What is the evidence of thrombate (antithrombin III) or any other pharmacological agent for patients with heparin resistance confirmed to have antithrombin deficiency of any cause not just hereditary?

Comment by InpharmD Researcher

In heparin-resistant patients with documented antithrombin deficiency, antithrombin concentrate or recombinant antithrombin restored heparin responsiveness and therapeutic ACT more effectively and faster than additional heparin or fresh frozen plasma. Randomized evidence with recombinant antithrombin 75 U/kg shows reduced fresh frozen plasma use and lower heparin requirements without a clear increase in serious adverse events, although bleeding signals have varied and pediatric ECMO data suggest labeled dosing may be inadequate, requiring higher doses and frequent AT monitoring. However, antithrombin supplementation may be insufficient and require adjuncts such as r-hirudin or tirofiban with unfractionated heparin reduce thrombin/fibrin generation.

pubmed and open-access search engines: thrombate antithrombin iii deficiency heparin resistance

Literature Review

A search of the published medical literature revealed 6 studies investigating the researchable question:

What is the evidence of thrombate (antithrombin III) or any other pharmacological agent for patients with heparin resistance confirmed to have antithrombin deficiency of any cause not just hereditary?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-6 for your response.

A Randomized Trial of Antithrombin Concentrate for Treatment of Heparin Resistance
Design

Randomized clinical trial

N= 85
Objective To determine if treatment with antithrombin (AT) concentrate is effective for treating heparin resistance in patients requiring cardiopulmonary bypass
Study Groups

AT concentrate group (n= 44)

Additional heparin group (n= 41)
Inclusion Criteria Adult patients undergoing cardiopulmonary bypass from May 1997 to April 1999 who were heparin resistant, defined as an activated clotting time (ACT) < 480 seconds after > 450 IU/kg heparin
Exclusion Criteria Patients who developed heparin resistance while on cardiopulmonary bypass despite having a prior adequate ACT
Methods Patients were randomized to receive either 1000 U AT concentrate or additional heparin. Blood samples were collected at randomization, 30 minutes after entering the study, and at the termination of bypass to assay AT activity levels, thrombin-antithrombin (TAT), and the prothrombin fragment (F1 1 2)
Duration May 1997 to April 1999
Outcome Measures

Primary: Achievement of therapeutic activated clotting time (ACT)
Baseline Characteristics   AT Group (n= 44) Heparin Group (n= 41)  
Age (y) 62.7 ± 16.3 64.6 ± 15  
Weight (kg) 78.9 ± 21.8 74.9 ± 15.5  
Gender (M:F) 29:15 23:18  
Preoperative heparin 34/44 (77%) 29/41 (71%)  
Results   AT Group Heparin Group p-Value
Total heparin (U/kg) 638 ± 173 869 ± 188 < 0.00001
Post protamine ACT (s) 124 ± 18 136 ± 30 0.018
Dosing cycles (number) 1.09 ± 0.42 1.95 ± 0.83 < 0.0001
Adverse Events No adverse events directly related to either administration of AT or additional heparin were reported
Study Author 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. AT concentrate should be used in heparin-resistant patients as it is faster and avoids the use of fresh frozen plasma.
Critique

The study effectively demonstrates the efficacy of AT concentrate in treating heparin resistance, with a clear methodology and significant findings. However, the study's follow-up period was limited to 24 hours, which may not capture long-term outcomes. Additionally, the study did not include a comparison with fresh frozen plasma, which is a conventional treatment option.

 

Table 1 References:
[1] Williams MR, D'Ambra AB, Beck JR, et al. A randomized trial of antithrombin concentrate for treatment of heparin resistance. Ann Thorac Surg. 2000;70(3):873-877. doi:10.1016/s0003-4975(00)01550-2
A Phase III, Double-blind, Placebo-controlled, Multicenter Study on the Efficacy of Recombinant Human Antithrombin in Heparin-resistant Patients Scheduled to Undergo Cardiac Surgery Necessitating Cardiopulmonary Bypass
Design

Multicenter, randomized, double-blind, placebo-controlled study

N= 54
Objective To evaluate the efficacy of recombinant human antithrombin (rhAT) for restoring heparin responsiveness in heparin-resistant patients undergoing cardiac surgery
Study Groups

rhAT group (n= 27)

