A randomized trial of antithrombin concentrate for treatment of heparin resistance

BACKGROUND: Heparin resistance is an important clinical problem traditionally treated with additional heparin or fresh frozen plasma. We undertook a randomized clinical trial to determine if treatment with antithrombin (AT) concentrate is effective for treating this condition. METHODS: Patients requiring cardiopulmonary bypass who were considered to be heparin resistant (activated clotting time < 480 seconds after > 450 IU/kg heparin) were randomized to receive either 1000 U AT or additional heparin. RESULTS: AT concentrate was effective in 42 of 44 patients (96%) for immediately obtaining a therapeutic activated clotting time. This compared favorably to 28 of 41 patients (68%) treated with additional heparin (p = 0.001). All patients who failed heparin therapy were successfully treated with AT. The patients receiving AT required less time to obtain an adequate ACT but there was no difference in clinical outcomes among the groups. Study patients had deficient AT activity at baseline (56%+/-25%), which improved in those given AT concentrate (75%+/-31% versus 50%+/-23%, p < 0.0005). CONCLUSIONS: Heparin resistance is frequently associated with AT deficiency. Treating this deficiency with AT concentrate is more effective and faster for obtaining adequate anticoagulation than using additional heparin.     

Antithrombin III substitution for optimization of the heparin effect during extracorporeal circulation in heart surgery

In a prospective randomised study 20 patients undergoing coronary bypass surgery were assigned to two groups. Patients in group I (n = 10) received initially 250 IU heparin X kg-1 before the start of extracorporeal circulation. Patients in group II (n = 10) were given the same amount of heparin and in addition 1 000 units of purified human antithrombin III (AT III) concentrate. A highly significant lower heparin coefficient [2.69 +/- 0.57 IU X kg-1 X min-1, which is a parameter of heparin consumption (units of heparin X kg-1 given per minute during the time of heparinisation)], was found in group II compared to group I (3.73 +/- 0.56 IU X kg-1 min-1). Heparin sensitivity, measured as an increase in the ratio of activated coagulation time (ACT) X IU heparin-1 X kg-1 as a response to initial heparin dose, was found to be significantly higher (1.22 +/- 0.30 sec X IU heparin-1 X kg-1) in patients receiving AT III as measured in the control group (0.95 +/- 0.23 s X IU heparin-1 X kg-1). Mean values of ACT during the period of heparinisation were comparable (group I: 533 +/- 81 s, group II: 512 +/- 62 s) in the two groups. The substitution of AT III led to an increase of plasma AT III activity of 1.4% per substituted unit AT III X kg-1. AT III plasma activity, corrected to initial haematocrit levels to avoid dilution dependency, decreased as a consequence of extracorporeal circulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Does the preparation of heparin influence anticoagulation during cardiopulmonary bypass?

Various preparations of heparin from different manufacturers are commercially available. The influence of bovine lung heparin (BLH) and porcine mucosal heparin (PMH) on anticoagulation and heparin plasma concentration was investigated in four groups of 10 patients undergoing elective aortocoronary bypass grafting either after single dose or repetitive dose (after 60 minutes) of one of these heparin preparations. Heparin plasma concentration increased significantly after injection of heparin (BLH: minimum, 1.67 U/mL; maximum, 2.10 U/mL; PMH: minimum, 1.69 U/mL; maximum, 2.15 U/mL). Sixty minutes after the initial dose, heparin plasma levels were higher in the patients who received PMH. Supplemental heparin doses 60 minutes after the loading dose increased plasma heparin concentration only with porcine mucosal heparin. Elimination of heparin in the urine was not different among the groups. Fibrinogen and antithrombin III concentrations, as well as activated clotting time (ACT; always greater than 400 seconds) and partial thromboplastin time (PTT; always greater than 300 seconds), did not differ among the groups, indicating effective anticoagulation during the bypass period with both types of heparin. It can be concluded that sufficient anticoagulation can be achieved with either kind of heparin. PMH seems to be longer acting and a repeat dose in these patients seems to be necessary only if cardiopulmonary bypass lasts longer than 90 minutes.     

