The Mysterious Tale of von Willebrand Disease

THE INTRIGUE BEGAN in 1924, when a physician named Erik von Willebrand described curious bleeding problems in 23 of 66 family members living on a remote island in the gulf between Sweden and the doctor’s home country of Finland. The symptoms he observed most commonly included bleeding from the gums, severe nosebleeds and excessive bleeding following tooth extraction, trivial wounds and menstruation.

But unlike hemophilia, which is sexlinked and thus affects males almost exclusively, these unusual bleeding episodes equally affected both males and females in that large Finnish family. When Dr. von Willebrand measured their whole blood coagulation time, it was normal. So, too, were their platelet counts. Yet, strangely, those who were affected had clearly prolonged bleeding times. He decided to call it “hereditary pseudohemophilia.” Soon afterward, others started to report patients with similar intermittent bleeding symptoms.

It would take nearly 50 years for scientists to finally identify the defective protein that accounts for the mysterious disorder that was renamed von Willebrand disease (VWD). This unusual protein, once called “factor VIII-related antigen” because it complexes with and stabilizes the critical factor VIII clotting protein, was formally named von Willebrand factor (VWF) in the 1970s.

Von Willebrand Factor: The Elephant in the Plasma

Remarkably, the elusive VWF also turns out to be the largest protein found in human plasma. But VWF is unique for yet another reason: It’s actually made up of a series of repeating subunits called “multimers.” Depending on the number of subunits, these multimers circulate in blood in sizes ranging from around 500 to 20,000 kilodaltons. The largest subgroup of these VWF proteins is appropriately called “high molecular weight multimers,” or HMWMs. 1

Today, we appreciate that VWF not only protects factor VIII (FVIII) against inactivation and clearance, but HMWMs in particular are essential for platelet plug formation by adhering to and then diverting circulating platelets to sites of vascular injury.¹

By the 1980s, specialized assays that measure the amount of VWF present in plasma (VWF:Ag) and its function (ristocetin cofactor activity, or VWF:RCo) helped hematologists definitively diagnose the cause of many cases of abnormal bleeding that couldn’t otherwise be explained

What this testing also revealed came as another surprise:VWD is by far the most frequent inherited bleeding disorder, with an estimated prevalence of roughly 1 percent in the general population. The vast majority of these individuals remain undiagnosed either because they’re generally asymptomatic or because their bleeding symptoms are too minor to prompt them to seek medical attention.

Only about one in 10,000 persons with VWD experiences significant recurring bleeding problems that lead to a diagnosis. Around 70 percent to 80 percent of these patients with “Type 1” disease have decreased levels of structurally normal VWF; most respond to intranasal or intravenous treatment with desmopressin, a synthetic hormone that promotes the release of FVIII and VWF from tissue storage sites.

An estimated one person per million in the U.S. population has the rare, severe “Type 3” form of the disease.² These individuals have virtually undetectable amounts of VWF. Without the VWF that serves as its natural stabilizer, very low levels of FVIII — a few percent of normal — may be present. The result is frequent serious bleeding problems that may involve the joints and soft tissues, as well as classical mucosal bleeding.

Most of the remaining 20 percent to 30 percent of persons diagnosed with VWD fall into one of several “Type 2” categories, resulting from a host of gene mutations that cause functional deficiencies in their circulatingVWF. Simply boosting the level of their dysfunctional VWF with desmopressin usually won’t adequately control bleeds in most of these individuals. Their own VWF isn’t up to the task of protecting FVIII from proteolysis or attracting and binding platelets at the site of injury.

These Type 2 and 3 patients, as well as Type 1 patients who fail to adequately respond to desmopressin, need replacement therapy with fully functional VWF.

Treating VWD: The Early Days

For many years, physicians had to rely on plasma transfusions to deliver a therapeutic amount of VWF. But, with only about one international unit (IU) of FVIII:C and one IU of VWF:RCo activity per milliliter, large volumes and repeated transfusions often were required to elevate circulating VWF to protective levels.

In the 1960s, multiple units of cryoprecipitate—with 80 IU to 120 IU of FVIII:C and VWF:RCo in each 15 milliliter bag — could be safely administered with much less risk of complications caused by fluid volume overload. Unfortunately, each unit of cryoprecipitate comes with a small but finite risk of infection and serious transfusion reactions. The VWF content also varies with each bag prepared from individual blood donors, creating the risk of inappropriate dosing.

What was really needed was a VWFcontaining product that could be dosed with very small volumes, with a better safety profile and consistentVWF content.

Humate-P: The First Product Labeled for VWD

Originally approved by the Food and Drug Administration (FDA) as a FVIII replacement therapy for hemophiliaA,CSL Behring’s Humate-P (Antihemophilic Factor/von Willebrand Factor Complex [Human]) was additionally approved in 1999 for the treatment of spontaneous and trauma-induced bleeding in severe VWD and mild and moderate VWD where desmopressin is known or suspected to be inadequate.

For the first time, patients could be dosed with a standardized product labeled with its VWF:RCo potency, with monitoring and additional infusions as needed to maintain a therapeutic level.In contrast with most other available plasma-based FVIII concentrates, the process used to manufacture Humate-P retains VWF and preserves the HMWM subfraction that is so important for platelet adhesion and hemostatic efficacy.

