Heparin and ACT response. Factors influencing results. Patient specific and lab. Looking for literature to review to investigate not achieving therapeutic ACT goals for cardiac procedures.

Comment by InpharmD Researcher

Several factors can influence the attainment of therapeutic activated clotting times (ACTs) during cardiopulmonary bypass (CPB) in cardiac surgery and subsequently the efficacy of systemic unfractionated heparin in preventing circuit thrombosis. These factors can be considered as patient-related, CPB-related, measurement-related, anticoagulant-related, and heparin resistance-related. Cohort studies have concluded that failure to achieve target ACT may not be due strictly to antithrombin deficiency but potentially also due to thrombocytosis and/or anemia (hemoglobin and hematocrit), older patient age and heart failure functional status. It is also uncertain whether these factors equally affect target ACT attainment across all cardiac surgeries, as studies have generally not mentioned the surgical procedures assessed.

heparin act cardiac

Background

A recent review summarized various mechanisms of heparin resistance during CPB in cardiac surgery and the resulting limitations of using ACT for monitoring. Factors linked to subtherapeutic ACTs despite appropriate weight-based heparin dosing are patient-related, CPB-related, measurement-related, anticoagulant-related, and heparin resistance-related. Patient-related factors include: preoperative medication use (e.g., antiplatelet agents, anticoagulants), platelet count and function, coagulation factor deficiencies (e.g., fibrinogen, factors II/V/VIII/XI/XII), antithrombin deficiency <80%, and proinflammatory states. CPB-related factors include hypothermia and hemodilution. Measurement-related factors include activating reagent used (e.g., kaolin vs glass), and real-time vs derived ACT measurement. Anticoagulant-related factors include source of unfractionated heparin (e.g., bovine vs porcine) and other systemic anticoagulants used perioperatively (e.g., bivalirudin). Heparin resistance-related factors include antithrombin deficiency (acquired vs congenital, due to prior heparin and/or CPB exposure) and non-antithrombin-based (e.g., protein binding by heparin in setting of heparin-induced thrombocytopenia and hypoalbuminemia, thrombocytosis, and hypovolemia). [1]

References: [1] Chen Y, Phoon PHY, Hwang NC. Heparin Resistance During Cardiopulmonary Bypass in Adult Cardiac Surgery. J Cardiothorac Vasc Anesth. 2022 Nov;36(11):4150-4160. doi:10.1053/j.jvca.2022.06.021
Relevant Prescribing Information

Dosage and Administration for heparin sodium: [2]
Cardiovascular Surgery:
Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight. Frequently, a dose of 300 units per kilogram is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

References: [2] Heparin sodium. Package Insert. Fresenius Kabi USA, LLC; May 2024.
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

Heparin and ACT response. Factors influencing results. Patient specific and lab. Looking for literature to review to investigate not achieving therapeutic ACT goals for cardiac procedures.

Level of evidence

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


Please see Tables 1-3 for your response.

 

An evaluation of factors affecting activated coagulation time

Design

Observational cohort study at a university medical center in the Netherlands

N=203

Objective

To determine the relationship between antithrombin (AT) and other coagulation-related factors that affect the activated clotting time (ACT) measurement and heparin sensitivity index before the establishment of cardiopulmonary bypass (CPB)

Study Groups

Low ACT (L-ACT, n=21), patients who did not achieve goal ACT ≥400 seconds after full heparinization

High ACT (H-ACT, n=281), patients who achieved goal ACT ≥400 seconds after full heparinization

Inclusion Criteria

All adult patients undergoing elective cardiac surgery were eligible for inclusion

Exclusion Criteria

None specified

Methods

The day prior to surgery, platelet (Plt) count, hemoglobin (Hb), and AT activity (using Siemens Berichrom Antithrombin III Kit, Marburg Germany) were measured.

The day of surgery, kaolin-activated ACT (using Hemotec ACT II Au tomated Coagulation Timer, Medtronic, Inc, Minneapolis, MN) was measured before and 5 minutes after administration of systemic heparin. Anti-Xa activity was also measured (using Biophen Heparin LRT, Hyphen Biomed, Neuville sur Oise, France) after heparinization but before CPB; anti-Xa activity was corrected for hemodilution.

Heparin sensitivity index (HSI) calculated as Δ ACT before and after heparin administration, divided by the heparin dose per kg body weight.

