TY - JOUR
AU1 - Dickinson, K J
AU2 - Troxler, M
AU3 - Homer-Vanniasinkam, S
AB - Abstract Background Disordered coagulation complicates many diseases and their treatments, often predisposing to haemorrhage. Conversely, patients with cardiovascular disease who demonstrate antiplatelet resistance may be at increased thromboembolic risk. Prompt identification of these patients facilitates optimization of haemostatic dysfunction. Point-of-care (POC) tests are performed ‘near patient’ to provide a rapid assessment of haemostasis and platelet function. Methods This article reviews situations in which POC tests may guide surgical practice. Their limitations and potential developments are discussed. The paper is based on a Medline and PubMed search for English language articles on POC haemostasis and platelet function testing in surgical practice. Results POC tests identifying perioperative bleeding tendency are already widely used in cardiovascular and hepatic surgery. They are associated with reduced blood loss and transfusion requirements. POC tests to identify thrombotic predisposition are able to determine antiplatelet resistance, predicting thromboembolic risk. So far, however, these tests remain research tools. Conclusion POC haemostasis testing is a growing field in surgical practice. Such testing can be correlated with improved clinical outcome. Introduction Assessment of haemostasis and platelet function is important in surgical practice. Haemostatic dysfunction may complicate numerous surgical pathologies and their management, including major trauma, cardiopulmonary bypass, liver transplantation and ruptured aortic aneurysm. In the assessment of bleeding tendencies, results of routine laboratory investigations provide only a snapshot of the clinical situation at the moment the sample was taken; furthermore, such results are often available only after a considerable delay. Point-of-care (POC) testing involves assays performed outside the laboratory by non-specialist personnel1. With regard to haemostasis, these tests provide a global assessment of thrombosis or information specific to platelet function or both. The major advantages over laboratory testing are that POC-generated results are produced more rapidly and frequently, so providing more contemporaneous data to guide patient care. For example, platelet aggregometry2,3 performed in the laboratory involves the measurement of changes in light transmission through platelet-rich plasma after the addition of an agonist. This technique has been described as the ‘gold standard’ of platelet function testing, but it takes time and trained laboratory personnel, and it is impossible to perform at the bedside. In contrast, a POC test such as the activated clotting time (ACT) requires no specialist staff, takes minutes to complete and may be performed on the ward or in the operating room. Surgical patients may also have thrombotic tendencies and POC tests have been developed to assess platelet function, including response to antiplatelet therapy. Such testing aims to classify patients by their reaction to aspirin or clopidogrel as ‘responders’, ‘non-responders’ (may exhibit antiplatelet resistance) or ‘hyper-responders’ (may be at increased risk of surgical bleeding while receiving antiplatelet medication). It is then possible to tailor medication according to a patient's therapeutic response. This article reviews the clinical situations in which POC testing of haemostasis and platelet function guides surgical practice. It describes the bedside tests that are available. Test limitations and precautions required for data interpretation are also discussed, together with possible future developments. Methods A search of Medline and PubMed was performed with manual searching of bibliographies for relevant key references. The following search terms were used: ‘(point of care or point-of-care) and surgery’, ‘surgery and (haemostasis or platelet or thrombosis or bleeding)’, ‘(thromboelastography or TEG® or thromboelastometry) and surgery’, ‘(VerifyNow® or Ultegra® Rapid Platelet Function Analyzer or Ultegra® RPFA) and surgery’, ‘(Platelet Function Analyzer-100 or PFA-100®) and surgery’, ‘(activated clotting time or ACT) and surgery’, ‘Sonoclot® and surgery’, ‘(Clot Signature Analyzer® or CSA) and surgery’, ‘trauma and (point of care or point-of care)’. Results Tests to identify bleeding tendency: high-risk patients Although POC haemostasis and platelet testing may aid care of any critically ill surgical patient, it is likely to be particularly helpful in certain groups vulnerable to haemorrhagic complications. These include patients undergoing hepatic, cardiac or arterial surgery and victims of polytrauma. Perioperative POC testing of haemostasis or platelet function would be invaluable if it could identify patients at increased risk of postoperative haemorrhage. This might guide the preoperative cessation of antiplatelet medication as well as the perioperative administration of heparin, protamine or blood products, optimizing haemostasis and possibly reducing complications. Hepatic surgery Liver tumours often develop against a background of parenchymal liver disease predisposing to portal hypertension and coagulopathy. The proportion of patients who require transfusion for liver surgery depends on the complexity of the resection and values of 40 per cent are common4. Although rates as low as 20 per cent have been reported, the median transfusion requirement with extended left hepatectomy is still 1·5 units4. Strategies to reduce blood loss and transfusion requirements may be employed. These include manual compression of the hepatic artery and portal vein (Pringle's manoeuvre), in situ hypothermic perfusion to allow hypothermic cellular protection and ex vivo resection, and the administration of recombinant factor VIIa (rVIIa)4–6. POC haemostasis testing should prove beneficial in this situation if it could detect preoperative coagulopathy. This would allow correction with appropriate blood factor transfusion, aiming to decrease subsequent intraoperative blood loss. In a similar fashion, intraoperative haemostasis monitoring might guide optimal use of expensive products, such as rVIIa. Cardiovascular surgery Patients undergoing major vascular surgery often have heparin to prevent thrombosis of stagnant blood. The use of heparin in elective open abdominal aortic aneurysm repair has been demonstrated not to affect the risk of bleeding or thromboembolic complications, but myocardial infarction (MI) is rendered less likely, presumably owing to reduced coronary thrombosis7. Perioperative MI occurred in 1·4 per cent of patients with heparin and 5·7 per cent of those not receiving heparin7. If heparin is used, protamine may be administered to reverse its effect, but this may cause severe non-immunological or immunological reactions8. Non-immunological reactions are thromboxane- and histamine-mediated and can be controlled by slowing the administration of protamine and giving vasopressors. Immunological reactions are unpredictable and can be difficult to manage. A selective policy with respect to protamine use is required to minimize adverse effects. Open thoracoabdominal aortic aneurysm repair is associated with significant haemostatic dysfunction, partly resulting from systemic heparinization, mild permissive hypothermia (32–34 °C) and left-heart bypass with centrifugal pump9. Consequently, significant haemorrhagic complications are common and the need for reoperation for bleeding in large series is 2·5–5·1 per cent10,11. Similarly, the use of cardiopulmonary bypass during coronary artery bypass grafting (CABG) has diverse and complex effects on haemostasis (Table 1)12–20. Following CABG, postoperative bleeding is relatively common, with 20 per cent of patients having perioperative haemostatic abnormalities, requiring reintervention