Pharmacokinetics of recombinant transgenic antithrombin in volunteers

Adequate levels of antithrombin (AT) III are essential for anticoagulation during cardiopulmonary bypass. Levels of AT are often decreased in patients receiving heparin before surgery. In these patients supplementation with exogenous AT can suppress the coagulation pathway and possibly decrease the risk of postoperative coagulopathy. However, the pharmacokinetics of AT have not been extensively analyzed. In this study we investigated the pharmacokinetics of transgenic recombinant AT in healthy volunteers. The concentrations of AT, after initial doses given over 30 min, were best described by a weight-normalized two-compartment model. The fast compartment volume was 41.1 mL/kg and the volume of distribution was 115.4 mL/kg. Intercompartmental clearance was 0. 0763 mL. kg(-1). min(-1) and elimination clearance was 0.0383 mL. kg(-1). min(-1). These variables are equivalent to a distribution half-life of 196 min and an elimination half-life of 2568 min. Approximately 75% of the supplemental dose is removed from plasma by the initial distribution process. A single supplemental dose of transgenic recombinant antithrombin restoring levels to 120%-150% of normal can provide adequate levels for the usual duration of cardiopulmonary bypass. IMPLICATIONS: A single supplemental dose of transgenic recombinant antithrombin restoring levels to 120%-150% of normal can provide adequate levels for the usual duration of cardiopulmonary bypass.     

Low preoperative antithrombin activity causes reduced response to heparin in adult but not in infant cardiac-surgical patients

We evaluated the interaction of preoperative antithrombin (AT) activity and intraoperative response to heparin in cardiac surgery. Heparin anticoagulation is essential during cardiopulmonary bypass (CPB). Heparin itself has no anticoagulant properties, however it causes a conformational change of the physiologic plasma inhibitor AT that converts this slow-acting serine protease inhibitor into a fast acting one. Thus, adequate AT activity is a prerequisite for sufficient heparin anticoagulation. AT activity is reduced by long-term heparin therapy. This prospective, observational study investigated 1516 consecutive cardiac-surgical patients (1304 patients >1 yr (Group A) and 212 patients < or = 1 yr (Group I)). AT activity was measured the day before surgery by a chromogenic substrate assay. The celite-activated activated clotting time (ACT) was used to guide intraoperative heparin administration. Heparin sensitivity was calculated and the postoperative blood loss and perioperative blood requirement was recorded. Infant patients had significantly less preoperative AT activity compared with older patients: 84 (33)% vs 97 (17)%, median (interquartile range) (P < 0. 05). The subgroup of patients aged <1 mo (n = 64) demonstrated a preoperative AT activity of 56 (27)% as compared with 90 (23)% in infant patients between one month and one year (n = 148). In adult patients, preoperative AT activity depended predominantly on preoperative heparin treatment: 62% of the patients with an AT activity <80% were pretreated with heparin. Five minutes after heparin but before CPB the ACT was 587 (334) s in Group A patients with AT activity > or = 80%, and 516 (232) in patients with AT activity < or = 80% (P < 0.05). The target ACT of 480 s was achieved in 70% of patients with normal AT activity in Group A compared with only 54% of patients with AT activity <80% (P < 0.05). In Group A patients with decreased AT activity, 18% demonstrated an inadequate ACT response-defined as ACT <400 s-to the first bolus injection of heparin. In Group I, preoperative AT activity did not influence the ACT response (ACT 5 min after heparin: 846 [447] s in patients with AT activity > or = 80% vs 1000 [364] s in patients with decreased AT activity). The heparin sensitivity was 2.4 (1.1) s/unit heparin/kg compared with 1.5 (0.8) s/unit heparin/KG in group A (P < 0.05). These results suggest that preoperative diminished AT activity causes reduced response to heparin in adult but not in infant patients. Infant patients demonstrate a higher heparin sensitivity despite lower preoperative AT activity. Measurement of preoperative AT activity identifies adult patients at risk of reduced sensitivity to heparin. Implications: In patients less than one year of age, low antithrombin (AT) activity is caused by the immature coagulation system. Despite low AT activity, these young patients demonstrate a normal or increased response to heparin anticoagulation before cardiopulmonary bypass (CPB). In contrast, in patients older than one year of age and adult patients decreased preoperative AT activity is mainly caused by preoperative heparin therapy and causes insufficient response to heparin anticoagulation with a standard heparin dosage. Measurement of preoperative AT activity identifies patients at risk of inadequate anticoagulation during CPB.     

