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The burden of heart disease continues to increase (Sans et al, 1997), and coronary artery bypass grafting (CABG) increases with it: to 400 000/year in the U.S.A. (Motwani & Topol, 1998) and >30 000/year in the U.K. Despite developments in ‘minimally-invasive’ surgery (Bryan & Angelini, 1996), nearly all CABG — together with surgery for valvular and congenital heart disease, transplantation and major aortic procedures — is performed on unbeating hearts supported by cardiopulmonary bypass (CPB). CPB pumps blood through an extracorporeal circuit with an oxygenator which exchanges O2 and CO2. This process consequently disturbs haemostasis, often leading to excess perioperative bleeding.

Consequent allogeneic transfusion of red cells (RBC) comprises 20% of all RBC transfused in the U.S.A. (Johnson et al, 1992). U.K. figures are unavailable, but one Regional Cardiothoracic Centre, doing 4% of U.K. heart surgery, calls for 4000 RBC units/year: 17.6% of transfused RBC, which is more than all other surgery, including trauma, combined. This has produced a rapidly growing cost pressure on cardiac services; in the U.K. universal leucodepletion of blood products, due to concern about possible transmission of the agent of new-variant Creutzfeld-Jakob disease (nvCJD) by lymphocytes (Aguzzi, 1997), together with nucleic acid testing for blood-borne viruses, may double the cost in the near future.

Understanding disordered haemostasis in CPB would benefit health and economics, but has proved difficult. Proponents of complexity and chaos theories in biomedicine can find rich material in the haemostasis of CPB. The evidence base is dispersed: surgeons, anaesthetists and coagulationists tend to publish in different journals and to have different preconceptions, aims and methodologies. Determined investigators have crossed these tribal boundaries to produce substantial data and therapeutic advances.

This article attempts to ask if anything important has changed since a magisterial review by Woodman & Harker (1990); readers seeking earlier references can find them there.

Post-bypass bleeding

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

After 60 years of evolution, blood anticoagulated with the same dose of heparin received by Gibbon's cats in 1937 (300 u/kg) is pumped over 1.5–2 m2 of non-biological surface, mostly in the oxygenator where flow is engineered to be non-laminar to maximize O2 transport (Stammers, 1997); the recent generation of hollow-fibre oxygenators have reduced these factors to a minimum. Surface composition of current CPB devices includes polyurethane, polyester, plasticized PVC, polypropylene and polycarbonate (Hsu, 1997). During surgery the sternum, mediastinum, pericardium, great vessels and heart are incised and cannulated, the aorta cross-clamped, and the pulmonary circulation converted to a low-flow venous conduit fed by bronchial vessels. Exposed myocardium and pericardium are bathed in a mixture of blood and cardioplegia solution, which is drained into the cardiotomy reservoir and often re-infused directly via the CPB circuit.

Resulting cross-talk between artificial surfaces, cells and proteins in the circulating blood, traumatized vascular endothelium and extravascular tissues, creates enormous complexity which is impossible to model in vitro. Seeking a single key to this complexity, whether platelet function defect or fibrinolysis, is a fallacy which can lead to conceptual problems in research, selective readings of the literature, and polarized advocacy of one mechanism or drug effect above all others.

Given differences in bleeding rates and definitions of what is normal, excess bleeding can probably be defined as >1 litre per procedure. There is twice the risk of bleeding after valve surgery than after CABG (Hardy et al, 1991), and repeat operations redouble this risk; significantly, 19% of CABG patients need re-grafting within 10 years (Motwani & Topol, 1998). Bleeding is usually manifest postoperatively, after protamine reversal of heparin, and shed from the operative field into mediastinal and pleural drains rather than seen at remote sites. If aspirin (ASA) or other antiplatelet therapy has been given, the operation may be ‘wet’ from the start.

Consequences

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

Critical rates of blood loss, formulated by Kirklin & Barrett-Boyes (1986), are >500 ml in the first postoperative hour, >400 ml/h in the first 2 h, >300 ml/h in the first 3 h, >1litre in 4 h, or >1.2 litres in 5 h. If bleeding attains these rates, is acute and massive, or begins again after ceasing, resternotomy becomes unavoidable. Volume per se can mislead if there is progression from blood to serosanguineous drainage; the haematocrit of the fluid in the drain tubing (not the reservoir) may indicate that blood loss is being overestimated if the patient is otherwise stable.

The need for re-sternotomy entails a 30% increase in perioperative mortality, and hence is a crucial endpoint in CPB studies. In 67% of cases bleeding vessels are found, often small mediastinal arteries or the aortotomy incision; such vessels might not bleed if haemostasis were normal, but a routine check of repeat offenders before closure is worthwhile. In the remainder, general microvascular oozing is seen (Unsworth-White et al, 1995).

Transfusion criteria in CPB

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

Allogeneic RBC transfusion post-CPB shows wide, apparently irrational, variance between centres (Goodnough et al, 1991). Female gender, by determining preoperative haematocrit and blood volume, is a consistent risk-factor for transfusion (reviewed by Stehling, 1998). Some centres transfuse RBC to fewer than a third of standard-risk CPB patients, others to more than two-thirds (Stover et al, 1998), despite access to evidence-based guidelines (Goodnough et al, 1990), with similar inconsistency in platelet and fresh frozen plasma use. The U.K. situation may be similar, although CPB is more centralized.

