Medical News

 

  • Joint Repair without Surgery
  • Joint Replacement
  • Inhibitors in Haemophilia
  • Pharmacokinetic Studies

Joint Repair Without Surgery

by Susan Mayer Roher (Courtesy of Hemalog)
An innovative technique shows promise for easier reduction of joint bleeds.

Joint RepairFirst, there is a peculiar sensation, or "aura", that a joint bleed is about to begin. A few hours later, some discomfort and mild limitation of motion set in. In another few hours, if the bleed has not been treated at the earliest warning sign, pain and swelling, warmth around the joint and some redness of the skin can be expected.

For some PWHs, this is an uncommon or even rare problem that can be controlled with factor therapy and does not lead to serious joint damage. But for others, joint bleeds are a frequent, ongoing problem, leading to long-term disability, deformity, pain and a reduced quality of life.

Dr Joist
"After two days, one can resume normal daily functions"
Dr. J. Joist.

A frequently bleeding joint, called a target joint, is often defined as one that bleeds more than four times within six months. Until recently, the only options for reducing the number and severity of such joint bleeds were preventative daily factor infusion (prophylactic therapy) or surgery to remove the inflamed, thickened synovial tissue that lines the inside of joints. This procedure, called synovectomy, has traditionally been performed by opening the joint via a surgical incision or by using an arthroscope. But now an alternative method is gaining considerable favour.

Called radionuclide synovectomy, this innovative procedure involved the injection of a radioactive substance, such as phosphorus-32 chronic phosphate (the substance Yttrium-90 is used in similar procedures in South Africa). Because it is performed on an outpatient basis, it does not require the hospital stay and lengthy rehabilitation period that surgery does. It also has fewer of the risks associated with surgery. Pioneered in Canada, this type of synovectomy has been performed in the U.S.A. in only about 150 patients since 1986. However, radionuclide synovectomy using other radioactive substances has been evaluated in patients with other forms of arthritis such as rheumatoid arthritis as long ago as the 1950s. The current procedure does have some risks associated with it, but early results show great promise.

How joint bleeds affect joints

Each episode of joint bleeding causes inflammation and swelling of the synovial membrane. If bleeding occurs often or is not treated adequately, the inflammation may become chronic and is called chronic synovitis. Then the inflammation leads to enlargement or thickening of the synovial membrane and the release of substances which, over time, can destroy cartilage and even bone. The possible long-term result: disabling joint deformity and loss of joint mobility and function. And once cartilage has been destroyed and there is a wearing away, or erosion, of the bone, the only option to restore mobility is joint replacement therapy -- a complicated procedure requiring a long rehabilitation process.
Traditional Alternatives

Beginning in 1969, a surgical approach was applied to the treatment of synovitis. This procedure, synovectomy, involved removal of the inflamed synovial membrane, allowing a new, normal membrane to form. Care is taken to preserve any undamaged cartilage. Synovectomy can be performed through an open incision (open synovectomy) or an arthroscope/tube (arthroscopic synovectomy). Although open synovectomy is effective in reducing the number and severity of bleeding episodes, it can cause a loss of motion. The surgical procedure also requires a major hospital stay and lengthy rehabilitation period. Factor therapy is required pre- and postoperatively as well as during the recovery period, until healing and adequate joint motion have been achieved.
Arthroscopic synovectomy requires a shorter rehabilitation period, and, in some cases, maintains or even improves range of motion. It is still considered major surgery, however, requiring a hospital stay and prophylactic factor for at least a two to three-week recovery period.
The Newest Approach: Radionuclide Synovectomy

Removal of the inflamed synovial membrane can relieve pain and possibly provide some protection against the progress of joint disease. But in time, the membrane grows back and may become inflamed again. Does temporary relief justify the risks and expense of a major surgical procedure? That concern has led to the development of a nonsurgical approach to synovectomy -- radionuclide synovectomy. Rather than actually removing the damaged synovial membrane, this technique destroys the membrane through radiation.
The main advantage of this new procedure: "One to two days after the procedure the patient can resume normal daily functions!" says J. Heinrich Joist, MD, PhD, professor of Internal Medicine and Pathology and Director of the Haemostasis and Thrombosis Unit and Adult Haemophilia Centre at the St. Louis University School of Medicine.
At this centre, where some of the first successful radionuclide synovectomies were performed beginning 1986, potential candidates for the procedure are those who experience four or more bleeds in the same joint within six months. But before the procedure is considered for these patients, Dr. Joist recommends trial of an alternative measure -- four to six weeks of prophylactic factor therapy. "About 50 to 60 percent of patients do well after this period of prophylaxis," he emphasises. They are able to stop therapy without a return to frequent bleeding. For the others, options are continued prophylaxis, perhaps indefinitely, or radionuclide synovectomy.
How the proceduce works