in 2–6 per cent21,22. This has important clinical implications as re-exploration is associated with a three to fourfold increase in mortality23. Table 1 Effects of cardiopulmonary bypass on haemostasis Feature of cardiopulmonary bypass . Effect on haemostasis . Contact with artificial surface of bypass circuit/air bubbles Decreased coagulation factors (primarily because of factor XII activation) Thrombin generation Activation of fibrinolysis Platelet dysfunction (decreased ADP and collagen-induced aggregation) Haemodilution (extracorporeal circuit primed with crystalloid solution) Decreased coagulation factors Thrombocytopenia, platelet dysfunction Activation of fibrinolysis Reperfusion of pericardial blood Activation of extrinsic coagulation Hypothermia Altered platelet function (e.g. aggregation) Heparin administration Binds antithrombin and increases binding affinity for factor Xa and thrombin Risk of heparin-induced thrombocytopenia type II Protamine administration Inhibits coagulation and platelet aggregation in high doses, with a paradoxical increased risk of bleeding Feature of cardiopulmonary bypass . Effect on haemostasis . Contact with artificial surface of bypass circuit/air bubbles Decreased coagulation factors (primarily because of factor XII activation) Thrombin generation Activation of fibrinolysis Platelet dysfunction (decreased ADP and collagen-induced aggregation) Haemodilution (extracorporeal circuit primed with crystalloid solution) Decreased coagulation factors Thrombocytopenia, platelet dysfunction Activation of fibrinolysis Reperfusion of pericardial blood Activation of extrinsic coagulation Hypothermia Altered platelet function (e.g. aggregation) Heparin administration Binds antithrombin and increases binding affinity for factor Xa and thrombin Risk of heparin-induced thrombocytopenia type II Protamine administration Inhibits coagulation and platelet aggregation in high doses, with a paradoxical increased risk of bleeding ADP, adenosine diphosphate. Open in new tab Table 1 Effects of cardiopulmonary bypass on haemostasis Feature of cardiopulmonary bypass . Effect on haemostasis . Contact with artificial surface of bypass circuit/air bubbles Decreased coagulation factors (primarily because of factor XII activation) Thrombin generation Activation of fibrinolysis Platelet dysfunction (decreased ADP and collagen-induced aggregation) Haemodilution (extracorporeal circuit primed with crystalloid solution) Decreased coagulation factors Thrombocytopenia, platelet dysfunction Activation of fibrinolysis Reperfusion of pericardial blood Activation of extrinsic coagulation Hypothermia Altered platelet function (e.g. aggregation) Heparin administration Binds antithrombin and increases binding affinity for factor Xa and thrombin Risk of heparin-induced thrombocytopenia type II Protamine administration Inhibits coagulation and platelet aggregation in high doses, with a paradoxical increased risk of bleeding Feature of cardiopulmonary bypass . Effect on haemostasis . Contact with artificial surface of bypass circuit/air bubbles Decreased coagulation factors (primarily because of factor XII activation) Thrombin generation Activation of fibrinolysis Platelet dysfunction (decreased ADP and collagen-induced aggregation) Haemodilution (extracorporeal circuit primed with crystalloid solution) Decreased coagulation factors Thrombocytopenia, platelet dysfunction Activation of fibrinolysis Reperfusion of pericardial blood Activation of extrinsic coagulation Hypothermia Altered platelet function (e.g. aggregation) Heparin administration Binds antithrombin and increases binding affinity for factor Xa and thrombin Risk of heparin-induced thrombocytopenia type II Protamine administration Inhibits coagulation and platelet aggregation in high doses, with a paradoxical increased risk of bleeding ADP, adenosine diphosphate. Open in new tab Traditional laboratory testing of haemostasis and platelet function, such as platelet aggregometry, is too complex and impractical for use in the management of bleeding after cardiac or arterial surgery. Platelet count, fibrinogen level and international normalized ratio are much more accessible haematological tests; these, unfortunately, correlate poorly with aberrant platelet function and are relatively insensitive for the prediction of postoperative bleeding24. Antiplatelet agents Although effective in preventing thrombotic complications, antiplatelet agents may promote bleeding during surgery. Most vascular surgical patients should be prescribed antiplatelet medication, but this results in increased blood loss and transfusion requirements if they are not discontinued before operation25. Patients undergoing CABG while receiving clopidogrel have an 85 per cent increase in platelet transfusion, owing to increased chest tube drainage, compared with those not receiving the drug26. However, if clopidogrel is withheld, the chance of ischaemic complications such as MI increases; drug-eluting coronary stents are particularly at risk. Continuation of dual antiplatelet therapy (aspirin plus clopidogrel) is associated with the lowest risk of in-stent thrombosis and is generally advised, accepting that bleeding complications will be increased. However, the balance of risk versus benefit must be carefully weighed for each patient27. Massive blood transfusion and trauma Massive transfusion (defined as the replacement of one total blood volume in 24 h28) often occurs after trauma or during emergency surgery for bleeding. Tissue perfusion and oxygenation must be restored by the replacement of blood volume, but it is important to correct any coagulopathy, which may occur for a number of reasons. These include hypothermia (exposure and administration of non-warmed blood products), citrate-mediated hypocalcaemia, dilution of platelets and coagulation factors with transfusion of packed red blood cells, and disseminated intravascular coagulation with further consumption of platelets and coagulation factors29. Geeraedts and colleagues30 suggest that blood loss after trauma cannot be estimated as accurately as during elective surgery. The patient may be subject to ‘blind’ massive transfusion, often deficient in fresh frozen plasma and platelets. POC testing could allow real-time monitoring of haemostasis during such resuscitation to guide blood product use, which might avoid under- or overtransfusion and the associated complications. Tests to identify bleeding tendency: the assays Activated clotting time Activated clotting time (ACT) is a measurement of whole blood clotting potential first described by Hattersley in 1966 (Table 2). ACT allows a quantified measurement of heparin activity, for example during cardiovascular surgery, and so the appropriate and judicious administration of protamine. ACT use has resulted in a reduction in chest drainage, operation length and the need for fresh frozen plasma, platelets and red blood cells in patients undergoing cardiac surgery11. This has the potential to reduce the risk of infection, immunosuppression and other complications of blood component therapy11, 35–37. In addition, the ACT is reproducible with a variability well below 10 per cent38. Table 2 Point-of-care tests to assess bleeding tendency in surgical patients Test . Methodology . Parameter assessed . Surgical use . Activated clotting time Kaolin/celite added to blood accelerates clotting by contact activation. Global assessment of haemostasis Widely available and commonly used to monitor heparin treatment during vascular and particularly cardiac surgery when high doses of heparin are administered (300 units/kg compared with ∼70 units/kg typical of abdominal aortic aneurysm repair)4 Subsequent clot formation is detected by inhibition of plunger movement in a well31 Detection limit is 0·5 unit/ml heparin, so it is suitable for monitoring high-dose