An initial heparin loading dose of 300 units/kg was adminsitered prior to CPB. Within 5 minutes, ACT was measured and CPB initiated if ACT ≥400 seconds. Additional heparin was given as needed to reach target ACT. Heparin was reversed with protamine sulfate at the end of CPB at a 1:1 ratio of the total loading dose used. 

Duration

6 months

Outcome Measures

Achievement of goal ACT ≥400 seconds after heparin, preoperative Plt count and Hb level, HSI

Baseline Characteristics

  

L-ACT (n=21)

H-ACT (n=182)

 p-value

Mean age, years

 66 ± 11 66 ± 10 0.737

Mean weight, kg

 77 ± 12 81 ± 13  0.208

Femal sex, n (%)

 5 (31.3%) 41 (29.2%) 0.894

Preoperative antithrombotic therapy

None

ASA/clopidogrel

LMWH

Coumarin

 

 

5 (23.8)

16 (76.2)

1 (4.8)

0 (0)

 

 

34 (18.9)

135 (74.2)

17 (9.3)

10 (5.5)

 0.595

Mean Plt count, x1000/mm3

290 ± 75

250 ± 65

 0.009

Mean AT, %

102 ± 8

99 ± 12

 0.215

Mean Hb, mmol/L

8.1 ± 1.2

8.7 ± 0.9

 0.011

Mean ACT, seconds

133 ± 13

139 ± 17

 0.137

Abbreviations: ASA = aspirin; LMWH = low-molecular weight heparin.

Results

Intraoperative characteristics

L-ACT (n=21)

H-ACT (n=182)

p-Value

Mean total heparin loading dose, units/kg

 398 ± 65 315 ± 35 <0.001

Mean ACT after heparin, seconds

 372 ± 28 534 ± 104 <0.001

Mean HSI, seconds/units/kg

 0.76 ± 0.14 1.27 ± 0.31 <0.001

Mean anti-Xa, units/mL

 8.1 ± 0.9 8.7 ± 1.5 0.02
  • 10% of patients did not achieve therapeutic ACT after heparinization (n=21 in the L-ACT group)
  • Plt count showed highest association with heparin responsiveness
  • Pearson correlation analysis for factors affecting HSI
    • AT activity (r=-0.068)
    • Preoperative Plt count (r=-0.308)
    • Hb (r=0.110)
  • HSI seemed to decrease with increasing Plt counts and to increase with higher Hb levels
  • Multivariable logistic regression analysis for significant predictors of ACT
    • Plt count (x1,000/mm3): 95% CI -0.013 to 0.001, p=0.071
    • AT (%): 95% CI -0.056 to 0.029, p=0.540
    • Hb (mmol/L): 95% CI -0.023 to 0.865, p=0.063

Adverse Events

Not specified

Study Author Conclusions

All these observations suggest that failure to achieve an adequate ACT is, in general, not an indicator of AT deficiency but could be affected by high platelet counts and low hemoglobin levels.

Critique

This study was limited by its observational design and unmatched sample sizes for the L-ACT and H-ACT groups. Significant baseline differences between groups were likely a consequence of the need for more heparin boluses to fully heparinize the patients in the L-ACT group. Characteristics of the cardiac surgery procedures and CPB itself were also not provided in the study, and this can confound and limit external validity to other cardiac surgery types. 



References:
[1] [1] Bosch YP, Weerwind PW, Nelemans PJ, Maessen JG, Mochtar B. An evaluation of factors affecting activated coagulation time. J Cardiothorac Vasc Anesth. 2012 Aug;26(4):563-8. doi:10.1053/j.jvca.2012.03.011
Factors influencing activated clotting time following heparin administration for the initiation of cardiopulmonary bypass
Design

Retrospective cohort study

N= 516
Objective To determine factors affecting activated clotting time (ACT) following heparin administration during the initiation of cardiopulmonary bypass (CPB)
Study Groups

Reach (ACT ≥ 450 s) (n= 334)

Short (ACT < 450 s) (n= 182)
Inclusion Criteria Adult patients who underwent open-heart surgery with CPB between January 2013 and December 2015 at Juntendo University Hospital
Exclusion Criteria Patients with heparin allergy, liver dysfunction, AST or ALT levels more than double the normal limit, or lacking preoperative data such as emergent cases
Methods