At the St. Louis University Health sciences Centre, a team composed of a nuclear medicine physician and an orthopaedic surgeon perform the procedure in the nuclear medicine department of the hospital.
The radioactive substance phosphorus-32 chronic phosphate is injected into the joint (Yttrium-90 in South Africa) at a time when the patient has not been bleeding, and preferably after a period of prophylactic therapy so that the swelling of the membrane is already reduced as much as possible. Right before the injection, the patient is given appropriate factor therapy because, although this is not considered surgery, it is an invasive procedure. After the injection the treated joint is splinted for one to two days. Even so, a patient can usually return to work or school the day after the procedure.
The clinical results of radionuclide synovectomy seem to be about the same as those of surgical synovectomy in terms of reducing the frequency of bleeds. There may be a greater improvement in range of motion, but since no more than 150 procedures have been performed in the few centres currently undertaking this technique in the United States, it is too early to tell for certain. As with surgical synovectomy, there is no guarantee that this procedure will prevent further joint damage.
What is certain is that radionuclide synovectomy costs less than surgical synovectomy; hospital and rehabilitation costs are lower and so are socio-economic costs since the person's life is not disrupted by a major surgical procedure. The radionuclide technique is also a good deal less expensive than long-term prophylactic therapy. Dr. Joist has calculated that the average savings in factor alone is about $54,000 (+-R250,000) per patient per year.
What about the risks of radiation

The greatest concern haematologists and other members of the haemophilia treatment team have is the risk of radiation toxicity or long-term effects of radiation therapy. Dr. Joist explains that there is always some risk associated with radiation therapy, especially if the procedure is not done correctly. But the P-32 colloid is used for this procedure specifically because it has little potential to leak out of the joint into other areas of the body. Also, radioactive synovectomy with P-32 colloid and other radionuclides has been performed for 30 years in various countries without evidence of an increased risk of cancer. Although P-32 is not yet approved by the FDA for use specifically in haemophillic synovitis, it is approved for rheumatoid arthritis, and most insurance carriers have agreed to pay for this procedure.
The Right Candidates

Because there is still a low level of risk involved with this procedure the decision to have it done should be made only after careful consultation with the haemophilia treatment team. But, as Dr. Joist points out, "For patients who don't want or cannot afford continued prophylaxis, extended perhaps indefinitely, this outpatient procedure can provide relief from frequent joint bleeding without the prolonged rehabilitation period and expense of surgery."
For more information about radionuclide synovectomy, contact your local Haemophilia Treatment Centre

Susan Roher is a healthcare writer in Chappaqua, New York.

Joint Replacement

by Susan Roessner Dodson & Susan Mayer Rohe (Courtesy of Hemalog)
Today's surgical techniques are giving many who thought they must live with a deformed joint a real alternative

Joint ReplacementMost adults with moderate to severe haemophilia never forget the feeling: a painless but distinct sensation, a tingling within a joint... the first inkling that a joint bleed has begun its predictable and potentially destructive course.

If this episode of joint bleeding happens to be among the first, joint function will most likely return to near normal afterwards. But unfortunately, once one joint bleed occurs, others tend to follow. It's as if the first episode predisposes the joint to future ones. And repeated episodes of bleeding into the joints can lead to advanced degenerative arthropathy.

In an ideal world where factor replacement was started the minute a joint bleed was detected, this downhill course toward joint deformity could be avoided. And, indeed, the percentage of people with haemophilia who reach an advanced stage of joint dysfunction is diminishing. But even with today's norm of early, effective treatment/prevention of joint bleeds, joint haemorrhage remains the most common bleeding manifestation of haemophilia A and B.

Eventually independent daily living is threatened by these problems:

  • pain
  • loss of range of motion
  • muscle wasting and weakness
  • changes in movement patterns of the arms and legs
  • abnormal gait or walking pattern

In many cases, the problems can be handled by conservative treatment. This includes factor replacement as needed, therapeutic exercises, medication to relieve pain and inflammation, and restriction of activity. For some other people with haemophilia, though, the problem becomes more severe even with these measures. The person reaches his thirties or forties facing considerable incapacity and disabling pain. This is when joint replacement surgery may be necessary to improve quality of life.

As orthopaedic surgeon Thomas Sculco of the Hospital for Special surgery in New York explains, "Pain is the greatest determinant. When we see extreme pain coupled with stiffness, deformity, loss of function, and x-ray confirmation that cartilage is destroyed, we consider joint replacement." Sandy Ganz, PT, physical therapist in the Rehabilitation Services Department of the same hospital, has helped many people with haemophilia through the recovery period after joint replacement. She shares the generally held view that surgery should be done "only when there is disabling pain that doesn't respond any longer to medical treatment." She adds that "people shouldn't seek joint replacement just to improve gait or reduce joint deformity."