heparin treatment, unlike activated partial thromboplastin time41 HemoSTATUS® (platelet-activated clotting test) Uses platelet-activating factor to shorten the kaolin-activated clotting time in whole blood32 Platelet responsiveness and whole blood procoagulant activity Potential for use in cardiovascular surgery Thromboelastography (TEG®) Dynamic measurement of physical properties of blood clot Coagulation and fibrinolysis Cardiac surgery: European Association for Cardio-Thoracic surgery guidelines state that TEG® can be used to guide postoperative transfusion, but further study is required before it can be recommended as the standard care for postoperative transfusion management Measurement of clot formation in an oscillating cylindrical cup at 37 °C. The rotation of a pin suspended within the blood is measured and converted to an electrical signal which is then amplified and charted33. A graph is produced, which represents clot formation and lysis and can be interpreted to determine speed and strength of clot formation (Fig. 1) Speed of clot formation and strength of this clot Liver transplant surgery Trauma Sonoclot® analyser Detects the change in impedance to movement of a vibrating probe within a developing clot. Like TEG®, it produces a characteristic graph of clot formation and fibrinolysis Coagulation and fibrinolysis Limited: not commonly used in cardiac surgery Clot Signature Analyzer® Platelet function is assessed by the time required for a platelet thrombus to occlude two small holes in tubing through which the blood flows. This is the platelet-mediated haemostasis time. A second flow system measures the platelet interaction with collagen under conditions of high shear. The time to occlusion of this pathway is the collagen-induced thrombus formation time Whole blood haemostasis and platelet function Not in routine clinical use Hemostasis Analysis System Measures the platelet ‘contractile force’ (representing the force generated during platelet-mediated clot retraction) to assess platelet cytoplasmic protein function as well as adhesive protein expression Platelet function and clot strength Potential use in cardiac surgery with cardiopulmonary bypass ICHOR/Plateletworks® Number of single platelets in a treated sample (ADP- or collagen-) and a baseline control sample are compared. Platelet aggregation is measured by the loss of single platelets. Percentage aggregation is equivalent to the percentage reduction from the baseline single platelet count to that after the addition of an agonist34 Platelet aggregatory function Potential to predict postoperative bleeding in those taking antiplatelet medication Test . Methodology . Parameter assessed . Surgical use . Activated clotting time Kaolin/celite added to blood accelerates clotting by contact activation. Global assessment of haemostasis Widely available and commonly used to monitor heparin treatment during vascular and particularly cardiac surgery when high doses of heparin are administered (300 units/kg compared with ∼70 units/kg typical of abdominal aortic aneurysm repair)4 Subsequent clot formation is detected by inhibition of plunger movement in a well31 Detection limit is 0·5 unit/ml heparin, so it is suitable for monitoring high-dose heparin treatment, unlike activated partial thromboplastin time41 HemoSTATUS® (platelet-activated clotting test) Uses platelet-activating factor to shorten the kaolin-activated clotting time in whole blood32 Platelet responsiveness and whole blood procoagulant activity Potential for use in cardiovascular surgery Thromboelastography (TEG®) Dynamic measurement of physical properties of blood clot Coagulation and fibrinolysis Cardiac surgery: European Association for Cardio-Thoracic surgery guidelines state that TEG® can be used to guide postoperative transfusion, but further study is required before it can be recommended as the standard care for postoperative transfusion management Measurement of clot formation in an oscillating cylindrical cup at 37 °C. The rotation of a pin suspended within the blood is measured and converted to an electrical signal which is then amplified and charted33. A graph is produced, which represents clot formation and lysis and can be interpreted to determine speed and strength of clot formation (Fig. 1) Speed of clot formation and strength of this clot Liver transplant surgery Trauma Sonoclot® analyser Detects the change in impedance to movement of a vibrating probe within a developing clot. Like TEG®, it produces a characteristic graph of clot formation and fibrinolysis Coagulation and fibrinolysis Limited: not commonly used in cardiac surgery Clot Signature Analyzer® Platelet function is assessed by the time required for a platelet thrombus to occlude two small holes in tubing through which the blood flows. This is the platelet-mediated haemostasis time. A second flow system measures the platelet interaction with collagen under conditions of high shear. The time to occlusion of this pathway is the collagen-induced thrombus formation time Whole blood haemostasis and platelet function Not in routine clinical use Hemostasis Analysis System Measures the platelet ‘contractile force’ (representing the force generated during platelet-mediated clot retraction) to assess platelet cytoplasmic protein function as well as adhesive protein expression Platelet function and clot strength Potential use in cardiac surgery with cardiopulmonary bypass ICHOR/Plateletworks® Number of single platelets in a treated sample (ADP- or collagen-) and a baseline control sample are compared. Platelet aggregation is measured by the loss of single platelets. Percentage aggregation is equivalent to the percentage reduction from the baseline single platelet count to that after the addition of an agonist34 Platelet aggregatory function Potential to predict postoperative bleeding in those taking antiplatelet medication ADP, adenosine diphosphate. Open in new tab Table 2 Point-of-care tests to assess bleeding tendency in surgical patients Test . Methodology . Parameter assessed . Surgical use . Activated clotting time Kaolin/celite added to blood accelerates clotting by contact activation. Global assessment of haemostasis Widely available and commonly used to monitor heparin treatment during vascular and particularly cardiac surgery when high doses of heparin are administered (300 units/kg compared with ∼70 units/kg typical of abdominal aortic aneurysm repair)4 Subsequent clot formation is detected by inhibition of plunger movement in a well31 Detection limit is 0·5 unit/ml heparin, so it is suitable for monitoring high-dose heparin treatment, unlike activated partial thromboplastin time41 HemoSTATUS® (platelet-activated clotting test) Uses platelet-activating factor to shorten the kaolin-activated clotting time in whole blood32 Platelet responsiveness and whole blood procoagulant activity Potential for use in cardiovascular surgery Thromboelastography (TEG®) Dynamic measurement of physical properties of blood clot Coagulation and fibrinolysis Cardiac surgery: European Association for Cardio-Thoracic surgery guidelines state that TEG® can be used to guide postoperative transfusion, but further study is required before it can be recommended as the standard care for postoperative transfusion management Measurement of clot formation in an oscillating cylindrical cup at 37 °C. The rotation of a pin suspended within the blood is measured and converted to an electrical signal which is then amplified and charted33. A graph is produced, which represents clot formation and lysis and can be interpreted to determine speed and strength of clot formation (Fig. 1) Speed of clot formation and strength of this clot Liver transplant surgery Trauma Sonoclot® analyser Detects the change in impedance to movement of a vibrating probe within a developing clot. Like TEG®, it produces a characteristic