von Willebrand factor (VWF) is produced via recombinant technology that promotes platelet aggregation It also enhances adhesion to damaged vascular endothelium and acts as a stabilizing carrier protein for factor VIII.

It is used in treatment and control of bleeding episodes and given as perioperative management of bleeding in adults with von Willebrand disease (VWD).

Willebrand factor (VWF) Dose in Adults

Dosage in the treatment of von Willebrand disease:

• Individualize dosage and frequency is based on patient weight, severity & type of the bleeding episodes/surgical intervention, and monitoring of appropriate clinical and laboratory measures.
• If baseline factor VIII coagulation (FVIII:C) activity is less than 40% or is unknown, then give factor VIII with the first infusion of VWF (recombinant) to ensure hemostasis.
• If an immediate rise in FVIII:C activity is not required or if the baseline FVIII:C activity is sufficient to ensure hemostasis, VWF (recombinant) can be administered without factor VIII.
• When repeated VWF (recombinant) infusions are needed then monitor FVIII:C activity to determine if factor VIII is also required.
• If the target laboratory measures of VWF or FVIII activity (VWF:RCo and FVIII:C) are not achieved or if bleeding persists, look for the presence of VWF or factor VIII inhibitors.

Dosage in On-demand treatment and control of bleeding episodes:

• The initial dose of VWF (recombinant) should achieve greater than 60% of VWF levels (based on VWF:RCo >60 units/dL)
• Factor VIII infusion should achieve FVIII:C activity more than 40% (>40 units/dL).
• For major bleeding, if FVIII:C activity is unknown, give factor VIII to achieve a target peak FVIII:C activity of 80 - 100 units/dL.

• Dosage in minor hemorrhage (eg, epistaxis [readily managed], menorrhagia, oral bleeding):

  • Initially, 40 to 50 units/kg is given
  • The maintenance dose is  40 to 50 units/kg every 8 to 24 hours (as clinically required);
  • Dose is adjusted based on the location and extent of bleeding.

• Dosage in major hemorrhage (eg, CNS trauma, severe or refractory epistaxis, GI bleeding, hemarthrosis, menorrhagia, traumatic hemorrhage):

  • Initially, 50 to 80 units/kg is given
  • Then maintenance dose is 40 - 60 units/kg every 8 to 24 hours for ~2 to 3 days (as clinically required)
  • Dose is adjusted based on the location and extent of bleeding.
  • Maintain trough levels of VWF:RCo more than 50% as long as deemed necessary.

Dosage in the Perioperative management of bleeding:

• Elective surgery:

  • Assess FVIII:C and VWF:RCo activity 12 - 24 hours prior to surgery
  • Administer VWF (recombinant) at that time for allowing endogenous FVIII:C activity to increase to more than 30 units/dL for minor surgery or more than 60 units/dL for major surgery.
  • Also assess FVIII:C activity within 3 hours before surgery.
  • If FVIII:C activity is more than 30 units/dL (minor surgery) or more than  60 units/dL (major surgery), then give VWF (recombinant) alone within 1 hour prior to surgery.
  • If the FVIII:C activity is less than recommended target levels then give VWF (recombinant) followed by factor VIII within 10 minutes.

• Emergency surgery:

  • Baseline VWF:RCo and FVIII:C activity is assessed within 3 hours prior to initiating the surgical procedure if possible.
  • The loading dose (1-hour preoperative dose) is calculated as follows :

  • the difference between target peak and baseline plasma VWF:RCo activity divided by the incremental recovery (IR).

  • If the IR is not available, consider an IR of 2 units/dL per units/kg.

  • If baseline VWF:RCo and FVIII:C activity is not available, then give loading dose (1-hour preoperative dose) of VWF (recombinant) 40 to 60 units/kg.
  • Factor VIII can be infused sequentially, preferably within 10 minutes after the VWF (recombinant) infusion in patients whose FVIII:C activity is already <40 to 50 units/dL (minor surgery) or <80 to 100 units/dL (major surgery).

Calculation of VWF (recombinant) dose to be given within 1 hour prior to surgery:

• Target peak plasma VWF:RCo activity – baseline plasma VWF:RCo activity] x BW (kg)/IR Baseline plasma VWF:RCo = VWF:RCo activity calculated within 3 hours before administration of 12 to 24 hours preoperative dose of VWF (recombinant) or if no dose is given 12 to 24 hours preoperatively, use the VWF:RCo activity prior to surgery.
• For patients who got an initial VWF (recombinant) dose 12 to 24 hours before surgery, the VWF:RCo activity attained before this dose may also be used to calculate the 1-hour pre-operative VWF (recombinant) dose.
• If baseline VWF:RCo activity is not available, give a weight-based loading dose of 40 to 60 units/kg.

IR = may assume an IR of 2 units/dL per units/kg or calculate  as follows:

• Measure baseline VWF:RCo, then give VWF (recombinant) 50 units/kg and calculate VWF:RCo 30 minutes after infusion and use the formula to calculate IR:
  • IR = VWF:RCo at 30 minutes (units/dL) – VWF:RCo at baseline (units/dL)/Dose (units/kg)

Willebrand factor (VWF) Dose in Childrens

Refer to adult dosing.