Placebo group (n= 27)
Inclusion Criteria Patients aged 18–85 years, scheduled to undergo elective cardiac surgery requiring sternotomy and CPB, with ACT < 480 s after 400 U/kg heparin, and either a baseline heparin dose response slope of 80 s or less or receiving intravenous heparin before surgery
Exclusion Criteria Patients who had recently received or were receiving warfarin, streptokinase, tissue plasminogen activator, abciximab, eptifibatide, tirofiban, or clopidogrel; patients with preexisting coagulopathy or receiving antifibrinolytic agents
Methods

Patients were randomized to receive either 75 U/kg rhAT or normal saline. If ACT remained < 480 s, 2 units of FFP were transfused. Additional heparin was administered during CPB as guided by automated protamine titration and ACT values. Blood samples were collected for hematologic analysis and antibody testing.
Duration Not explicitly stated
Outcome Measures

Primary: Reduction in transfusion of FFP and heparin administration

Secondary: Comparisons of ACT values and plasma antithrombin activity levels in the peri-CPB period
Baseline Characteristics   Placebo (n= 27) rhAT (n= 26)
Age, yr (Mean) 66.0 67.6
Male (%) 67 88
Weight, kg (Mean) 74.5 78.4
Results   Placebo (n= 27) rhAT (n= 27) p-Value
Patients receiving FFP intraoperatively (%) 81 19 <0.001
Patients receiving FFP during hospitalization (%) 85 48 0.009
Mean total heparin during CPB (U/h) 6,890 3,884 0.005
Adverse Events Increased blood loss 12 h postoperatively (p= 0.05) with a trend toward increased 24-h bleeding in the rhAT group (p= 0.06). No increase in serious adverse events associated with rhAT
Study Author Conclusions

Treatment with 75 U/kg rhAT is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation in the majority of heparin-resistant patients. Treating heparin-resistant patients with rhAT may decrease the requirement for heparin and fresh frozen plasma.
Critique

The study was well-designed as a randomized, double-blind, placebo-controlled trial, providing strong evidence for the efficacy of rhAT. However, the high incidence of heparin resistance in the study population may not reflect typical clinical settings. The study did not address long-term outcomes or potential differences in adverse event reporting across sites.

 

Table 2 References:
[2] Avidan MS, Levy JH, Scholz J, et al. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass. Anesthesiology. 2005;102(2):276-284. doi:10.1097/00000542-200502000-00007
Initial Experience with Recombinant Antithrombin to Treat Antithrombin Deficiency in Patients on Extracorporeal Membrane Oxygenation
Design

Retrospective chart review

N= 5
Objective To examine the relationship of recombinant antithrombin (rAT) dose to measured plasma antithrombin activity in patients on ECMO
Study Groups All patients (n= 5)
Inclusion Criteria Patients on ECMO at Medical City Children’s Hospital who received ATryn between December 2011 and April 2012
Exclusion Criteria Not specified
Methods

Retrospective review of patients receiving ATryn while on ECMO. Data collected included patient weight, bolus dose of ATryn, drip rate of ATryn, and AT blood levels. The starting dose of ATryn was based on the manufacturer's labeled indication for prevention of thromboembolic events in patients with hereditary AT deficiency.
Duration December 2011 to April 2012
Outcome Measures

Primary: Relationship of rAT dose to measured plasma AT activity

Secondary: Time to reach target AT activity level (80-120%)
Baseline Characteristics   All patients (n= 5)
Median age, months (range) 1 (1 day to 3.75 years)
Median weight, kg (range) 4 (3-15)
Baseline AT activity level, % (range) 45.4 (39.8-52.2)
rAT bolus dose, units (range) 131 (65-312)
rAT infusion rate, IU/kg/day (range) 480 (104-520)
Maximum AT activity level achieved, % (range) 111 (49.4-125.1)
Time until target level achieved, hours (range) 11 (10-17)
Results Patient No. Weight (kg) Age Baseline AT Activity Level (%) rAT Bolus Dose (units) rAT Infusion Rate (U/kg/day) Maximum AT Activity Level Achieved (%) Time Until Target Level Achieved (hours)
1 3 4 days 50.2 65 320 70.8 N/A
2 4 2.5 months 45.4 95 480 111.6 10
3 15 3 years 52.2 312 104 111 11
4 3 1 month 46.7 70 520 125.1 17
5 5 1 day 39.8 131 177 49.4 N/A
Adverse Events No issues with excessive bleeding or clotting were reported. Some patients experienced mild to moderate bleeding, but it was managed with coagulation adjustments
Study Author Conclusions

The published ATryn dose may be inadequate for pediatric patients on ECMO to reach desired AT activity concentrations. Frequent monitoring and timely adjustments of AT levels are necessary to achieve and maintain target AT activity levels.
Critique

The study is limited by its small sample size and retrospective design, which may affect the generalizability of the findings. The lack of a control group and potential variability in ECMO protocols across different centers may also limit the applicability of the results.