The dose of heparin was calculated based on patient body weight (300 IU/kg) and adjusted by baseline ACT (bACT). ACT was measured using a coagulation analyzer after 3 minutes of initial heparin administration. Patients were divided into Reach and Short groups based on ACT values.
Duration January 2013 to December 2015
Outcome Measures Primary: Factors influencing ACT after heparin administration Secondary: Association of age, NYHA classification, and platelet count with ACT
Baseline Characteristics   Reach (ACT ≥ 450 s) (n= 334) Short (ACT < 450 s) (n= 182)
Number (%) 334 (64.7%) 182 (35.3%)
Male sex (%) 179 (54.5%) 102 (56.0%)
Age, years 65.3 ± 14.0 68.9 ± 12.3
Body weight, kg 58.8 ± 11.8 57.1 ± 11.3
Preoperative heparin use (%) 107 (32.0%) 78 (42.9%)
Results   Odds Ratio (OR) 95% Confidence Interval (CI) p-value
Age ≥ 80 years 2.53 1.41–5.24 <0.01
NYHA classification 4 4.44 1.59–15.35 <0.05
Platelet count below lower limit 0.37 0.31–0.85 <0.01
Adverse Events Not specifically reported in the study
Study Author Conclusions Old age, heart failure, and lower platelet counts affected heparin activity. The dose of heparin should be considered in these patients to reach the target ACT.
Critique

The study provides valuable insights into factors affecting heparin activity, particularly in older patients and those with heart failure. However, the retrospective design and lack of assessment of clinical outcomes limit the ability to generalize findings. Additionally, the study did not establish an upper limit for ACT, which could impact safety assessments.

 

References:
[1] [1] Matsushita S, Kishida A, Wakamatsu Y, Mukaida H, Yokokawa H, Yamamoto T, Amano A. Factors influencing activated clotting time following heparin administration for the initiation of cardiopulmonary bypass. Gen Thorac Cardiovasc Surg. 2021 Jan;69(1):38-43. doi:10.1007/s11748-020-01435-x
Factors Affecting the Activated Clotting Time
Design

Controlled study with 21 adult male patients undergoing CPB for coronary artery bypass graft

N= 21)
Objective To investigate the relationship between hematocrit, pH, pCO2, total protein concentration and the ACT
Study Groups All patients (n= 21)
Inclusion Criteria Adult male patients aged 40-70 years, weighing 55-105 kilograms, undergoing CPB for coronary artery bypass graft
Exclusion Criteria Patients requiring the addition of blood or additional heparin during CPB
Methods Duplicate ACT samples were drawn (one in a 37°C heat block and one at room temperature). Concurrent blood gas analysis, hematocrit, and total protein measurements were made. ACT's were performed using a modified Hattersley technique and a Lab-Line Instruments heat block at 37°C. Data were analyzed using linear regression and correlation coefficient.
Duration Not specified
Outcome Measures Primary: Correlation between ACT and hematocrit, pH, pCO2, total protein concentration
Baseline Characteristics   All patients (n= 21)
Age, years 40-70
Weight, kg 55-105
Results   Heat Block ACT Room Temperature ACT
Baseline 100±13.4 150.9±40.7
5 min post Heparin 351.5±69.5 803.3±239.5
5 min on Bypass 372±70.6 910.5±363.5
Hypothermia 346±52.3 825±237.1
Rewarm 317±88.3 646±308.9
20 min post Protamine 101±12 161.5±34.5
Adverse Events Not specified
Study Author Conclusions

Conditions under which the ACT is measured are very important for accuracy. It may be desirable to adjust a patient's dose response based on the hematocrit. The use of a heat block is recommended for rapid and accurate measurement of the patient's coagulation potential at all phases of the open heart procedure.
Critique

The study highlights the importance of standardizing conditions for ACT measurement and provides insights into the relationship between ACT and hematocrit. However, the study is limited by its small sample size and lack of diversity in the patient population, which may affect the generalizability of the findings. Further investigation is needed to explore the relationship between acid-base balance and ACT.
References:
[1] Kase PB, Dearing JP. Factors Affecting the Activated Clotting Time. J Extra Corpor Technol. 1985;17(1):27-30. doi:10.1051/ject/1985171027