graph of clot formation and fibrinolysis Coagulation and fibrinolysis Limited: not commonly used in cardiac surgery Clot Signature Analyzer® Platelet function is assessed by the time required for a platelet thrombus to occlude two small holes in tubing through which the blood flows. This is the platelet-mediated haemostasis time. A second flow system measures the platelet interaction with collagen under conditions of high shear. The time to occlusion of this pathway is the collagen-induced thrombus formation time Whole blood haemostasis and platelet function Not in routine clinical use Hemostasis Analysis System Measures the platelet ‘contractile force’ (representing the force generated during platelet-mediated clot retraction) to assess platelet cytoplasmic protein function as well as adhesive protein expression Platelet function and clot strength Potential use in cardiac surgery with cardiopulmonary bypass ICHOR/Plateletworks® Number of single platelets in a treated sample (ADP- or collagen-) and a baseline control sample are compared. Platelet aggregation is measured by the loss of single platelets. Percentage aggregation is equivalent to the percentage reduction from the baseline single platelet count to that after the addition of an agonist34 Platelet aggregatory function Potential to predict postoperative bleeding in those taking antiplatelet medication Test . Methodology . Parameter assessed . Surgical use . Activated clotting time Kaolin/celite added to blood accelerates clotting by contact activation. Global assessment of haemostasis Widely available and commonly used to monitor heparin treatment during vascular and particularly cardiac surgery when high doses of heparin are administered (300 units/kg compared with ∼70 units/kg typical of abdominal aortic aneurysm repair)4 Subsequent clot formation is detected by inhibition of plunger movement in a well31 Detection limit is 0·5 unit/ml heparin, so it is suitable for monitoring high-dose heparin treatment, unlike activated partial thromboplastin time41 HemoSTATUS® (platelet-activated clotting test) Uses platelet-activating factor to shorten the kaolin-activated clotting time in whole blood32 Platelet responsiveness and whole blood procoagulant activity Potential for use in cardiovascular surgery Thromboelastography (TEG®) Dynamic measurement of physical properties of blood clot Coagulation and fibrinolysis Cardiac surgery: European Association for Cardio-Thoracic surgery guidelines state that TEG® can be used to guide postoperative transfusion, but further study is required before it can be recommended as the standard care for postoperative transfusion management Measurement of clot formation in an oscillating cylindrical cup at 37 °C. The rotation of a pin suspended within the blood is measured and converted to an electrical signal which is then amplified and charted33. A graph is produced, which represents clot formation and lysis and can be interpreted to determine speed and strength of clot formation (Fig. 1) Speed of clot formation and strength of this clot Liver transplant surgery Trauma Sonoclot® analyser Detects the change in impedance to movement of a vibrating probe within a developing clot. Like TEG®, it produces a characteristic graph of clot formation and fibrinolysis Coagulation and fibrinolysis Limited: not commonly used in cardiac surgery Clot Signature Analyzer® Platelet function is assessed by the time required for a platelet thrombus to occlude two small holes in tubing through which the blood flows. This is the platelet-mediated haemostasis time. A second flow system measures the platelet interaction with collagen under conditions of high shear. The time to occlusion of this pathway is the collagen-induced thrombus formation time Whole blood haemostasis and platelet function Not in routine clinical use Hemostasis Analysis System Measures the platelet ‘contractile force’ (representing the force generated during platelet-mediated clot retraction) to assess platelet cytoplasmic protein function as well as adhesive protein expression Platelet function and clot strength Potential use in cardiac surgery with cardiopulmonary bypass ICHOR/Plateletworks® Number of single platelets in a treated sample (ADP- or collagen-) and a baseline control sample are compared. Platelet aggregation is measured by the loss of single platelets. Percentage aggregation is equivalent to the percentage reduction from the baseline single platelet count to that after the addition of an agonist34 Platelet aggregatory function Potential to predict postoperative bleeding in those taking antiplatelet medication ADP, adenosine diphosphate. Open in new tab The HemoSTATUS® (Medtronic Blood Management, Parker, Colorado, USA) test is a modification of the ACT, designed to assess platelet function as well as whole blood procoagulant activity (Table 2). Transient platelet dysfunction is the most important defect in haemostasis following cardiopulmonary bypass and cannot be adequately detected by the ACT alone. Thrombocytopenia during bypass can be treated with desmopressin, which stimulates factor VIII production from endothelial cells. Patients who have had cardiac surgery and have received desmopressin or platelet transfusion have significantly improved clot ratios measured by this assay40. This shortening of ACT has been attributed to the indirect or direct platelet activating factor procoagulant action on platelets, and the HemoSTATUS® assay may therefore be useful in detecting patients who would benefit from platelet or desmopressin administration39,40. Despite this theoretical advantage, the HemoSTATUS® test has been shown to correlate poorly with total blood loss and transfusion requirements after CABG with cardiopulmonary bypass42–44. ACT does have limitations. It lacks sensitivity at lower heparin concentrations, but this has relatively little clinical relevance as heparin reversal is more likely to be beneficial when serum concentrations are high (over 1 unit/ml). In addition, although ACT is useful in detecting persistent heparin, it may not be sensitive enough to detect ‘heparin rebound’44 because of its relatively high threshold. This ‘rebound’ effect may contribute to the microvascular bleeding seen after bypass and its associated morbidity. One solution is to give heparinase to degrade heparin to smaller, inactive fragments; this improves the detection of residual low heparin concentrations by ACT. Although ACT is a POC assay in common clinical use, it provides only a global assessment of haemostasis and cannot, without modification, distinguish between the causes of coagulopathy. During cardiopulmonary bypass, in addition to the effect of heparin, the ACT can become significantly prolonged by haemodilution and hypothermia31. This observation has led to development of an individualized heparin management system using the Hepcon® device (Medtronic, Minneapolis, Minnesota, USA)45–47. This measures heparin concentration during bypass and calculates protamine doses based on residual heparin levels. This avoids the use of ‘best guess’ doses of protamine and appears to be associated with reduced haemostatic activation, postoperative blood loss and blood product requirement32,48. However, Slight and co-workers49 have recently suggested that the heparin management system is no more efficacious than ACT as a guide to heparin administration. Viscoelastic methods These POC tests are also global tests of haemostasis that assess fibrinolysis and coagulation (Table 2; Fig. 1). Thromboelastography (TEG®) has classically been used in patients having cardiac surgery and a number of studies support its use. Microvascular bleeding, attributed to transient platelet dysfunction, is the primary haemostatic defect with cardiopulmonary bypass. Mongan and colleagues50 found TEG® to be predictive of risk of increased postoperative