Hemostasis and Circulation

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However, other studies failed to demonstrate a difference 61 63 Previous studies suggested that excessive bleeding may be related to the use of greater doses of bovine heparin during CPB guided by dosing protocols based on body weight and ACT values 69 or based on maintenance of a defined heparin concentration However, more recent studies found no differences in blood loss when either bovine 63 or porcine heparin was used 4 65 The discrepant results between these studies may be related to differences between studies in one or more of the previously described demographic, operative, or procedure-related issues.

We performed a study to determine whether heparin dose was related to either blood loss or transfusion requirements in a large series of patients 4. Patients who received lower initial and total heparin dosage had increased blood loss and transfusion requirements. In view of the previously observed inverse relationship between heparin concentration and thrombin activity as reflected by fibrinopeptide A concentrations 64 , a formal comparison between various POC measurements and anti-Xa heparin concentration measurements was performed This trial demonstrated a good correlation between whole-blood heparin concentration values compared with an anti-Xa assay 71 , a finding substantiated by a subsequent study In the same study 71 , ACT values correlated poorly with anti-Xa heparin concentrations, in part related to the effects of hypothermia and hemodilution on these assays Fig.

However, others have reported that heparin measurements derived with an automated protamine titration method can vary appreciably from anti-Xa measurements Studies that examined the effect of higher heparin doses directly or indirectly by using different anticoagulation monitoring protocols on perioperative blood loss and transfusion outcomes. Comparison of ACT values obtained with two different contact activating agents and heparin concentration measurements by a laboratory-based and POC method obtained in 32 patients during CPB.

Blood specimens were obtained before heparin administration and 10 min after heparin administration A , initiation of CPB B , achievement of hypothermia C , and rewarming D as well as immediately before discontinuation of CPB E. Comparison of activated coagulation time and whole blood heparin measurements to laboratory plasma anti-Xa heparin concentration in cardiac surgical patients. J Thorac Cardiovasc Surg ;— Reprinted with permission. In a prospective trial we evaluated the impact of heparin and protamine administration based on a POC, whole-blood hemostasis system Hepcon; Medtronic Blood Management on bleeding and blood transfusion when compared with an ACT-based protocol This system allows estimation of patient-specific anticoagulant response to heparin, assay of kaolin ACT values, and whole-blood heparin concentration via a previously validated, automated protamine titration method Patients were randomly assigned to either a control or intervention group.

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Heparin was neutralized with an initial fixed dose of protamine 0. The protamine dose was based on the measured, residual heparin concentration. No differences between the two treatment groups were identified in regard to demographic, preoperative anticoagulant medications, preoperative hemostatic data, number of reoperations or combined procedures, and duration of CPB. Patients in the intervention cohort received greater doses of heparin and had lower protamine to heparin ratios when compared with control patients. We found indirect evidence for consumption of coagulation factors and platelets in the control patients who had more prolonged whole-blood PT and aPTT values after CPB.

Furthermore, patients in the control cohort received substantially more platelets, fresh frozen plasma FFP , and cryoprecipitate. Twice as many control patients required transfusion of these blood components during the perioperative interval. Control patients also had longer operative times after CPB for closure and had greater mediastinal chest tube drainage in the first 4 h after surgery. Thus, higher heparin doses in the intervention group were not associated with excessive postoperative bleeding and in fact may have contributed to preservation of hemostasis.

In contrast to the study by Jobes et al. ACT-based anticoagulation protocols may contribute to a hemostatic consumptive state, particularly in patients requiring prolonged use of CPB because the ACT may be prolonged by factors other than heparin such as hemodilution or hypothermia leading to inappropriately low heparin concentrations during CPB Fig. Because generation of fibrinopeptide A 64 74 and inhibition of clot-bound thrombin 75 have been shown to be inversely related to heparin concentration, maintenance of therapeutic heparin concentrations may more effectively preserve hemostasis through antiithrombin III or possibly heparin cofactor II-mediated inactivation of thrombin This hypothesis was recently tested in a trial involving 31 patients requiring repeat or combined cardiac procedures i.

We found more effective suppression of excessive hemostatic system activation as reflected by decreased concentrations of fibrinopeptide A and fibrinolysis D-dimer. More importantly, maintenance of higher heparin concentrations resulted in better preservation of consumable antithrombin III and factors I, V, and VIII in the intervention patients. Evaluations have demonstrated a dose-related inhibition of collagen-mediated platelet aggregation by heparin 63 Inhibition of platelet function by heparin 16 may be mediated through suppression of factor VIII-mediated platelet aggregation 79 or von Willebrand factor-related mechanisms In the past, blood component administration in patients with excessive MVB after CPB and heparin neutralization has been generally empiric and not based on direct assessment of hemostasis because turnaround times of laboratory-based tests are too long Thus, transfusion of erythrocytes, platelets, and FFP to cardiac surgical patients requiring CPB varies considerably among institutions, in part because of prophylactic administration of FFP and platelets 81 , despite evidence that this practice is unwarranted 24 Furthermore, FFP and platelets are frequently administered in an attempt to distinguish between MVB related to hemostatic system impairment vs surgical bleeding 83 Neither approach appears to be efficient and safe and therefore both are inappropriate.