John Stewart (not his real name), a 27-year-old with severe haemophilia, suffered terrible pain in his left knee because the cartilage was destroyed. Whenever he tried to exercise, he was incapacitated for several days afterward. At first, when he asked about the possibility of knee replacement surgery, doctors told Stewart that the surgery was more appropriate for older people, that for now he should continue his regimen of therapeutic exercises and medication to relieve pain. His reaction: "When I'm older, I'll probably be slowing down anyway. Now is the time that I need to be most active." Ultimately his doctors agreed and the procedure was done. Although Stewart was younger than most patients who undergo joint replacement surgery, his medical history and level of motivation made him a prime candidate for the operation.

Which joints are affected and why?

The joints that most often suffer frequent bleeds and consequent arthritic deterioration are hinge-type joints such as the knee, elbow and ankle. These joints are more susceptible to bleeding and subsequent joint damage for several reasons. They have a relatively large amount of synovium, the membrane that lines the capsule in which the joint resides. The more synovium there is in a joint, the more "rubbing" there is within the joint as it moves. These joints also lack a protective muscle coverage and aren't as able to withstand the stresses of rotary and angulatory motion. Socket-type joints like the hip and shoulder are involved with moderate frequency. Wrists, fingers, toes and vertebral joints are only rarely affected.

Once bleeding into a joint becomes a recurrent event, joint damage progresses through three stages:

    Acute Stage
  • the 24-48 hours following a bleeding episode
    Subacute Stage
  • joint may be mildly swollen and warm, slightly stiff and may lack full range of motion
  • muscle wasting may be present
    Chronic Stage
  • joint capsule and its lining are chronically swollen
  • progressive loss of joint motion, increased pain, joint deformity
  • chronically boggy swelling not relieved by factor replacement
  • if target joint is a knee or ankle, person may walk with a limp
  • if target joint is an elbow, activities of daily living such as driving a car or combing hair may be difficult
Who are likely candidates?

Joint replacement surgery is never a simple undertaking in someone with haemophilia; it requires aggressive factor replacement pre- and postsurgery, a long hospital stay, and considerable rehabilitation.

The best candidates are those who are like John Stewart -- basically healthy, motivated and mentally ready for the discomfort and demands that will be placed on them by the surgery and the intensive postoperative physical therapy and rehabilitation. They must have already exhausted the appropriate nonsurgical methods of preserving joint function and mobility, and must be patient enough to work through an extended recovery period. Looking back on his own experience, the young man points out: "You need to be motivated to make it a success, because it requires a lot of work to build up strength. What you get out of it depends on how much you put in."

Since aggressive factor replacement is necessary to prevent excessive bleeding during surgery, people with factor inhibitors are not generally considered good candidates for replacement surgery. Especially if a person with inhibitors is a high-level responder, it may be impossible to give enough factor to control bleeding during and after surgery.

People who are HIV positive may also be candidates for joint replacement surgery. In these individuals, as in others, the decision is based on the risk versus the benefit they are likely to get from the operation. As always, no decision is made without a comprehensive team evaluation and multiple discussion among team members and with the candidate and his family.

Finally, the cost of joint replacement surgery is significant; a person must have insurance that covers some or all of the cost, or he or his family must be able to pay.

Where should the surgery be done?

A recent textbook describes total knee replacement in a person with haemophilia as a "technically formidable" procedure. Dr. Sculco points out that such a procedure should be done only at an institution where orthopaedic surgeons have done many such replacements and every member of the treatment team has experience with the special demands of haemophilia.

Sandy Ganz, PT, whose institution does joint replacement on patients with haemophilia from all over the United States and the world, believes that it is not just the experience of the surgeon that is critical. "A haemophilic total joint is very different from the average total joint that you work with in physical therapy," she points out. "At a centre, the physical therapist is an experienced member of a team that includes the orthopaedic surgeon and the haematologist. It's not uncommon for a joint bleed to occur during physical therapy. Only a therapist with special experience knows what to look for and what to do."

Success Rates

Overnight miracles do not occur, as Stewart is quick to point out. "It took about a year of rehabilitation before I stopped being concerned about my knee all the time," he recalled. "At first I could just exercise a little at a time. Eventually I worked up to walking four or five miles." The "ultimate achievement" was when he recently walked a full eight miles in a fund-raising event. Dr. Sculco adds that complications, including infections, are also a possibility. Some patients have circulating anti-coagulants and continue to bleed into the muscle despite surgery.

