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An international normalized ratio (INR) higher than 9 is associated with a high risk of bleeding, yet most studies have focused on outpatients with lower INR. We retrospectively analyzed diagnosis, bleeding, treatment, and mortality in 162 patients with INR higher than 9, including inpatients and outpatients with and without warfarin treatment. Patients without anticoagulant treatment with INR higher than 9 had a poor prognosis, 67% experienced bleeding and 74% died. Among outpatients receiving warfarin with INR higher than 9, 11% had bleeding, but none died. Among inpatients receiving warfarin, 35% had bleeding and 17% died. Factors associated with bleeding were older age, renal failure, and alcohol use. Withholding warfarin or giving vitamin K treatment was ineffective at reducing the INR within 24 hours, whereas plasma infusion immediately dropped the INR to 2.4 ± 0.9. Because of underlying disease, comorbidities, and medications, hospitalized patients with INR higher than 9 may not respond quickly to withholding warfarin or vitamin K treatment, and plasma infusion may be needed to reduce INR and the risk of bleeding within 24 hours.

We compared 2 commercial plasma procoagulant phospholipid activity (PPA) assays, chromogenic, using bound annexin V to capture phosphatidylserine-containing microparticles, and clot-based. In both, anionic phospholipids accelerated activation of prothrombin by factor Xa. PPA levels were lower in the chromogenic vs the clot-based assay, with poor correlation between methods: normal samples, mean ± SD, 27 ± 17 vs 590 ± 414 nmol/L (n = 24; r(2) = 0.29) and patient samples, mean ± SD, 45 ± 44 vs 401 ± 330 nmol/L (n = 51; r(2) = 0.26). Recovery of phosphatidylserine added to normal, heparinized, and warfarin plasma samples averaged 109% ± 39% using the chromogenic assay but was higher and more varied (mean ± SD, 176% ± 59%) in the clot-based assay. Lupus anticoagulants caused low recovery in both assays. Removal of microparticles by 0.22-μm filtration reduced PPA by 91% in the clot-based and 65% in the chromogenic assay. The clot-based assay showed higher correlation (r(2) = 0.82 vs 0.23) with flow cytometric platelet microparticle counts. The 2 assays measure different aspects of PPA in plasma, with the chromogenic assay primarily measuring smaller microparticles.

Objective: Because infants have relatively more blood loss (mL/kg) than older children during cardiac surgery involving cardiopulmonary bypass (CPB), the authors compared hemostatic activation between infants and older children undergoing cardiac surgery., Design: Observational study., Setting: University-affiliated children's hospital., Participants: Twenty-eight children (18 infants <1 year and 10 children >1 year) undergoing cardiac surgery with CPB., Interventions: None., Measurements and Main Results: Markers of coagulation and fibrinolysis were evaluated at 9 sample points before, during, and after CPB in the 28 children. Infants had greater chest tube output, longer CPB times, and a larger drop in platelet counts during CPB than children. Active tissue plasminogen activator (tPA) increased during CPB in both groups, with infants showing lower levels than children (p < 0.001). In both groups, active plasminogen activator inhibitor type 1 (PAI-1) first decreased during CPB and then increased above baseline postoperatively. Infants had higher PAI-1 than children near the end of CPB (p = 0.01). Thrombin-antithrombin complex levels increased during and after CPB, with infants showing lower levels only during CPB (p = 0.01). D-dimer and prothrombin activation peptide (F1.2) levels increased in a similar pattern for both groups during and after CPB. The length of aortic cross-clamp time and the level of F1.2 after protamine administration correlated significantly and independently with 12-hour chest tube output., Conclusions: Compared with children, infants had greater blood loss (mL/kg), greater drop in platelets during CPB, lower active tPA, and higher active PAI-1. Cumulative thrombin generation after CPB, indicated by F1.2 levels, correlated with early blood loss.

