FRCA Notes

Anticoagulation During Cardiopulmonary Bypass

A CRQ question on the topic from March 2020 (64% pass rate) had the examiners 'surprised at the lack of knowledge displayed'.

In particular, it seems they were seeking greater detail on the mechanisms of heparin function, and the tests one might use to monitor the degree of anticoagulation.

A repeat question in 2024 was 'well answered' although examiners wanted more information on a failure of anticoagulation before CPB.

Resources

  • The primary indication for anticoagulation in cardiac surgery is to prevent clot formation within the cardiopulmonary bypass circuit
  • Exposure to the artificial surfaces of the bypass circuit is a potent activator of complement, thrombin and thus the clotting process
  • Other CPB factors affect coagulation, including:
    • The degree of haemodilution, which prolongs ACT
    • The duration of CPB
    • The use of cardiotomy-suctioned blood which is highly exposed to tissue factor and therefore highly activated
    • The presence of hypothermia, particularly DHCA
  • As such, full anticoagulation is mandatory during cardiopulmonary bypass
  • Some patients may already be taking anti-platelet or anti-coagulant drugs

  • Heparin is the most commonly used anticoagulant for CPB
    • Typically 300 - 400 IU/kg of actual body weight is given at the end of the IMA harvesting period
    • A further 5,000units is present in the CPB prime solution
    • Re-dosing occurs to maintain anticoagulation in the face of haemodilution, hypothermia and altered clotting factor concentrations
      • E.g. 90mins after start give further dose at 1/3rd of the initial bolus, with repeat doses every 60mins

  • Heparin benefits from being titratable, easily measurable and readily reversable

Mechanism of anticoagulation

  • Heparin is a potentiator/activator of anti-thrombin III
  • It's anionic and binds to the positive residues on anti-thrombin III, resulting in a conformational change & increasing activity up to 1000x

  • Anti-thrombin III itself works by:
    • Direct inhibition of thrombin in low doses
    • Indirect inhibition of thrombin formation by inhibiting factor Xa (as well as other serum proteases such as factors IXa, XIa and XIIa) at higher doses

  • Heparin also inhibits platelet macro-aggregation

Heparin resistance

  • Heparin resistance is an inability to achieve adequate anticoagulation (ACT >480s) despite using an adequate dose of heparin (300 - 400IU/kg)
  • Causes include:
    • Antithrombin III deficiency (<80% of normal concentration)
    • ↓ bioavailability due to ↑ volume of distribution from ↑ proportion of extracellular positive proteins e.g. sepsis, infective endocarditis, thrombocytosis
    • Pseudo-resistance e.g. increased fibrinogen or factor VIII activity

  • Management is with:
    • Additional heparin, though strongly consider failure of heparinisation once 600IU/kg have been given
    • Supplementing anti-thrombin (FFP, synthetic anti-thrombin)
    • Using alternative drugs
  • Failure of heparinisation is rare

Protamine

  • Protamine is used to reverse the effects of heparin
  • The classically described dose is 1mg per 100IU heparin, although:
    • Aiming for a protamine-to-heparin ratio of 0.6-0.8 avoids excessive anticoagulant effects of protamine
    • A low dose infusion (25mg/hr for 6hrs) reduces the risk of heparin rebound

Heparin rebound

  • Describes detectable residual heparin in the blood despite reversal with protamine
  • Arises due to:
    • Heparin sequestration in fat stores/bound to plasma proteins, which redistributes after protamine neutralization
    • Incorrect protamine dosing
  • Avoided by using the low dose protamine infusion post-operatively (25mg/hr for 6hrs)

Danaparoid

  • Danaparoid is a mixture of glycosaminoglycan heparinoid molecules
  • It is a factor Xa inhibitor
  • It has been used in patients undergoing CPB with HIT, although there is some HIT cross-reactivity
  • It is monitored using anti-factor Xa levels

Hirudin derivatives

  • Hirudin is a naturally occurring thrombin inhibitor derived from the medical leech
  • Its recombinant derivatives lepirudin and bivalirudin also inhibit thrombin directly
    • Lepirudin is no longer available in the UK due to manufacturing cessation (as opposed to safety concerns)
    • Bivalirudin should be considered in patients for whom heparin/protamine is contraindicated

  • Bivalirudin has a short half-life so is given via an infusion after an initial bolus dose
  • Suffers from:
    • Lower availability and higher cost
    • Lack of specific reversal agent
    • Prolonged action in those with renal failure
    • Difficulty monitoring