Heparin sensitivity test for patients requiring cardiopulmonary bypass

Anticoagulation for the open heart surgery patient undergoing cardiopulmonary bypass (CPB) is achieved with the use of heparin. The industry standard of activated clotting time (ACT) was used to measure the effect of heparin. The commonly acceptable target time of anticoagulation adequacy is 480 seconds or greater. Some patients, however, exhibit resistance to standard dosing of heparin and do not reach target anticoagulation time (480 seconds). Antithrombin III deficiency has been previously cited as the cause of heparin resistance. Early detection of heparin resistance (HR) may avoid both the delayed start of CPB and inadequate anticoagulation, if emergency bypass is required. An anticoagulation sensitivity test (AST) was developed by adding 12 units of porcine mucosa heparin to the ACT tube (International Technidyne, celite type). Before anticoagulation, 4 mL of blood was drawn from the patient arterial line. Following the manufacturer's instructions, 2 mL of blood was added to each tube (ACT-baseline and ACT-AST). Three minutes after anticoagulation with 4 mg heparin/kg body weight, a second sample (ACT-CPB) was taken to determine anticoagulation adequacy. The ACT times of each sample were recorded for 300 procedures occurring during 2004 and were retrospectively reviewed. Heparin resistance occurred in approximately 20% of the patients (n = 61). In 54 patients, heparin resistance was predicted by the ACT-AST. This was determined by the presence of an ACT-AST time and an ACT-CPB that were both < 480 seconds. The positive predictive value was 90%, with a false positive rate of 3%. Heparin resistance occurs in patients undergoing CPB. We describe a simple and reliable test to avoid the delays of assessing anticoagulation for CPB (90% positive predictive value). Depending on program guidelines, patients can be given additional heparin or antithrombin III derivatives to aid in anticoagulation. An additional ACT must be performed and reach target times before CPB initiation. Testing of patient blood before the time of incision for sensitivity to heparin is a way to avoid a delay that can be critical in the care of the patient. Commercial tests are available, but efficacy data are limited, and they lead to added inventory expense. This method of titrating a diluted heparin additive, mixed with patient blood in a familiar ACT test, has proven to be an inexpensive and reliable test to predict patient's sensitivity to heparin.     

The effects of argatroban on thrombin generation and hemostatic activation in vitro

We evaluated argatroban, a direct thrombin inhibitor, as a heparin adjunct for anticoagulation. Platelet-poor plasma (PPP) was isolated from blood collected from 12 volunteers. Thrombin generation measurements were performed in donor PPP that was mixed with antithrombin (AT)-poor plasma to yield AT levels of 0%, 20%, 60%, and 100%. Effects of argatroban (0-1.0 microg/mL), heparin (0.25 U/mL), or the combination of argatroban (0.5 microg/mL) and heparin were also studied. The addition of increasing concentrations of argatroban, heparin, or both to donor PPP (AT level approximately 100%) caused progressive decreases in the lag time and peak formation of thrombin generation. Heparin (0.25 U/mL) at small AT concentrations had a minimal effect on lag time or peak thrombin formation; its effectiveness of inhibiting thrombin was directly correlated with the concentration of AT. Argatroban at 0.5 microg/mL was effective in decreasing thrombin formation at both low and normal AT levels, but it was most effective when combined with heparin. Additionally, blood samples were obtained from 47 cardiac surgical patients, and the interaction of heparin (>1.5 U/mL) and AT or argatroban on clot formation was evaluated with kaolin activated clotting times (ACTs). Significant increases of ACTs at all heparin levels were observed with the addition of argatroban (0.125 and 0.25 microg/mL). The addition of AT (0.2 U/mL) to heparinized blood samples further prolonged ACTs. In summary, we showed that argatroban, unlike heparin, could effectively reduce thrombin generation regardless of AT levels and could prolong ACTs in vitro at clinically used concentrations.     

Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass

OBJECTIVES: We sought to evaluate the efficacy of recombinant human antithrombin III for restoration of heparin responsiveness in heparin-resistant patients scheduled for cardiac surgery. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing elective cardiac surgery. Patients were considered heparin resistant if the activated clotting time was less than 480 seconds after 400 U/kg heparin. Fifty-two heparin-resistant patients were randomized into 2 cohorts. One cohort received a single bolus (75 U/kg) of recombinant human antithrombin III (n = 28), and the other, the placebo group (n = 24), received a normal saline bolus. If the activated clotting time remained less than 480 seconds, this was defined as treatment failure, and 2 units of fresh frozen plasma were transfused. Patients were monitored for adverse events during hospitalization. RESULTS: Six (21%) of the patients in the recombinant human antithrombin III group received fresh frozen plasma transfusions compared with 22 (92%) of the placebo-treated patients ( P < .001). Two units of fresh frozen plasma did not restore heparin responsiveness. There was no increased incidence of adverse events associated with recombinant human antithrombin III administration. Postoperative 24-hour chest tube bleeding was not different in the 2 groups. Surrogate measures of hemostatic activation suggested that there was less activation of the hemostatic system during cardiopulmonary bypass in the recombinant human antithrombin III group. CONCLUSION: Treatment with recombinant human antithrombin III in a dose of 75 U/kg is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for cardiopulmonary bypass in the majority of heparin-resistant patients. Two units of fresh frozen plasma were insufficient to restore heparin responsiveness. There was no apparent increase in bleeding associated with recombinant human antithrombin III.     

Inhibitory effect of heparin and/or antithrombin III on intraperitoneal fibrin formation in continuous ambulatory peritoneal dialysis

The intraperitoneal fibrin formation and its inhibition by intraperitoneal heparin and/or antithrombin III (AT III) were examined in 8 patients on continuous ambulatory peritoneal dialysis (CAPD). With 1,000 and 2,000 U/L of heparin added to inflow dialysate, the concentration of fibrinopeptide A (FPA) in plasma decreased from 39.43 +/- 5.30 (mean +/- SEM) to 8.00 +/- 2.20 and to 0.74 +/- 0.12 ng/ml, respectively. The FPA concentration in outflow dialysate decreased from 34.20 +/- 5.75 to 12.94 +/- 2.10 ng/ml (1,000 U/l of heparin) and to 4.54 +/- 0.79 ng/mg (2,000 U/l of heparin). The AT III concentration was 0.47 +/- 0.07 mg/dl in dialysate and that in plasma was 24.20 +/- 2.76 mg/dl. With 100 U/bag of AT III added to inflow dialysate, the AT III concentration increased from 0.47 +/- 0.07 to 3.36 +/- 0.17 mg/dl in outflow dialysate but did not increase in plasma. The inhibition of fibrin formation of intraperitoneal heparin was increased by addition of AT III without a systemic inhibitory effect on fibrin formation. These data suggest that intraperitoneal administration of heparin without AT III would be sufficient for the purpose of preventing fibrin formation in CAPD patients without any trouble, and additional AT III might increase inhibitory effect of heparin.     

Anticoagulation of children undergoing cardiopulmonary bypass is overestimated by current monitoring techniques