These differences confound studies using volume as an end-point, since a transfusion-prone team out-ranks other risk-factors for RBC transfusion (Stover et al, 1998). As pointed out by Laupacis et al (1997), transfusion risk reflects the number of allogeneic exposures; studies reporting only transfused volumes (particularly as means, when marked skewing is likely) do not adequately measure this risk.

Witholding RBC unless the systemic haematocrit fell to <25% (Hb <8 g/dl) post-CPB had no adverse clinical or physiological impact in standard-risk patients (Johnson et al, 1992). Observing this threshold is likely to reduce allogeneic transfusion as much as any foreseeable method of improving haemostasis. The role of cardiac surgeons and anaesthetists in U.K. hospital transfusion committees will be vital as a means toward audit and effective guidelines in this area; without such participation, increasing scrutiny of cardiac surgery outcomes may lead to a defensive retreat from rational transfusion practice.

Space disallows consideration of reducing allogeneic exposure by pre-operative autodonation or acute normovolaemic haemodilution; a useful annotated bibliography is provided by Stowell et al (1998).

Determinants of haemostasis in CPB

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

This account covers CPB events in sequence; to avoid repetition, relevant interventions are discussed alongside, e.g. aprotinin vis-à-vis fibrinolysis.

Preoperative factors

Bleeding increases if aspirin (ASA) continues up to surgery (Kallis et al, 1994b). This effect is eliminated if ASA is stopped 7 d before, and re-started 1–6 h after, surgery. If ASA cannot be stopped, haemostasis should be enhanced by antifibrinolytic therapy (see below).

The calcium antagonist nimodipine was associated with excess post-CPB bleeding in one report (Wagenknecht et al, 1995), but this has not been confirmed, nor found with other drugs of this class (Hynynen et al, 1996).

Coumarin anticoagulation (e.g. in transplantation when a donor heart arrives too suddenly to omit warfarin) requires replacement therapy with prothrombin complex concentrate (PCC) containing factor VII (e.g. Beriplex®) if the INR is >1.7.

Coronary angioplasty/stenting with the hybrid anti-GpIIb/IIIa monoclonal agent abciximab (c7E3, ReoProTM) may need urgent conversion to CABG (Boehrer et al, 1994). Intra- and post-operative bleeding occurs, particularly if the interval between abciximab and CPB is <12 h (Gammie et al, 1998) or if standard doses of heparin are used for CPB. Reducing heparin (to ACT 400 s) with postoperative (±pre-operative) platelets is one approach (Ferguson et al, 1998). Others suggest aprotinin with platelet transfusion (6 units) given at the end of bypass (Alvarez, 1998). True and pseudo-thrombocytopenia can occur after abciximab therapy and must be distinguished from heparin-induced thrombocytopenia; an algorithm for this was provided by Berkowitz et al (1997).

Patients with congenital heart disease may acquire a deficiency of high-molecular weight von Willebrand factor (VWF; Gill et al, 1986) which rarely poses a problem since it corrects immediately post surgery (Turner-Gomes et al, 1992). Right-to-left shunts can lead to increased platelet size with misleading automated counts (check the blood film). Children with Noonan syndrome may have coagulation factor deficiencies (Sharland et al, 1992) and can bleed during surgery for heart defects; they need a haemostatic work-up before cardiac surgery.

Patients with haemophilia of any degree of severity may require CPB; the safest operative cover in all cases is high-purity plasma-derived or recombinant VIII:C or IX:C. In von Willebrand's disease a product with a reliably high content of high-molecular-weight (HMW-VWF) multimers should be used. All such patients should be managed at centres with comprehensive expertise in haemophilia.

Pre-operative thrombocytopenia compounds the bypass-induced platelet function defect (see below). The minimum acceptable pre-operative platelet count is 100 ×  109/l, requiring steroid or intravenous immunoglobulin (IVIG) therapy in immune thrombocytopenia.

CPB: the first 15 min

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

Platelet counts fall by 25–60% within 15 min of first passage of blood through the primed CPB circuit (Salzman, 1963). Simultaneously, a platelet function defect marked by the bleeding time develops (Harker et al, 1980). The speed of this effect is due to the exposure of circulating platelets to early conditions of bypass: the high concentration of unfractionated heparin (UFH), haemodilution by oxygenator prime, and the non-biological surface of the extracorporeal circuit.

Heparin effects

A direct platelet effect of UFH (3–8 U/ml) was suggested by studies that showed the fall in platelet count to begin between heparinization and the first passage of CPB (Mazer et al, 1995; Wahba et al, 1996).

