Approach

Treatment of von Willebrand disease (VWD) is given for bleeding symptoms or to prevent bleeding following a surgery or other invasive procedure. Prophylactic therapy may be necessary for patients with recurrent haemorrhage, such as haemarthrosis, gastrointestinal bleeding, or heavy menstrual bleeding (HMB). The treatment approach varies according to the type of VWD. Patients with bleeding require resuscitation as appropriate, along with treatment specific for VWD.

In general, patients with type 1 VWD undergoing complex procedures or who have bleeding symptoms unresponsive to therapy, and patients with type 2 or 3 VWD, should be managed by, or in collaboration with, a haematologist with expertise in the care of patients with bleeding disorders.

Standard therapies for VWD may be ineffective for acquired von Willebrand syndrome and expert advice should be sought when treating these patients.

Haemostatic treatment

The main treatment options to prevent or control bleeding include desmopressin, von Willebrand factor (VWF)-containing concentrate, and antifibrinolytic therapy (tranexamic acid or aminocaproic acid). Choice of treatment depends on the type of VWD, severity and risk of bleeding, and involvement of mucous membranes.

Patients with bleeding and unknown VWD type should be treated with VWF-containing concentrate until historical and/or laboratory information allows identification of the specific type of VWD. Antifibrinolytic therapy may be added as needed.

Except in an emergency situation where virally inactivated VWF-containing concentrate is unavailable, cryoprecipitate should be avoided because it does not undergo viral inactivation.[60] Antifibrinolytic therapy may be used as an adjunct if cryoprecipitate is used in an emergency setting.

Platelets are a useful source of VWF in all patients with bleeding refractory to all other VWD-specific therapies.

Hormonal therapy is an option for heavy menstrual bleeding.[61][62]

Type 1 VWD

Patients with type 1 VWD and VWF levels <0.30 IU/mL should be tested to see whether they respond to desmopressin, unless its use is contraindicated (e.g., patients with atherosclerosis, cardiac insufficiency or other conditions that are treated with diuretics, polydipsia, or seizure disorders).[61] Adults with VWF levels ≥0.30 IU/mL can be presumed desmopressin responsive.[61][63]

  • Desmopressin use results in release of VWF and factor VIII (FVIII) from endothelial stores.[64] Patients should have at least a twofold increase in VWF levels 30 minutes to 1 hour after administration, with resulting values >0.50 IU/mL.[61] Some patients with type 1 VWD have accelerated clearance of VWF, and so a measurement should also be obtained 4 hours after administration.[61]

  • Fluid retention may occur as a result of the action of desmopressin in the kidneys; thus, it is important to practice fluid restriction following desmopressin administration to reduce the risk of hyponatraemia. Because of this, desmopressin is usually avoided in older adults and young children (<2 years old) for whom hyponatraemia is a particular danger. Use in children aged ≥2 years is possible with careful monitoring.[20]

  • Due to tachyphylaxis and the risk of hyponatraemia, desmopressin should not be administered for more than three consecutive days.[61][65] 

  • Thus, desmopressin is generally reserved for less severe bleeding and minor surgical or invasive procedures, whereas VWF-containing concentrate is administered for severe bleeding and major surgeries when more prolonged therapy is necessary. Patients who do not respond to desmopressin, or who have contraindications to its use, should also receive VWF-containing concentrate.

VWF-containing concentrate is the preferred option for severe bleeding or major surgeries, and when desmopressin is ineffective or contraindicated.

  • Most VWF concentrates are plasma-derived and undergo treatment to minimise the risk of viral transmission. Recombinant VWF concentrate is also available. VWF-containing concentrates may differ in the amount of FVIII, the VWF:FVIII ratio, and the multimeric composition of VWF.

  • Plasma-derived VWF concentrates that contain both VWF and FVIII are effective immediately.[66] 

  • Recombinant VWF concentrate contains only VWF and following infusion, it takes approximately 6 hours for the endogenous levels of FVIII to reach haemostatic levels if they are low beforehand.[67] Thus, an initial loading dose of FVIII concentrate must be given when serious or life-threatening bleeding is treated with recombinant VWF concentrate. The FVIII infusion should not need repeating. In some countries, a high-purity plasma-derived VWF concentrate with very low levels of FVIII is available; an initial loading dose of FVIII may also be required if this is used for serious or life-threatening bleeding.[61][68]

  • VWF and factor VIII levels should be monitored if VWF-containing concentrate is administered repeatedly. Dosing should be adjusted such that factor VIII levels are not excessively elevated because of a potential risk of thrombosis.[69]

In patients who are bleeding or undergoing surgical or invasive procedures, antifibrinolytic therapy can be used prophylactically or therapeutically, alone or in conjunction with desmopressin or VWF-containing concentrate as necessary, especially for bleeding or invasive procedures involving the mucous membranes (i.e., oral mucosa, gastrointestinal or genitourinary tract).[20][61]​​

  • Tranexamic acid and aminocaproic acid may be given orally or intravenously. The choice between the two routes depends on patient factors and convenience. For example, the intravenous route will mostly be used for patients undergoing surgery. If available, tranexamic acid mouthwash is also extremely useful for bleeding in the oral cavity. It can be swallowed or not, as preferred.

