Ann Thorac Surg 2001;71:270-277
© 2001 The Society of Thoracic Surgeons
Original article: cardiovascular
Safety and efficacy of a heparin removal device: a prospective randomized preclinical outcomes study
Joseph B. Zwischenberger, MDa,c,
Weike Tao, MDb,
Donald J. Deyo, DVMb,
Roger A. Vertrees, PhDc,
Scott K. Alpard, MDa,
Gerald Shulman, MDc
a Department of Surgery, University of Texas Medical Branch, Galveston, Texas, USA
b Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA
c Department of Medicine, University of Texas Medical Branch, Galveston, Texas, USA
Address reprint requests to Dr Zwischenberger, Division of Cardiothoracic Surgery, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555-0528
e-mail: jzwische{at}utmb.edu
Presented at the Forty-Sixth Annual Meeting of the Southern Thoracic Surgical Association, San Juan, Puerto Rico, Nov 4–6, 1999.
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Abstract
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Background. Systemic protamine sulfate for heparin reversal after cardiopulmonary bypass (CPB) is associated with uncommon, but life-threatening adverse reactions.
Methods. In a prospective randomized 3-day outcomes study, a heparin removal device (HRD) group (n = 12; 60-, 80-, 100-kg subgroups) was compared with a matched systemic Protamine group (Protamine; n = 6) for safety and efficacy using an adult swine model of CPB (60 minutes, 28°C).
Results. HRD run time was 25 to 38 minutes depending on weight without complications. After HRD, heparin concentration decreased from 4.77 ± 0.17 to 0.45 ± 0.06 U/mL (activated clotting time [ACT] 776 ± 83 to 180 ± 12 seconds), and in Protamine, 3.94 ± 0.63 to 0.13 ± 0.02 U/mL (ACT 694 ± 132 to 101 ± 5 seconds) (p = 0.01 between groups, but no significant differences 60 minutes later). No significant difference between HRD and Protamine to 72 hours was seen in plasma-free hemoglobin C3a, heparin concentration, thromboelastogram index, platelet count, activated partial thromboplastin time, anti-thrombin III, fibrinogen, ACT, and tissue histology.
Conclusions. In a prospective randomized outcomes study, HRD achieved predictable reversal of systemic heparinization after CPB with no difference in safety or outcomes compared with protamine.
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Introduction
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Severe adverse reactions including pulmonary hypertension, systemic hypotension, and anaphylactic shock have been reported (approximately 10.7% incidence) with the use of protamine sulfate for systemic heparin reversal [1–4]. An alternative, to avoid exposure to protamine, is heparin removal by affinity adsorption using an extracorporeal circuit [5]. Our previous studies have shown the heparin clearance profile with this heparin removal device (HRD; Research Medical, Midvale, UT) after cardiopulmonary bypass (CPB) follows a first-order exponential depletion curve [6–9]. Compassionate use of the HRD has also been reported by our group as an alternative in patients with documented severe adverse reactions to protamine [10, 11].
The HRD consists of a veno-venous circuit utilizing a dual-lumen cannula inserted via the existing right atriotomy after CPB [8]. Incorporated within the circuit is a pheresis chamber where plasma separation occurs. In this chamber, the plasma fraction that contains heparin is exposed to a poly-cation (poly-L-lysine). Heparin becomes tightly bound and therefore is removed from the plasma, returning to the blood stream by affinity adsorption.
Before multicenter clinical trials, the efficacy of the HRD for removal of heparin must be characterized under circumstances of different body weight and plasma volume. Because the HRD involves an extracorporeal circuit and plasma separation, immediate and long-term effects on cellular blood components, complement activation, and coagulation profiles are also necessary. To address these issues, we designed a prospective randomized protamine-controlled 3-day outcomes study using our adult swine model of CPB (60 minutes, 28°C). We compared the HRD with systemic protamine as follows: 1) heparin clearance in different weight ranges (60-, 80-, 100-kg subgroups); 2) directly measured and global profiles of blood coagulation, including use of the heparinase thromboelastogram (TEG); and 3) safety by determining complement activation and organ histology.