Alien contact

Blood–surface interactions begin with adsorption of fibrinogen on the surface, which recruits and activates phagocytes (Tang & Eaton, 1993) initiating the post-CPB inflammatory state (Hall et al, 1997); it also attracts and activates platelets (Sly et al, 1995). In flow chamber experiments, platelet adhesion to an artificial surface in the presence of UFH is no different from that in non-anticoagulated blood (Badimon et al, 1987). In-vitro, adsorbed fibrinogen is replaced within 15 min of continued exposure to plasma (Vroman & Evans, 1967). The dominant protein becomes kinin-free high-molecular weight kininogen [HKa], bradykinin having been released by surface-activated XIIa and kallikrein (Schmaier et al, 1984; Brash et al, 1988). HKa has anti-adhesive effects on platelets (Asakura et al, 1992) and blocks their activation by thrombin (Meloni & Schmaier, 1991), so ‘passivation’ of the artificial surface may be mediated by HKa, although this has not been proved in CPB.

During this period a shower of microparticles can be detected in the circulating blood, many of which are aggregates of platelets and white cells, predominantly monocytes (Rinder et al, 1992), and the peripheral monocyte count decreases (Parrat & Hunt, 1998).

The CPB platelet lesion

There is incomplete consensus on the pathophysiology of the CPB platelet lesion, but it is plausible that contact with surface-adsorbed fibrinogen and thrombin early in CPB activates platelets, causing transient adhesion, releasing alpha-granule contents and down-modulating surface receptors for VWF and fibrinogen. The resulting circulating platelets are functionally compromised (reviewed by Woodman & Harker, 1990; Addonizio, 1990).

Platelet binding to surface-bound fibrinogen is a statistical phenomenon, rates of adhesion and detachment at different shear forces determining the density of the platelet layer (Jen et al, 1996). At high shear rates platelets adopt fully spread GpIIb/IIIa-dependent forms; further shear stress tears central holes in them (Wu et al, 1997). By analogy, in CPB, GpIIb/IIIa ‘footprints’ are found on the oxygenator surface (Wenger et al, 1989) and platelet microparticles in the blood (Abrams et al, 1990).

In CPB, platelet alpha-granule constituents are detectable in the plasma and both ultrastructure and aggregometry reveal alpha-granule depletion (reviewed by Woodman & Harker, 1990). Flow cytometry, particularly using platelet-rich plasma (Shigeta et al, 1997; Wahba et al, 1996) but also in whole blood (Mazer et al, 1995), may reveal alpha-granule P-selectin on the platelet surface; several studies using whole blood dispute this (Kestin et al, 1993; Ray & Martin, 1997; Maquelin et al, 1998). Agonist-induced alpha-granule depletion is a subtle platelet function defect; disaggregated thrombin-aggregated platelets are refractory to thrombin and vulnerable to plasmin dissociation of new aggregates (Kinlough-Rathbone et al, 1992), both defects relevant to the CPB environment.

Many flow cytometric studies in CPB demonstrate reduction of surface GpIb (van Oeveren et al, 1990), whole-platelet GpIb by radioassay being preserved (Orchard et al, 1993). Ristocetin-induced platelet aggregation (RIPA; GpIb-dependent) decreases during CPB (Lu et al, 1991); both RIPA and surface GpIb have been found to correlate with blood loss (Unsworth-White et al, 1996). Aprotinin, which reduces post-bypass bleeding (Laupacis et al, 1997; see below), seems to preserve surface GpIb when used during CPB (Van Oeveren et al, 1990), and permit the return of GpIb when used at the end (Kallis et al, 1994a). GpIb reduction is consistent with the nature of CPB bleeding; the oozing seen in 23% of patients is from small vessels with high shear rates, predictable if the GpIb–VWF binding critical to haemostasis in such vessels (Goto et al, 1998) were disturbed.

These GpIb effects would fit protease-driven receptor trafficking between the platelet surface and the canalicular system (Nurden, 1997), but evidence for this phenomenon in CPB is circumstantial, trafficking being inferred rather than directly demonstrated. Glycoprotein trafficking, both in and out of CPB, is the subject of radical disagreement: whether it occurs at all (White et al, 1995); in CPB, whether platelet-surface GpIb and GpIIa/IIIb changes are artefactual (Kestin et al, 1993); and whether aprotinin has any effect on platelet membrane GpIb in CPB (Ray et al, 1997).

Kestin et al (1993) came close to falsifying the CPB platelet hypothesis by finding no loss of GpIb, alteration in surface markers, or alpha-granule secretion in CPB using whole-blood flow cytometry. They suggested that findings by others (e.g. van Oeveren et al, 1990) were due to using centrifuged and gel-filtered platelets, compared to minimally disturbed whole blood, for flow cytometry. However, ~35% loss of surface GpIb has been found in subsequent studies using whole blood and FITC-conjugated monoclonal antibodies (McAbs) (Kallis et al, 1994a; Mazer et al, 1995; Unsworth-White et al, 1996; Maquelin et al, 1998). Differences in sampling, case-mix, CPB techniques, or the use of biotinylated versus FITC-conjugated McAbs may account for this; in CPB the scope for such variation between studies is vast (Royston, 1992). Kestin et al (1993) analysed platelets shed from skin incisions during CPB, and proposed an extrinsic platelet defect due to heparin-mediated thrombin deficiency, but it is now known that thrombin generation is supra-basal throughout CPB (Boisclair et al, 1993a).