  • For minor surgery or invasive procedures, the 2021 ASH ISTH NHF WFH (American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia) guidelines suggest using desmopressin or VWF-containing concentrate with adjunctive tranexamic acid over using desmopressin or VWF-containing concentrate alone.[61] However, this recommendation was based on very low certainty evidence with a focus on patients with severe bleeding phenotypes, and there is some concern for overtreatment or increased adverse effects.[61]

  • In patients with type 1 VWD with baseline VWF activity levels >0.30 IU/mL and a mild bleeding phenotype undergoing minor mucosal procedures, the guidelines suggest using tranexamic acid alone as monotherapy.[61] One dose of antifibrinolytic therapy before dental cleanings may be effective to prevent oozing. Repeated dosing of antifibrinolytic therapy may be effective alone to treat bleeding from mucosal surfaces.

  • Evidence comparing different haemostatic therapy options is limited, and the treatment plan should be individualised according to the bleeding risk associated with the specific procedure and the patient’s bleeding history and phenotype.[60]​​​​[61]

  • Antifibrinolytics should not be used in upper renal tract bleeding or in the presence of disseminated intravascular coagulation.

Type 2 or 3 VWD

Some patients with types 2A and 2M VWD may have a response to desmopressin, allowing its use for minor bleeding or minor procedures, particularly in combination with antifibrinolytic therapy. These patients should be tested to assess desmopressin response before any planned treatment, as described for type 1 VWD above.[61] VWF-containing concentrate (with or without antifibrinolytic therapy) should be used for severe bleeding or major surgeries when more prolonged therapy is necessary, and for patients who do not respond or have contraindications to desmopressin.[20][61]​​

Patients with types 2B and 2N VWD are treated with VWF-containing concentrate. Desmopressin is generally ineffective and contraindicated in type 2B VWD (although its use in this setting has been reported) and it may worsen thrombocytopenia.[20][61]​​​ Rarely, patients with type 2B VWD require platelet transfusion. Desmopressin is generally ineffective in type 2N VWD, but some patients may have a response.[20][60]​​​

Patients with type 3 VWD do not respond to desmopressin and require treatment with VWF-containing concentrate.[60][61]​​ Platelet transfusion may be useful in the rare patient with continued bleeding despite treatment with VWF-containing concentrate.[70]

  • Most VWF-containing concentrates are plasma-derived and undergo treatment to minimise the risk of viral transmission. Recombinant VWF concentrate is also available. VWF concentrates may differ in the amount of FVIII, the VWF:FVIII ratio, and the multimeric composition of VWF.

  • Plasma-derived VWF concentrates that contain both VWF and FVIII are effective immediately.[66]

  • Recombinant VWF concentrate contains only VWF and following infusion, it takes approximately 6 hours for the endogenous levels of FVIII to reach haemostatic levels if they are low beforehand.[67] Thus, an initial loading dose of FVIII concentrate must be given when serious or life-threatening bleeding is treated with recombinant VWF concentrate. The FVIII infusion should not need repeating. In some countries, a high-purity plasma-derived VWF concentrate with very low levels of FVIII is available; an initial loading dose of FVIII may also be required if this is used for serious or life-threatening bleeding.[68][61] 

  • Patients with type 3 VWD can occasionally develop antibodies to VWF after treatment with VWF-containing concentrate. VWF and factor VIII levels should be monitored if VWF-containing concentrate is administered repeatedly. Dosing should be adjusted such that factor VIII levels are not excessively elevated because of a potential risk of thrombosis.[69]

In patients who are bleeding or undergoing surgical or invasive procedures, antifibrinolytic therapy can be used prophylactically or therapeutically, in conjunction with desmopressin or VWF-containing concentrate, especially for bleeding or invasive procedures involving the mucous membranes (i.e., oral mucosa, gastrointestinal or genitourinary tract).[20][61]​​

  • Tranexamic acid and aminocaproic acid may be given orally or intravenously. The choice between the two routes depends on patient factors and convenience. For example, the intravenous route will mostly be used for patients undergoing surgery. If available, tranexamic acid mouthwash is also extremely useful for bleeding in the oral cavity. It can be swallowed or not, as preferred.

