Contaminant in the Recalled Unfractionated Heparin Preparations: Where is the Problem?

Debra A. Hoppensteadt, Ph.D., Jawed Fareed, Ph,D, Rakesh Wahi, M.D., Cafer Adiguzel, M.D., Rodger L. Bick, M.D., Ph.D.

March 10, 2008/ 4:38 p.m. (EST): In a recently held press conference, the USFDA briefed the press that the potential contaminant in the recalled Baxter product is a heparin-like substance.  The USFDA commented that utilizing high tech methods, heparin-like molecules have been identified. No specifics regarding these contaminants were given.  The Baxter personnel did not agree with this interpretation.  The manufacturing process of heparin is such that other heparin-like contaminants such as the dermatan sulfate, heparin sulfate, and chondroitin sulfate are removed effectively.  These represent the main contaminants in heparin. 

However, the usual contaminants are unlikely to produce any allergic effects and produce the reported adverse reactions.  Because of the carbohydrate nature of the contaminants identified in the special method known as the nuclear magnetic resonance technique (NMR), it is quite disturbing to note that such a contaminant may have been added to the recalled heparin or heparin like materials are also isolated from the shellfish, marine plants, bones, skin of mammalian origin.  There are various proteins contaminants that can be expected along with the carbohydrates.  Thus, it is likely that besides the carbohydrate contaminants, some unknown protein contaminant may also be present in these products. 

The statement that a heparin-like material was identified using high tech methods is ambiguous and misleading.  Such statements should be specific and clear regarding the nature of the contaminant detected. It is very unlikely that such contaminants as dermatan sulfate, heparan sulfate or chondroitin sulfate, which are the most likely contaminants in heparin, are responsible for the reported complex adverse reactions and/or death in patients treated with heparin. It is quite conceivable that excessive amounts of degradation products and chemically modified sugars maybe present resulting in unusual signals in some of the methods used to analyze these products.

Glucosamine sulfate is a representative building block of heparin and related agents.  It is widely present as a structural component of the products isolated from mammalian tissue and shellfish.  Based on the limited information, and the reported adverse reactions, it is likely that the possibility of bacterial contaminants such as endotoxin and other toxic bacterial products may also contribute to the observed adverse effects. It is prudent to test the recalled products for these contaminants.  The inspection by the US
FDA has already identified various deficiencies in the plant responsible for producing and processing  the related heparins.  Heparin is extracted from porcine mucosa.  The proper processing of mucosal including the initial cleaning and extraction represent important steps in the manufacturing process of heparin.  It is at this stage trace amounts of bacterial cellular products, toxins and other undesirable contaminants can be incorporated with the products.  The pharmacopeial methods used for the potency of heparin such as the sheep blood recalcification time and pyrogen testing of the finalized products are not capable of detecting these contaminants.  It is important that a comprehensive testing of these products for the potential trace protein contaminants is also considered.

The USFDA has stated that the recalled batches contain somewhere from 5-20% heparin-like contaminants.  It is highly unlikely that the standard manufacturing process may result in such a high degree of contaminants.  The most likely cause of these may be mixing of batches or intentional mixing of heparin like substances.  This may be an oversight issue.

While techniques such as capillary electrophoresis and NMR are useful in identifying carbohydrate impurities, these methods do not detect trace protein contaminants, which maybe helpful in identifying the source of the contamination such as marine allergens. This is a reflection of the complexity of the heparin structure and the need for methods to assure the quality of the product. There are no controls at this time except for the pharmacopoieal assay specifications, which are stated, in biologic units.  

We believe that the public statements from the FDA and Baxter are not clear and that supportive information should be provided. Both have the responsibility to provide clear information on this matter.  Moreover, there appears to be a difference of opinion on the origin and nature of contaminant between the regulatory bodies and the suppliers. Because of the magnitude of the severe adverse reactions, it is likely that multiple factors may be responsible for the reported adverse events and deaths related to the use of recalled heparins. Therefore, unless a definitive cause and effect is established, such statements are premature.

Bacterial contamination during the final fabrication of unfractionated heparin has also been reported. This issue may be more complex than what has been stated. Regardless, it has a major public health impact. It is not acceptable that such problems should arise from poor quality assurance at the bulk material supplier level and sub-standard practices at the fabrication sites. These should have been addressed. We have not had this problem previously and it’s only because of the increased demand for heparin to manufacture LMWHs that such problems are encountered.