These unexplained inconsistencies call the GpIb hypothesis of the CPB platelet lesion into question. Positive studies find surface GpIb reduced by ~35%; not enough to cause bleeding in Bernard-Soulier heterozygotes, nor to reduce platelet adhesion to collagen under flow conditions (Van Zanten et al, 1998). Others have demonstrated that the tethered-ligand thrombin receptor (PAR1) is down-regulated during CPB, also a potential protease-induced traffic flow, while the high-affinity binding site for thrombin located on GpIb is preserved (Ferraris et al, 1996). No doubt studies of PAR3 ‘et al’ in CPB will follow.

The CPB platelet defect is evidently composed of multiple lesions, individually weak, but in concert disabling parallel platelet systems to such an extent that a temporary but dangerous bleeding disorder occurs. Clinical correlates permit the model of platelet malfunction outlined at the beginning of this section until something more robust comes along.

Von Willebrand factor and CPB

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

If DDAVP improves haemostasis it suggests that circulating VWF is a determinant of post-CPB bleeding. Reduced plasma VWF (Perrin et al, 1995) and platelet VWF (Kallis et al, 1994a) continue to be found in CPB; others have detected post-CPB depletion of HMW-VWF, if only in patients who bleed the most (Unsworth-White et al, 1996). However, meta-analysis indicates no significant blood-sparing effect in the totality of trials of pre-CPB DDAVP (Laupacis et al, 1997). Perhaps DDAVP-induced release of endothelial tissue-type plasminogen activator (tPA) (Wall et al, 1998) removes any benefit by increasing post-bypass fibrinolysis (see below). Low VWF is associated with blood group O (Gill et al, 1987): re-analysis of DDAVP/CPB trials to see if improved haemostasis was restricted to individuals of blood group O would be of interest.

Platelet protection

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

If platelet damage in CPB follows the interaction with surface-adsorbed fibrinogen, blocking it might preserve platelet function during CPB. Platelet adhesion to surfaces can be reduced by nitric oxide (NO) (Radomski, 1987), which also inhibits fibrinogen–platelet binding (Gries et al, 1998); infusion of the NO donor, S-nitrosoglutathione, did not modify CPB-induced changes in platelet expression of GpIb or P-selectin (Langford et al, 1997), but 500 ppm of NO added to the sweep gas reduced platelet adhesion to the oxygenator membrane by 95%, at the cost of 4% methaemoglobinaemia (Sly et al, 1996). This direct approach, taking advantage of the gas transfer function of the platelet-activating surface itself, looks both elegant and promising; further studies are required.

Fibrinogen receptor blockade with monoclonal anti-GpIIb–IIIa, despite being associated with higher post-CPB platelet counts after urgent conversion to CABG (Ferguson et al, 1998), is too potent and long-lasting, resulting in increased blood loss. However, eptifibatide (integrelin), a short-acting synthetic heptapeptide antagonist of the fibrinogen receptor, has been used with success in a preliminary trial (Uthoff et al, 1994) and deserves further investigation.

Autologous platelets can bypass the bypass via pre-operative platelet apheresis, returning the platelet autodonation to the patient post-CPB (Giordano et al, 1989). Prospective trials of this fundamental test of the platelet hypothesis of post-CPB bleeding are in progress. The platelets are still exposed to shear stress and artificial surfaces, and time and expense are forbidding.

Platelet replacement

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

Current practice is to transfuse 2 UK units (=100 × 109/l) of platelets post-CPB when excess chest tube blood drainage becomes evident, whatever the platelet count. Although accounting for 23% of platelet usage in one regional centre, and empirically supported by the evidence quoted above, there is no prospective trial data proving this effective, or to indicate the ideal dose or frequency. However, platelet transfusion is associated with reduction in the rate of blood loss in most cases.

‘Real’ fresh whole blood was given a last hurrah in a study which confirmed its haemostatic efficacy (Mohr et al, 1988), but because it is virally unsafe, contravenes good manufacturing practice, and would leave blood banks defenceless in product liability litigation, it is unusable.

Thrombin generation during CPB: not the contact factor system

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

CPB is a test bench for the new central dogma of the coagulation pathway, in which tissue factor complexed with activated factor VII (TF/VIIa) generates thrombin by cleaving both factor X and factor IX. Activated factor XII, kallikrein and HMWK are no longer thought to contribute to thrombin generation in vivo (Rapaport & Rao, 1995).

This contradicts the commonsense notion that contact with the CPB circuit initiates clotting via a pathway which seems to be lying in wait for just such an unnatural event. Contact activation has generally been assumed rather than proven in CPB; nascent factor XIIa and kallikrein were detected in enzyme–inhibitor complexes in CPB (Wachtfogel et al, 1989), but in a later study a change in the ratio of kallikrein–C1 esterase inhibitor complexes (kal-C1Inh) to prekallikrein, late in CPB, was the only detectable marker (te Velthuis et al, 1997). In the new model this somewhat reticent contact activation generates bradykinin and activates complement rather than thrombin.

