Craig J. Beavers, PharmD, BCCP, BCPS-AQ Cardiology, CACP, and Jayant Bagai, MD, FSCAI

Introduction

Cath lab procedures, such as percutaneous coronary interventions (PCIs), percutaneous mechanical circulatory support, transcatheter therapies, and ablation, are dependent on the use of anticoagulation therapy to reduce the associated thrombogenic potential. A key principle when using anticoagulation is to prevent the unintended consequences of bleeding and thrombosis. In order to optimize the safety of anticoagulation use, operators and cath lab staff need to be aware of the nuances of various tests, testing devices, and therapeutic goals. In this Tip of the Month, we focus on highlights related to anticoagulation monitoring in the cath lab. The following summary is not an exhaustive review and will not discuss the specifics of anticoagulation therapy in depth.

Anticoagulants Used in the Cath Lab

The ideal anticoagulant should have an effect that is of short duration, be easy to monitor, and potentially reversible. ^1,2 A point-of-care (POC) test for monitoring, such as during a case, has obvious advantages over a test that requires traditional venipuncture and laboratory measurement. The anticoagulant agents listed (Table 1) have been studied and/or are commonly used peri-procedurally for cardiac cases and meet several of the criteria listed above.

Overview of the Anticoagulation Monitoring Tests

Activated Clotting Time (ACT)^1-6

• ACT is a whole blood- clotting time test that initiates clotting and measures the time until clot formation.
• Clotting is initiated in the blood sample by an activator of the intrinsic pathways (such as celite, kaolin, and glass).
• It is generally, a point of care (POC) method, with a normal range of 80-130 seconds.
• It is typically used to monitor moderate- to high-dose heparin or direct thrombin inhibitor (DTI) doses during invasive procedures, due to the fact that at lower concentrations there is more variability in results.
• It is predominantly determined by anti-IIa activity and, thus, not reliable to monitor the effect of LMWH, which predominantly inhibits factor Xa.
• Results can be affected by several factors including platelet count, platelet function, lupus anticoagulants, factor deficiency, testing method, blood volume, warfarin use, technique employed, ambient temperature, and hemodilution.
• The ACT result is device-specific, even if the activator used is the same (Table 2).
• Target ranges may depend on the device, specific test, and if a high- or low-range calibrating range card is used (e.g. typically a low-range card is used for PCI). For example, Hemochron devices yield higher results than the Hepcon or the i-STAT.
  • In a recent study, i-STAT device values were generally 43 seconds lower than Hemochron and 23 seconds lower than the Hepcon devices. All devices correlated strongly with anti-factor Xa levels.
• If the ACT is not responding as expected to the anticoagulation and/or dose given, ensuring that the appropriate cartridge is used prior to increasing the drug. Furthermore, if you have time, an aPTT or heparin anti-factor Xa level can be checked to verify anticoagulation effect.

Activated Partial Thromboplastin Time (aPTT)^1-6

• aPTT is a global assay of coagulation; assesses the integrity of the intrinsic and extrinsic pathways of coagulation.
• It measures time in seconds from the activation of factor XII to the formation of a fibrin clot.
• Results can be impacted via the same factors mentioned above in the ACT section. The use of POC can also increase variability.
• Instruments to detect clot may be dependent on plasma turbidity; lipemic and icteric specimens can affect turbidity.
• The relationship between factor activity in the blood and the aPTT results are logarithmic.
• Heparin response:
  • aPTT reagents vary in their response by manufacturer and lot number; thus, the aPTT range will vary depending on the reagent and instrument employed.
  • The heparin therapeutic range may need to be re-established with each new lot or change in manufacturer.
  • The correlation between anti-factor Xa activity, the gold standard for heparin due to less biologic variables, is stronger with laboratory-based aPTT than with a POC aPTT.
• DTI response:
  • The DTI aPTT therapeutic range is not the same as the heparin aPTT therapeutic range.
  • aPTT range, typically 1.5–2.5x baseline and/or 50–80 seconds, has been established in multicenter trials that used multiple reagents.
  • Higher concentrations of DTI lead to a flattening of the dose response curve of aPTT.

Anti-Factor Xa^1-4

• Every anticoagulant requires a unique calibration curve before use, and use of the same curve for a different agent can overestimate or underestimate the effect (e.g., using the UFH curve to monitor LMWH).
• The typical therapeutic range for heparin is 0.3–0.7 IU/mL.
• Variability arises in different instruments as some require exogenous antithrombin and each has differences in the process of creating the standard curve.
• It is less influenced by biological variables.
• POC testing is unavailable, so it is not ideal for periprocedural monitoring.