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Material and methods
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The experimental protocol was approved by the Institutional Animal Care and Use Committee of The University of Texas Medical Branch (Galveston, Texas), and animals received humane care in compliance with published guidelines. The study was performed using female Yorkshire swine selected for weight in groups of 60, 80, and 100 kg to match humans for size. The animals were randomized to receive the HRD or systemic protamine after weaning from CPB. Twelve animals were assigned to the HRD group, with 4 animals from each of the weight subgroups (60, 80, and 100 kg). Six animals were assigned to the Protamine group, with 2 per weight subgroup. Randomizing animals into the HRD or Protamine group with subgroups by body weight allows comparison of collective safety data with direct comparison of performance data from different body weights and plasma volume, without excessive use of animals.
Animals were sedated with 1 mg/kg tiletamine, 1 mg/kg zolazepam, 1 mg/kg xylazine, and 1 mL/kg ketamine. Endotracheal intubation was followed with inhalation anesthesia using 1.0% to 1.5% halothane. After routine skin preparation, median sternotomy was performed and the right internal mammary artery and vein were exposed for arterial pressure line and Swan-Ganz catheter placement. Porcine intestinal heparin (ESI, Cherry Hill, NJ) was given every 3 minutes in four separate doses in order to construct a heparin dose-response curve (35, 50, 95, and 120 U/kg, respectively), for a total dose of 300 U/kg to activated clotting time (ACT) >450 seconds for the duration of CPB. An additional 5,000 U of heparin was added to the extracorporeal circuit prime solution consisting of 1,000 mL balanced electrolyte fluid (Plasma-Lyte A) and 500 mL of 6% hetastarch. The ascending aorta and right atrium were cannulated with an aortic cannula (20 to 24 French) and a two-stage venous cannula (32 to 36 French), respectively. Hypothermic (28°C), non-cross-clamped CPB was initiated using a membrane oxygenator with an integral heat exchanger (Plexus, Irvine, CA) and a roller pump (5000; Sarns, Ann Arbor, MI). CPB flow was maintained at 100 mL/kg/min during normothermia and reduced to 70 mL/kg/min during hypothermia (28°C) to keep the mixed venous oxygen saturation (SvO2) greater than 70%. Standard perfusion parameters of SvO2, mean arterial pressure, and central venous pressure were continuously monitored, and plasma-free hemoglobin (FHb; tetramethylbenzidine colorimetric assay; Sigma, St. Louis, MO) was measured at baseline, before, and after the HRD or protamine. After 60 minutes of hypothermic CPB, all animals were rewarmed to 36°C then weaned from CPB. Animals were then randomized to receive the HRD or protamine to reverse systemic heparinization.
In the HRD group, a dual-lumen cannula was inserted via the existing right atriotomy with the drainage port positioned into the inferior vena cava and reinfusion port at the level of the right atrium oriented to face the tricuspid valve in order to minimize blood flow recirculation between the uptake and reinfusion ports of the HRD cannula [8]. The HRD circuit was primed with crystalloid solution (0.9% NaCl) that was purged before connection of the HRD circuit to the reinfusion cannula; therefore, no crystalloid was introduced into the systemic circulation. HRD blood flow was controlled by a roller pump (Travenol, Deerfield, IL) and maintained at a flow of 1400 mL/min. Actual HRD blood flow was measured by a real-time ultrasonic flow probe (Model H6X; Transonic Systems, Ithaca, NY) and displayed by a flowmeter (Model HT 109; Transonic Systems). Total HRD run time was predetermined by a mathematical model of first-order exponential depletion [6] to achieve a targeted total body heparin removal of 90%. In the Protamine group, 1 mg of protamine for every 100 U of heparin was infused over 15 minutes.
Heart rate (HR), mean arterial pressure (MAP), pulmonary arterial pressure (PAP), central venous pressure (CVP), cardiac output (CO), arterial blood gases (ABG), activated complement C3a (Western blot chemiluminescence assay), and hematocrits were measured. Blood coagulation variables including celite ACT (Hemochron 400; International Technidyne, Edison, NJ), activated partial thromboplastin time (APTT; MDA 180, photometric analysis; Organon Teknika, Durham, NC), anti-thrombin III (ATIII; functional chromogenic assay, MDA Antithrombin III; Organon Teknika), fibrinogen (modified fibrinogen II Clauss method, MDA Fibrinquik; Organon Teknika), platelet count (HST 302, SE 9500; Sysmex, Long Grove, IL), and heparin concentration (anti-Xa chromogenic assay, HEPRN; Dade International, Newark, DE) were obtained before, during, and after the use of the HRD or before and after protamine administration.