Thrombin, tracked by assays of thrombin-modified antithrombin (ATm) (Lu et al, 1991), thrombin–antithrombin complex (TAT) and prothrombin activation peptide (F1 + 2) (Boisclair et al, 1993a, b; Parratt & Hunt, 1998), appears throughout CPB despite high UFH and TFPI levels (Cardigan et al, 1996), and is incriminated in the platelet lesion and hyperfibrinolysis of CPB (Teufelsbauer et al, 1992). The source of this thrombin is elusive; although dependent on the CPB circuit (Hunt et al, 1998), it is evident before factor IX activation (Boisclair et al, 1993b) and despite very low inherited levels of factor XII (Burman et al, 1994), tending to exclude an origin in contact activation and suggesting TF/VIIa activity during CPB. Generation of factor Xa during CPB also precedes factor IXa, indicating that TF/VIIa working through factor X activation is the initiator rather than factor XIIa (Philippou et al, 1995).

One potential site of TF/VIIa is the surface of circulating monocytes (Mø). Mø-platelet aggregates detected during CPB (Rinder et al, 1992) are highly procoagulant (Nieuwland et al, 1997), and likely to be linked by platelet P-selectin (Larsen et al, 1989) which can up-regulate Mø-TF expression (Celi et al, 1994). Mø-TF expression by flow cytometry was found to be increased in CPB blood by Kappelmeyer et al (1993), but delayed for 20 h (Ernofsson et al, 1997) or undetectable (Parratt & Hunt, 1996) by others. Plasma VIIa, by clot-based assay after heparin removal, is sub-basal during CPB (Unsworth-White et al, 1996; Cardigan et al, 1996), coinciding with a surge of UFH-released TFPI (Cardigan et al, 1996), so if Mø TF/VIIa is responsible for thrombin generation in CPB it must be inaccessible to plasma assay and protected from TFPI. It must also evade the heparin/AT complex, which blocks TF/VIIa activity (Rao et al, 1995). Proponents of the TF/VIIa origin of thrombin in CPB need an explanation for escape from the heparin-mediated double lock on TF/VIIa.

Increased procoagulant activity is expressed by Mø adherent to the oxygenator (Barstad et al, 1996) and in blood shed into the pericardial sac (Chung et al, 1996). The Mø surface receptor CD11b activates factor X directly (Plescia & Altieri, 1996), and increased Cd11b-mediated Xa generation by Mø, without evidence of Mø TF/VIIa expression, has been detected in clinical CPB by Parrat & Hunt (1998), who also found deposition of CD11b-expressing Mø on the walls of oxygenator fibres. Monocytes, acting at different sites by different mechanisms, are currently the most plausible source of thrombin in CPB.

This draws attention to the blood that has drained across the exposed TF-rich myocardial surface to mix with cardioplegic solution in the cardiotomy reservoir and be re-infused into the CPB circuit. Regarded as worthy salvage material decreasing the need for allogeneic RBC, the haematocrit of cardiotomy drainage is usually low, and it allows unwanted proteases access to the circulation. As well as TF-expressing Mø (Chung et al, 1996), cardiotomy drainage contains procoagulant cell microparticles derived from platelets and leucocytes at 10 times the concentration found in systemic CPB blood (Nieuwland et al, 1997). A prospective trial to find if thrombin generation during CPB depended on this re-infusion would be interesting. The cardiotomy reservoir is also a site of brisk fibrinolysis (Tabuchi et al, 1993; see below).

Heparin/AT: more?

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

A simpler cause of thrombin generation in CPB, despite high-dose heparin, would be insufficient heparin/AT activity. Heparin in CPB is monitored by point-of-care devices which measure a celite-activated whole blood clotting time, the ACT. The ACT is affected by factors other than heparin concentration and can mislead as a measure of circulating heparin, particularly in children (Chan et al, 1997). Adaptations of the test (e.g. Hepcon® or Hemachron® RxDx, which introduce heparin sensitivity and/or protamine titration steps) have been explored in an attempt to optimize heparin dosage and reversal by protamine. When guided by these devices, more heparin and less protamine tends to be given (Despotis et al, 1996) and there is evidence of decreased thrombin generation, but reductions in bleeding and blood product use have not been confirmed (Shore-Lesserson et al, 1998).

Plasma antithrombin (AT) levels decrease during CPB (Hashimoto et al, 1994) to a degree that limits heparin action in vitro (Despotis et al, 1997). Supplementation by plasma-derived AT concentrate reduces markers of thrombin generation during CPB (Hashimoto et al, 1994). Further prospective trials of AT in CPB are indicated.

Heparin/AT: less?

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

The opposite tack has been taken by bonding heparin to the surface of the CPB circuit and oxygenator, the most sophisticated version creating a vertical array of heparin molecules exposing the AT-binding pentasaccharide. Despite a fall in markers of the inflammatory response to CPB, and reduction of systemic heparin dose to 100–150 u/kg, such circuits have not shown clinically significant reduction of bleeding or exposure to allogeneic blood (reviewed by Levy & Hartman, 1996).