HYPOTHESIS: Children who undergo cardiopulmonary bypass (CPB) are proportionally more hemodiluted than adults who undergo CPB. Current methods of monitoring high-dose heparin sulfate anticoagulation are dependent on fibrinogen level. Because of the decreased fibrinogen levels in children, current methods of monitoring heparin anticoagulation overestimate their level of anticoagulation. DESIGN: Prospective controlled trial. MAIN OUTCOME MEASURE: Production of thrombin (adequacy of anticoagulation). METHODS: Children and adults undergoing cardiac surgery who received CPB were anticoagulated in the standard fashion as directed by activated clotting time (ACT) results. Each subject had blood sampled at baseline; heparinization; start of the CPB; CPB at 30, 60, and 90 minutes; and at termination of CPB. Samples were used to assess anticoagulation with the Heparin Management Test (less dependent on fibrinogen level than ACT). We also assessed 2 subclinical markers of thrombosis, thrombin-antithrombin complexes and prothrombin fragment F1.2; a marker of procoagulant reserve, fibrinogen; the natural antithrombotic, antithrombin; and heparin concentration. RESULTS: Ten children and 10 adults completed the study. Children had lower fibrinogen levels than adults throughout CPB (P<.05). All adults had both therapeutic ACT and Heparin Management Test levels measured throughout CPB. Although children had therapeutic ACT levels, their Heparin Management Test levels were subtherapeutic while undergoing CPB. The children had significantly higher thrombin-antithrombin complexes and prothrombin fragment F1.2 than adults, indicating ongoing thrombin production (P<.01). The increases in thrombin-antithrombin complexes and prothrombin fragment F1.2 in children were inversely proportional to their weight. CONCLUSIONS: Children undergoing CPB with heparin dosing adjusted to optimize the ACT manifest inadequate anticoagulation (ongoing thrombin formation). High-dose heparin anticoagulation therapy in children undergoing CPB should be directed by tests (like the Heparin Management Test) that are less dependent on fibrinogen level than ACT.     

先天性心脏病患儿肝素效应与凝血酶抑制因子水平的临床检测

本研究观察了体外循环（CPB）下行心脏手术的先天性心脏病患儿3种凝血酶抑制因子[抗凝血酶Ⅲ（ATⅢ）、肝素辅助因子Ⅱ（HCⅡ）、α-2-巨球蛋白（α2M）]水平与临床不同检测肝素效应方法间的关系。118例患儿分为6个年龄组：〈1个月龄．1～3个月龄，3—6个月龄，6～12个月龄，12～24个月龄，〉10岁。测定基础ATⅢ、HCⅡ、α2M数值。同时测定白陶土法活化凝血时间（k-ACT）、硅藻土法活化凝血时间（c-ACT）的基础值并在应用标准剂量400U／kg肝素3分钟后再次测定k-ACT和c-ACT。计算每例患儿应用肝素前、后ACT的差值和肝素量-效关系。给予肝素后k-ACT较c-ACT的变异性小。与既往在成人中证实的结果不同，ATⅢ以及其他凝血酶抑制因子与肝素效应的临床检测间无正性相关；而且〈1个月龄组患儿不仅ATⅢ、HCⅡ水平低．α2M水平也较低。研究结果对肝素是否能在新生儿体外循环手术中发挥充分的抗凝效应提出了疑义，并对ACT延长作为反映抗凝程度的精确性提出了挑战。     

Anticoagulation for cardiac surgery in patients receiving preoperative heparin: use of the high-dose thrombin time

Patients receiving heparin infusions have an attenuated activated clotting time (ACT) response to heparin given for cardiopulmonary bypass (CPB). We compared patients receiving preoperative heparin (Group H) to those not receiving heparin (REF group) with respect to ACT, high-dose thrombin time (HiTT), and markers of thrombin generation during CPB. Sixty-five consecutive patients (33 Group H, 32 REF group) undergoing elective CPB were evaluated. ACT and HiTT were measured at multiple time points. Plasma levels of thrombin-antithrombin III complex and fibrin monomer were determined at baseline, during CPB, and after protamine administration. Transfusion requirements and postoperative blood loss were measured and compared. ACT values after heparinization increased less in Group H and were significantly lower than those in the REF group (P < 0.01). HiTT values did not differ significantly between the two groups. Blood loss and transfusion requirements were not significantly different between the two groups. Plasma levels of thrombin-antithrombin III complexes and fibrin monomer also did not differ between groups at any time, despite a lower ACT in Group H after heparinization and during CPB. Our data suggest that thrombin formation and activity are not enhanced in patients receiving heparin therapy, despite a diminished ACT response to heparin. The utility of ACT and the threshold values indicative of adequate anticoagulation for CPB are relatively undefined in patients receiving preoperative heparin. HiTT should be investigated as a safe and accurate monitor of anticoagulation for CPB in patients receiving preoperative heparin therapy. Implications: The diminished activated clotting time response to heparin, in patients receiving preoperative heparin therapy, poses difficulties when attempting to provide adequate anticoagulation for cardiopulmonary bypass. Current data suggest that heparin resistance is not observed when high-dose thrombin time is used to monitor anticoagulation and that a lower activated clotting time value in these patients may be safe.     