bleeding. Other studies have specified the maximum amplitude of the trace (Fig. 1) as a predictor of both postoperative bleeding51,52 and blood product use53. In addition, TEG®-directed desmopressin therapy13 and fresh frozen plasma transfusion54 have led to reduced blood transfusion requirements. Reported benefits are clinically significant, with one study reporting a 2-unit reduction in transfusion requirements with TEG® and a decline in surgical revision from 5·7 to 1·5 per cent33. The benefits of TEG® are not restricted to cardiopulmonary bypass; it may also predict bleeding and graft thrombosis complicating off-pump CABG21. However, TEG® has a lower predictive accuracy in patients having revisional cardiac surgery for recurrent disease55. Fig. 1 Open in new tabDownload slide A typical thromboelastography (TEG®) trace. It measures the time to fibrin formation within a clot (R time), determined by clotting factors and inhibitor balance; the clot formation rate, given by the angle between the initial slope of the TEG® and the horizontal (α angle), which represents speed of clot strengthening by fibrin cross-linkage; and the strength of the clot, determined by the maximum amplitude (MA), which is the greatest amplitude of the TEG® trace and depends on the integrity of platelet function and fibrinogen binding The advantages of haemostasis assessment with TEG® extend beyond cardiac surgery. TEG® is also used widely during liver surgery, particularly transplantation56,57. As noted above, severe coagulopathy can occur following a number of contributing factors, which can be challenging to manage. Transfusion algorithms guided by TEG® results are associated with decreased red cell transfusions58. A further application of TEG® is in monitoring rVIIa. Hendriks and colleagues59 suggested that rFVIIa affected the physical properties of clot and its speed of formation which, they argued, could not be reliably detected by routine coagulation tests, but were demonstrated by TEG®. In a similar vein, Rugeri and co-workers60 suggested that TEG® could rapidly detect in vivo coagulation changes after trauma and might help guide transfusion. They reported good correlation between TEG®, standard coagulation parameters and platelet counts. In a lethal haemorrhage animal model, Kheirabadi and colleagues61 demonstrated TEG® to be a better indicator of coagulopathic bleeding and mortality than prothrombin time measurement. However, further clinical studies are required to establish whether TEG® use alters patient outcome. One limitation of TEG® is that the measurement time can last from 30 to 45 min and requires technical expertise. Clearly in an emergency the haemostasis profile may have changed by the time these ‘snapshot’ results are available. Furthermore, a wide variability in sample results when processed in the first 30 min after collection has also been observed62. The main limitation of TEG® is that a baseline trace is desirable for comparison, as the range of ‘normal’ values is wide. In addition, although POC tests such as the prothrombin time and activated partial thromboplastin time have been validated for algorithm use, this is not the case with TEG®63. The Sonoclot® Analyzer (Sienco, Denver, Colorado, USA), another viscoelastic POC haemostasis test64, is less widely used than TEG® (Table 2). It has the advantage of being subject to less intraoperator variability than TEG® and is faster to perform. Tuman and co-workers65 have shown the Sonoclot® Analyzer to be better than standard coagulation tests at predicting the risk of postoperative bleeding after cardiopulmonary bypass, with a sensitivity of 74 per cent. Yamada and colleagues66 demonstrated that a modified Sonoclot® assay could predict postoperative haemorrhage by comparing results before and after bypass. Clot Signature Analyzer® The Clot Signature Analyzer® (CSA) assay (Xylum, Scarsdale, New York, USA) measures global haemostasis as well as platelet function (Table 2). Although this POC test may be more physiological by using conditions of flow, it is not in widespread clinical use. Despite this, Faraday and colleagues67 have shown that the CSA can detect a clinical coagulopathic state after cardiopulmonary bypass and that this is independently predictive of the need for transfusion. Hemostasis Analysis System The Hemostasis Analysis System (Hemodyne, Richmond, Virginia, USA) measures the platelet ‘contractile force’ and can be used to monitor bleeding tendency after cardiopulmonary bypass (Table 2). During bypass, platelet surface adhesive ligands such as glycoproteins Ib alpha (CD42b) and IIIa (CD61) are shed68,69. The consequent reduction in contractile force measured by this device has been demonstrated to be related to early postoperative blood loss70. Criticisms of this assay include a lack of flow conditions and its high concentration of heparin (1 unit/ml). In addition, heparinase I is added after blood sampling, as the test is sensitive to residual heparin. All these factors mean that it is uncertain whether the results obtained are a true reflection of the situation in vivo. ICHOR/Plateletworks® The American College of Cardiology and the American Heart Association recommend the cessation of aspirin 7–10 days before coronary artery bypass surgery to reduce the risk of blood loss71. More recently, the European Association for Cardiothoracic Surgery has suggested discontinuing aspirin for 2–10 days and clopidogrel for 5–7 days before surgery, if the patient's condition allows72. Craft and colleagues34 demonstrated a good correlation between platelet aggregometry and the ICHOR/Plateletworks® (PW) assay (Helena Laboratories, Beaumont, Texas, USA) to measure recovery from clopidogrel; subsequently, the PW assay was used after bypass to try to predict increased risk of postoperative bleeding from preoperative aspirin ingestion73. This study found that, compared with platelet aggregometry, the PW assay was less able to identify patients who had recently ingested aspirin and less able to predict postoperative mediastinal blood loss. The PW assay has also been shown to overestimate recovery from clopidogrel74. Tests to identify thrombotic tendency: high-risk patients Antiplatelet therapy Platelets play an important role in atherothrombosis and hence the pathogenesis of cardiovascular diseases75. The Antiplatelet Trialists Collaboration found that aspirin administration in high-risk patients reduced stroke, MI and vascular death by 22 per cent76. More recent evidence suggests that not all patients respond in a uniform manner to antiplatelet agents, with some being non-responders (resistant) and others hyper-responders77,78. The concept of aspirin or clopidogrel resistance is controversial but can be defined as antiplatelet medication ingestion with failure to achieve the expected level of platelet inhibition79,80. The mechanism for this is uncertain and much debated. Possible explanations include reduced drug bioavailability (for example, poor absorption), altered platelet function (for example, increased platelet sensitivity to agonists such as adenosine diphosphate (ADP) and collagen) and abnormal platelet interactions with other blood cells (for example, endothelium and leucocytes)75. The label of ‘resistance’ is debated; some authors consider differences between individuals merely to reflect natural biological variations in the response to aspirin or clopidogrel and platelet physiology together with multiple factors that influence atherothrombosis. Aspirin resistance is said to occur in between 5 and 40 per cent of patients depending on the population studied; a recent systematic review gives a figure of 1 in 481,82. Although the debate over the existence of drug resistance continues, there are without doubt patients who benefit less from antiplatelet monotherapy. Neither the optimal management of a non-responder, nor