Objective: Heparin and other oxygenator coatings have been used in attempts to reduce hemostatic activation during cardiopulmonary bypass (CPB). This study evaluated whether an oxygenator coated with poly 2-methoxyethylacrylate (PMEA) (X-coating; Terumo Corporation, Tokyo, Japan) would cause less activation of coagulation and fibrinolytic systems during CPB in children than a noncoated oxygenator., Design: Observational study., Setting: University-affiliated children's hospital., Patients: Twenty-six patients, 3 months to 5 years old, who underwent congenital heart surgery for repair of a ventricular septal defect, atrial septal defect, or both., Interventions: Patients were divided into 2 age-matched groups based on the type of oxygenator used: a noncoated oxygenator (group NC) versus a PMEA-coated oxygenator (group C)., Measurements and Main Results: Blood samples for coagulation and fibrinolytic markers were compared before, during, and after CPB. Despite increases in thrombin generation markers (F1.2 and TAT) at certain times during CPB in group C compared to group NC, a comparison over all times during CPB were not statistically different between groups. Overall D-dimer concentrations during CPB were elevated in group C compared to group NC (p = 0.02). Active tPA and active PAI-1 were not different between groups during or after CPB. Group C had higher platelet counts (181,000 +/- 29,000) during CPB than group NC (155,000 +/- 57,000, p = 0.04) but not postoperatively. Twelve hours postoperatively, chest tube outputs were 8.8 +/- 3 mL/kg in group C and 19.1 +/- 12 mL/kg in group NC (p = 0.003). The corresponding outputs 24 hours after surgery were 12.4 +/- 3 mL/kg and 24 +/- 11 mL/kg, respectively (p = 0.005)., Conclusions: Except for a somewhat higher platelet count during CPB, there was no indication that PMEA coating resulted in less activation of coagulation and fibrinolytic systems. The lower postoperative chest tube output observed after CPB with PMEA-coated oxygenators needs to be studied further.

Objective: Recanalization is common after acute deep venous thrombosis, but the factors that contribute to its variable extent are unknown. The purpose of this study was to examine the relationship between recanalization and plasma markers of coagulation and fibrinolysis., Methods: Subjects with an ultrasound-confirmed deep venous thrombosis had prothrombin fragment 1+2 (F 1+2), tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor (PAI-1) activity, and t-PA antigen levels determined before anticoagulation therapy. Ultrasound and plasma studies were repeated at 14 days, 1 month, and every 3 months for 1 year., Results: Among 71 enrolled subjects, F 1+2 levels normalized within 14 days. The mean t-PA activity was within the normal range at all follow-up intervals. However, the mean t-PA antigen (10.7 plus minus 10.5 to 13.6 plus minus 13.5 ng/mL; P =.04) and PAI-1 (9.0 plus minus 8.1 to 13.2 plus minus 17.3 U/mL; P =.05) levels increased between the time of presentation and day 14. The mean reduction in thrombus score among 44 patients who completed 9 months of follow-up was 60.9% (plus minus 42.1%). Percent recanalization was directly associated with initial t-PA activity levels (R =.4; P =.006) and inversely related to F 1+2 (R = minus sign. 5; P =.004), t-PA antigen (R = minus sign.5, P =.002), and PAI-1 (r = minus sign. 5, P =.001) levels. However, only initial F 1+2 (P =.0009) and t-PA antigen (P =.004) levels were independent predictors of the degree of recanalization., Conclusion: Although the mechanisms by which the venous lumen is restored are still being elucidated, recanalization is inversely related to levels of activated coagulation (F 1+2) and fibrinolytic inhibition (t-PA antigen) at the time of presentation.

Extracorporeal membrane oxygenation (ECMO) can be life-saving, but suffers from thrombus formation in the circuit with associated risks of oxygenator occlusion, hemolysis and arterial embolism. The formation of thrombin is the key step to thrombus formation and two factors are needed for sustained thrombin generation, a coagulation activator to initiate the process and a procoagulant phospholipid surface for the coagulation system to assemble on. The purpose of this study was to use thrombin generation potential (TGP) and other assays to determine the specific coagulation activators and sources of procoagulant phospholipid that are present in ECMO patient plasma. Samples were collected from 60 patients on ECMO (age 1d-19y) followed evaluation of native and stimulated TGP, measurement of factor II levels and determination of procoagulant extracellular vesicle levels by flow cytometry. During ECMO, native (unstimulated) TGP was increased, followed by a decrease back towards normal after ECMO ended. The main activator of TGP in ECMO plasma was increased FXIa (100% of samples tested), while increased tissue factor activity was present in 7%. Procoagulant phospholipids were present in plasma from ECMO patients in the form of circulating platelet and red cell extracellular vesicles, which were increased 2 to 7-fold compared to normal. Procoagulant extracellular vesicle levels correlated with increased plasma native TGP activity. ECMO activates coagulation in plasma primarily through activation of the contact system and formation of activated factor XIa and generation of circulating procoagulant extracellular vesicles through platelet and red cell activation. • In pediatric patients, ECMO stimulates increased thrombin generation potential. • ECMO activates the contact system generating activated factor IXa. • ECMO increases procoagulant phospholipids through extracellular vesicle release. • Maquet circuits showed higher TGP and platelet activation than Cardiohelp circuits. [ABSTRACT FROM AUTHOR]