The treatment of heparin resistance with Antithrombin III in cardiac surgery

PURPOSE: To report three patients who developed heparin resistance during cardiac surgery which was successfully managed with 1000 U Antithrombin III (AT III). CLINICAL FEATURES: We observed heparin resistance prior to cardiopulmonary bypass (CPB) in one patient and during the CPB in two patients. In the first patient who was scheduled for mitral valve replacement, although heparin was administered sequentially up to 500 U x kg(-1) prior the CPB, the ACT value was 354 sec. After 1,000 U ATIII were administered the ACT was 395 sec and CPB was initiated. The ACT remained between 496 and 599 sec throughout CPB and a total of 260 mg protamine sulfate was given. In the other two patients following 300 U x kg(-1) heparin, the ACT was up to 400 sec and CPB was initiated. During CPB, ACT were decreased 360 sec and 295 sec in patients II and III respectively. Although heparin was added 1,500 U, ACT increased to > or = 400 sec could not be achieved. In the second patient ATIII activity was found 10%. After the administration of 1,000 U ATIII, ATIII activity was found to be 67% 40 min later and ACT were increased up to 400 sec. There was no thrombosis within the extracorporeal circuit, additional heparin was not required, less protamine was administered (< or = 3 mg x kg(-1)) and no excessive postoperative bleeding was observed in all patients. CONCLUSION: We recommend that AT III supplementation should be considered to manage heparin resistance prior or during CPB in patients undergoing open heart surgery.     

Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery

OBJECTIVE: The purpose of this report is to describe the clinical use of antithrombin III concentrate in 53 patients who were found, in the operating room before cardiopulmonary bypass, to be heparin resistant. METHOD: Resistance to heparin was determined to be present when greater than 600 U/kg body weight of heparin failed to prolong the kaolin-activated clotting time to more than 600 seconds in 53 aprotinin-treated patients. Blood samples were obtained for subsequent antithrombin III activity determination. Patients were then administered 500 U of antithrombin III concentrate, and the activated clotting time was remeasured. If the activated clotting time remained less than 600 seconds, a second 500-U dose was given. RESULTS: Of the 53 patients, 45 (85%) had subnormal measured antithrombin III activity, and the mean plasma antithrombin III activity level for the entire group was 67% (normal 80%-120%). Administration of antithrombin III concentrate (500 U in 45 patients and 1000 U in 8 patients) resulted in prolongation of the mean activated clotting time from 492 to 789 seconds without additional heparin. The mean heparin dose response increased from 36.5 to 69.3 s x U(-1) x mL(-1) with antithrombin III treatment. Only one patient did not achieve the target activated clotting time, despite administration of greater than 600 U/kg heparin and 1000 U of antithrombin III concentrate, and was treated with fresh-frozen plasma. CONCLUSIONS: On the basis of the criterion used in this report, most of the patients defined as being heparin resistant had subnormal plasma antithrombin III activity. Treatment with antithrombin III concentrate resulted in potentiation of the heparin effect to meet predetermined activated clotting time thresholds and allow for cardiopulmonary bypass.     