Heparin reversal and protamine

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

Polyanionic protamine from salmon semen inactivates heparin electrostatically. Even if the 1 mg protamine/100 u UFH dose is optimized by bedside titration (see above), there remains concern over under-reported toxicity, including anaphylaxis and haemodynamic instability, which occurs in up to 13% of exposees (Kimmel et al, 1998). Protamine-heparin mimics immune complexes, activating complement via the classic pathway, particularly in individuals with partial deficiency of C4A (Shastri et al, 1997). Rebound VIIa (Unsworth-White et al, 1996) naturally appears after protamine reversal, but protamine has been defended against guilt-by-association for post-CABG myocardial infarction (Horrow, 1994), and in any case rapid heparin reversal can hardly be avoided. Alternatives to protamine include heparinase I (Ammar & Fisher, 1997) and recombinant platelet factor 4 (D'Ambra, 1996); they reverse heparin rapidly and specifically, but these theoretical benefits do not yet justify the increase in cost.

CPB and HIT: alternatives to heparin

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

The antibody-mediated drug reaction heparin-induced thrombocytopenia (HIT) may explain anecdotes of catastrophic filter occlusion and arterial embolization in CPB. Up to 60% of CPB patients develop anti-heparin/PF4 antibodies (Visentin et al, 1996), but only 10% are likely to develop thrombocytopenia (Warkentin et al, 1995), usually at the postoperative stage and self-limiting, although thrombocytopenia and venous thromboembolism have been reported 11 d post-CPB (Munver et al, 1994). Asymptomatic cases should be documented in case repeat CPB is needed. Reference methods of confirming HIT are rarely available, and the false-negative rates of aggregometry and ELISA mean that the weighty decision to rule out heparin for CPB may have to be made on probability (e.g. a rising platelet count off heparin).

Danaparoid (Orgaran), a mixture of non-crossreacting LMW heparinoids, is the best-documented substitute for UFH in CPB (Magnani, 1993). A dose of 7500 u i.v./1500 u to the prime, then 1500 u i.v. if anti-Xa assay <0.8 u/ml (Gillis et al, 1997) minimizes excess bleeding. Danaparoid is undetectable by ACT, poorly reversed by protamine, and has a long half-life, features not popular with surgical teams. Persistent clot formation in atrial cannulae has been reported in CPB with Orgaran in the presence of HIT (Grocott et al, 1997).

Pre-operative infusion of the fibrinogenolytic snake enzyme ancrod allows CPB in non-HIT CABG patients when plasma fibrinogen is <0.5 g/l (Zulys et al, 1989), and has been used for CPB in HIT (O-Yurvati et al, 1994); its effect can be reversed by fibrinogen (cryoprecipitate). In one case of CPB with ancrod in HIT, atrial cannula clot occurred despite a plasma fibrinogen of 0.1 g/l; this paradoxical clot formation indicates that HIT patients, who have severe acquired thrombophilia, are not comparable to fit individuals in their responses to anticoagulants, and may need individualized protocols, e.g. combination of ancrod and intermediate-dose (7000 u) danaparoid (Kanagasabay et al, 1998). Such steps into the unknown require maximum in-theatre liaison between surgeon, anaesthetist and haematologist.

Delaying CPB until HIT antibody is no longer detectable is not recommended in view of the insensitivity of commonly-available assays. Iloprost works but causes haemodynamic instability, and r-hirudin and argatroban have occasionally been used with success (reviewed by Slaughter & Greenberg, 1997). Further exploration of these alternatives is required.

Fibrinolysis in CPB

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

The endothelia of the mammalian heart and coronary circulation are rich in tissue-type plasminogen activator (t-PA; Jern et al, 1997), and heart surgery releases it (Valén et al, 1994). Resulting fibrinolysis in the pericardial cavity (Tabuchi et al, 1993) and throughout the surgical field defibrinates the blood shed into the mediastinal drains, rendering it incoagulable; when salvaged and re-infused it is at best equivalent to a colloidal blood expander if a heparin-coated salvage circuit is used (Unsworth-White et al, 1996): at worst, its content of fibrin degradation products may compromise haemostasis (de Haan et al, 1993).

Many studies have confirmed active systemic fibrinolysis in CPB (e.g. Orchard et al, 1993; Mannucci et al, 1995; Chan et al, 1997) and related it to excess bood loss (Gram et al, 1990). Phasic fibrinolytic activator/inhibitor patterns occur in 40% of individuals: t-PA activity rises 30 min into CPB, but is quenched by rising PAI-I so little t-PA activity is left post-operatively. Other patients (26%) show strong t-PA release unmodified by PAI-I, or PAI-I excess throughout CPB (24%); in 10% the fibrinolytic system remains inert in CPB (Chandler et al, 1995). This study did not correlate fibrinolytic patterns with blood loss. It would be interesting to look for a relationship between different CPB responses and 4G/5G polymorphism at the PAI-I promoter region, particularly since CABG selects 4G homozygotes (Wiman, 1995). Postoperatively, there is a rebound increase in fibrinogen lasting up to 30 d (Mannucci et al, 1995).