Procedure/Device Specific Considerations

Percutaneous Coronary Intervention^1-4,7

• ACT is most commonly used due to ease of use and quick results.
• The target value for PCI is 200 to 250 seconds if the glycoprotein IIb/IIIa inhibitor (GPI) is used and 250–300 seconds (for a Hemotech Device) or 300–350 seconds (for Hemochron) if no GPI then per the AHA/ACC/SCAI Guidelines.
• Higher levels are not associated with lower ischemic risk but correlate with an increased bleeding risk.
• Variations in ACT results between blood drawn the side-arm of the arterial sheath and the long tubing of automated injectors has been described. It is important to correlate results obtained from each source in an individual cath lab and develop protocols for accurate measurement (such as discarding 10 ml of blood from the tubing before drawing a sample)
• ACT monitoring for DTI effect is not routinely performed during PCI; however, best practice is to check an ACT 10 minutes after bolus and infusion to ensure an anticoagulation effect.

Percutaneous Ventricular Assist Devices (pVADs)⁸

• Impella devices
  • The manufacturer recommends administering a heparin bolus before device insertion to achieve an ACT of 250 seconds or longer (200 seconds with GPI).
  • After insertion, the recommended ACT is between 160-180 seconds or as per institutional aPTT protocol.
  • There is limited data for anti-Factor Xa monitoring with these devices
  • Use of a combination of tests (ACT and anti-factor Xa) may be more ideal, but more research is needed.
• TandemHeart
  • The manufacturer recommends heparin with a target aPTT of 65–-80 seconds or ACT 180–220 seconds.

Extracorporeal Membrane Oxygenation (ECMO)¹

• Both ACT and aPTT per institutional protocol, have been supported by the Extracorporeal Life Support Organization (ELSO) for monitoring heparin or DTI. For example, if ACT is used, the target goals are 375–400 seconds with the insertion of cannulas and 160–180 seconds goal for maintenance.
• Historically, ACT has been the most commonly used test due to ease of use; however, it is more likely to be impacted by biological variables affected by ECMO cannulation and the shock state.
• Anti-factor Xa levels are emerging as an option for monitoring heparin.
• No anticoagulation test is ideal; the most optimal solution may be to use a combination of tests. However, it should be noted that different tests may have poor correlation.
• More research is needed in this space.

Conclusion

A pillar of cardiac procedures is the use of anticoagulation therapy. In order to reduce both thrombotic and bleeding risk, monitoring of anticoagulation therapy is mandatory. Cath lab and intensive care unit (ICU) staff should be aware of the strengths and limitations of POC and lab coagulation tests.

References

1. Dager WE, Gulseth MP, Nutescu EA. Anticoagulation Therapy: A Clinical Practice Guide. 2^nd Bethesda, MD: American Society of Health-System Pharmacists, 2018.
2. Yost GW, Steinhubl SR. Monitoring and Reversal of Anticoagulation and Antiplatelets. Interv Cardiol Clin. 2013 Oct 2;(4): 643–663.
3. Spinler SA, Wittkowsky AK, Nutescu EA, Smythe MA. Anticoagulation monitoring part 2: Unfractionated heparin and low-molecular-weight heparin. Ann Pharmacother. Jul-Aug 2005;39(7):1275–1285.
4. Hussein HM, Georgiadis AL, Qureshi AI. Point-of-care testing for anticoagulation monitoring in neuroendovascular procedures. AJNR Am J Neuroradiol. 2012 Aug;33(7):1211–1220.
5. Thompson TZ, Kunak RL, Savage NM, et al. Intraoperative Monitoring of Heparin: Comparison of Activated Coagulation Time and Whole Blood Heparin Measurements by Different Point-of-Care Devices with Heparin Concentration by Laboratory-Performed Plasma Anti-Xa Assay. Lab Med. 2019 Oct 10; 50(4): 348–356.
6. Van Cott EM, Roberts AJ, Dager WE. Laboratory Monitoring of Parenteral Direct Thrombin Inhibitors. Semin Thromb Hemost. 2017 Apr; 43(3):270–276.
7. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society of Cardiovascular Angiography and Interventions. Circulation. 2011 Dec 6;124(23):e574–e651.
8. Allender JE, Reed BN, Foster JL, et al. Pharmacologic Considerations in the Management of Patients Receiving Left Ventricular Percutaneous Mechanical Circulatory Support. Pharmacotherapy. 2017 Oct;37(10):1272–83.