TEG (Hemoscope, Chicago, IL) was used to assess the global blood coagulation pattern. The TEG was used at timed intervals before, during, and after CPB to measure initiation of coagulation (R time), clot stability (K time), clot formation rate (
-angle), and clot elasticity and fibrin polymerization (maximum amplitude [MA]). The TEG index identifies the coagulation state by discriminant analysis with the following equation:
Because TEG is affected by heparin, and heparin loading during CPB would generate a nondiagnostic tracing to mask the possible effect of the HRD on blood coagulation, heparinase TEG was used for the study. Citrated blood samples were collected for TEG analysis. The TEG machine was calibrated and tested according to manufacturer’s instructions. All TEG data were interpreted by a hematologist (G.S.) blinded as to study group.
A temporary pericardial drainage tube was connected to -15 cm H2O suction during chest closure (typically lasting 25 to 30 minutes) and the drainage amount was recorded. If the pericardial drainage was less than 50 mL during chest closure, the temporary chest tube was removed along with all other monitoring lines before transporting animals to the recovery area. Animals were allowed to ambulate and had free access to food and water. All animals were constantly observed postoperatively and examined every 8 hours by a veterinary anesthesiologist (D.J.D.) for signs of major complications. Intramuscular buprenorphine (0.3 mg) was given every 8 hours for pain control, and routine prophylactic cefazolin (1.0 g) was given intramuscularly every 8 hours. Postoperative blood samples were taken through the ear vein. Seventy-two hours after surgery, femoral and pulmonary arterial lines were inserted for final hemodynamics and blood samples under halothane anesthesia. Animals were euthanized with saturated potassium chloride. The cardiac chambers, valves, and the pulmonary arterial distribution were examined at necropsy for clot formation, and tissue specimens of the heart, lungs, liver, kidney, and cerebrum were obtained for histologic evaluation by a pathologist blinded as to study group.
Data are expressed as mean ± standard deviation and were analyzed with SigmaStat (Jandel Scientific, San Rafael, CA). Variables were compared data versus baseline using one-way analysis of variance (ANOVA), with time treated as repeated measures, and data between groups using Student’s t test.
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Results
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All animals survived the 72-hour experiment. They were able to ambulate 4 to 6 hours after surgery, and there were no clinical signs of major complications, including the cardiovascular, respiratory, gastrointestinal, and central nervous systems. Specifically, there were no postoperative bleeding complications in either group. Central venous pressure was found to be significantly elevated on postoperative day 3 in both groups, but there were no signs of pericardial tamponade, and all other hemodynamic variables were within physiologic range. The average body weight in the HRD group was 79.2 ± 4.8 kg, with subgroups weighing 60.3 ± 1.9 (60 kg), 78.8 ± 2.2 (80 kg), and 98.5 ± 2.4 kg (100 kg). Similarly, the average body weight in the Protamine group was 79.3 ± 6.8 kg, with subgroups weighing 62.5 ± 0.5 (60 kg), 76.5 ± 0.5 (80 kg), and 99.0 ± 4.0 kg (100 kg), without any statistical differences between the HRD and the Protamine groups or subgroups. Use of HRD required an additional 45 to 60 minutes after CPB for cannulation, setup, HRD run-time, and decannulation. Protamine, however, required only 15 minutes for infusion after CPB. There were no statistically significant changes in hemodynamics (compared with baseline) associated with the use of the HRD or protamine, including HR, MAP, PAP, CVP, or CO. In the HRD group, arterial-to-alveolar O2 pressure ratio (a/A ratio) was significantly lower than baseline, and was significantly lower than protamine after the HRD run. Hemodilution was similar in both groups as indicated by the hematocrit. FHb showed typical changes related to CPB and hemodilution, and was significantly lower in the HRD group at the end of the HRD run, which may have been due to nonspecific binding of hemoglobin to the poly-L-lysine sorbent.