In general, the goals by which health care providers and patients measure the success of joint replacement surgery in haemophilia are as follows:

  1. Decrease in pain at the affected joint
  2. Decrease in pain and stress at joints surrounding the affected joint
  3. Decrease in frequency and number of joint bleeds
  4. Increase in FUNCTION and mobility

These goals are long-term and should not be assumed that they will be reached quickly. After surgery, a staged exercise and physical therapy program will begin as soon as possible -- before the patient leaves the hospital -- and will become part of an ongoing process of rehabilitation. The overall goal is to make the person able to function independently with little or no disability. Prevention of joint bleeds is optimal, but is not always possible.

The success of total joint replacement depends on many factors, including such things as the type of artificial joint implanted, prior surgery on the joint and the surgeon's experience. The experience of several institutions follows, according to the joint involved.

Knees

The knee joint is most likely to cause severe pain and disability and is the joint most frequently replaced. Maintaining range of motion presents a particular challenge, which appears to be met better by some of the newer techniques and prosthetic materials in use today. As part of a 20-year (1967-1987) study, 46 knee replacements were done in people with haemophilia at the University of Southern California and the Haemophilia Centre, Orthopaedic Hospital in Los Angeles. These were the reported failure rates:

  • Problems with prosthetic implants -- 2,4%
  • Need to reoperate (1-14 years after first operation) due to problem with prosthetic implant -- 6,8%

Of 24 total knee replacements done in 14 people with haemophilia at the Hospital for Special surgery in New York, 21 (88%) had a good or excellent result in terms of pain relief and improvement in the joint's range of motion.

A report on total knee replacements done between 1983 and 1992 at a haemophilia centre in England included a comparison of the number of joint bleeds and the factor units required before and after joint replacement. In 10 people with severe haemophilia who had a total of 15 knees replaced, the average number of bleeds in the operated knees fell from ten to two a year; the average yearly amount of factor needed fell from 15,500 units to 2,200 units per knee.

Ankles

The ankle is a close second to the knee as the joint most frequently involved in destructive joint bleeds. But only a small portion of people who suffer repeated ankle bleeds wind up with joint pain and deformity serious enough to warrant ankle replacement surgery. In an overview of the 20-year California study mentioned above, only one ankle replacement was reported compared with 46 knee replacements. Eleven years after his surgery, the patient who received the ankle replacement was symptom-free, without pain or bleeding into the joint.

Hips

Hip replacement is moderately frequent in people with haemophilia. Its success can be affected by the fact that PWHs so often have knee and ankle problems as well, giving them a stiff-legged gait. Without the normal shock absorption of the knees and ankles, the hip is put under additional stress. Over time, the increased stress of a stiff-legged gait can cause the artificial hip to loosen. This and other complications can necessitate reoperation.

At the two California hospitals, investigators rated their long-term success with hip replacement as "fair", with reoperation becoming necessary in about 60% of people over the 20-year period. They noted, however, that all these people were doing well, were free of hip pain and able to walk without assistance. They were all doing substantially better than before their initial hip surgery.

A New Lease on Life

Complications to hip replacement surgery can occur, and some, such as infection, can be serious. But thanks to today's advanced surgical techniques and improved artificial joint materials, problems associated with the procedure occur less often than in the past. The overwhelming majority of people with haemophilia who reach the point of needing this surgery function significantly better with their new joint than with their old one. Pain is relieved or reduced, the number of joint bleeds goes down, and they can walk more normally and enjoy life more fully. As Stewart describes it, "Even now, four years after my surgery, every time I take a long walk, I realise it's a very special thing."

For more information about joint replacement, contact your local Haemophilia Treatment Centre


Susan Roessner Dodson and Susan Roher are healthcare writers living in Southampton and Chappaqua, New York.

Inhibitors in Haemophilia

by Donna M DiMichele, M.D.
Introduction

Throughout life, persons with haemophilia battle the complications of both the disease and its treatment. One of the most serious of these problems is the development of an inhibitor. An inhibitor is a type of antibody. The function of antibodies in the body is to try to destroy substances they do not recognize. In a person with haemophilia A or B, inhibitors directed against either factor VIII or IX may be created by the body following treatment to replenish the missing factor. The antibody attaches to the factor VIII or IX and neutralizes=97 or inhibits=97 its ability to stop bleeding.