Methods are now available for rapid POC assessment of coagulation to allow appropriate, targeted therapy for post-CPB hemostatic defects. Persistent concentrations of circulating heparin, resulting from inadequate neutralization 85 86 or heparin rebound 86 87 , can contribute to MVB after CPB.

In fact, one study demonstrated that blood loss can be reduced if heparin rebound is detected with ACT values and treated with additional protamine. However, the ACT may not be the most appropriate method for assessment of postoperative heparin rebound because it has been shown to have a relatively high detection limit for heparin concentrations, e.

Thus, whole-blood POC heparin concentration measurements are more suitable for detecting heparin rebound than the ACT Heparinase IBEX , an enzyme that degrades heparin to smaller, inactive fragments, also has been used to improve the detection of residual low concentrations of heparin by the ACT In addition, a whole-blood thrombin time with protamine neutralization HNTT; International Technidyne is available to assess residual heparin or heparin rebound in the post-CPB period 65 94 Because of the complex and often serious nature of bleeding disorders after CPB, several treatment paradigms with laboratory-based tests have been suggested for management of patients with post-CPB MVB.

The clinical usefulness of these approaches has not been formally evaluated in randomized, prospective, controlled trials. A transfusion algorithm was used according to previously published guidelines for transfusion on the basis of coagulation assays 98 99 The algorithm-treated patients received fewer blood products, had shorter operative times, and had less blood loss after identification of MVB.

Reduced transfusion requirements and blood loss may have been a consequence of optimal management of bleeding 2 , identification of patients with a surgical source of bleeding, a change in the transfusion trigger, or some combination of these The usefulness of preset critera for transfusion was confirmed in two other recent studies that demonstrated that preset transfusion triggers can dramatically affect transfusion requirements of patients undergoing cardiac surgery with either laboratory-based or POC methods In the first study, the efficacy of strict transfusion criteria as a sole blood conservation strategy was evaluated by comparing homologous blood product use in consecutive patients undergoing coronary artery bypass grafting procedures treatment group with that in a retrospective series of patients control group who were transfused without preset, defined criteria.

The two groups had similar demographic, operative, and laboratory profiles.

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The authors concluded that adherence to defined transfusion criteria can be a simple, safe, and effective strategy for decreasing blood product utilization. Another algorithm that combines laboratory-based platelet counts and fibrinogen concentrations with thromboelastogram-based measurements was utilized by Spiess A retrospective analysis revealed that use of this approach can reduce transfusion requirements Furthermore, POC testing may be justified from an economic perspective.

For example, by reducing transfusion requirements and operative time, use of platelet count, whole-blood PT, and aPTT to manage post-CPB bleeding can substantially reduce expenditures related to these outcome variables. Newer POC technologies have become available that provide rapid hemostasis results with whole blood. The whole-blood PT was shown to correlate well with laboratory PT in two previous studies In addition, both Coaguchek and laboratory PT methods responded similarly to factors V, VII, and X as assessed by the comparison of the slopes between respective regression relationships In an initial evaluation, the whole-blood aPTT correlated well with the laboratory aPTT, with correlation coefficients ranging from 0.

In contrast, other studies with either linear regression or bias analysis have demonstrated discrepant results between whole-blood and laboratory aPTT methods In one study , variability between whole-blood Coaguchek Plus and laboratory aPTT was found to be most likely related to differences in normal reference ranges and responsiveness to coagulation factor concentrations between the two assay systems.

In this same study, the disease state was defined as detection of at least one coagulation factor less than a defined concentration e.

Hemostasis and bleeding disorders

Finally, POC whole-blood fibrinogen assays have recently been evaluated that may help identify occasional patients with post-CPB MVB who might benefit from administration of fibrinogen-rich cryoprecipitate in addition to FFP It has been suggested that routine preoperative coagulation tests can predict blood loss after cardiac surgery However, other studies have not confirmed this with coagulation tests performed either pre- or postoperatively In particular, transient platelet dysfunction, considered to be the most common and important hemostatic defect in the early postoperative period after CPB 3 5 36 37 38 , cannot be readily determined with routine laboratory-based or POC tests.