In the HRD group, the mean HRD run time targeted to remove 90% plasma heparin was 24.5 ± 0.6, 31.8 ± 0.8, and 38.0 ± 0.7 minutes for the 60-, 80-, and 100-kg weight subgroups, respectively. No HRD adverse events, including broken fibers or tubing rupture, were noted. In the Protamine group, the full dose of protamine was able to be given intravenously over 15 minutes in all animals without adverse hemodynamic reactions. Heparin concentration immediately after CPB was 4.77 ± 0.17 U/mL (ACT 776 ± 83 seconds) in the HRD group and 3.94 ± 0.63 U/mL (694 ± 132 seconds) in the Protamine group (p = NS). Immediately after the HRD run, the heparin concentration had decreased to 0.45 ± 0.06 U/mL (ACT 180 ± 12 seconds) in the HRD group and 0.13 ± 0.02 U/mL (ACT 101 ± 5 seconds) in the Protamine group (p = 0.01); however, no significant differences were present 60 minutes later. Because the HRD processes heparin at a constant rate and the heparin load is body weight dependent, the heparin concentration and ACT are also stratified by weight subgroups (Fig 1). Plasma heparin concentration (Fig 2) closely followed the clearance profile predicted by our mathematical model of first-order exponential depletion [8] (r2 = 0.94 to 0.98 for all weight ranges) (60 kg, r2 = 0.98; 80 kg, r2 = 0.97; 100 kg, r2 = 0.94).
APTT returned to baseline levels in both groups. ATIII consumption pattern was not significantly different between groups (Fig 3). Fibrinogen levels remained unchanged during CPB, and rebounded postoperatively in both groups. Likewise, platelet count was similar in both groups (Fig 4).
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Fig 3. ATIII consumption pattern was not statistically different between groups throughout the study ( p = 0.01 vs baseline). (POD = postoperative day.)
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Fig 4. Platelet count was similar in both groups during CPB, and remained above baseline through postoperative day 3 (*p = 0.05 between groups; p = 0.01 vs baseline). (POD = postoperative day.)
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There was no difference in TEG variables or index (Fig 5) between the two groups. There was also no significant difference in activated C3 (R time, K time, -angle, MA, LY60) percentage between the two groups (Fig 6).
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Fig 5. TEG index was not significantly different between the HRD and Protamine groups throughout the study. (POD = postoperative day.)
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Fig 6. Percent activated C3 was not significantly different between the HRD and Protamine groups throughout the study. (POD = postoperative day.)
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At necropsy, thin blood clots were noted with the pericardium. There were no clots in the right atrium, right ventricle, or pulmonary artery in either group. There was no thromboembolism, bleeding, necrosis, or other pathologic findings in specimens of the brain, liver, kidney, heart, lungs, and intestines upon necropsy. The primary histopathology in both the HRD group and the Protamine group is related to the sequelae of CPB and intubation with recovery (Table 1). Extensive organizing pericarditis with overlying fibrinous pericarditis is seen in all cases from both groups. The depth of organization was deep, so that in some tangential sections, the replacement of myocytes with macrophages appeared to be in the myocardial wall. In 1 animal in the HRD group, a small necrotic area was seen on the endocardial surface, probably catheter-induced injury. Several animals in the HRD group showed small foci (< 1 mm) of myocyte necrosis and calcification that cannot be explained by the above mechanism. Pulmonary lymphoid hyperplasia surrounding bronchi was commonly seen in both groups, as was occasional mucus plugging of bronchi. Finally, minute foci (none larger than 1 mm) of either adrenal or hepatic subcapsular hematoma were seen in 4 animals in the HRD group, but none in the Protamine group.
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Comment
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To avoid severe adverse reactions, including fatal anaphylaxis, to protamine, several alternatives have been proposed. Yang and associates reported heparin "removal" using extracorporeal blood circulation through hollow fibers that incorporated immobilized protamine [12]. The efficacy of this technique was limited by blood flow and available binding sites. Most importantly, this technique retains protamine and/or protamine-heparin complexes still in the blood path. Contact between blood and these complexes has been shown to result in tight bindings to platelets and neutrophils, inhibition of platelet phospholipase A2 release [13], and generation of free radicals [14]. Another alternative, a heparinase-immobilized bio-reactor [15], was inadequate. At a device flow of 120 mL/minute, heparin concentration never decreased to below 4 U/min from the baseline of 5 to 6 U/mL over 60 minutes. Recombinant platelet factor 4 (rPF4), a polypeptide that has a high affinity for heparin, has been used to neutralize heparin in CPB blood aliquots [16, 17], during experimental CPB [18], after cardiac catheterization [19], and after CPB [20]. Platelet factor 4 is derived from platelet granules and may possess other biologic properties. During evaluation of rPF4 after CPB in baboons [18], complement activation was demonstrated. Application of rPF4 after cardiac catheterization [19] and CPB [20] in small series of humans reported no serious side effects. To assess the incidence and severity of complement activation and antibody formation from rPF4 will require larger scale clinical trials [18]. Hexadimethrine, another heparin antagonist, has also been proposed to have a wider therapeutic range than protamine without adversely affecting the activated clotting time [20].