An inhibitor is usually detected in one of two ways. Although the person with haemophilia may have no symptoms, the inhibitor may be discovered during routine screening performed at a comprehensive evaluation. Alternatively, an inhibitor may be suspected when, suddenly and unexpectedly, bleeding does not stop as quickly as it should in response to treatment with factor.=20

The presence of an inhibitor is usually confirmed using a specific blood test called the Bethesda inhibitor assay. The amount of antibody can be measured using this test, and is reported as a number of Bethesda units, or a Bethesda titer. Therefore, the higher the number of Bethesda units (or, the higher the Bethesda titer) the more inhibitor there is present.

Now for the last definition. When an antibody is detected, it will usually be classified as either high or low responding depending on how a person=92s immune system is stimulated upon repeated exposure to factor VIII or IX. If the immune system reacts briskly and strongly, the amount of inhibitor directed against factor VIII or IX can rise quickly to high levels (reflected in a high Bethesda titer). Without further exposure to the factor, the Bethesda titer may drop down to a low level, but this process could take many months to occur. When it has these characteristics, the inhibitor would generally be called high responding. Alternatively, the immune system may be stimulated in a different way such that its response to factor exposure is slower and weaker, and the Bethesda titer will remain low. This type of inhibitor is generally characterized as "low responding." Interestingly, the characteristics of an inhibitor can change over time, and at times the inhibitors have been noted to disappear spontaneously within several weeks or months without apparent treatment.=20=AO

Frequency and Nature of Inhibitors

Based on a number of studies from around the world, it is estimated that the incidence of antibody development in persons with severe (less than 1% factor) or moderately severe (1% to 5% factor) haemophilia A is between 20% and 33%. This information suggests that one third to one fifth of persons with factor VIII levels of 5% or less may develop an inhibitor sometime in their lives. However, among persons with haemophilia B, inhibitors are much less frequent, affecting only 1% to 4%.

The risk of developing an inhibitor does not remain the same during the lifetime of a person with haemophilia. Historically, the majority of inhibitors have been known to develop during childhood. Recent studies have been conducted with persons with haemophilia A who have received only the recombinant (genetically-engineered) factor VIII; these individuals have been more closely observed for inhibitor development than individuals who have received human plasma derived products. These studies suggest a trend toward earlier inhibitor development, that is, at a younger age and after fewer treatments with recombinant factor VIII. These same studies have made another interesting observation about the nature of the inhibitors that are developing with these newer factor VIII products. Historically, with the use of human plasma derived products, about 80% of inhibitors were of the high responding type and very few were temporary, that is, they disappear on their own. However, with the exclusive use of recombinant factor VIII, less than one half of the developing inhibitors were high responding, and as many as one third of them were temporary. We need more long-term experience with the new highly-purified factor VIII preparations, whether plasma-derived or genetically engineered, in order to determine whether we are truly observing a change in the nature of newly developing inhibitors with these products. Similar information on the nature of factor IX inhibitors is less available due to the low prevalence of inhibitors in the haemophilia B population. (Note: a short article on inhibitors in haemophilia B by WFH VP Medical, Carol Kasper appears on page 4 of the June 1997 Haemophilia World, published by the World Federation of Haemophilia)

Who will develop an Inhibitor and why?

Inhibitor development occurs more frequently in individuals with certain inherited conditions. As already mentioned, persons with haemophilia A are much more likely to develop inhibitors than those with haemophilia B. The incidence of inhibitors is highest among those with severe or moderately severe haemophilia. Inhibitor development occurs rarely among persons with mild disease, that is, factor levels of greater than 5%. Development of inhibitors also tends to be familial and occurs more frequently in the U.S.A. for example, among individuals of African heritage. Although the current explanation for these observed trends is far from complete, researchers are actively studying both the haemophilia gene and the immune system for answers.

Treatment of bleeding in the presence of the Inhibitors

The treatment of hemophilic bleeding in a person with an inhibitor can be a challenging experience for both the patient and the treater. In persons with low responding inhibitors and low Bethesda titers, therapy with either factor VIII or IX replacement is frequently possible. In these cases, there is usually good control of both minor and more serious bleeds, although higher doses of the factor and/or more frequent factor infusions may be required to overcome the antibody. However, when there is a large amount of antibody in the system as reflected in a high Bethesda titer, specific treatment with factor VIII or IX is usually not possible because even large factor doses are neutralized by the inhibitor. In rare instances, when high levels of inhibitor exist but there is life-threatening bleeding that can only be treated with specific factor therapy, some of the antibody can be removed from the body through a process called plasmapheresis. This is only a temporary measure, however, since giving the factor will then stimulate the body to make large amounts of new antibody within several days. For most bleeding episodes, the person with haemophilia and high responding inhibitor will usually have to rely on alternative treatment that is selected on the basis of the type of haemophilia and the nature of the bleed.