Similar allergic reactions and two deaths have been reported from Germany recently, and as a result, the German regulatory agency has recalled the unfractionated heparin from RotexMedica. The source of RotexMedica heparin is also a Chinese supplier suggesting that the problem is related to the manufacturing of the heparin preparations. As a result, the European Community countries have cautioned responsible parties to monitor patients’ anticoagulated with heparin of imported origin. Therefore, this issue has become a global problem, which should be addressed at the World Health Organization level.

The USFDA’s statement that 5-20% of heparin like substances are found in the recalled
heparin only points out to the failure of current quality assurance methods in determining non-heparin contaminants in heparin preparations.  It doesn’t provide any information on the relevance of these contaminants to the observed adverse effects.  If the USFDA believes that these substances are responsible for the adverse effects than a clear approach to isolate these and test these agents for the potential adverse effects in animal models may be essential. 

Unfractionated heparin, used in the US and Europe, represents the most widely used anticoagulant for various indications, such as hemodialysis, apheresis and surgical procedures, and has been used for these indications for a long time without any problems.  Although isolated incidences of heparin allergy and adverse reactions have been reported, the frequency of recently reported reactions and death are alarming and represent a public health issue.  Heparin is a biologic product of complex nature and the likelihood of contaminants in substandard products may cause various adverse reactions.

The heparin currently available in the US and Europe is mostly extended from the raw material/finished products originating in China.  Recently, several reports have noted the substandard quality of imported heparin preparations.  Moreover, reports on the health of live stock imperative in drug and food products have also been published.  Recently, the Chinese swine population has suffered from blue ear syndrome.  The importance of animal health on the food and drug products cannot be ignored.

The suppliers of heparin, regulatory bodies, and pharmacopial organizations are primarily responsible to enforce proper quality assurance and oversight in assuring the quality of heparin, or other drugs which has been used for over half a century.  Simply stating that the recalled products contain 5-20% heparin like structures is misleading and irresponsible.  The ongoing problems with the use of heparin require a comprehensive investigation and may have additional implications on the production of all of the other heparin related drugs.  

Addendum: March 18, 2008; 5:18 p.m. (EST): In reference to Dr. Hoppensteadt’s editorial on the contaminants in heparin, preliminary studies on the Baxter’s heparin lots used in the hemodialysis unit of Loyola University Medical Center have revealed the presence of a high molecular weight contaminant in heparin which is not digestible by heparinase I. Additional studies on the digestion of this substance with chondroitinases suggest that this may be a modified form of chondroitin sulfate such as the hyper-sulfated form. Additional studies are needed to further characterize this substance. Since this contaminant is found in heparin’s used at Loyola where no adverse reactions were reported, it is unlikely that this contaminant is responsible for the observed adverse reactions. However, the delayed effect in terms of antibody production in response to this unique material cannot be ruled out.

Contaminated Heparin: An Update

Jawed Fareed, Ph.D, D.SC – Maywood, IL., USA.

Click here to view "Contaminated Heparin: An Update" slide set.

April 4, 2008; 11:10 p.m. (EST): The current issues related to Heparin have been addressed by both the scientific and clinical community in a stepwise fashion. This situation has resulted in implementing additional compliance regulations and oversight to assure the quality of Heparin and related drugs.  Regulatory bodies around the world have already taken initial steps to assure that the quality of Heparin meets the original specifications and is free of any contaminants, such as the reported Hyper sulphated Chondrotin sulphate. The proposed methods to analyse the active pharmaceutical ingredients (API) for the presence of non-heparin Glycosaminoglycans is the first step in assuring the quality of Heparin. With the advances in analytical methods, including the use of PCR technology, the presence of other biologic contaminants can also be readily checked.  As low molecular weight heaprins (LMWH) are manufactured using porcine mucosal heparin, source verification is also mandatory. The same methods can be used to check the LMWHs for potential contaminants. With a biologic and complex drug such as heparin, the possibility of contaminants and carry over substances can be expected. However, with modern technology, pure heparin preparations can be readily obtained.  Heparin has withstood the test of time and the current crisis will gradually fade away, making this irreplaceable drug available without concern.

In the event of a heparin shortage, alternate agents such as the parenteral antithrombin agents (e.g. argatroban and bivalirudin) are available for surgical and procedural anticoagulation. Other agents such as arixtra may not be useful for these indications because of the lack of anticoagulant activities.  Similarly, the newly developed synthetic oral antiXa and antiIIa agents are not useful for acute anticoagulation.  Replacing Heparin for acute anticoagulation may not be an easy task and will take some time.