The HRD uses poly-L-lysine to directly adsorb heparin from the plasma in an extracorporeal circuit [5]. This prospective, randomized, protamine-controlled, 3-day outcomes study of HRD safety and efficacy indicates the HRD is capable of predictable heparin removal in adult human-sized animals (pigs) after CPB, returning heparin concentration to near baseline levels after a targeted 90% heparin removal without exposure to systemic protamine with no difference in safety or outcomes. This study was unique in comparing animals of clinically comparable size and blood volume for heparin clearance, detailed coagulation profiles, compliment activation, adverse events, and necropsy over a 3-day study period. These data build upon our previous experimental [6–9] and initial clinical [10, 11] studies confirming the efficacy of the HRD for reversal of systemic anticoagulation after CPB. In this study, heparin concentration during the HRD run closely followed our mathematical model predicting first-order exponential depletion [6].
Protamine may cause severe adverse reactions after CPB through a variety of mechanisms, particularly complement activation [21, 22], mediated via the classic pathway initiated by the protamine-heparin complex [23]. Complement activation via the alternative pathway may occur during exposure to biomaterial surfaces possessing hydroxyl and primary amines, such as the CPB and HRD circuit components. Complement activation was present in both HRD and Protamine groups during CPB in a pattern typical of CPB [24, 25], but there was no additional complement activation associated with the HRD or protamine. Likewise, the HRD did not cause hemodynamic instability or blood cell damage in either the HRD or the Protamine group in this or previous studies [6–11].
Heparinase TEG was used to determine a detailed coagulation profile associated with the HRD. TEG allows measurement of clot formation rate and clot strength, and gives point-of-care testing for evaluating viscoelastic properties of whole blood during the perioperative period [26–28]. With the TEG, hemostatic function of a single blood sample may be assessed, documenting the interaction of platelets with the protein coagulation cascade from initial platelet-fibrin interaction, through platelet aggregation, clot strengthening, and fibrin cross-linkage to eventual clot lysis. Information on clotting factor activity, platelet functional activity, and fibrinogen function is available within 15 to 20 minutes from the time of test onset. Heparinase removes the effect of heparin in the blood to allow analysis of changes in coagulation, fibrinolysis, platelet count, and platelet function. In theory, the positively charged PLL could remove other plasma proteins, including blood coagulation factors. Because assays for swine coagulation factors are not available, analysis of overall clot production and performance is essential. Our TEG data indicate the HRD is not associated with significant changes in clotting properties, implying the HRD does not alter or damage blood coagulation factors and platelet functions.
Organ necropsy and tissue histology of animals in the HRD group did not reveal end-organ damage or thromboembolism in animals receiving the HRD. Most histopathology findings listed in Table 1 are the result of cannulation and CPB, or intubation and recovery, not of the HRD per se. The lack of emboli may be due to the fact that only 26% of the total HRD blood flow is separated into the adsorption chamber as plasma [6]. Therefore, blood returning to the animals will still be a mixture of nonseparated plasma containing heparin and separated heparin-depleted plasma. Thus, blood in the returning tubing will always contain some heparin that will inhibit clot formation.
The targeted heparin removal by the HRD of 90% was chosen as a compromise to balance between the level of heparin removal and HRD run time. The first-order exponential heparin depletion profile [6] of the HRD indicates that heparin removal beyond 90% would take considerably longer time with the diminishing benefits described by an asymptotic curve. Despite the ability of the HRD to remove heparin, the time to achieve the targeted heparin clearance is blood volume dependent and varies from 25 minutes (60 kg) to 38 minutes (100 kg). With protamine, blood coagulation variables return to normal as soon as the full-prescribed dose of protamine has been administered and circulated. The HRD is a partial extracorporeal blood circulation system (1,400 mL/min, or approximately 25% of the cardiac output), with 26% of the HRD blood flow separated into the plasma adsorption chamber. Heparin-depleted blood reinfused into the right atrium continuously mixes with the systemic circulation containing residual heparin. Therefore, HRD clearance is characterized by a first-order exponential depletion profile.