 

Table 3 References:
[3] Niimi KS, Fanning JJ. Initial experience with recombinant antithrombin to treat antithrombin deficiency in patients on extracorporeal membrane oxygenation. J Extra Corpor Technol. 2014;46(1):84-90.
Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass
Design

Multicenter, randomized, double-blind, placebo-controlled study

N= 52
Objective To evaluate the efficacy of recombinant human antithrombin III for restoration of heparin responsiveness in heparin-resistant patients scheduled for cardiac surgery
Study Groups

Recombinant human antithrombin III (n= 28)

Placebo (n= 24)
Inclusion Criteria Patients 18 to 85 years of age scheduled for elective cardiac surgery requiring CPB, with ACT < 480 seconds after 400 U/kg heparin
Exclusion Criteria Patients who had recently received warfarin, streptokinase, tissue plasminogen activator, abciximab, eptifibatide, tirofiban, or clopidogrel; or had preexisting coagulopathy
Methods Patients were randomized to receive a single bolus of 75 U/kg rhATIII or placebo. If ACT remained < 480 seconds, 2 units of FFP were transfused. ACT and plasma ATIII activity levels were monitored during CPB
Duration Not specified
Outcome Measures

Primary: Restoration of heparin responsiveness

Secondary: ACT values, plasma ATIII activity levels, inhibition of thrombin and fibrinolytic activity
Baseline Characteristics   rhATIII (n= 28) Placebo (n= 24)
Age, years Not specified Not specified
Sex Not specified Not specified
Weight, kg Not specified Not specified
Results   rhATIII (n= 28) Placebo (n= 24) p-Value
Patients receiving FFP 6 (21%) 22 (92%) <0.001
ACT increase during CPB Significant Not significant <0.001
Adverse Events No increased incidence of adverse events associated with rhATIII administration. Postoperative 24-hour chest tube bleeding was not different between groups
Study Author Conclusions

Treatment with recombinant human antithrombin III is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for CPB in heparin-resistant patients without increasing bleeding risk.
Critique

The study's strengths include its randomized, double-blind, placebo-controlled design and clear demonstration of rhATIII efficacy. Limitations include a small sample size and lack of long-term follow-up data.

 

Table 4 References:
[4] Avidan MS, Levy JH, van Aken H, et al. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2005;130(1):107-113. doi:10.1016/j.jtcvs.2004.10.045
Management of Heparin Resistance During Cardiopulmonary Bypass: The Effect of Five Different Anticoagulation Strategies on Hemostatic Activation
Design

Randomized, prospective clinical investigation

N= 100
Objective To assess different strategies of managing patients with heparin resistance during CPB
Study Groups ACT management (n= 20) UFH level-based management (n= 20) UFH + AT III (n= 20) UFH + r-hirudin (n= 20) UFH + tirofiban (n= 20)
Inclusion Criteria Patients diagnosed as heparin resistant and scheduled for elective standard cardiac surgery with normal renal function
Exclusion Criteria No reoperations, no complex operations, no operations with hypothermia, no coumadin or antiplatelet therapy within 10 days before surgery
Methods

Five groups were managed with different anticoagulation strategies: maintenance of target ACT, maintenance of target UFH level, and supplementation of UFH with AT III, r-hirudin, or tirofiban. Platelet count and generation of factor XIIa, thrombin, and soluble fibrin were assessed before and after CPB.
Duration Not specified
Outcome Measures