Heparin has been a life saving anticoagulant for decades.  The low molecular weight heparins represent a refined use of heparin. The current issue related to the presence of the unusual contaminant is an unfortunate situation, which has stirred up a major controversy.  This may be partly due to an increased demand for this anticoagulant resulting in compromised production procedures and increased yield from the sources utilizing alternative approaches.  Unfortunately, this has resulted in major adverse reactions and deaths.  Regardless of this situation, if manufactured and quality assured properly, the drug would remain the anticoagulant of choice.  The current issues eventually will be resolved as these stem from non-compliance and deviation from standard procedures.  A more astringent oversight by regulatory bodies and suppliers of heparin will eventually resolve this issue. The attached slides are provided as a briefing on the ongoing issues with heparins and their resolutions.  These slides will be periodically updated to include additional information on the developments related to this issue. 

Do you have a question or comment regarding this article?  Submit a response to: comments@NATFonline.org

Proactive Thrombosis Prevention 2008

To help kick off DVT Awareness Month 2008, we held our third annual "Proactive Thrombosis Prevention" Harvard Medical School CME accredited community event at Brigham and Women’s Hospital on Saturday, March 1, 2008. This event, sponsored by the North American Thrombosis Forum (NATF), is a comprehensive multidisciplinary overview of current thrombosis prevention methods geared to physicians, nurses, physician assistants, pharmacists, hospitalists, and hospital administrators. In addition to health care professionals, patients and caregivers were encouraged to attend.

Overview of Venous Thromboembolism Epidemiology–Samuel Z. Goldhaber, MD

Pulmonary embolism (PE) and deep venous thrombosis (DVT) afflict millions of individuals worldwide and account for several hundred thousand deaths annually in the United States. Few health care providers realize that the case fatality rate for PE, approximately 15 percent, exceeds the mortality rate for acute myocardial infarction. During the past 5 years, a remarkable transition started in North America. The lay public began to become aware of the magnitude of disability from venous thromboembolism (VTE), which encompasses PE and DVT.

The same features of VTE that fascinate the public have kept clinical scientists spellbound by this illness. VTE is a common problem, yet often difficult to diagnose. It strikes a wide range of individuals, from teenagers to nonagenarians. Its onset is usually unpredictable, and the likelihood of recurrence after completing a time-limited course of anticoagulation remains uncertain. Though most individuals survive, VTE impairs quality of life by increasing susceptibility to chronic thromboembolic pulmonary hypertension and chronic venous insufficiency. It also exerts a psychological toll on patients who wonder whether they will suffer a recurrent event, whether it will affect their family members, and whether it will lower their quality of life as well as shorten their lifespan.

The incidence of VTE has also risen, primarily because of an increase in the diagnosis of DVT. The incidence is similar among men and women. VTE strikes immobilized hospitalized patients with comorbid disease. Less well appreciated are risk factors out-of-hospital: 1) obesity, 2) cigarette smoking, 3) age, 4) cancer (including liquid tumors), 5) long-haul air travel, and 6) “asymptomatic” DVT.

The previous uncertainty about the clinical relevance of asymptomatic proximal DVT no longer exists. Asymptomatic proximal leg DVT has a high associated mortality rate among patients hospitalized with medical illnesses. The 90-day mortality rate in hospitalized medical patients was 14% for those with asymptomatic proximal leg DVT at Day 21, compared with a 1.9% 90-day mortality rate for those with no DVT at Day 21. This finding underscores the appropriateness of targeting asymptomatic proximal leg DVT as an endpoint in clinical trials of thromboprophylaxis.

An especially problematic risk factor is obesity, which has become pandemic in the United States. Obesity doubles or triples the likelihood of VTE. As patients survive longer with cancer, the frequency of VTE is increasing, because cancer patients have twice the incidence of VTE as noncancer patients. This increased risk of VTE is present not only in adenocarcinomas of the pancreas, stomach, lung, esophagus, prostate, and colon, but also threatens patients with “liquid tumors” such as myeloproliferative disease, lymphoma, and leukemia. The VTE incidence is highest among patients initially diagnosed with metastatic disease. Less well known acquired risk factors include acute infection and chronic obstructive pulmonary disease.

The epidemiology of PE is also a women’s health issue. Pregnancy, hormonal contraception, and postmenopausal hormonal therapy each contribute to increased risk.