Despite its contact initiation by kallikrein, the urokinase pathway, as currently measurable, does not seem active in post-CPB hyperfibrinolysis (Chandler et al, 1995; Ray & Martin, 1997). This mirrors the loss of role for contact activation in thrombin generation in CPB. It implies that the operative field drives post-CPB fibrinolysis; see the lack of activation of fibrinolysis in simulated, vascular endothelium-free CPB (Wachtfogel et al, 1995). This begs the question why similar operations without CPB (Buffolo et al, 1990) do not lead to bleeding. Cross-talk between the extracorporeal circuit and operative field, mediated by platelets, monocytes, thrombin and vascular endothelium, must be invoked (Teufelsbauer et al, 1992).

FFP and cryoprecipitate in CPB

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

Because of the perceived depletion of fibrinogen and other coagulation factors in the immediate postoperative period, post-CPB bleeding is routinely treated with fresh frozen plasma (FFP) or cryoprecipitate in the U.K. The rationale for FFP use in CPB is debatable. Long coagulation screen times correlated poorly with bleeding in CPB in one study (Gelb et al, 1996); in another a prothrombin time >12.5 s (INR not given) was moderately predictive of post-CPB bleeding when submitted to receiver operator characteristic (ROC) analysis (Ereth et al, 1998). Giving post-CPB FFP only if the prothrombin time is prolonged seems justifiable, but heparin, platelets and fibrinolysis — the three main actors in CPB bleeding — are unaffected. A well-known reflex (bleeding = 2 × FFP) may be operating. No prospective data exists on FFP efficacy post-CPB. This single donor product (×2) undergoes no anti-viral processing in the U.K. at present.

A dose of 12 units of cryoprecipitate provides fibrinogen in poorly-standardized form with unknown content of cold-activated proteases. No prospective data exists on its efficacy in CPB. In England and Wales this multi-donor product undergoes no anti-viral processing, so is no longer used in hereditary bleeding disorders; giving it to those with an acquired bleeding disorder therefore involves a double standard, although lifetime exposure is obviously less. Intermediate purity virus-inactivated fibrinogen concentrates are expensive and restricted to large Haemophilia Centres in the U.K.

The risk–benefit equations for cryoprecipitate, and to a lesser degree FFP, in CPB are questionable; they subvert the aim of reducing allogeneic blood exposure. Whole-blood thrombo-elastography (TEGTM), distrusted in near-patient mode by many coagulationists (another simple reflex?), may help. A complete post-CPB TEG trace takes 45–60 min and could be regarded as signalling risk more slowly than the real system it models. However, the initial parameters are available relatively quickly, and restricting FFP to cases with prolonged TEG®-R may reduce usage. This possibility, together with TEG modified by heparin inactivation or clot promoters, is being explored in prospective studies which may resolve the potential for reducing blood product usage in CPB.

Plasmin inhibition: aprotinin and tranexamic acid

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

Aprotinin in CPB was pioneered by Royston et al (1987) who found it reduced blood loss after primary and repeat operations. Aprotinin (Trasylol®, Bayer AG) a mast-cell polypeptide extracted from bovine lung, pancreas and parotid, is the prototypic broad-specificity (Kunitz-type) proteinase inhibitor, co-discovered by Kunitz & Northrop (1936). It consists of a single domain with homology to TFPI. Its activity is measured in kallikrein inhibitor units (KIU) but it is a more potent inhibitor of human plasmin than of human kallikrein (reviewed by Fritz & Wunderer, 1983). Strongly basic, it binds to artificial surfaces and heparin, preserves platelet function in storage (Bode et al, 1990), inhibits platelet adhesion to vascular endothelium (Royston et al, 1992) and prevents platelet aggregation by plasmin (Watabe et al, 1997). The bovine source of aprotinin has not escaped notice in the era of spongiform encephalopathies; it is currently extracted from Uruguayan herds and the manufacturing process has demonstrated 18 log reduction of added prions (scrapie agent) in spiking experiments (Golker et al, 1996).

Discovery of the aprotinin effect on CPB blood loss led to the standard (Munich) dose regimen: 2 × 106 KIU bolus to the patient, 2 × 106 KIU to the prime then 0.5 × 106 KIU/h; usual total dose 6 × 106 KIU (reviewed by Royston, 1992).

A meta-analysis by investigators of the International Study of Peri-Operative Transfusion (ISPOT) of 45 aprotinin trials reporting exposures to units of allogeneic RBC showed that aprotinin reduced such exposure by two-thirds and re-sternotomy by one-half; these beneficial outcomes were seen in all operations, primary or repeat, on or off ASA, and at transfusion thresholds of 10 g/dl or 8 g/dl. Reduced-dose aprotinin (4–6 × 106 KIU) was as effective as 6 × 106 KIU; an insignificant trend to less efficacy was only seen at <2 × 106 KIU (Laupacis et al, 1997). The authors caution that small sample sizes in individual studies and ‘unexplained heterogeneity’ in their results meant that meta-analysis should be a prologue to definitive large randomized trial(s), and remind us that meta-analyses in other contexts, based on larger studies than those available on CPB, have proved false-positive when compared to subsequent definitive studies.

