Approach

Except in patients with recurrent spontaneous hemorrhage, where prophylactic therapy may have a role, treatment of VWD is given for bleeding symptoms or to prevent bleeding with a surgical or other procedure. The treatment approach varies by the type of VWD. Patients with severe hemorrhage, when the type is unknown, should be treated as if they have severe (type 3) VWD until more historical and/or laboratory information allows identification of the specific type of VWD. Patients with active severe hemorrhage require resuscitation as appropriate, along with treatments specific for VWD.

In general, patients with type 1 disease undergoing complex procedures or who have bleeding symptoms unresponsive to therapy, and patients with type 2 or 3 disease, should be managed by, or in collaboration with, a hematologist 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.

Type 1 VWD

All patients with type 1 VWD should be tested to see whether they respond to desmopressin, unless its use is contraindicated (for example, patients with atherosclerosis, cardiac insufficiency or other conditions that are treated with diuretics, psychogenic polydipsia, and polydipsia in alcohol dependence). Therefore, it is usually avoided in older patients and young children (<2 years old) for whom hyponatremia is a particular danger. Use in children is possible with careful monitoring. Desmopressin use results in release of von Willebrand factor (VWF) and factor VIII from endothelial stores.[3] Patients should have at least a 3- to 5-fold increase in factor VIII and VWF 30 minutes to 1 hour after intravenous or subcutaneous administration and 1 hour after intranasal administration, with resulting values within the normal range. Some patients with type 1 VWD have accelerated clearance of VWF, and so a fall-off measurement should also be obtained at 4 to 6 hours after administration. Patients with low VWF who have a bleeding history may respond well to desmopressin even though VWF deficiency is not the primary cause of bleeding.

In patients undergoing surgical procedures where any increase in bleeding carries risk, such as a neurosurgical procedure and/or when sustained levels of VWF are needed for several days, a VWF-containing concentrate should be used. Antifibrinolytic therapy (tranexamic acid or aminocaproic acid) can be used prophylactically or therapeutically, in conjunction with desmopressin or factor concentrate as necessary, for procedures involving mucous membranes (i.e., gastrointestinal [GI] tract, mouth, or genitourinary tract). In patients who do not respond to desmopressin, or who have contraindications to its use, VWF and/or antifibrinolytic therapy can be used before procedures involving mucous and nonmucous membranes.

Pregnancy

  • 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 term, so that no treatment or special measures are required. If VWF activity does not rise to normal then, as in other circumstances, desmopressin or VWF-containing concentrate should be used.[2] Desmopressin is safe to administer during pregnancy but should not be used in the presence of pre-eclampsia.

  • Prenatal care should be provided in a specialist center by a multidisciplinary team, including hemotologists and obstetricians with expertise in this field.

Type 2 VWD

Some patients with types 2A and 2M VWD may have a response to desmopressin, allowing its use for minor procedures, particularly in combination with antifibrinolytic therapy. These patients should be tested to assess response >1 week before any planned treatment.[3]

Desmopressin is generally ineffective in type 2B (although its use in this setting has been reported) and it may worsen thrombocytopenia. Desmopressin is ineffective in type 2N, as it results in the release of a defective protein, although the brief rise in factor VIII may sometimes be beneficial. In these patients, VWF-containing concentrates can be used for nonmucous membrane bleeding.

Mucous membrane bleeding (i.e., GI tract, mouth, or genitourinary tract) may respond to antifibrinolytic therapy. Most surgical procedures and bleeding refractory to antifibrinolytic therapy require VWF-containing concentrates.[3][23][24] Rarely patients with type 2B VWD require platelet transfusion.

Pregnancy

  • Although VWF levels may rise during pregnancy, the functional activity in type 2 VWD will rarely enter the normal range and VWF replacement will be necessary.[2]

  • If VWF activity does not rise to normal and the patient is responsive to desmopressin, this treatment can be used as an alternative to VWF-containing concentrate.[2] Desmopressin is safe to administer during pregnancy but should not be used in the presence of pre-eclampsia.

  • In type 2B VWD, thrombocytopenia can worsen with pregnancy, and factor concentrate and platelet transfusion are needed for delivery.

  • Prenatal care should be provided in a specialist center by a multidisciplinary team, including hemotologists and obstetricians with expertise in this field.

Type 3 VWD

Patients with type 3 VWD require treatment with VWF-containing concentrates.[3][23] Except in an emergency, cryoprecipitate should be avoided because it does not undergo viral inactivation. In most countries a virally inactivated VWF concentrate is available.

Most VWF concentrates contain both VWF and factor VIII and are therefore effective immediately. In patients given VWF alone, it takes approximately 6 to 8 hours for the endogenous levels of factor VIII to reach hemostatic levels.[3] Therefore, an initial loading dose of factor VIII must be given when bleeding is treated with high-purity plasma VWF concentrate or recombinant VWF concentrate.

For elective surgery, treatment with high-purity VWF concentrate should begin at least 8 hours before the planned surgery. Antifibrinolytic therapy is a useful treatment alone or as adjunctive therapy for mucosal bleeding (i.e., GI tract, mouth, or genitourinary tract) or procedures, although patients with type 3 VWD are more likely to need factor concentrates for bleeding episodes due to their more severe bleeding phenotype. Platelet transfusion may be useful in the rare patient with continued bleeding despite treatment with VWF-containing concentrates.[23]

Pregnancy

  • In type 3 VWD there is no rise in VWF during pregnancy and VWF replacement is required for delivery and procedures. Replacement during gestation is not usually required, unless there is bleeding or an additional risk factor.[2]

  • Prenatal care should be provided in a specialist center by a multidisciplinary team, including hemotologists and obstetricians with expertise in this field

All types of VWD with chronic or recurrent menorrhagia

Hormonal therapy may be used to treat menorrhagia where benefits of treatment outweigh any risks. Estrogen-containing compounds may also be effective in refractory GI bleeding, but evidence is anecdotal. For menorrhagia, combined estrogen/progestogen and progesterone-only contraceptives usually decrease menstrual blood flow.[20][25]

Antifibrinolytic therapy has been documented to be effective in treatment of menorrhagia in women without bleeding disorders. The efficacy of aminocaproic acid in treating menorrhagia is assumed from studies using tranexamic acid; a lower dose may be effective and better tolerated.[19]

Desmopressin is an alternative therapy for menorrhagia for those who do not respond to, or cannot tolerate, other measures, but evidence for benefit is inconclusive.[26][27] Although evidence in women with VWD is sparse, the progestin-releasing IUD has been shown to be effective in treatment of menorrhagia in women without bleeding disorders.

All types of VWD with significant chronic or recurrent bleeding or with treatment-refractory menorrhagia

Prophylactic VWF-containing concentrate has been used to prevent bleeding in patients who have had recurrent bleeding. 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. VWF and factor VIII levels should be monitored if VWF concentrate is administered repeatedly. Dosing should be adjusted such that factor VIII levels are not excessively elevated, because of a potential risk of thrombosis.[28]

Prenatal care should be provided in a specialist center by a multidisciplinary team, including hemotologists and obstetricians with expertise in this field. VWF-containing concentrate is the treatment of choice for recurrent bleeding. There are no data on the long-term administration of tranexamic acid in pregnancy, but it is known to cross the placenta.

Use of this content is subject to our disclaimer