which platelet function test is best for demonstrating ‘resistance’, has yet been resolved82. Patients labelled ‘aspirin resistant’ have platelets that are unusually sensitive to ADP, and the use of antiplatelet agents that inhibit ADP has been suggested78. However, the indiscriminate use of combination antiplatelet medication cannot be advocated, as bleeding risk may be increased without any reduction in atherothrombotic events83,84. POC platelet function testing would revolutionize pharmacotherapy if it could accurately identify antiplatelet resistance and allow stratification of atherothrombotic risk. This would allow antiplatelet therapy to be tailored to the individual. Tests to identify thrombotic tendency: the assays Thromboelastography The Thromboelastograph® (TEG®) system (Haemoscope, Niles, Illinois, USA) has recently been modified to allow monitoring of antiplatelet therapy (mTEG®) (Table 3; Fig. 1)85. To achieve this, the maximum amplitude of the standard TEG® is compared with that from the mTEG®. Agarwal and colleagues86 have suggested a use for mTEG® in monitoring the individual response to antiplatelet agents. Bliden and co-workers87 used it to predict postprocedural ischaemic events in patients taking clopidogrel undergoing percutaneous coronary intervention (PCI). Hobson and colleagues88 have similarly used mTEG® to calculate the ‘percentage clotting inhibition’ (calculated as the area under the clotting response curve at 15 min) in an attempt to determine individual response to antiplatelet agents. Although this POC test is not in routine use, it has the potential to detect antiplatelet resistance and possibly to predict postoperative bleeding complications in hyper-responders. This test has also been used to detect hypercoagulability after liver transplantation89 and major abdominal surgery90 that could not have been detected by routine laboratory investigation. Table 3 Point-of-care tests to assess thrombotic tendency in surgical patients Test . Methodology . Parameter assessed . Surgical use . Modified thromboelastography (mTEG®) Within the TEG® assay, thrombin is the strongest platelet agonist, and determines the MA. If the effects of thrombin are ameliorated then other agonists, e.g. ADP or AA are ‘unmasked’ and their effects can be monitored Platelet function Not in routine use Heparin inhibits thrombin and addition of this to the blood, as well as reptilase plus factor XIIIa, forms a fibrin network and the platelets are able to interact independently of thrombin. With the addition of AA or ADP the MA increases to near normal, but not in patients with adequate aspirin or clopidogrel response65. To monitor antiplatelet therapy, the MA of the standard TEG® is compared with that from the mTEG® Potential to detect non-responders to aspirin and clopidogrel and tailor individual antiplatelet regimens Potential to detect hyper-responders to predict patients at increased risk of bleeding while on antiplatelets Platelet function analyser device PFA-100® Whole blood flows at high shear rate (5000-6000/sec) through an aperture (147 µm in diameter) within a capillary membrane. This membrane is coated with either CEPI or CADP. Platelets in the flowing blood form a plug at the aperture and the time taken for this to happen is the CT (Fig. 2) Platelet function and whole blood haemostasis International Society on Thrombosis and Haemostasis Subcommittee of the Scientific and Standardization Committee has recommended further study before routine clinical use Maximum CT is 300 sec; some controversy exists regarding reference ranges, but these are defined as 85–65 sec for CEPI and 64–114 sec with CADP.43,71 CT is affected by vWF levels, haematocrit, platelet count, blood group (blood group O is associated with lower vWF levels and longer CT)72 and leucocyte count Ultegra® Rapid Platelet Function Analyzer and VerifyNow® aspirin and clopidogrel assays The Ultegra® Rapid Platelet Function Analyzer detects activated platelets binding to fibrinogen. Whole blood is added to a lyophilized preparation of human fibrinogen-coated beads and a platelet agonist such as TRAP. With activation, platelet agglutination to the beads occurs with a consequent increase in light transmission, detected by a light absorbance meter. The change in light absorbance over time is expressed as platelet aggregation units Platelet function. With test modifications, this can detect individual response to aspirin or clopidogrel Algorithms exist for use during vascular/coronary interventional radiology; however, these tests are not in routine clinical practice VerifyNow® P2Y12: ADP in whole blood stimulates platelet aggregation via both P2Y1 and P2Y12 receptors. Prostaglandin E1 is added to the assay to suppress free intracellular calcium to reduce the activation caused by ADP binding to the P2Y1 receptor. A second channel in the assay uses the agonist isoTRAP to give a baseline platelet function (isoTRAP-induced aggregation occurs independently of P2Y12 receptors). Changes in light transmission with platelet agglutination are measured. The results of this assay are expressed in P2Y12 reaction units VerifyNow® aspirin: the platelet agonist used is AA and results are expressed as aspirin reaction units Test . Methodology . Parameter assessed . Surgical use . Modified thromboelastography (mTEG®) Within the TEG® assay, thrombin is the strongest platelet agonist, and determines the MA. If the effects of thrombin are ameliorated then other agonists, e.g. ADP or AA are ‘unmasked’ and their effects can be monitored Platelet function Not in routine use Heparin inhibits thrombin and addition of this to the blood, as well as reptilase plus factor XIIIa, forms a fibrin network and the platelets are able to interact independently of thrombin. With the addition of AA or ADP the MA increases to near normal, but not in patients with adequate aspirin or clopidogrel response65. To monitor antiplatelet therapy, the MA of the standard TEG® is compared with that from the mTEG® Potential to detect non-responders to aspirin and clopidogrel and tailor individual antiplatelet regimens Potential to detect hyper-responders to predict patients at increased risk of bleeding while on antiplatelets Platelet function analyser device PFA-100® Whole blood flows at high shear rate (5000-6000/sec) through an aperture (147 µm in diameter) within a capillary membrane. This membrane is coated with either CEPI or CADP. Platelets in the flowing blood form a plug at the aperture and the time taken for this to happen is the CT (Fig. 2) Platelet function and whole blood haemostasis International Society on Thrombosis and Haemostasis Subcommittee of the Scientific and Standardization Committee has recommended further study before routine clinical use Maximum CT is 300 sec; some controversy exists regarding reference ranges, but these are defined as 85–65 sec for CEPI and 64–114 sec with CADP.43,71 CT is affected by vWF levels, haematocrit, platelet count, blood group (blood group O is associated with lower vWF levels and longer CT)72 and leucocyte count Ultegra® Rapid Platelet Function Analyzer and VerifyNow® aspirin and clopidogrel assays The Ultegra® Rapid Platelet Function Analyzer detects activated platelets binding to fibrinogen. Whole blood is added to a lyophilized preparation of human fibrinogen-coated beads and a platelet agonist such as TRAP. With activation, platelet agglutination to the beads occurs with a consequent increase in light transmission, detected by a light absorbance meter. The change in light absorbance over time is expressed as platelet aggregation units Platelet function. With test modifications, this can detect individual response to aspirin or clopidogrel Algorithms exist for use during vascular/coronary interventional radiology; however, these tests are not in routine clinical practice VerifyNow® P2Y12: ADP in whole blood stimulates platelet aggregation via both P2Y1 and P2Y12 receptors. Prostaglandin E1 is added to the assay to suppress free intracellular calcium to reduce the activation caused by ADP binding to the P2Y1 receptor. A second channel in the assay uses the agonist isoTRAP to give a baseline platelet function (isoTRAP-induced aggregation occurs independently of P2Y12 receptors). Changes in light transmission with platelet agglutination are measured. The results of this assay are expressed in P2Y12 reaction units VerifyNow® aspirin: the platelet agonist used is AA and results are expressed as aspirin reaction units ADP, adenosine diphosphate; MA, maximum amplitude; AA, arachidonic acid; CEPI, collagen and epinephrine; CADP, collagen and adenosine diphosphate; CT, closure time; vWF, von Willebrand factor; TRAP, thrombin receptor activating peptide. Open in new tab Table 3 Point-of-care tests to assess thrombotic tendency in surgical patients Test . Methodology . Parameter assessed . Surgical use . Modified thromboelastography (mTEG®) Within the TEG® assay, thrombin is the strongest platelet agonist, and determines the MA. If the effects of thrombin are ameliorated then other agonists, e.g. ADP or AA are ‘unmasked’ and their effects can be monitored Platelet function Not in routine use Heparin inhibits thrombin and addition of this to the blood, as well as reptilase plus factor XIIIa, forms a fibrin network and the platelets are able to interact independently of thrombin. With the addition of AA or ADP the MA increases to near normal, but not in patients with adequate aspirin or clopidogrel response65. To monitor antiplatelet therapy, the MA of the standard TEG® is compared with that from the mTEG® Potential to detect non-responders to aspirin and clopidogrel and tailor individual antiplatelet regimens Potential to detect hyper-responders to predict patients at increased risk of bleeding while on antiplatelets Platelet function analyser device PFA-100® Whole blood flows at high shear rate (5000-6000/sec) through an aperture (147 µm in diameter) within a capillary membrane. This membrane is coated with either CEPI or CADP. Platelets in the flowing blood form a plug at the aperture and the time taken for this to happen is the CT (Fig. 2) Platelet function and whole blood haemostasis International Society on Thrombosis and Haemostasis Subcommittee of the Scientific and Standardization Committee has recommended further study before routine clinical use Maximum CT is 300 sec; some controversy exists regarding reference ranges, but these are defined as 85–65 sec for CEPI and 64–114 sec with CADP.43,71 CT is affected by vWF levels, haematocrit, platelet count, blood group (blood group O is associated with lower vWF levels and longer CT)72 and leucocyte count Ultegra® Rapid Platelet Function Analyzer and VerifyNow® aspirin and clopidogrel assays The Ultegra® Rapid Platelet Function Analyzer detects activated platelets binding to fibrinogen. Whole blood is added to a lyophilized preparation of human fibrinogen-coated beads and a platelet agonist such as TRAP. With activation, platelet agglutination to the beads occurs with a consequent increase in light transmission, detected by a light absorbance meter. The change in light absorbance over time is expressed as platelet aggregation units Platelet function. With test modifications, this can detect individual response to aspirin or clopidogrel Algorithms exist for use during vascular/coronary interventional radiology; however, these tests are not in routine clinical practice VerifyNow® P2Y12: ADP in whole blood stimulates platelet aggregation via both P2Y1 and P2Y12 receptors. Prostaglandin E1 is added to the assay to suppress free intracellular calcium to reduce the activation caused by ADP binding to the P2Y1 receptor. A second channel in the assay uses the agonist isoTRAP to give a baseline platelet function (isoTRAP-induced aggregation occurs independently of P2Y12 receptors). Changes in light transmission with platelet agglutination are measured. The results of this assay are expressed in P2Y12 reaction units VerifyNow® aspirin: the platelet agonist used is AA and results are expressed as aspirin reaction units Test . Methodology . Parameter assessed . Surgical use . Modified thromboelastography (mTEG®) Within the TEG® assay, thrombin is the strongest platelet agonist, and determines the MA. If the effects of thrombin are ameliorated then other agonists, e.g. ADP or AA are ‘unmasked’ and their effects can be monitored Platelet function Not in routine use Heparin inhibits thrombin and addition of this to the blood, as well as reptilase plus factor XIIIa, forms a fibrin network and the platelets are able to interact independently of thrombin. With the addition of AA or ADP the MA increases to near normal, but not in patients with adequate aspirin or clopidogrel response65. To monitor antiplatelet therapy, the MA of the standard TEG® is compared with that from the mTEG® Potential to detect non-responders to aspirin and clopidogrel and tailor individual antiplatelet regimens Potential to detect hyper-responders to predict patients at increased risk of bleeding while on antiplatelets Platelet function analyser device PFA-100® Whole blood flows at high shear rate (5000-6000/sec) through an aperture (147 µm in diameter) within a capillary membrane. This membrane is coated with either CEPI or CADP. Platelets in the flowing blood form a plug at the aperture and the time taken for this to happen is the CT (Fig. 2) Platelet function and whole blood haemostasis International Society on Thrombosis and Haemostasis Subcommittee of the Scientific and Standardization Committee has recommended further study before routine clinical use Maximum CT is 300 sec; some controversy exists regarding reference ranges, but these are defined as 85–65 sec for CEPI and 64–114 sec with CADP.43,71 CT is affected by vWF levels, haematocrit, platelet count, blood group (blood group O is associated with lower vWF levels and longer CT)72 and leucocyte count Ultegra® Rapid Platelet Function Analyzer and VerifyNow® aspirin and clopidogrel assays The Ultegra® Rapid Platelet Function Analyzer detects activated platelets binding to fibrinogen. Whole blood is added to a lyophilized preparation of human fibrinogen-coated beads and a platelet agonist such as TRAP. With activation, platelet agglutination to the beads occurs with a consequent increase in light transmission, detected by a light absorbance meter. The change in light absorbance over time is expressed as platelet aggregation units Platelet function. With test modifications, this can detect individual response to aspirin or clopidogrel Algorithms exist for use during vascular/coronary interventional radiology; however, these tests are not in routine clinical practice VerifyNow® P2Y12: ADP in whole blood stimulates platelet aggregation via both P2Y1 and P2Y12 receptors. Prostaglandin E1 is added to the assay to suppress free intracellular calcium to reduce the activation caused by ADP binding to the P2Y1 receptor. A second channel in the assay uses the agonist isoTRAP to give a baseline platelet function (isoTRAP-induced aggregation occurs independently of P2Y12 receptors). Changes in light transmission with platelet agglutination are measured. The results of this assay are expressed in P2Y12 reaction units VerifyNow® aspirin: the platelet agonist used is AA and results are expressed as aspirin reaction units ADP, adenosine diphosphate; MA, maximum amplitude; AA, arachidonic acid; CEPI, collagen and epinephrine; CADP, collagen and adenosine diphosphate; CT, closure time; vWF, von Willebrand factor; TRAP, thrombin receptor activating peptide. Open in new tab Platelet function analysis The platelet function analyser device PFA-100® (Dade Behring, Marburg, Germany) was designed to be more