Pregnancy Risk Factor: C

• Patients with von Willebrand disease may be at greater risk of bleeding after an abortion, miscarriage, or antenatal procedure.
• Patients with vWD who are pregnant should be closely monitored.
• Clotting factors should always be checked at the first antenatal appointment, during pregnancy, once or twice in the last trimester and before any surgical or invasive procedures.
• Variations in von Willebrand factor levels may occur during pregnancy depending on the type.
• If the concentration is less than 0.5%, factor replacement may be necessary during pregnancy to stop maternal bleeding (including delivery), or in case of a miscarriage.
• After procedures or postpartum, hemostatic concentrations should be maintained at least for 3 to 5 days.
• While other agents may be used to treat von Willebrand disease during pregnancy, it is possible to use them as well. However, when replacement therapy is needed, a recombinant or product from safe plasma sources with viral testing, which has both factor VIII (and von Willebrand factor) is recommended.

VWF use during breastfeeding:

• It is unknown if breast milk contains recombinant von Willebrand Factor, (VWF).
• According to the manufacturer breastfeeding during therapy should be considered in light of the risks to infants and the benefits to mothers.

Willebrand factor (VWF) Dose in Renal Disease:

There are no dosage adjustments given in the manufacturer’s labeling.

Willebrand factor (VWF) Dose in Liver Disease:

There are no dosage adjustments given in the manufacturer’s labeling.

Side Effects of von Willebrand factor (VWF) Include:

• Cardiovascular:

  • Chest Discomfort
  • Deep Vein Thrombosis
  • Hypertension
  • Inversion T Wave On ECG
  • Tachycardia

• Central Nervous System:

  • Dizziness
  • Vertigo

• Dermatologic:

  • Pruritus

• Endocrine & Metabolic:

  • Hot Flash

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Dysgeusia

• Immunologic:

  • Antibody Development

• Local:

  • Infusion Site Reaction

• Neuromuscular & Skeletal:

  • Tremor

Rare side effects of vWF:

• Hypersensitivity:

  • Hypersensitivity reaction

Contraindication to von Willebrand factor (VWF) Include:

• Life-threatening allergic reactions to Von Willebrand factor (recombinant), hamster, or mouse proteins or any portion of the formulation

Warnings and precautions

• Formation of antibodies:
  • It is possible to produce neutralizing antibodies (inhibitors), for von Willebrand factor, VWF and/or factor VIII.
  • Therapy might not work for patients with high levels of inhibitors to VWF and factor VIII.
  • Use of VWF (recombinant), can cause severe hypersensitivity reactions
  • These patients should be treated by an experienced physician. Alternative therapies should also be considered.
  • Patients who have a poor response to treatment or severe reactions should be tested for inhibitors.
• Hypersensitivity reactions
  • Anaphylaxis and allergic reactions may occur.
  • If hypersensitivity reactions occur, discontinue use and seek appropriate treatment.
  • If you experience severe allergic reactions, stop immediately.
  • Anaphylactic reactions in patients should be checked for inhibitors.
• Thrombotic events
  • Thromboembolic reactions can include pulmonary embolism (DIC), disseminated intravascular coagulation, venous thrombosis and stroke.
  • This is especially true for patients who have known risk factors for thrombosis (low ADAMTS13 levels).
  • Patients who need frequent doses of VWF (recombinant), in combination with factor VIII, are at greater risk
  • It could cause an excessive increase in FVIII-C activity
  • Watch out for signs and symptoms that could indicate thrombosis.
• Protein for mouse/hamster:
  • There are also trace amounts of hamster and mouse proteins in UT that could cause an allergic reaction.
• Polysorbate 80
  • Polysorbate 80, also known as Tweens, could be found in some dosage forms.
  • Some individuals have reported hypersensitivity reactions (often a delayed reaction) after being exposed to polysorbate 80.
  • Preterm neonates who received parenteral polysorbate 80 have experienced thrombocytopenia and ascites.

Monitor:

• Plasma activity of VWF:RCo and FVIII:C ( before, during, and after treatment)
• Formation of VWF and/or factor VIII inhibitors
• Signs of bleeding
• Signs of hypersensitivity reactions or thrombosis

How to administer VWF?

• It is administered intravenously slowly (maximum rate: 4 mL/minute).
• If tachycardia occurs then slow infusion rate or withhold administration.
• If also administering factor VIII, give the complete dose of VWF (recombinant) followed by factor VIII within 10 minutes.

Mechanism of action of VWF:

• It is made using recombinant technology, which promotes platelet accumulation
• It also enhances adhesion in damaged vascular endothelium, and acts as a stabilizing protein carrier protein for factor VIII.

Half-life elimination: 19.1 - 22.6 hours

International Brands of von Willebrand factor (VWF):

• Wilfactin
• Willfact
• Wilstart

Willebrand factor (VWF) Brands in Pakistan:

vWF is not available in Pakistan