Continuing Education Activity

Replacement therapy with Von Willebrand factor (vWF) can be used to manage and treat Von Willebrand disease (vWD), especially in patients who are refractory to treatment with desmopressin. It is available as plasma-derived concentrates and, more recently, recombinant form. This activity reviews the indications, actions, and contraindications for using vWF as a therapeutic agent in the management of vWD. This activity will highlight the mechanism of action, adverse event profile, and other key factors like dosing, monitoring, and relevant interactions pertinent for interprofessional team members involved in the care of patients with vWD.

Objectives:

• Describe the physiology of the Von Willebrand factor in the body and its role in hemostasis.
• Outline the indications in the administration of the Von Willebrand factor.
• Review the pharmacokinetics of the Von Willebrand factor.
• SUmmarize some interprofessional strategies that can help to improve patient outcomes when using von Willebrand factor therapeutically.

Indications

Von Willebrand disease (vWD) is a common bleeding disorder caused by quantitative or qualitative defects of the von Willebrand factor (vWF). The clinical management of vWD has evolved over the past few decades, but it continues to pose a diagnostic and therapeutic challenge. In current practice, desmopressin is the treatment of choice for type 1 vWD because it corrects the FVIII/vWF levels.[1] However, in patients with type 3 vWD and some forms of type 1 and 2 vWD, desmopressin is not effective, and for these patients, replacement therapy containing FVIII and vWF concentrates are the mainstay of treatment.[2] 

Replacement therapy in the management of Von Willebrand disease has advanced over the past few years. Initially, cryoprecipitate was the commonly used form of replacement therapy and is currently no longer recommended in the United States or Europe. Since then, there has been a progression in the replacement forms of vWF, from crude preparations of plasma proteins to plasma concentrate mixtures that contain both von Willebrand factor and factor VIII (FVIII). More recently, the replacement therapy in vWD has transitioned from plasma-derived concentrates of vWF/FVIII mixture with higher FVII component to a recombinant vWF with a much lower concentration of FVII.[3] Earlier concentrates had high factor VIII levels with vWF:ristocetin cofactor (RCo)/FVIII ratios ≤1 compared to more recent recombinant VWF with lower FVIII levels with vWF:RCo/FVIII ratios >10.[4]

Desmopressin is regarded as first-line therapy in managing vWD in cases of acute bleeding and prophylactically before minor surgeries. However, it is imperative to understand the limitations of desmopressin. It can be limited by tachyphylaxis, and data correlating the biologic response to desmopressin with efficacy are limited. There are also concerns about metabolic adverse events such as hyponatremia with desmopressin administration. Physicians may prefer to use replacement therapy in certain high-risk individuals. Certain types of vWD have poor/minimal response to desmopressin. Desmopressin is also contraindicated for use in patients with vWD Type 2B or 3. Currently, there are no clear guidelines that are universally in place for the use of replacement therapy in the management of patients with vWD.

The most common indications for the use of the von Willebrand factor in clinical practice are listed below:

• Patients with vWD who do not respond or are minimally responsive to desmopressin[5]
• Patients with vWD undergoing major surgery and procedures with high bleeding risk[6]
• Patients with type 3 vWD; As a response to desmopressin is limited or absent in these patients[7]
• Patients with certain variants of Type 2 vWD:

a) Subtypes 2B and 2 M wherein there is altered vWF-dependent platelet adhesion[8]

b) Subtypes 2A wherein there are high-molecular-weight vWF multimer deficiencies or abnormalities[1]

c) Subtype 2N wherein there is decreased  affinity for FVIII binding[9]

• Patients with very severe type 1 vWD (vWF:RCo activity less than 10 IU/dL / FVIII activity less than 20 IU/dL)
• Some clinicians also prefer vWF replacement therapy in certain high-risk conditions like puparium, major surgery, in pediatric populations below two years of age, elderly patients with extensive comorbidities, patients at high risk for thrombosis (old age, cancer surgery, orthopedic surgery),
• Prophylactically before major surgeries or procedures in patients with acquired Von Willebrand syndrome type (AVWS)
• It can be used along with FVIII in patients with monoclonal gammopathy of unknown significance (MGUS) who have failed to respond to desmopressin.
• Indicated in children with Hemophilia (HA) who have previously failed immune tolerance induction with pure recombinant FVIII alone and is used along with FVIII concentrates;(Immune tolerance induction (ITI) protocols are particularly recommended for hemophilia A children who have developed an inhibitor against FVIII and is one of the most serious complications of substitutive treatment in hemophilia.)
• Secondary prophylaxis may be useful in patients with type 3 vWD with concomitant low FVIII levels who may experience frequent hemarthrosis, frequent and chronic epistaxis, development of chronic arthropathy, and recurrent gastrointestinal bleeding.

