vitro studies show an improvement in thrombus formation under shear stress in all types of VWD, which may extend its clinical use beyond VWD type 3 [209].

Preclinical gene transfer studies for von Willebrand factor (VWF) already exist. However, there are no ongoing clinical studies specifically focused on VWD [210- 215].

Studies are currently being conducted in various phases on VGA039 (a monoclonal antibody that targets human protein S and inhibits its cofactor activity for tissue factor inhibitor α and activated protein C) and BT200 (rondoraptivon pegol). BT200 is a pegylated aptamer that binds specifically to the A1 domain of VWF and slows down the clearance of VWF and FVIII, thereby increasing their concentrations in the blood [216- 220].

For further information, see chapter 10 Clinical Studies and Approval Status (German Version).