Perhaps the most frequently discussed acquired risk factor is longhaul air travel. The risk of fatal PE in this setting is less than 1 in 1,000,000. However, when death occurs, it is dramatic and especially tragic because the victim is often an otherwise healthy young person. It appears that among some individuals, there is activation of the coagulation system during air travel. The reason for hypercoagulability remains uncertain. However, the mechanism does not appear to be due to hypobaric hypoxia.

Hospitalized patients with medical illnesses such as pneumonia or congestive heart failure are at high risk of developing VTE. The stasis and immobilization associated with postoperative venous thrombosis may paradoxically increase after hospital discharge, because with short hospital lengths of stay, patients may be too weak and debilitated at home to ambulate after surgery. Vigilance is required to ensure that appropriate patients receive extended VTE prophylaxis at the time of hospital discharge.

The VTE cost burden is high. VTE is often a chronic illness, with a high recurrence rate. DVT and PE impair the quality of life. The DVT FREE Registry is improving our understanding of VTE epidemiology.

REFERENCES

1. Goldhaber SZ, Tapson VF: A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis. Am J Cardiol 93:259-262, 2004.
2. Stein PD, Kayali F, Olson RE: Estimated case fatality rate of pulmonary embolism, 1979 to 1998. Am J Cardiol 93:1197-1199, 2004.
3. Stein PD, Beemath A, Olson RE: Trends in the incidence of pulmonary embolism and deep vein thrombosis in hospitalized patients. Am J Cardiol 95:1525-1526, 2005.
4. Cushman M, Tsai AW, White RH, et al: Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 117:19-25, 2004.
5. Bova C, Marchiori A, Noto A, et al: Incidence of arterial cardiovascular events in patients with idiopathic venous thromboembolism: A retrospective cohort study. Thromb Haemost 96:132-136, 2006.
6. Vaitkus PT, Leizorovicz A, Cohen AT, et al: Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients. Thromb Haemost 93:76-79, 2005.
7. Stein PD, Beemath A, Olson RE: Obesity as a risk factor in venous thromboembolism. Am J Med 118:978-980, 2005.
8. Stein PD, Beemath A, Meyers FA, et al: Incidence of venous thromboembolism in patients hospitalized with cancer. Am J Med 119:60- 68, 2006.
9. Chew HK, Wun T, Harvey D, et al: Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 166:458-464, 2006.
10. Smeeth L, Cook C, Thomas S, et al: Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 367:1075-1079, 2006.
11. Tillie-Leblond I, Marquette CH, Perez T, et al: Pulmonary embolism in patients with unexplained exacerbation of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Intern Med 144:390-396, 2006.
12. David PS, Boatwright EA, Tozer BS, et al: Hormonal contraception update. Mayo Clin Proc 81:949-954, 2006.
13. Curb JD, Prentice RL, Bray PF, et al: Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med 166:772-780, 2006.
14. Parkin L, Bell ML, Herbison GP, et al: Air travel and fatal pulmonary embolism. Thromb Haemost 95:807-814, 2006.
15. Schreijer AJ, Cannegieter SC, Meijers JC, et al: Activation of coagulation system during air travel: a crossover study. Lancet 367:832-838, 2006.
16. Toff WD, Jones CI, Ford I, et al: Effect of hypobaric hypoxia, simulating conditions during long-haul air travel, on coagulation, fibrinolysis, platelet function, and endothelial activation. JAMA 295:2251-2261, 2006.
17. Heit JA: The epidemiology of venous thromboembolism in the community: implications for prevention and management. J Thromb Thrombolysis 21:23-29, 2006.

Program Presentations: Saturday, March 1, 2008

1.	Stroke Update Farzaneh A. Sorond, MD, PhD
2.	Coronary Stent Thrombosis Frederic S. Resnic, MD, MSc
3.	Peripheral Arterial Disease Update Marie Gerhard-Herman, MD
4.	PE Diagnosis Paul D. Stein, MD
5.	Heparin-Induced Thrombocytopenia Education Programs Steven Baroletti, PharmD, MBA
6.	Generic vs. Brand Name Drugs Jawed Fareed, PhD
7.	Electronic Alerts to Prevent DVT Karen Fiumara, PharmD
8.	Novel Anticoagulants John Fanikos, RPh, MBA
9.	Anticoagulation Update Samuel Z. Goldhaber, MD
10.	Patient Education and Patient Compliance Rita M. Morrison, RN, BSN and Ruth B. Morrison, RN, BSN, CVN
11.	Point-of-Care INR Testing Jack E. Ansell, MD
12.	Patient Advocacy Kelly Clark, NATF Patient Advocate

 

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