Stabilized Infective Endocarditis and Altered Heparin Responsiveness During Cardiopulmonary Bypass

Background  Although active infective endocarditis (IE) is known as a risk factor for decreased heparin responsiveness during cardiopulmonary bypass (CPB), evidence is lacking in patients with stabilized IE. We investigated whether heparin responsiveness was still altered in stabilized IE patients undergoing cardiac surgery in a prospective, controlled trial. Methods  A total of 16 patients with stabilized IE without signs of active inflammation (IE group) and 48 patients without systemic infection (control group) undergoing valve surgery were included. Heparin responsiveness was assessed using the heparin sensitivity index (HSI), whereas heparin resistance was defined as an activated clotting time (ACT) occurring less than 400 s after the initial heparinization. Results  Preoperative antithrombin III activity was lower and fibrinogen level was higher in the IE group. ACT after initial heparinization was shorter in the IE group. The HSI was lower and the number of patients with HSI <1.0 was greater in the IE group. Heparin resistance occurred more frequently in the IE group. Conclusions  Heparin responsiveness during CPB was significantly reduced in the IE group, and it seems to be associated with preoperative hypercoagulability and reduced antithrombin III activity. Therapeutic measures such as the administration of antithrombin III concentrate should be considered in these patients even when they are in a stabilized condition without active inflammation.     

An investigation of a new activated clotting time "MAX-ACT" in patients undergoing extracorporeal circulation

Activated clotting time (ACT) is a test used in the operating room for monitoring heparin effect. However, ACT does not correlate with heparin levels because of its lack of specificity for heparin and its variability during hypothermia and hemodilution on cardiopulmonary bypass (CPB). A modified ACT using maximal activation of Factor XII, MAX-ACT (Actalyke MAX-ACT; Array Medical, Somerville, NJ), may be less variable and more closely related to heparin levels. We compared MAX-ACT with ACT in 27 patients undergoing CPB. We measured ACT, MAX-ACT, temperature, and hematocrit at six time points: baseline; postheparin; on CPB 30, 60, and 90 min; and postprotamine. Additionally, we assessed anti-Factor Xa heparin activity and antithrombin III activity at four of these six time points. With institution of CPB and hemodilution, MAX-ACT and ACT did not change significantly but had a tendency to increase, whereas concomitant heparin levels decreased (P = 0.065). Neither test correlated with heparin levels. ACT and MAX-ACT did not differ during normothermia but did during hypothermia, and ACT was significantly longer than MAX-ACT (P = 0.009). At the postheparin time point, ACT-heparin sensitivity (defined as [ACT postheparin - ACT baseline]/[heparin concentration postheparin - heparin concentration baseline]) was greater than MAX-ACT-heparin sensitivity (analogous calculation for MAX-ACT; 520 [266 - 9366] s. U(-1). mL(-1) vs 468 [203 - 8833] s. U(-1). mL(-1); P = 0.022). IMPLICATIONS: MAX-ACT (a new activated clotting time [ACT] test) uses more maximal clotting activation in vitro and, although it is less susceptible to increase because of hypothermia and hemodilution than ACT, lack of correlation with heparin levels remains a persistent limitation.     

Clinical measures of heparin's effect and thrombin inhibitor levels in pediatric patients with congenital heart disease

In this investigation, we examined the relationship among three thrombin inhibitors, antithrombin III (ATIII), heparin cofactor II (HCII), and alpha-2-macroglobulin (alpha2M), and several clinical tests of heparin's effect in pediatric patients with congenital heart disease undergoing cardiopulmonary bypass. One hundred eighteen children were stratified into six age groups: <1 mo, 1-3 mo, 3-6 mo, 6-12 mo, 12-24 mo, and >10 yr. Baseline ATIII, HCII, and alpha2M values were measured. Baseline celite- and kaolin-activated clotting times (ACT) were also measured and repeated 3 min after a standard heparin dose of 400 U/kg. Differences in ACT values before and after heparin administration and a heparin dose-response relationship were calculated for each patient. Kaolin-activated ACT tests showed less variation after heparin administration than celite-activated tests. In contrast to what has been demonstrated in adults, ATIII showed no positive correlation with the clinical tests of heparin's effect nor did the other thrombin inhibitors. Additionally, patients <1 mo old had unexpectedly low levels of alpha2M accompanying their expected low levels of ATIII and HCII. Our findings raise concerns about the ability of heparin to adequately anticoagulate these neonates during cardiopulmonary bypass and, consequently, challenge the accuracy of ACT prolongation to truly reflect the extent of their anticoagulation.     