For both haemophilia A and B, the mainstay of this therapy is generally either prothrombin complex concentrates (PCC=92s) or activated prothrombin complex concentrates (APCC=92s). These products contain other activated clotting factors that can stimulate the formation of a clot and stop bleeding, thus bypassing the specific requirement for factor VIII or factor IX. Used in the treatment of inhibitor bleeding since the late 1970s, they are generally effective. However, there are several drawbacks which limit the use of =97 and satisfaction with =97 this treatment. This type of therapy is short-acting by its very nature, and when given too frequently may cause either more bleeding or excess clotting. This clotting problem can be made worse if antifibrinolytic drugs (Amicar=AE or Cyclokapron=AE) are used along with PCCs or APCCs. Furthermore, because of small amounts of factor VIII and larger amounts of factor IX in these products, they too can stimulate new antibody production to factor IX in haemophilia B. Finally, these products still have the potential to transmit hepatitis and other viruses to the recipient.

Recombinant factor VIIA, a new clotting factor currently being researched for the treatment of bleeding in persons with haemophilia A and B who have inhibitors, may solve some of the problems associated with PCC or APCC therapy. However, recombinant factor VIIA is not yet licensed by the United States Food and Drug Administration, and more experience with this treatment is necessary before we truly understand its effectiveness and any potential side effects. Such studies are currently underway.

For persons with haemophilia A, the use of porcine factor VIII=97 derived from pig plasma=97 is similar enough to its human counterpart to work effectively in the human clotting system, yet is different enough to go unrecognized by some of the human factor VIII inhibitors. This product has been shown to be effective in stopping major bleeds in patients whose inhibitor does not destroy porcine factor VIII. However, allergic side effects and a temporary drop in the platelet count can occur with the use of this product; the latter almost never causes problems. Importantly, porcine factor VIII can stimulate the immune system to produce more antibodies against both itself and factor VIII.

Immune tolerance: Treatment of the Inhibitor=20

Although there are several therapeutic options for haemophilia bleeding in persons with an inhibitor, there are none that can guarantee the same good outcome as specific factor VIII or IX treatment. Consequently, persons with inhibitors frequently suffer from many more infectious, orthopaedic, and life-threatening complications from their haemophilia and have greater disability in their day-to-day lives than those in whom inhibitors do not appear. Importantly, they also may not benefit from the potential future cure of haemophilia with gene therapy.

Therefore, for most such individuals, the eradication of the inhibitor is the best option. The only currently available method to accomplish this is a process called immune tolerance. In this therapy, regular (usually daily or every other day) infusions of factor VIII or IX are administered for a period of weeks to years, with or without drugs that dampen the immune system=92s reaction to the factor. The goal is to train the immune system to better accept treatment with the missing clotting factor, that is, to be more tolerant of it. Immune tolerance treatment, although time-consuming and costly, is effective 60% to 80% of the time, based on almost twenty years of experience with its use. And, with safer factor V111 and 1X products on the market, it is gradually gaining greater acceptance among patients and treaters. There is a national study currently in progress which is designed to help determine the most effective and cost-efficient method of administering immune tolerance therapy.

Inhibitors: The future=20

Despite the very serious nature of this haemophilia complication, there are reasons for a person with an inhibitor to be truly optimistic. Never has there been more interest in the problem of inhibitor development on the part both of the researcher and the treater. Through this intensive and cooperative effort eventually will come the knowledge needed to treat this problem more effectively, and, most importantly, to prevent it altogether.

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Dr Donna DiMichele is director of the Regional Haemophilia Care Center at the New York Hospital/Cornell University Medical Center. The above article originally appeared in The National Haemophilia Foundation (U.S.A.).

Pharmacokinetic Study of Continuous Infusion of Intermediate-Purity Factor VIII in Haemophilia-A Patients Undergoing Elective Surgery or with Severe Haemorrhage

by Carolyn Rochat

To obtain more information or any articles on continuous infusion, please E-Mail Sr Anne Gillham or Caroline Rochat on: gillhama@nbi-kzn.org.za or natalnbi@iafrica.com

Abstract

Continuous infusion of factor VIII (FVIII) has been shown to be a safe, effective and practical approach to the treatment of haemophilia A patients.

This method prevents peaks and troughs in the plasma FVIII level, thereby lessening the risk of breakthrough haemorrhage. If the local, intermediate-purity product can be shown to be effective when administered as a continuous infusion, it can also contribute to substantial cost savings for the haemophilia community. An open study, involving up to six patients with moderate to severe haemophilia A who require prophylaxis with FVIII during and after major surgery or for serious bleeds is proposed. A pre-operative pharmacokinetic study will be conducted in patients undergoing elective surgery to determine the initial dose for the continuous infusion. A retrospective control group will be identified, matched by type of surgery and severity of haemophilia, allowing for comparisons between bolus and continuous infusion administration. Surgical and severe haemorrhage patients will receive an initial bolus dose of FVIII to increase their levels to approximately 1 iu/ml. FVIII will then be administered by continuous infusion for a minimum of 5 days. Regular assessment of FVIII:C (biologically active moiety of FVIII) levels to maintain a minimum level of 0.5 iu/ml will be undertaken. Patients will also be monitored for vital signs and thrombophlebitis at the infusion site.