  • For minor surgery or invasive procedures, the 2021 ASH ISTH NHF WFH guidelines suggest use of desmopressin or VWF-containing concentrate in combination with tranexamic acid over using desmopressin or VWF-containing concentrate alone.[61] However, this recommendation was based on very low certainty evidence with a focus on patients with severe bleeding phenotypes, and there is some concern for overtreatment or increased adverse effects.[61]

  • ​Evidence comparing different haemostatic therapy options is limited, and the treatment plan should be individualised according to the bleeding risk associated with the specific procedure and the patient’s bleeding history and phenotype.[60][61]​​

  • Antifibrinolytics should not be used in upper renal tract bleeding or in the presence of disseminated intravascular coagulation.

Pregnancy

Antenatal care should be provided in a specialty centre by a multidisciplinary team, including haematologists and obstetricians with expertise in this field.[14][71]

During pregnancy, patients with type 1 VWD, especially if mild, may experience a significant rise in VWF levels. This may result in VWF levels that are within the normal range at the time of delivery term, so that no treatment or special measures are required. In type 2 VWD, the VWF levels may rise during pregnancy; however, the functional activity will rarely enter the normal range, necessitating VWD-specific treatment.[14][72][73] In type 3 VWD, there is no rise in VWF levels during pregnancy, so treatment is required for delivery. VWD-specific treatment during gestation is not usually necessary, unless there is bleeding or an additional risk factor.[14] If treatment during gestation is necessary, pregnant women should generally receive the same treatment as nonpregnant women.

VWF levels and FVIII activity should be assessed in the third trimester to determine a plan for delivery.[61] It is recommended to target VWF levels 0.50 to 1.50 IU/mL prior to neuraxial anesthesia. There is uncertainty regarding the target VWF level postpartum, but targeting higher VWF levels >1.50 IU/mL, often achieved in pregnant women without VWD, may reduce the risk of postpartum haemorrhage.[61][73]​​ If VWF levels do not rise to target, as in other circumstances, desmopressin or VWF-containing concentrate should be used.[14] Responsiveness to desmopressin should ideally be established prior to pregnancy.[14][74]​​ Desmopressin is safe to administer during pregnancy but should not be used in the presence of preeclampsia or cardiovascular disease.[61][75] In type 2B VWD, thrombocytopenia can worsen with pregnancy, and a platelet transfusion may be needed for delivery.[14][73]

All women with VWD are at increased risk of postpartum haemorrhage, especially delayed. Tranexamic acid should be considered in the postpartum period, and patients should be reassured that it is safe to use if breastfeeding.[14][61]​​

Heavy menstrual bleeding (HMB)

Patients with HMB should be managed jointly by haematologists and gynaecologists in the context of multidisciplinary clinics when feasible.[61][62][76]​ Haematologists may not be familiar with aspects of gynaecology or hormonal therapy, and similarly gynaecologists may be unfamiliar with haemostasis.

First-line options for management of HMB include hormonal therapy or antifibrinolytic therapy.[61][62]​ Hormonal therapy may be used to treat HMB in those who do not wish to conceive, and where benefits of treatment outweigh any risks.[61] For HMB, combined oral contraceptives and progestin-only contraceptives usually decrease menstrual blood flow.[20][77]​​ Although evidence in women with VWD is sparse, a progestin-releasing intrauterine device (IUD) has been shown to be effective for the treatment of HMB in women without bleeding disorders.[62][76]​​

Antifibrinolytic therapy can be used to treat HMB in those who wish to conceive and those who do not wish to conceive.[61] Antifibrinolytic therapy has been documented to be effective in treatment of HMB in women without bleeding disorders. The efficacy of aminocaproic acid in treating HMB is assumed from studies using tranexamic acid.[54]

Desmopressin is an alternative therapy for HMB for those who do not respond to, or cannot tolerate, other measures, but evidence for benefit is inconclusive.​[61]​​[62][78] Similarly, VWF-containing concentrate may be used.[62][66]​​ Combination therapy (e.g., tranexamic acid combined with either hormonal therapy or desmopressin) may be another option if first-line treatment is ineffective, but there is a lack of data on its efficacy, impact on quality of life, and adverse effects.[62][79]

Significant chronic or recurrent bleeding

Prophylactic VWF-containing concentrate can be used to prevent bleeding in patients with significant chronic or recurrent bleeding, typically due to haemarthrosis, GI bleeding, or HMB.[61] Prophylaxis is most often necessary in patients with more severe VWD, such as types 2 and 3 VWD. Patients and/or family members can be instructed in home infusion. 

Patients with type 3 VWD can occasionally develop antibodies to VWF after treatment with VWF-containing concentrate. VWF and FVIII levels should be monitored if VWF-containing concentrate is administered repeatedly. Dosing should be adjusted such that FVIII levels are not excessively elevated, because of a potential risk of thrombosis.[69]

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