Mechanism of Action

Von Willebrand factor is an adhesive glycoprotein multimer synthesized by endothelial cells in Weibel-Palade bodies and megakaryocytes in alpha-granules.[1] It plays various functions that are essential for both primary and secondary hemostasis. Its primary function is facilitating platelet adhesion to subendothelium when exposed to vascular injury.[9] vWF also acts with fibrinogen in platelet–platelet interactions, aiding in the growth and stabilization of the thrombus. Another critical function of vWF is to act as a carrier protein for FVIII in plasma, thereby protecting it from proteolytic degradation.[10]

These pleiotropic functions of von Willebrand factor can be tested with different laboratory assays. The deficiency or abnormality of vWF causes von Willebrand disease, which is the most common autosomal inherited bleeding disorder. Replacement therapy in vWD works by correcting the dual defect of hemostasis, i.e., the abnormal platelet adhesion–aggregation and the abnormal intrinsic coagulation due to low and unstable circulating FVIII. Replacement of deficient or abnormal vWF and correction of low levels of FVIII are both equally important in restoring normal hemostasis in patients with vWD.

Administration

Different human mixtures of vWF/FVIII products are available for replacement therapy. These concentrates were originally introduced in clinical practice for the management of Hemophilia. The mixture of vWF/FVIII concentrates available are plasma-derived and vary in the quantity of FVIII.[2] There is also a recombinant vWF concentrate approved by the Food and Drug Administration in December 2015 for use in adult patients with vWD with bleeding episodes.

The vWF:Rco activity is expressed in international units. One international unit corresponding to the level of vWF:Rco present in 1 mL of human plasma concentrate. An infusion of 1 IU/kg of vWF:Rco is said to raise the plasma level of vWF:Rco by around 1.5 IU/dL. In general, an initial dose of plasma vWF concentrate of 40 to 60 international units (expressed as units of ristocetin cofactor activity [vWF:RCo]) per kg/body weight is given to obtain plasma levels of 50 to 100 IU/dL.[9] Subsequent doses required depend on the clinical response. Subsequent doses of 20 to 40 IU/Kg body weight every 12 hours generally sustains the plasma concentration at 50 to 100 percent in a patient without a shortened vWF half-life.

Patients with acquired WS or the presence of inhibitors require higher and more frequent doses to achieve desired vWF levels. Rarely continuous infusion of vWF can be used in patients whose levels cannot be maintained with intermittent infusions and fail to respond clinically; the doses range between 2 and 15 international units per kg per hour.[11]

The recommended general dose range varies from 30 to 100 vWF:RCo units/kg. However, this can be adjusted based on the patient's residual activity, the presence of autoantibodies and inhibitors, and the severity of bleeding.

The dose given is also dependent upon the severity of bleeding, as seen below:

• Spontaneous bleeding episodes - Daily dose/ Single dose of 30 to 60 IU/kg of vWF to maintain FVIII:C levels greater than 30 U/dL or until bleeding stops (generally 2 to 4 days)
• Major Surgery - Daily doses of 50 to 60 IU/kg of vWF to achieve preoperative levels FVIII:C and vWF:RCo levels of 80 to 100 U/dL until 36 hours postoperatively and then levels greater than 50 U/dL until recovery is complete (usually 5 to 10 days)
• Minor Surgery - Daily doses of 30 to 60 IU/kg of vWF to obtain FVIII:C levels greater than 30 U/dL until completion of healing  (2 to 4 days)
• Dental Extraction/Invasive procedures - Single dose of 30 IU/kg of vWF to obtain  FVIII:C levels greater than 50 U/dL for 12 to 24 hours
• Delivery/ Postpartum - Daily doses of 50 IU/kg of vWF to obtain FVIII:C levels greater than 50 U/dL for 3 to 4 days

There is limited data available on the use of recombinant vWF in avWS; theoretically, it has more advantages due to its longer half-life and lack of factor VIII content, particularly in patients who already have high factor VIII levels and are at high risk for thrombosis. The usual starting dose is 80 mcg/kg intravenously.[9][5][3][12][6][7]

Adverse Effects

Despite extensive screening protocols for detecting viruses and other infections, the risk of transmission of various blood-borne infections cannot be excluded.[1][3][13]

Studies have shown some rare adverse effects seen in very few subjects who received replacement therapy with von Willebrand factor: mild infusion site paresthesia, moderate dysgeusia, moderate tachycardia, mild generalized pruritus, and hot flush. Few serious adverse events were noted, such as mild ECG T-wave inversion, chest discomfort, and increased heart rate. There is also a risk of developing alloantibodies such as anti-VWF binding antibodies; FVIII neutralizing antibodies was noted post replacement therapy.[12][14]

There can be high levels of FVIII in the plasma when multiple closely spaced infusions are given in cases of severe bleeding or prophylactically before major surgeries. This accumulation is due to exogenous FVIII infused with the concentrate mixture along with an increase in endogenous FVIII synthesized by the infused vWF. There is concern that such high levels of persistent FVIII may increase the risk of postoperative thrombotic events such as deep vein thrombosis.[15]

