A Red-Blooded Medical Challenge: Creating a Safer Treatment to Counteract the Effect of Blood Thinners Print E-mail
By Sebastian Thaler   
Friday, 14 January 2011 01:36

November 19, 2007 was the worst day of Dennis Quaid’s life.  On that Monday morning, the famous actor and his wife, Kimberly, rushed to Los Angeles’s Cedars-Sinai hospital, where their 12-day-old twins Thomas Boone and Zoey Grace had been admitted two days earlier for treatment of routine Staph infections. 

As Quaid related in a profile in AARP: The Magazine in September, a pediatrician then informed the couple that their twins had inadvertently been massively overdosed with a blood thinner called heparin, putting them at risk of bleeding to death.

To reverse the effects of the heparin overdose, doctors gave Thomas Boone and Zoey Grace protamine sulfate, a drug that reverses the effects of heparin.  Late on the second day of the emergency, the infants’ blood coagulation levels inched back into the normal range.  Quaid’s children miraculously suffered no lasting ill effects, and the experience inspired Quaid to take up a new cause:  preventing negligence-caused medical mishaps.

Yet this happy ending obscures a disturbing reality:  Quaid’s family was doubly lucky that day in 2007.  The first bit of luck involved the fact that the children survived unscathed.  The second lucky break was that the protamine they were given to stop their bleeding didn’t harm them as well.  This is because the use of protamine—in spite of its ability to counteract the effects of the blood thinner heparin—harbors multiple risks of its own.  In this article, we will explore these risks and see how one company is taking steps to produce a safer alternative treatment.

Blood Clotting: Stopping It and Starting It

Every day in hospitals around the world, surgeons are faced with a daunting task:  making sure that their patients do not experience blood clotting as they are undergoing an invasive procedure.  There is a simple and important reason for this.  Blood clots can be potentially life-threatening, since the clot has a chance of lodging in the patient’s brain and causing a stroke, or lodging in the patient’s heart and triggering a heart attack.

As a matter of routine, heparin, which has anticoagulant properties, is used for this purpose in certain acute surgical situations.  These situations include coronary artery bypass procedures and other cardiothoracic procedures, all in the hopes of preventing blood clots from forming while the patient is under the knife.  Once the surgical procedure is complete, however, the action of the heparin needs to be reversed.  This step is needed in order to allow the patient’s blood to clot, letting them heal normally and avoid the risk of potentially life-threatening uncontrolled bleeding, such as that reportedly experienced by Quaid’s children.        

Meanwhile, there exists a separate challenge that involves the need to minimize the potential for blood clotting in patients who require longer-term care outside the setting of a hospital.  In order to satisfy this particular need, a class of substances known as Low Molecular Weight Heparins (LMWH)—which are different from ordinary heparin—are usually prescribed for some patients as a method of preventing clotting.  These substances are usually given for the chronic treatment of thrombosis, including deep vein thrombosis, after hip replacement surgery, following a heart attack, as well as in some cancer patients.  Examples of LMWHs include Lovenox, Fragmin, Sandoparin, Innohep and Fraxiparin.  Clinical studies have revealed a 1% to 4% rate of major bleeding episodes in those patients who have been prescribed LMWH.  In certain patient populations the overall bleeding rate has been shown to rise as high as 20%.  The group most at risk of experiencing these rates of bleeding may include patients with uncontrolled hypertension, impaired renal function, cancer, bacterial endocarditis, or congenital or acquired bleeding disorders.  Also at risk of such major bleeding episodes are those patients who have experienced active ulceration, angiodysplastic gastrointestinal disease, or hemorrhagic stroke, or those who have recently undergone brain, spinal or ophthalmological surgery.  The bleeding can take place at any location on one’s body either during or after therapy.

At the present time, a substance known as protamine sulfate is the only agent in the world that is commercially available to reverse the blood-thinning of heparin.  Protamine binds to the heparin and, in doing so, forms a stable ion pair that does not possess anticoagulant properties.  The complex of heparin and protamine is then removed and broken down by the patient’s body.

