Management of specified bleeds or invasive procedures

Bleeds from nose and mouth

Bleeds from nose and mouth are relatively common especially in younger patients with VWD. Tranexamic acid given orally (mixture or tablets) or locally is often sufficient to stop these bleeds. In case of oral bleeds, mouthwash with tranexamic acid (the i.v. solution or a chewed tablet) may be effective.

If tranexamic acid is not sufficient to control the bleeds, DDAVP or a VWF-containing concentrate is indicated.

Prolonged or recurrent nasal bleeds may require local treatment, e.g., nasal cautery or laser, and treatment with tranexamic acid over a longer period. Regular local treatment with Vaseline or similar may reduce the bleeding tendency from nosebleeds.

Dental extractions

In mild cases, minor dental extractions with local anesthesia may be carried out under the cover of tranexamic acid only. The treatment could start the day before or at least 4 hrs prior to the extraction and can be repeated three times daily for several days. In more severe VWD cases, or in connection with extensive procedures, and if regional anesthesia, or an inferior dental block is given, DDAVP or a VWF-containing concentrate should be added to tranexamic acid. A single dose of DDAVP or VWF-concentrate is often sufficient. Tranexamic acid should be continued for about 5-7 days both as mouthwash and per orally. The respective dosage levels are specified above. All local procedures fostering primary hemostasis, such as fibrin glue, are recommended.

Menorrhagia – heavy menstrual bleed

Treatment options for menorrhagia in females with VWD include tranexamic acid, DDAVP, VWF concentrates, oral combined contraceptive pills, and intra-uterine progesterone contraceptives. Tranexamic acid reduces menstrual blood loss with about 50%. Tranexamic acid is to be taken only during the menstrual period, in some cases only during the first days of menstruation. If tranexamic acid and oral contraceptives are not sufficient, DDAVP or a VWF concentrate is needed to control the menstrual bleed. DDAVP and concentrates are typically needed only during the menstruation days. DDAVP is usually restricted to three consecutive days because of the risk of fluid retention. NSAIDs should be avoided, but selective Cox-2 inhibitors (coxibs) may be of value as pain medication.

Gastrointestinal bleeds

Gastrointestinal (GI) bleeding is the most frequent cause of hospitalization in VWD. Patients often present with recurrent overt or occult GI bleeding from an unidentified source and clearcut anemia. This clinical picture is assumed to be related to an increased incidence of GI angiodysplasia in VWD.

The mechanism is associated with dysregulated angiogenesis related to the lack of VWF high molecular weight multimers since GI bleeding from angiodysplasia is most frequent in VWD types 2A, 2B, and 3 and in acquired von Willebrand syndrome.

Diagnostics: The management of angiodysplasia has been improved with the advent of video capsule endoscopy (VCE), which is now the gold standard investigation to detect small-bowel angiodysplasia. If bleeding source is not identified with conventional endoscopy, VCE is the tool to identify lesions eligible to argon plasma coagulation (APC), the most effective endoscopic therapy that can be performed using the double balloon endoscopy.

Despite a high prevalence of angiodysplasia in VWD, specific guidelines are not available for the modalities of GI tract exploration in patients with GI bleeding.

Treatment: Argon plasma coagulation (APC).

Angiogenesis inhibitors have successfully been used in some case reports.

Red blood cells and iron deficiency

Management of anemia, usually due to iron deficiency is critical in VWD. VWF mediates platelet adhesion to vascular injury sites under high shear rates, exceeding 800 1/s. The shear forces are dependent on blood flow rates and hematocrit, which assists VWF to reach the mechano-resistance for the platelets at the hemostatic site [1]. Red blood cells have also other roles in hemostasis, as they bind to fibrin, provide procoagulant surface platform and transform to polyhedrocytes sealing the wound site [2]. Overall, anemia is impairing the physiological VWF functions, and should be avoided. Typically, repeated bleeding episodes will lead to iron deficiency anemia (IDA). It should be managed, at an elective situation by peroral iron substitution. In case of poor absorbance and response and emergency situations or repetitive bleeding episodes, intravenous iron administration is the method of choice for the treatment target [3].