Introduction

Haemophilia A is a sex-linked disorder characterised by a deficiency of factor VIII (FVIII) resulting in bleeding episodes either spontaneously or from trauma. The principal form of therapy has been replacement of the missing factor with concentrates of factor VIII prepared from pooled cryoprecipitate.

Treatment of haemorrhage and prophylaxis against bleeding following surgery is based on the infusion of coagulation factor. Major surgery or life threatening bleeds require normal factor VIII levels to be maintained at all times. Frequent bolus injections or intermittent infusions resulting in high peaks are required to keep the trough factor VIII plasma level above the minimum haemostatic level. A minimum haemostatic level of 0.3 iu/ml is usually necessary to treat relatively mild bleeding episodes, and a level of 0.5 iu/ml is generally considered the minimum for serious bleeding into joints and muscles. This is achieved by frequent monitoring of plasma factor VIII levels. The quantity of factor VIII infused needs to be sufficient to allow for distribution of factor throughout the body and clearance from plasma. An infusion of 1 iu of factor VIII/kg body weight will increase plasma factor VIII level by 0.02 iu per ml.

The short half-life of FVIII in the main obstacle in maintaining such a high blood level of factor VIII x VIII. This limitation is reduced by the administration of intermittent infusions to maintain the desired plasma levels but it would seem more physiological and economical to maintain a steady plasma level of factor VIII activity above that at which there is a risk of bleeding. Therefore continuous infusion therapy has been suggested. Continuous infusion has been shown to be a safe, effective and practical approach to treatment of patients with haemophilia A in a number of studies.

McMillan et al first studied continuous infusion in five boys and concluded that this method provides more precision in replacement therapy than by intermittent infusion alone. Hathaway et al compared continuous and intermittent infusions in 12 severe haemophilia A patients undergoing surgical procedures and found that a higher minimal plasma level (50 iu/dl vs 35 iu/dl) was seen with the same amount of product if infused continuously. They established the following dosage guidelines for surgical procedures: a continuous infusion of 2 iu/kg/h produces a mean FVIII:C level of 0.5 iu/ml. They gave an initial infusion to raise the levels to 100% (1 iu/ml) FVIII:C by application of the following formula: Dosage (iu) = (wt kg)(0.5)(desired plasma level (iu/100ml)). Matucci et al developed a programme for continuous infusion with the dosage adjusted according to the daily calculation of the clearance of FVIII. The dosage was adjusted on a daily basis since they found a progressive decrease in the clearance during the first 3-5 days, which can result in additional cost savings of product as less is required to maintain factor VIII levels. They proposed that the reason for this was the saturation of intracellular storage of FVIII:C during the infusion. They used minipumps to overcome the use of large volumes associated with the additional dilution of product in saline.

Martinowitz et al outlined the following advantages of continuous infusion:


  1. It obviates the need for multiple daily bolus injections of factor concentrates
  2. Constant blood levels appear to be more efficacious: subtherapeutic trough levels or excessive peak levels may result from bolus injections.
  3. Reduces cost of coagulation factor replacement by 30% when fixed dose infused or as much as 50-90% if adjusted dose infused by using less plasm product.
  4. The drawing of blood samples is simpler.

A large variety of procedures employed during the manufacture of factor concentrates are known to cause various degrees of inactivation and/or denaturation of the FVIII molecule. It is important to assess the behaviour of each product when infused in the haemophilic patient. Since a relationship has been established between clinical efficacy and the level of circulating FVIII:C in haemophilic patients, the evaluation of in vivo recovery and the measurement of biological half-life have proven to be valuable efficacy tests. Factor VIII decay curves are normally biphasic (single dose) with an early distribution phase and a late elimination half-life. In practice it can be approximated to a monophasic curve. Traditionally, FVIII pharmacokinetics were evaluated by means of compartmental models which followed the use of graphical techniques. Recently there has been a move to analyse decay curves by means of model-independent analysis, which is of value in problematic kinetic cases such as protein kinetics, such as factor VIII where the assay is not accurate or precise and time-concentration curves do not always fit the model. Model-independent methods also have the advantage that they do not require the assumption of a specific compartmental model. The choice of a compartmental model is problematic because, for unknown reasons, the decay of plasma FVIII activity after a single dose is normally biphasic.