  • Although effects can be monitored with APTTr and ACT, they do not correlate to bivalirudin plasma concentrations
  • For CPB, the ecarin clotting time is used to monitor hirudin anticoagulation
  • Effects cannot be readily reversed so use is reserved for patients who cannot tolerate heparin e.g. in HIT

Argatroban

  • A non-peptide arginine derivative
  • A direct thrombin inhibitor which binds to the active catalytic site of both free and clot-bound thrombin
  • Should be considered in those for whom heparin/protamine is contraindicated where there is significant renal dysfunction due to hepatic elimination

  • Use in cardiac surgery is complicated by:
    • Variable responses of ACT and APTTr to argatroban
    • General lack of availability of the ecarin clotting time, which is a specific measurement of anticoagulation with argatroban
    • Lack of reversal agent

  • Use in CPB is associated with increased bleeding & need for blood product transfusion, although decreasing the dose is associated with clot formation

Prostacyclin (PGI2)

  • Naturally occurring substance used to inhibit platelet aggregation
  • Mainly used in patients for whom heparin is contraindicated or ancillary benefits are required (pulmonary vasodilation)

  • Formal, conventional tests of anticoagulation such as APTTr are the gold standard for measuring heparin effect
  • However, they are too slow for use in CPB and point-of-care testing is preferred owing to the rapidly changing physiological state during cardiopulmonary bypass

Activated clotting time (ACT)

  • Most commonly used test of heparin effect
  • Blood is warmed to 37°C in the Haemochron system
  • Similar to whole-blood clotting time, but uses an activator (kaolin, celite) to achieve results more rapidly

  • Normal range is 90 - 140s
  • It is prolonged by the effects of heparin, warfarin, aprotinin, hypothermia or thrombocytopaenia

  • The target range in CPB is:
    • >300s prior to cannulation of the aorta
    • 480s (400-500s) prior to starting bypass (i.e. 3-4x baseline)

    • Although ACT is a reliable measure in the early stages, its efficacy wanes during longer procedures owing to variable activation of the clotting cascade
    • It is also unreliable in the presence of aprotinin

Other tests

  • Direct heparin concentration assay (Hepcon)
    • Determines plasma concentration of heparin by protamine assay

  • High-dose thrombin time

  • Anti-factor Xa levels e.g. danaparoid, LMWH
    • Quantify the inhibitory effect of anti-thrombin III on factor Xa
    • Not point-of-care tests and the delay in results makes them impractical

  • Ecarin clotting time e.g. bivalirudin and argatroban

  • APTTr
    • If plasma heparin concentration <1IU/ml, APTT has a stronger correlation with plasma heparin concentration than ACT

Visco-elastic haemostatic assays

  • Provide rapid, quantitative and qualitative assessment of clotting function
  • Use of assays containing a heparinase (e.g. HEPTEM) will exclude the effect of heparin to provide an assessment of coagulation even during full anti-coagulation
  • Allows more targeted use of blood products
  • Are a more reliable predictor of post-operative bleeding compared to APTTr or PT/INR, perhaps because they use whole blood

Anti-phospholpid syndrome

  • Characterised by the presence of antiphospholipid antibodies; anti-thrombin, anti-cardiolipin and anti-β-2-glycoprotein
  • Results in a higher risk of arterial or venous thrombosis, with some patients on long-term anti-platelet or anti-coagulation therapy
  • The activation of phospholipids may lead to a net reduction in coagulation factors, especially prothrombin complexes, which may be associated with bleeding issues post-operatively

  • Issues include:
    • In vivo hypercoagulation
    • In vitro anticoagulation e.g. prolonged baseline ACT and APTTr

  • Management involves considering use of
    • Celite ACT instead of kaolin ACT
    • Hepcon haemostasis management system functions
    • Less protamine than normal to reverse the effects

Factor V Leiden

  • Autosomal dominant inherited thrombophilia which causes increase risk of thrombotic complications
  • Usually managed with heparin/protamine, but optimal dosing strategies aren't known

Protein C&S deficiency

  • Inherited protein C or protein S deficiencies confer an increased risk of thromboembolic complications
  • No guidelines for anticoagulation but consider:
    • Higher doses of heparin with protamine reversal
    • Lower dose (or even avoidance of) anti-fibrinolytic drugs

Haemophilia & other inherited coagluopathies

  • Aim to restore deficient clotting factors to >80% of normal levels pre-operatively, as this:
    • Aids patient blood management
    • Normalises in vitro clotting tests
  • This facilitates use of heparin/protamine as normal