physiological and to simulate primary haemostasis in vitro (Table 3; Fig. 2). The PFA-100® has been used to monitor the effects of aspirin therapy in patients with cardiovascular disease as aspirin selectively prolongs the collagen and epinephrine closure time (CEPI-CT). Roller and colleagues91 concluded that 40 per cent of patients with peripheral arterial disease had an inadequate response to aspirin using the PFA-100®, although they did not relate this to clinical outcome. Ziegler and co-workers92 showed a correlation between ‘non response’ to clopidogrel and increased restenosis in a small study of 98 patients undergoing angioplasty for peripheral arterial disease. In patients having cardiac surgery, shorter PFA-100® closure times were related to the development of postoperative myocardial ischaemia93. Fig. 2 Open in new tabDownload slide The platelet function analyser PFA-100® assay uses conditions of blood flow and a membrane impregnated with collagen and epinephrine or collagen and adenosine diphosphate (ADP) to stimulate vascular injury. The closure time is the time taken for a platelet plug to occlude the membrane For patients with coronary artery disease, there is better evidence correlating PFA-100® results with clinical outcome than for other vascular beds. In those having PCI, a CEPI-CT of less than 190 s measured within the first 24 h after surgery predicts death or MI94. In addition, a recent meta-analysis of eight prospective studies involving 1227 patients used PFA-100® closure time to predict cardiovascular events in aspirin-treated patients with cardiovascular disease95. Data from these studies demonstrated an odds ratio of 2·1 for recurrence of an ischaemic event in non-responders compared with responders. This suggests that POC testing can stratify patients based on their aspirin response status in relation to clinical outcome. However, these studies include patients with recent ischaemic events and their results cannot be extrapolated to those with stable coronary artery disease. Limitations of the PFA-100® include the potential overestimation of the prevalence of aspirin resistance96–100. Wide variability in duplicate testing has also been noted and may exceed 10 per cent101. Levels of von Willebrand factor antigen levels markedly affect closure times and are raised as part of the acute-phase response or following PCI99. This may render the PFA-100® less reliable after an acute thrombotic event or endovascular procedure. Mueller and co-workers96 have demonstrated that the PFA-100® is relatively insensitive to the variability of clopidogrel response or in determining clopidogrel resistance. This may be because of the high concentration of ADP in the assay24,102. Importantly, there is a paucity of literature defining at what closure times bleeding is likely to occur or the safe threshold for intervention24. Because of the inconsistencies in the literature, recommendations against routine use of the PFA-100® have been made103,104. Ultegra® and VerifyNow® systems The VerifyNow® aspirin and clopidogrel assays (Accumetrics, San Diego, California, USA), were initially developed as the Ultegra® Rapid Platelet Function Analyzer (RPFA) to monitor the effects of glycoprotein IIb IIIa inhibitors. The original assay is based on detection of activated platelets binding to fibrinogen with corresponding changes in light absorbance (Table 3, Fig. 3). However, the clinical application of this test has yielded conflicting results. In a large multicentre study, Wheeler and colleagues105 demonstrated that the accuracy and precision of the Ultegra® RPFA assay was equivalent to platelet aggregometry and to a receptor-binding assay with 125I-abciximab. Conversely, Hochholzer and co-workers106 showed that, in patients with stable coronary artery disease awaiting PCI, the correlation between Ultegra® RPFA results and aggregometry was poor. However, the GOLD study107 found that, in patients undergoing PCI and receiving glycoprotein IIb or IIIa receptors, the level of platelet inhibition as measured by the Ultegra® RPFA predicted future major adverse cardiac events but were not correlated with another platelet function assay. Fig. 3 Open in new tabDownload slide The VerifyNow® P2Y12 assay uses adenosine diphosphate (ADP) as an agonist to activate platelets via the P2Y12 and P2Y1 receptors. To ensure specificity for clopidogrel (a P2Y12 antagonist) prostaglandin E1 (PGE1) is used to attenuate P2Y1-mediated effects. As the platelets are activated and aggregate with the fibrinogen-coated beads, increased light absorbance is measured and expressed as P2Y12 reaction units. For example, patients responding to clopidogrel have lower light absorbance than those not taking the drug because of decreased platelet aggregate formation This assay has been modified to monitor the effects of aspirin and clopidogrel (VerifyNow® aspirin assay, VerifyNow® P2Y12 or clopidogrel assay; Table 3). The VerifyNow® P2Y12 assay results correlated well with ADP-induced platelet aggregation as assessed by aggregometry108 and have been used to determine clopidogrel response in clinical trials109. The potential role of these assays in surgical practice lies in the monitoring of a patient's response to antiplatelet medication. For example, therapy for outpatients or patients immediately after surgery could be tailored to the individual depending on the results. Chen and colleagues110 have recently used the VerifyNow® aspirin assay to predict risk of adverse clinical outcomes in patients with stable coronary artery disease. One limitation of the RPFA assay is the absence of flow conditions, which renders it less physiological than, for example, the PFA-100®. Harrison and co-workers111 have also shown a lack of consistency over time for this assay in the identification of aspirin-resistant individuals. Before these assays (especially the newer aspirin and clopidogrel assays) progress from being research tools to guiding clinical decisions, large prospective studies are required112,113. Discussion POC tests such as ACT and TEG® to assess haemostatic function in surgical patients are well established in clinical practice. There is good evidence that these tests can guide transfusion algorithms and also predict which patients are at increased risk of postoperative bleeding. Current shortage of blood products and risks associated with transfusion ensure that early identification of haemostatic abnormalities using these tests is desirable. POC tests have also been shown to guide rVIIa and desmopressin administration, although the evidence base is less impressive. For identifying surgical patients with cardiovascular disease who are at increased risk of thromboembolic complications, POC tests appear less robust. The PFA-100® arguably offers the most physiological POC assessment of platelet function and so antiplatelet response in vitro. However, it cannot be recommended for clinical use because of conflicting reports in the literature. More work is needed on the correlation of these tests with surgical outcomes, for instance restenosis following peripheral angioplasty or graft thrombosis in patients with peripheral arterial disease. Correlation between non-responders and increased risk of complications is also required. Studies in patients with coronary artery disease are numerous, and many show some correlation with outcome in stable disease. However, few have assessed patients with peripheral arterial disease. 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TI - The surgical application of point-of-care haemostasis and platelet function testing
JF - British Journal of Surgery
DO - 10.1002/bjs.6359
DA - 2008-10-09
UR - https://www.deepdyve.com/lp/oxford-university-press/the-surgical-application-of-point-of-care-haemostasis-and-platelet-ZTFKslTl6G
SP - 1317
EP - 1330
VL - 95
IS - 11
DP - DeepDyve
ER -