Three basic pharmacokinetic parameters are measured:

  1. Total body clearance (CL) -- the overall rate at which plasma is cleared
  2. Volume of distribution at steady state (Vss) -- the ratio of the amount of substance present in body at any time and the corresponding plasma concentration.
  3. Mean residence time (MRT) -- is a practical function similar to half-life. The estimation of these from single dose data is based on the calculation of AUC (area under the curve) and AUMC (area under the moment curve). The MRT is the time for 63,2% excretion, therefore in an ideal pharmacokinetic model:
  • MRT = 1.443 t CL = D/AUC
  • MRT = AUMC/AUC
  • MRTiv = MRT - T/2
  • Vss = CL MRT iv

T (h) duration of continuous infusion (Correction made to account for the duration of infusion)

In vivo recovery (IVR) is a distribution parameter which is calculated as the ratio of the measured peak to declared units (expected peak) per plasma volume. However, there are uncertainties in the calculation of this parameter:

  1. The labelled potency (specifications allow for potency plus-minus 20%) may differ from the actual content.
  2. There is conflict regarding time to peak value which may be 10, 15, 60 or even 120 minutes after end of infusion. The unpredictable "post-infusion activation" of FVIII makes the calculation of IVR dependent on early blood sampling.
  3. Plasma volume is measured empirically resulting in errors (obesity, underweight, low haematocrit, etc.). The actual plasma volume is not usually known accurately and different methods are employed to estimate the volume which yields different values. Also, IVR increases with body weight but this is actually an incorrect deduction as plasma volume as a fraction of total body weight actually decreases with increasing weight.

MRT adjusted to iv bolus case.

IVR calculated by using the highest FVIII:C plasma level after infusion as the actual peak of FVIII activity. The theoretical FVIII:C value is calculated as follows:

  • Plasmavolume(ml) = 80xkgbodyweightx(100-haematocrit) / 100
  • TheoreticalpeakofFVIII:C = amountofFVIII:Cinjected / Plasmavolume
  • PercentIVR = ActualFVIII:Cx100 / TheoreticalFVIII:C

Amount of FVIII:C injected = value given by 1 or 2 stage assay x injected volume.

  1. It assumes FVIII:C distributes only into plasma.

Therefore it is suggested alternative methods to report pharmacokinetics are used e.g. volume of distribution at steady state, as methods for calculation are standardised and the parameter is determined from the entire decay curve and there is no indirect measure of plasma volume involved. When calculating pharmacokinetic parameters in mild haemophiliacs, caution must be exercised, as the baseline FVIII:C level (endogenous synthesis) must be subtracted from the post-dose FVIII:C concentrations to prevent large errors in the half-life.

This study is being undertaken as in South Africa no product is registered for use as a continuous infusion and there is no data of this kind for the intermediate-purity product that is widely used. Research work which can evaluate the local product for this use will be invaluable to the haemophilia community both to provide improved therapy and to reduce costs. Factor VIII therapy is costly. Continuous infusion, in addition to being safe, efficacious and convenient, is highly cost effective. At the same time, the opportunity to more fully elucidate the pharmacokinetic parameters of the Factor VIII product will be taken. To date only in vivo recovery and half-life studies (t 1/2 = 13.1 hours) have been performed.

Objectives

  1. To evaluate the pharmacokinetic behaviour of intermediate purity FVIII during continuous infusion to haemophiliacs undergoing elective surgery procedures or with haemorrhage of a severity requiring a minimum of 5 days of infusion with FVIII, and thereby establish an optimum regimen for continuous infusion.
  2. To characterise the pharmacokinetic parameters of intermediate purity FVIII, by undertaking a pre-operative pharmacokinetic study, using-model independent methods.
  3. To evaluate the cost-benefit of continuous infusion of FVIII versus intermittent bolus infusions.
Study Design

Open, non-randomised trial of continuous infusion therapy in moderate to severe haemophilia A patients undergoing elective surgery (preceded by a pre-operative pharmacokinetic study) or with severe haemorrhage. Due to the small number of patients available, it would be difficult to recruit enough patients in the given time to carry out a randomised, prospective study. Therefore, a retrospective control group of haemophilia A patients who received intermittent bolus infusions after elective surgery will be identified for comparisons with continuous infusion patients. These comparisons will take the form of comparing total FVIII usage, in terms of number of units administered over treatment period.

Site of Study

The study was conducted at the Johannesburg Hospital under the supervision or Dr. R..Schwyzer, Dr. J. Poole, Sr. Anne Gillham and Sr. A.L. Cruickshank.