Surgery and other invasive procedures

Surgery and other invasive procedures should be performed in close association with or at a center with clinical and laboratory expertise in bleeding disorders including VWD, and with a coagulation laboratory that can measure VWF and FVIII activities around-the-clock. Both FVIII and VWF levels must be evaluated, depending on the type of procedure. Active VWF is needed to cease mucous membrane bleeds, and VWF should be normalized in connection with invasive procedures involving mucous membranes. FVIII activity is an important determinant for surgical and soft tissue bleeds and therapeutic levels should be reached during and after surgery for a period of 3-10 days (depending on the type of procedure). FVIII:C and VWF activity (VWF:RCo or VWF:CB) should be monitored in association with all major surgical procedures.  During surgery and the first post-operative day, normal levels of FVIII:C and VWF:RCo levels should be reached. Anemia and thrombocytopenia need attention. With a prolonged bleeding, especially from GI tract, FXIII levels may be consumed, and it is worthwhile to monitor them.

Repeated infusions of a VWF/FVIII concentrate may induce unnecessarily high levels of FVIII:C in plasma, due to the additive effect of the endogenously released FVIII. Very high FVIII:C levels (>150 IU/dL) or VWF:RCo (>200 IU/dL) over a longer period postoperatively should be avoided, because of the risk of thromboembolic complications.  A concentrate devoid of FVIII is suitable for patients having risk of thrombosis. Thromboprophylaxis is not traditionally used, but may become an issue in obese and cancer patients.

DDAVP and surgery

DDAVP can be used in responsive patients (prior laboratory and clinical efficacy testing), but the risk of water retention and tachyphylaxis must be considered if repeated doses are given. This may limit the usefulness of DDAVP. In some cases, a combination of DDAVP and a VWF concentrate may be useful. DDAVP may be administered via intranasal spray before minor procedures, but in connection with major procedures, it is advisable to give DDAVP parenteral either i.v. or s.c.

DDAVP intranasal spray in a dose of 300 µg i.n. (150 µg if BW <30 kg) should be administered about 60 minutes before the invasive procedure. Intravenous (i.v.) or subcutaneous (s.c.) DDAVP should be given at a dose of 0.3 µg /kg about 30 (i.v.) or 60 minutes (s.c.), respectively, before the procedure. Fluid and electrolyte balance should be monitored when prolonged treatment is given.

VWF/FVIII concentrate for surgery and invasive procedures

Patients who do not respond to DDAVP should be given an approved concentrate containing VWF. In case of major surgery, in patients with severe VWD, treatment should be given for at least 1-2 weeks post surgery. As the recovery of VWF:RCo is about 1.5 – 2.0 IU/dL per infused IU VWF:RCo/kg BW, a loading dose of 50-60 IU VWF:RCo/kg i.v. is recommended for patients with very low basal levels of VWF:RCo. The ensuing doses can usually be lower, about 25-40 IU VWF:RCo/kg i.v. every 12-24 hours. After 24-48 hours a once daily dose, or a dose every other day, may be sufficient for the first post-operative week. FVIII:C should be monitored to avoid high levels over a longer period of time. FVIII and VWF activity levels of ≥0.50 IU/dL for at least 3 days after major surgery is usually recommended. NB! Purely VWF containing product should be started on the preoperative day or together with FVIII replacement just before the intervention.

Tranexamic acid and surgery

Tranexamic acid should be given in addition to DDAVP or VWF concentrate, especially if the procedure involves mucous membranes.

Tranexamic acid is administered at a dose of 10 mg/kg i.v. about 30 minutes before surgery or 20-25 mg/kg orally about 2 h before surgery. Thereafter the tranexamic doses are repeated with 6-8 h intervals for at least a week postoperatively.

Platelet transfusions

Platelet concentrates should be considered if treatment with VWF concentrate fails to control a bleed in patients with severe VWD. The patient’s platelets are also devoid of functional VWF and therefore donor platelets may be of help at the local site of hemostasis.

Thromboprophylaxis

Thromboprophylaxis should not be given routinely to patients with VWD undergoing surgery. Low molecular weight heparin in a prophylactic dose may be considered in patients with multiple or severe prothrombotic risk factors in association with high doses of a VWF/FVIII concentrate. Furthermore, VWF activity and FVIII:C should be >50 IU/dL if thromboprophylaxis is given. Compression stockings are recommended in association with major surgery.

1.

Turitto VT, Weiss HJ. Red Blood Cells: Their Dual Role in Thrombus Formation. Science 1980;207:541–3. doi:10.1126/science.7352265.

2.

Lassila R, Weisel JW. Role of red blood cells in clinically relevant bleeding tendencies and complications. Journal of Thrombosis and Haemostasis 2023;21:3024–32. doi:10.1016/j.jtha.2023.05.009.

3.

UpToDate. Treatment of iron deficiency anemia in adults 2023.