Use of the HRD will prolong the operation by 45 to 60 minutes (including setup, cannula insertion, HRD runtime, and decannulation) and will be certainly more expensive than protamine. The purpose of developing the HRD, however, was to avoid life-threatening reactions to protamine. In patients with known protamine hypersensitivity, the time to achieve 90% heparin removal by metabolism alone would have been approximately 3.33 half-lives or 5 hours, with the half-life of heparin being 90 minutes [7]. Based on our collective experience, we feel if HRD was commercially available, all patients with known severe protamine reactions or anaphylaxis to an initial infusion of protamine should receive heparin removal with HRD.
In conclusion, the HRD is capable of predictably achieving reversal of systemic heparinization in an adult swine model of hypothermic CPB. The time to achieve 90% heparin removal is weight dependent and ranges from 25 minutes (60 kg) to 38 minutes (90 kg). The HRD does not cause additional cell damage or complement activation compared with protamine and no hemodynamic instability or thromboembolic events. We recommend the HRD receive continue development as a clinical alternative to protamine.
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Acknowledgments
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Supported in part by Research Medical, Inc.
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Discussion
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DR EDWARD R. MUNNELL (Oklahoma City, OK): I enjoyed this paper very much. I do have one pragmatic question. From the slides, the HRD versus the protamine will add 1% to outcome. I am wondering what this adds to the cost of the procedures.
DR ZWISCHENBERGER: I think that is an excellent question; in addition, do not forget the time required. I certainly would never advocate the HRD for routine use; however, there is a significant portion of the population in which you can identify a severe or a previously known anaphylactic reaction to protamine. I do not know the cost because currently the device is a prototype. The additional time in surgery was 25 to 38 minutes for the run. When you add the setup time, putting the circuit up on the field, and inserting the cannula, the use of the HRD adds about an hour to the procedure. I would never advocate adding an hour for routine use during cardiopulmonary bypass. But, in patients with a known previous anaphylactic reaction, the HRD can be life saving. As we were doing the feasibility study on the HRD, I started receiving calls from all over the world and, of course, I had to fend them off because the HRD is just in prototype form. There is a significant subgroup of patients in Alaska and Scandinavia where workers in factories that package salmon have been exposed to the antigens of salmon and are extremely reactive to protamine. Therefore, there are subgroups in which this device would clearly have an application.
DR JOHN W. HAMMON (Winston-Salem, NC): That was a very nice presentation, Dr Zwischenberger, and I think this is clearly the kind of work that needs to be done at this point.
I would like to ask two questions that have a little bit more of a clinical bearing on the work. Number one, because it takes 20 to 38 minutes to remove most of the protamine from the circulation, in your experimental preparation, did you measure clinical bleeding in the pericardial space or from around the aorta or cannulas? Because when you give IV protamine, the bleeding usually stops immediately. When did clots appear in the pericardium, and at what level of heparin? One other thing I would like to ask is whether there is some way that this device could be used with a cannula insertion, say through the neck or the groin, so you would not have to wait and close the patient after the cannula was removed?
DR ZWISCHENBERGER: While it takes 25 to 38 minutes for the HRD run to remove the heparin, you have an open chest. You can use the cardiotomy sucker to suction any blood that accumulates during that time. So, while you are undergoing first-order exponential depletion of heparin, cardiotomy suction is returning blood to circulation, and that is part of the mathematical model to predict HRD runtime. Second, we saw no difference in bleeding during the perioperative period in the swine, and no bleeding complications in the postoperative period. The HRD prototype was designed to access a right atrial cannulation site; however, it would be simple to gain vascular access through percutaneous cannulas because the flow is only 1,400 mL/min. As you know, we have already developed percutaneous cannulas for venovenous ECMO that can exceed those flow rates, and the HRD could easily be adapted. As you can easily imagine, the HRD could be applied to any circumstance of systemic heparinization, not just cardiopulmonary bypass.
DR ALVAN W. ATKINSON (Raleigh, NC): There was another technology that was initially tried where there was a heparin antibody and the blood was circulated through a catheter with heparin antibody coated. The company that did that apparently is not making it anymore, so it is not available. Do you have any experience with that or are there any prototypes along that line with a heparin antibody on a recirculating catheter?
DR ZWISCHENBERGER: There have been a number of clever designs of circuits and different techniques to try to eliminate heparin from the circulation. Most of them had protamine attached to a sorbent, creating a protamine-heparin complex, which, of course, does not eliminate the problem because you still expose the blood to protamine. The device you allude to removed an inadequate amount of heparin, so the prototype development was stopped. I personally did not participate in those studies.
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Abstract
Introduction