Primary: Thrombin generation, fibrin formation, platelet preservation

Secondary: Postoperative blood loss
Baseline Characteristics   ACT (n= 20) HC (n= 20) HC + AT III (n= 20) HC + r-H (n= 20) HC + Tf (n= 20)
Sex 8 F, 12 M 9 F, 11 M 9 F, 11 M 7 F, 13 M 10 F, 10 M
Age (yr) 64.4 ± 11.5 60.5 ± 14.6 65.1 ± 11.5 59.5 ± 13.4 62.4 ± 12.7
Surgery 12 CABG, 8 VR 10 CABG, 10 VR 9 CABG, 11 VR 12 CABG, 8 VR 11 CABG, 9 VR
Results   ACT (n= 20) HC (n= 20) HC + AT III (n= 20) HC + r-H (n= 20) HC + Tf (n= 20)
AntiXa (IU/mL) 2.41 ± 0.98 3.1 ± 0.92 3.5 ± 0.78 3.4 ± 0.82 3.5 ± 0.74
AT III (%) 35.5 ± 10.5 40.1 ± 12.6 99.8 ± 13.7 44.4 ± 12.5 48.9 ± 10.9
aPTT (s) 41 ± 6.7 37 ± 5.1 48 ± 7.1 56 ± 5.2 36 ± 6.1
12-h Blood Loss (mL) 890 ± 545 744 ± 456 776 ± 546 773 ± 566 658 ± 212
Adverse Events No significant differences in postoperative blood loss among groups. No increased blood loss observed with r-hirudin despite prolonged aPTT
Study Author Conclusions In heparin-resistant patients, anticoagulation during CPB with UFH should be supplemented with AT III, a direct thrombin inhibitor, or a platelet glycoprotein IIb/IIIa antagonist to effectively inhibit hemostatic activation.
Critique The study effectively compares different anticoagulation strategies in heparin-resistant patients, providing valuable insights into managing hemostatic activation during CPB. However, the study's focus on laboratory data rather than clinical outcomes limits its applicability to real-world settings. Further studies are needed to evaluate the clinical impact of these strategies.

 

Table 5 References:
[5] Koster A, Fischer T, Gruendel M, et al. Management of heparin resistance during cardiopulmonary bypass: the effect of five different anticoagulation strategies on hemostatic activation. J Cardiothorac Vasc Anesth. 2003;17(2):171-175. doi:10.1053/jcan.2003.42
Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery
Design

Retrospective analysis

N= 53
Objective To describe the clinical use of antithrombin III concentrate in patients who were found to be heparin resistant before cardiopulmonary bypass
Study Groups All patients (n= 53)
Inclusion Criteria Patients identified as heparin resistant in the operating room before cardiopulmonary bypass, receiving aprotinin
Exclusion Criteria Not specified
Methods Resistance to heparin was determined when >600 U/kg heparin failed to prolong the kaolin-activated clotting time to >600 seconds. Patients were administered 500 U of antithrombin III concentrate, with a second dose if needed. Blood samples were obtained for antithrombin III activity determination
Duration November 1995 through May 2000
Outcome Measures Primary: Prolongation of activated clotting time Secondary: Increase in heparin dose response
Baseline Characteristics   All patients (n= 53)
Age, years 71
Female 24 (45%)
Urgent operations 36
Emergency operations 7
Elective operations 10
Coronary artery bypass 37
Valve replacement 14
Repeat sternotomy 13 (25%)
Preoperative heparin exposure 41 (77%)
Results   All patients (n= 53)
Mean heparin dose before AT concentrate 49,745 U (642 U/kg)
Mean postheparin ACT duration 492 seconds
Mean total heparin dose for procedure 71,032 U
Mean CPB time 125 minutes
Mean plasma AT activity level 67%
ACT after AT concentrate 789 seconds
Adverse Events Not specified
Study Author Conclusions Most patients defined as heparin resistant had subnormal plasma antithrombin III activity. Treatment with antithrombin III concentrate potentiated the heparin effect to meet activated clotting time thresholds, allowing for cardiopulmonary bypass.
Critique The study effectively identified patients with antithrombin III deficiency and demonstrated the efficacy of antithrombin III concentrate in prolonging activated clotting time. However, the retrospective design and lack of comparison with fresh-frozen plasma or untreated patients limit the ability to claim improved outcomes or necessity for antithrombin III repletion.

 

Table 6 References:
[6] Lemmer JH Jr, Despotis GJ. Antithrombin III concentrate to treat heparin resistance in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg. 2002;123(2):213-217. doi:10.1067/mtc.2002.119060