Yet there may be complications and problems related to the use of protamine.  Despite the fact that it is currently the only clinical reversing agent that is available for use with heparin, protamine exhibits a series of limitations and potentially serious toxicities.  To begin with, as ironic as it may sound, protamine itself possesses the properties of an anticoagulant, and it can affect both clot formation and a related process known as platelet aggregation in human blood.  If protamine is administered in higher doses than what is needed, it may actually exacerbate bleeding in the patient.  As a result, the dose may need to be carefully adjusted by the caregiver via multiple doses.  This means that when it is used in a clinical setting, protamine may have to be given in several injections over a period of time.  Blood clotting tests may need to be performed between each of the dosings, all in an effort to reach but not to exceed the dose required to restore the blood’s clotting capabilities.  This can make protamine complicated and expensive to administer.  

Yet this is just the first of protamine’s drawbacks.  Protamine, it turns out, is derived from an animal protein—namely, salmon sperm—and as a result it may set off allergic or immune system reactions, potentially of life-threatening intensity, in some patients.  These allergic reactions are not common, but they are generally unpredictable, and may in fact be fatal.  In addition, the creation of a substance that is derived from a natural source such as fish may be a complicated affair, and it can raise problems with quality control over the raw material.  Heparin itself is manufactured using animal parts as the raw material.  In the case of heparin, most of this raw material comes from China.  In recent years, there have been significant problems with adulterated raw material and counterfeiting, with dangerous additives being mixed into the raw material.  This resulted in reports of significant adverse reactions as well as patient deaths.  In general, a medical manufacturer could have much better control over the quality of the raw materials and ingredients incorporated within a fully synthetic medical product.     

Additionally, certain groups of patients, such as diabetics who are receiving zinc insulin (which is made from protamine), or males who have had vasectomies (because they may have developed pre-existing antibodies that counter the action of sperm-derived products), may also be at greater risk of experiencing an immune reaction to protamine and thus experience difficulties when it is administered.  

Another difficulty with the use of protamine is rooted in the fact that it has poor fibrokinetics, meaning that it negatively affects both clot formation and platelet aggregation in human blood, and therefore can interfere with normal clot formation.  Clots that are formed after the administration of protamine are considered to be structurally impaired, and in fact lack the integrity exhibited by normal clots, meaning that such clots may break up and leak.  Thus, there is a very real risk that bleeding may recur after the administration of protamine.  This is often observed in the form of post-operative bleeding that occurs after many procedures, which therefore must be monitored to ensure that patients do not experience dangerous blood loss.  In serious cases of post-operative bleeding, a second operation may be necessary in order to find and to stop the source of the bleeding.  This also adds a potentially significant cost to the post-operative care of patients.   

Finally, protamine’s activity against LMWH suffers from a lack of consistency and it is not approved for this specific use.  While it is sometimes used as a rescue agent of last resort in such cases, protamine is not generally clinically effective at reversing the risk of bleeding that is associated with the use of LMWH.  Indeed, no clinically effective antidote for the LMWHs has ever been identified.  Current treatments for the bleeding that is associated with the use of LMWH generally consist of transfusion, hospitalization, and surgery, but of course these measures can be expensive and their effectiveness can be inconsistent.         

Given this situation, there is clearly a need for a new drug that is both easier and safer to use than protamine for the purpose of reversing the effects of heparin.  There is also a significant need for a reversing agent for LMWH, as none exists at the current time.

One Company’s Alternative Approach

The search for viable alternatives to protamine is clearly an important one, but to date it has generated few successes.  One prominent new player in the quest is PolyMedix (OTC:PYMX), based in Radnor, Pennsylvania.  The company has developed novel small molecules, which it has dubbed “heptagonists,” that act to reverse the anticoagulant properties of both heparin and its low molecular weight variant.  They are designed to be administered whenever bleeding that results from the use of blood thinners is diagnosed.  