Contraindications

In patients at high risk for thrombotic events such as advanced age, cancer, and orthopedic surgery, multiple doses of Von Willebrand factor should be given with caution due to the increased risk of arterial thrombosis. Venous thromboembolic complications have been noted in a few patients with vWD, which can be attributed to sustained high levels of FVIII due to multiple closely spaced infusions of FVIII/vWF concentrates. Low molecular weight heparin can be used prophylactically in such patients, and von Willebrand factor should be used with caution in patients with a high risk of venous thrombosis.[14]

Some patients with vWD- type 3 can develop alloantibodies after multiple transfusions; in such patients, infusion of vWF concentrates is ineffective and can also cause life-threatening post-infusion anaphylaxis due to the formation of immune complexes.[16] In these patients, vWF should be avoided, and r-FVIII should be used alone and administered at high doses by continuous intravenous infusion, considering the short half-life of FVIII without its vWF carrier.[11]

Monitoring

Close monitoring of clinical response, and measurements of von Willebrand factor activity, is required for dose adjustments and intervals. The standard parameters essential to monitor are factor VIII coagulant (FVIII:C), vWF antigen (VWF:Ag), and ristocetin cofactor (VWF:RCo). It is primarily the FVIII: C assay and the VWF:RCo essay required to monitor replacement therapy. The general goal is to sustain the activity of factor VIII and of VWF (which is generally measured as VWF:RCo) between 50 to 100 percent for 3 to 14 days in patients with significant bleeding episodes or before major surgery. It is important to note that the half-life of infused VWF is short in AVWS, especially in patients with AVWS associated with the presence of inhibitors or Monoclonal gammopathy of unknown significance (MGUS).[17]

It is essential to obtain levels of vWF:RCo and factor VIII activity immediately before and soon after the infusion to determine the half-life of the infused products. Levels are then measured at 4, 8, and 12 hours after the first infusion to obtain half-life information, with more spaced out testing performed subsequently (every 12 hours to 24 hours) depending on the clinical status and response of the patient. In major surgeries, it is recommended to obtain plasma levels of FVIII:C (and vWF:RCo) initially every 12 hours on the day of surgery, subsequently every 24 hours.[7]

It is also important to monitor Factor VIII activity to ensure that it is maintained below 200 international units/dL; high levels of FVIII increase the risk of thrombosis. Post-infusion, the half-life of FVIII:C is approximately double that of vWF:Ag (20 to 24 vs. 10 to 14 hours). This is because of the endogenous increase of FVIII levels, which is stabilized by the additionally infused exogenous von Willebrand factor.[9]

Continuous infusion of factors can be used in patients whose levels cannot be maintained with intermittent infusions and who fail to respond clinically. And such patients will require closer monitoring.[18]

Toxicity

Data shows that VFW:rFVIII is generally safe and effective in patients with severe in a variety of clinical bleeding presentations.[7][15] Studies have not shown detected inhibitors for vWF:RCo, vWF:Ag, vWF:CB, and FVIII:C developed after repeated treatment.[11] However, using multiple infusions precipitating antibodies to factor VII/von Willebrand factor can develop in patients with severe homozygous-like von Willebrand disease.

Enhancing Healthcare Team Outcomes

Von Willebrand disease is one of the most frequently encountered inherited bleeding disorders, with a prevalence of 1 in 1000. The clinical management of vWD is complex, and there are no clear, standardized guidelines for biological therapies and treatment protocols that are followed universally. Desmopressin remains the treatment of choice for patients with type 1 vWD; however, in patients with type 3 and severe forms of type 1 and 2 vWD, desmopressin is ineffective, and replacement therapy with plasma concentrates containing FVIII and vWF are the mainstay of treatment. Clinicians also prefer replacement therapy in certain high-risk populations. 

Replacement therapy with vWF has evolved from crude plasma protein preparations to plasma-derived concentrates containing mixtures of von Willebrand factor and factor VIII (FVIII).[4] However, the varying contents of vWF and FVIII have contributed to the lack of a systematic approach to replacement therapy in vWD.  Recently the treatment of vWD has advanced from plasma-derived vWF/FVIII concentrates (vWF:ristocetin cofactor (RCo)/FVIII ratios ≤1) to recombinant vWF with very low levels of FVIII (vWF:RCo/FVIII ratios >10)

The management of patients with vWD aims to correct the dual defect of hemostasis - abnormal coagulation reflected by low levels of FVIII and abnormal platelet adhesion as expressed by the prolonged bleeding time. Therefore adequate restoration of hemostasis requires correction of deficient or dysfunctional vWF and correcting low FVIII levels.

Although the treatment of vWD has evolved tremendously, it still poses a challenge, particularly in terms of management strategies. There is a dire need for treatment options that are effective, individualized, and standardized to prevent dangerous acute bleeding episodes and improve the quality of life in patients with vWD.