The ISPOT meta-analysis also studied 12 trials of the synthetic lysine analogue tranexamic acid (TA; Cyclokapron) with 882 patients and concluded that TA (10 mg/kg bolus followed by 1 mg/kg/h) halved CPB blood loss, but did not reduce re-sternotomies. When aprotinin was compared to TA (seven studies, 474 patients) no significant difference was seen in exposure to allogeneic blood. A cost-effectiveness study comparing aprotinin with a lysine analogue (Bennett-Guerrero et al, 1997) unsurprisingly found in favour of the cheaper agent (EACA).

Problems of thrombogenesis and graft occlusion

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

However much post-CPB hyperfibrinolysis increases bleeding and antifibrinolytic therapy decreases it, the purpose of most CPB is to replace diseased coronary arteries with vein grafts. Aortocoronary saphenous vein graft disease (ASVGD) occurs in 15% of grafted vessels within a year; between 3% and 12% become occluded within a month of CPB (Motwani & Topol, 1998). Platelet and thrombin-mediated events at the disturbed venous endothelium in the early postoperative period are likely to determine this risk (Moor et al, 1994; Motwani & Topol, 1998). If antifibrinolytic therapy decreased the 5% who bleed but increased the 15% with ASVGD it might be an anti-benefit; via more repeat operations it could paradoxically increase net allogeneic transfusion for CPB.

There is robust debate between those persuaded that the haemostatic benefit of aprotinin extends to the greatest possible number (Royston, 1992) and those who, alarmed by reports of postoperative thrombotic events (Cosgrove et al, 1992), would restrict it to very few (Westaby, 1993). This worry persists despite universal adjustment of target ACT to >700 s in the presence of aprotinin. Its rebuttal depends on statistically insignificant numbers of thrombotic events in prospective studies (Bidstrup et al, 1993) rather than on attempts at theoretical demolition (Royston, 1994).

Even in meta-analysis the number of patients in prospective studies of aprotinin does not provide enough power to exclude thrombotic risk expressed as postoperative myocardial infarction or graft occlusion (Laupacis et al, 1997); given this, ‘disagreement’ between trials showing statistically insignificant rates of thrombotic events and case reports of such events (e.g. Umbrain et al, 1994) is predictable, e.g. in the subgroup of patients having CPB under deep hypothermia for major aortic procedures (Ehrlich et al, 1998; Alvarez et al, 1998).

The ISPOT meta-analysis indicates the broad applicability of aprotinin required if the aim of therapy is to reduce total blood usage in CPB; the current exponential increase in the cost of blood seems to mandate this approach.

On the other hand, if the target is restricted to the dangerous bleeding seen in 5% of patients it is reasonable to give aprotinin (or TA) only in patients (see above) most likely to bleed; unpredicted bleeding could then be treated with postoperative aprotinin (Kallis et al, 1994a).

The large definitive prospective trial of aprotinin with sufficient power to resolve postoperative thrombosis and ASVGD called for by the ISPOT investigators is badly needed. Until then, individual units must plan their use of aprotinin or TA according to their casemix and priorities.

CPB futures

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References

Control of post-CPB bleeding involved ‘… packed cells, platelets, plasma, protamine and prayer’ (Hall, 1998). Potential refinements are discussed above but I have not given a single management algorithm for post-CPB bleeding; the evidence admits different interpretations, and any plan has to be agreed between the surgeons, anaesthetists and haematologists who work together in local teams. Every unit should have a plan, stick to it and audit it, wherever possible enlisting in prospective randomized trials. In general, proper trials, rather than basic studies, have taught us what to do in CPB.

Haematologists must get involved or they will be sidelined. Proliferating near-patient devices, testing whole-blood coagulation, platelet function and heparin by novel means, dominate the current anaesthetic literature. Independent comparative evaluation of these devices away from the CPB point-of-care has been limited, lacks appropriate methodology, and needs the attention of coagulationists.

It is likely that the cauldron contents (lung of pig, pancreas of cow, sperm of salmon, etc.) swirling around the CPB patient will be replaced by recombinant products with greater specificity, as in other areas of haemostatic medicine. Fears of their expense will recede as human blood itself becomes a luxury.

References

  1. Top of page
  2. Post-bypass bleeding
  3. Consequences
  4. Transfusion criteria in CPB
  5. Determinants of haemostasis in CPB
  6. CPB: the first 15 min
  7. Von Willebrand factor and CPB
  8. Platelet protection
  9. Platelet replacement
  10. Thrombin generation during CPB: not the contact factor system
  11. Heparin/AT: more?
  12. Heparin/AT: less?
  13. Heparin reversal and protamine
  14. CPB and HIT: alternatives to heparin
  15. Fibrinolysis in CPB
  16. FFP and cryoprecipitate in CPB
  17. Plasmin inhibition: aprotinin and tranexamic acid
  18. Problems of thrombogenesis and graft occlusion
  19. CPB futures
  20. References
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