The company has shown that its heptagonist compounds, including the lead compound known as PMX-60056, exhibits a number of positive characteristics that may make it useful for this purpose.  For example, PMX-60056 has been shown to act rapidly, within minutes of dosing; it is fully synthetic, and thus should not trigger allergic reactions in patients to whom they are given; and it should be able to be simply dosed, which should allow healthcare providers to avoid the often complicated dosing procedures required with the use of protamine.  The heptagonists demonstrate more normal clot formation compared with protamine.  Finally, PMX-60056 has been shown effective in reversing the action of LMWH.   

PolyMedix has completed four clinical studies with PMX-60056, including three studies that were designed to assess efficacy.  In October 2009, the company successfully completed the first Phase 1B/2 pilot efficacy study with PMX-60056.  In all subjects receiving the drug, there was a rapid and complete reversal of the anticoagulant action of  heparin.

In June 2010, PolyMedix completed a second Phase 1B/2 clinical study, this one with the aim of testing PMX-60056’s ability to reverse LMWH.  In all subjects receiving the drug, there was a rapid reduction in anti-Xa activity, a measurement of LMWH action, and a rapid and complete reversal of the anticoagulant action of tinzaparin, a specific form of LMWH.   

More recently, in August 2010, the company completed a Phase 1B/2 dose-ranging clinical study.  This was designed as an open label, dose titration study to evaluate PMX-60056 in the reversal of surgical levels of heparin, and also allowing for the possibility of re-anticoagulation.  The results indicated that PMX-60056 met the study endpoint regarding the reversal of varying heparin levels, with an excellent correlation between the amount of PMX-60056 needed to reverse a given amount of heparin.  This study also showed that it was possible to give a second administration of heparin and re-anticoagulate the subjects, and then re-reverse with PMX-60056.  This can be important because in some surgical cases, re-operation may be required, which can be complicated if re-heparinization is needed after receiving protamine.

The company hopes that its PMX-60056 will be able to address the drawbacks associated with the use of protamine that have been outlined above, and perhaps even more importantly, it may represent the first viable inhibitor of anticoagulation appropriate for use to reverse the action of LMWHs.  PolyMedix hopes to start a larger Phase 2 clinical study in reversing heparin in coronary bypass patients by the end of this year.        

PolyMedix’s efforts would not represent the first attempt of their kind.  The most significant previous attempt to create a marketable anticoagulant reversal agent took place about two decades ago, when Biomarin developed a drug known as heparinase.  Intended to cleave heparin, it actually resulted in exacerbating bleeding in some patients to which it was given.  The results of an international clinical trial led by Duke University researchers in 2005 confirmed that heparinase is not a suitable replacement for protamine, and the compound was discontinued from development.

A search of the relevant research literature reveals some additional attempts to identify alternatives to protamine, but little in the way of concerted efforts to develop them for market.  For example, a 1995 study by Dehmer et al. assessed the reversal of heparin’s effects by a compound known as recombinant platelet factor 4 (rPF4).  After evaluating the safety and effectiveness of intravenous rPF4 to neutralize heparin anticoagulation, the authors concluded that, given in sufficient amounts, it could completely and rapidly reverse the anticoagulant effects of heparin.  However, a study conducted the same year by Kurrek et al. concluded that rPF4 produces acute pulmonary hypertension in lambs.  The following year, Kikura et al. examined the effectiveness of three substances—methylene blue, hexadimethrine, and vancomycin—to neutralize heparin.  They concluded that hexadimethrine could reverse heparin-induced anticoagulation after cardiopulmonary bypass as well as protamine could, while methylene blue and vancomycin did not neutralize heparin in vitro.

Any challenge as complex as the creation of a superior alternative to protamine will not be easy to overcome.  However, given the widespread use of heparin and LMWH by healthcare providers today, and given the need for a safer and more widely applicable solution than protamine to the problem of anticoagulant reversal, it is to be expected that exciting advances lie ahead.


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