In pivotal U.S. and European studies evaluating VWD patients undergoing a range of major and minor surgeries, Humate-P provided excellent or good hemostatic efficacy in well over 90 percent of subjects. More than 25 percent of patients enrolled in both trials had severe Type 3 disease.

Interestingly, while the physiologic ratio of VWF:RCo to FVIII:C is 1:1, Humate-P contains 2.4 IU of VWF:RCo for every IU of FVIII:C. But, regardless of this ratio, recommended dosing of all products is based on VWF activity expressed as VWF:RCo.

Alphanate: A Second VWF Option

Grifols’ Alphanate (Antihemophilic Factor/von Willebrand Factor Complex [Human]) is another product originally indicated for use in hemophilia A. The particular type of affinity column chromatography used to purify Alphanate retains the entireVWF:FVIII complex, in contrast to other affinity-purified products that capture only the FVIII protein.

In 2007, Alphanate was FDA-approved for surgical and/or invasive procedures in patients with VWD in whom desmopressin is ineffective or contraindicated. Like Humate-P, Alphanate was shown in pivotal trials to be effective in preventing excessive bleeding in well over 90 percent of subjects undergoing a variety of surgical procedures.

Alphanate is not indicated for treatment of spontaneous bleeding in VWD or for use in patients with severe (Type 3) VWD undergoing major surgery. But this shortcoming in the product labeling may soon be rectified if Alphanate is shown to effectively prevent excessive surgical bleeding in a U.S. trial involving 15 subjects with Type 3 VWD. That trial was scheduled to complete enrollment in December 2010.

While the labeling for Alphanate guarantees that it contains not less than 0.4 IU of VWF:RCo per IU of FVIII:C, the VWF:RCo potency is actually similar to or modestly higher than FVIII:C in most production lots. Like Humate-P, both VWF:RCo and FVIII:C potency values for Alphanate are indicated on the vial label.

Wilate: Designed Specifically for VWD

Protein chemists at Octapharma have gone to great lengths to develop a purification process that preserves the structural integrity of VWF and to create a physiologic balance in the content of VWF:RCo. The result is Wilate (Antihemophilic Factor/von Willebrand Factor Complex [Human]), which received FDA approval in December 2009 for the treatment of spontaneous and trauma-induced bleeding episodes in patients with severe VWD, as well as patients with mild or moderate VWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated. Wilate is not indicated for prevention of excessive bleeding during and after surgery in VWD patients, but Octapharma is currently organizing a clinical trial designed to address this label limitation.

The Wilate process applies gentle size exclusion chromatography to try to minimize degradation of VWF proteins, including the fragile HMWMs. While specific purification steps vary between the three preparations, there are currently no available data to clearly document important differences in HMWM content or integrity. But, if measurable differences actually did exist, would they translate into hemostasis efficacy differences? Answering this hypothetical question would require large, carefully designed crossover or head-to-head trials.

With whatever VWF:FVIII concentrate that is chosen, the physician needs to vigilantly monitor circulating levels of both VWF and FVIII. The goal is to elevate and maintain the patient’s plasma VWF:RCo activity to protective levels during the bleeding risk period, while avoiding raising the FVIII level too high above its normal range. Repeated administration of VWF:FVIII without adequate monitoring can result in “supranormal” FVIII levels. A FVIII level of 200 percent of normal or higher may be associated with a risk of venous thromboembolism (VTE).³

Promising Advances for VWD on the Horizon

Aside from some Type 3 patients with recurrent joint or gastrointestinal (GI) tract hemorrhages, it is uncommon to prescribe a VWF:FVIII prophylaxis regimen to prevent spontaneous bleeds in persons with VWD. Administration of VWF:FVIII concentrates is generally limited to surgical coverage or treatment of spontaneous bleeding episodes. But, as we’ve learned with hemophilia patients suffering from recurrent joint or soft tissue hemorrhage, it’s far from ideal to simply allow persons with VWD to experience repeated GI, joint, menstrual or other potentially serious bleeds.

Recognizing the proven efficacy of prophylactic care in many hemophilia patients, in 2007 Swedish and U.S. investigators initiated the von Willebrand Disease International Prophylaxis Study (VIP). This ambitious clinical trial is currently recruiting subjects to evaluate escalating dosages of VWF:FVIII products — including Humate-P, Alphanate and Wilate — with the goal of reducing bleeding episodes in patients who meet certain eligibility criteria. If results from this largest-ever 200-subject VWD treatment trial prove compelling, individualized prophylaxis with VWF:FVIII products could become the new standard of care for thousands of people living with VWD.

A little farther out on the horizon, the first fully recombinant VWF:FVIII product is now being tested by Baxter Healthcare in a Phase I safety and tolerability trial. This extraordinary feat of genetic engineering comes to clinic 25 years after the VWF gene was cloned and the protein was successfully sequenced.

If shown to be safe and effective, Baxter’s novel rVWF:rFVIII could set a new theoretical safety standard relating to risk of viral transmission. Of course, it’s difficult to take issue with the viral safety record for plasma-based VWF:FVIII and FVIII-only concentrates; there have been no reports of viral transmission involving any licensed product since 1986.

Nearly nine decades after Dr. von Willebrand first alerted the world about a strange disease he discovered on a small archipelago, physicians now have a set of easy diagnostic tools to identify those who have it. Just as important, they also now have several very effective treatment options for people affected withVWD — with the promise of still better ones to come.