However, they are time-consuming, involve long turnaround times, and require considerable technical expertise in both performance and interpretation, which limits their clinical utility. POC tests for evaluation of qualitative platelet function such as in vitro bleeding time , clot retraction , other tests of clot viscoelastic properties , agglutination of fibrinogen-coated beads , or clot formation have been evaluated or are currently being studied. Development of the dual-channel Thrombostat VDG-von der Goltz, Seeon, Germany instrument now allows automated measurement of in vitro bleeding time with either citrate-anticoagulated platelet-rich plasma, or whole blood The Hemodyne instrument is a POC method that can detect qualitative platelet abnormalities by measuring clot retraction Measurements of platelet force derived from this instrument have been shown recently to correlate with blood loss after cardiac surgery in a small series of patients Data from an early study indicate that Sonoclot measurements may identify patients with MVB when compared with either a nonbleeding control group or patients with a surgical source of bleeding.

Another POC assay is based on the ability of platelets in whole blood to rapidly agglutinate fibrinogen-coated beads when stimulated with a peptide iso-S FLLRN that activates a platelet thrombin receptor but resists inactivation by plasma aminopeptidase M We evaluated another recently developed POC test for assessment of platelet function based on whole-blood ACT measurements. PAF-accelerated coagulation clot ratio values was assessed at four different time points in a series of patients: before institution of CPB, before discontinuation of CPB, after protamine administration, and after arrival in the ICU A dose-dependent reduction in clot ratios by c7E3 was also demonstrated in this study , which supports the notion that this relatively simple and robust POC test may detect platelet dysfunction induced by certain drugs.

Thromboelastography has been shown by some to predict the risk of postoperative bleeding , but others have failed to confirm its ability to predict either intraoperative or postoperative bleeding DDAVP has been shown to be efficacious in patients with von Willebrand disease and mild hemophilia A , as well as in those with uremia or cirrhosis , in certain cardiac surgical patients such as those requiring prolonged use of CPB , and in patients on platelet-inhibiting drugs Although, in general, prophylactic administration of DDAVP to cardiac surgical patients has not been shown to be clinically beneficial , certain patients identifiable by the TEG may benefit In a follow-up trial at the same institution, use of the TEG to direct DDAVP therapy in cardiac surgical patients at high-risk for MVB also resulted in reduced blood product utilization in the intervention cohort Although the effects of DDAVP on in vitro platelet function have been variable , the effects of DDAVP on expression of glycoprotein Ib receptors , generation of platelet microparticles , and release of platelet von Willebrand factor may be important.

Major limitations of the TEG method are the relatively long measurement time 30—45 min and the requirement for considerable technical expertise. TEG measurements have been shown to be useful during liver transplantation when used to detect and treat hyperfibrinolysis The TEG may also potentially help in identifying patients that have excessive post-CPB fibrinolysis and who may respond to aminocaproic acid administration Others, however, have not been able to demonstrate substantial correlations between TEG measurements and D-dimer The thrombolytic assessment system TAS, Cardiovascular Diagnostics is a portable, lightweight instrument that utilizes a dry reagent system and can be used to measure whole-blood PT and aPTT and detect the onset of clot lysis in samples of citrated whole blood or plasma.

This instrument is currently being evaluated clinically. The SimpleRED test Agen Diagnostics, Queensland, Australia allows assessment of D-dimer concentrations within 5 min with whole blood obtained by fingerstick or venipuncture. Data from two recent studies indicate that this assay may be useful in ruling out deep vein thrombosis when used in combination with bilateral impedance plethysmography With new technological developments, it may become possible not only to identify patients at risk for excessive blood loss but also to determine specific hemostatic defects in a timely fashion that can then be corrected by specifically targeted treatment Fig.

Finally, further intraoperative inspection or exploration may be considered postoperatively when relatively normal POC hemostasis test results are obtained in patients with diffuse pericardial bleeding MVB intraoperatively or excessive mediastinal chest tube drainage postoperatively. WB HC , whole-blood heparin concentration cartridge Hepcon instrument.

PF , platelet force measurements Hemodyne Instrument. Platelets , platelet transfusion 6 units of random donor or apheresis unit equivalent. Antifibrinolytic Rx , antifibrinolytic therapy e. See text for detailed description. POC tests of hemostasis are beneficial in monitoring heparin therapy during and its reversal after extracorporeal circulation. In addition, the usefulness of POC tests for evaluation of platelet number and function, coagulation factors, and fibrinogen may facilitate optimal, targeted administration of pharmacologic agents and blood components in patients with excessive bleeding after CPB.

Factors related to anticoagulation that may in part, explain the discrepant results between studies are included.

Hemostasis

Patient-specific monitoring for ACT values anticoagulant response or heparin concentration are also included. Numeric values represent the mean values for each group.

Bovine, bovine lung; porcine, porcine mucosal. The arrows indicate transfusion requirements in the high-heparin cohort; for CPB time, data from both cohorts were combined.

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Skip to main content. Other Oak Ridge Conference. George J. Despotis , J. Heinrich Joist , Lawrence T.