Antithrombin replacement during extracorporeal membrane oxygenation

Heparin remains the predominant anticoagulant during extracorporeal membrane oxygenation (ECMO). Heparin acts by potentiating the anticoagulant effect of antithrombin (ATIII). Acquired ATIII deficiency, common in pediatric patients requiring ECMO, may result in ineffective anticoagulation with heparin. ATIII replacement may result in increased bleeding. Our objective is to determine ATIII's effect on anticoagulation and blood loss during ECMO. A retrospective chart review was performed of all patients at Children's Hospital of Wisconsin who received ATIII while supported on ECMO in 2009. ATIII activity levels, heparin drip rate, and activated clotting times (ACT) were compared before, 4, 8, and 24 h after ATIII administration. Chest tube output and packed red blood cell (pRBC) transfusion volume were compared from 24 h before ATIII administration to 24 h after. Twenty-eight patients received ATIII as a bolus dose during the course of 31 separate times on ECMO support. The median age of these patients was 0.3 years (range 1 day-19.5 years). ATIII activity increased significantly at 8 and 24 h after administration. No significant difference was noted in heparin drip rate, ACT levels, chest tube output, or pRBC transfusion volume. ATIII administration resulted in higher ATIII activity levels for 24 h without a significant effect on heparin dose, ACT, or measures of bleeding.     

Anticoagulation management in a patient with an acquired antithrombin III deficiency.

We report a case of heparin resistance and its management during cardiopulmonary bypass (CPB). A 63-year-old, 96 Kg female with a posterior myocardial infarction (MI) with previous deep venous thrombosis was treated with intravenous (IV) heparin infusion for 7 days before myocardial revascularization surgery. The patient required 1200 IU/Kg of beef lung heparin to extend the activated clotting time (ACT) in order to initiate CPB. A total of 1562 IU/Kg of heparin was administered throughout the procedure. This acquired heparin resistance was attributed to an antithrombin (AT III) deficiency, and was treated with fresh frozen plasma (FFP) to restore adequate anticoagulation. The patient's heparinized ACTs ranged between 368 seconds and 387 seconds before FFP administration as opposed to 626 seconds to 1329 seconds after treatment with FFP and additional heparin once on CBP. The patient experienced an uneventful postoperative course. Future treatment with AT III concentrate rather than FFP may reduce heparin requirements that will, in turn, reduce protamine reversal dose, postoperative bleeding attributable to heparin rebound, and its associated complications.     

Intermittent hirudin versus continuous heparin for anticoagulation in continuous renal replacement therapy

BACKGROUND: Besides possible bleeding complications a further problem in anticoagulation during continuous renal replacement therapy (CRRT) is the development of heparin-induced thrombocytopenia type II (HIT II) where further anticoagulation with heparin is contraindicated. The application of continuous hirudin as alternative for heparin caused bleeding complications by comparable filter efficacy. Aim of this prospective-controlled pilot study was to compare the efficacy and safety of intermittent hirudin and continuous heparin for anticoagulation during CRRT in critically ill patients. METHODS: 26 patients receiving CRRT were randomly allocated to two groups: Heparin group (14 patients): continuous administration of 250 IU/h heparin, dose was adjusted in 125 IU/h steps with a targeted activated clotting time (ACT) of 180-210 s. Hirudin group (12 patients): initial bolus application of 2-2-5 microg/kg hirudin, dose was adjusted in 2 microg/kg bolus steps with a targeted ecarin clotting time (ECT) >80 s. Observation time was 96 hours. RESULTS: Measured filter run time was virtually longer for heparin. No bleeding complications were observed in the hirudin group, two bleeding complications in the heparin group. CONCLUSIONS: Intermittent hirudin can be used safely for anticoagulation in CRRT. However, the in tendency better filter survival for heparin elucidates the need for further investigations to find the right dosage equilibrium between filter clotting and bleeding complications.