The authors discuss a study by S. Bloemen and colleagues, published within the issue which described development of reference intervals for thrombin generation assay (TGA) in whole blood, platelet-rich plasma, and platelet-poor plasma. Topics include clinical situations where altered TGA results have been described, problems that limit the clinical use of TGA, and development of fully automated TGAs by manufacturers on coagulation instruments.

BACKGROUND: Trauma patients are at risk of developing an acute coagulopathy of trauma (ACT) related to tissue injury, shock, and hemodilution. ACT is incompletely understood, but is similar to disseminated intravascular coagulation (DIC) and is associated with poor outcome. STUDY DESIGN AND METHODS: Thrombin generation assays were used to evaluate plasma hemostasis in 42 trauma patients, 25 normal subjects, and 45 patients on warfarin and in laboratory-prepared factor reduced plasma. RESULTS: Prolonged prothrombin time (PT), more than 18 seconds, or an international normalized ratio of greater than 1.5 was present in 15 trauma patients indicating possible ACT. Native thrombin generation (no activator added, contact activation blocked) showed that Trauma with ACT patients had lag times 68% shorter and peak thrombin generation threefold higher than normal patients indicating the presence of circulating procoagulants capable of initiating coagulation systemically. Trauma patients had lower platelet counts and fibrinogen and Factor (F)II levels putting them at increased risk of bleeding. In laboratory-prepared isolated factor-reduced samples and in patients with vitamin K–dependent factor deficiency due to warfarin, thrombin generation decreased in direct proportion to FII levels. In contrast, in diluted plasma and in trauma patients with reduced factor levels, thrombin generation was increased and associated with slower inhibition of thrombin generation (prolonged termination time) and decreased antithrombin levels (43% of normal in Trauma with ACT). CONCLUSIONS: Thrombin generation studies indicate that Trauma with ACT patients show dysregulated hemostasis characterized by excessive non–wound-related thrombin generation due to a combination of circulating procoagulants capable of activating coagulation systemically and reduced inhibitor levels allowing systemic thrombin generation to continue once started. [ABSTRACT FROM AUTHOR]

Context.—The international normalized ratio (INR) is widely used to monitor oral anticoagulation and to evaluate patients with coagulation disorders. Objective.—To examine the variability of the performance and reporting of the INR and to evaluate laboratory calculation of the INR. Design.—Between 1993 and 2003, laboratories participating in proficiency testing were surveyed. Participants provided the international sensitivity index and the mean normal prothrombin time used to calculate the INR. The INR was calculated from the data provided and compared with the INR reported to determine if the calculation was correct. Results.—Survey data regarding the INR collected between 1993 and 2003 demonstrate an improvement in reporting, using appropriate anticoagulant, using lower international sensitivity index reagents, and matching international sensitivity index and prothrombin time method. The all-method coefficient of variation of the INR improved from 18% to 5.8%. Among 3813 laboratories studied in 2002 and 2003, 4.1% miscalculated INR. Of 29 laboratories that reported investigation of the INR miscalculation, 11 (38%) reported correcting an INR that was being reported in patient results and that this error was corrected as a result of the study. Since beginning grading of the INR calculation, miscalculation of the INR has fallen to lessthan 1%. Conclusions.—Recommendations for change in laboratory practice made by consensus conferences are implemented during the course of many years. Difficulty calculating the INR was documented, and both the calculation and the variability in the reporting of the INR showed improvement. Proficiency testing, when closely evaluated and acted on, can have a direct impact on the quality of patient care. [ABSTRACT FROM AUTHOR]

Context.—Fondaparinux, a factor Xa inhibitor, is approved for thromboprophylaxis after orthopedic surgery and for treatment of venous thromboembolism. It may also be efficacious, safe, and cost-effective for other patients; thus, more widespread use of fondaparinux is likely. The effect of fondaparinux on coagulation testing needs to be thoroughly examined. Objective.—To report the effects of fondaparinux on coagulation tests (prothrombin time, activated partial thromboplastin time, fibrinogen, antithrombin, factor VIII, thrombin time, anti-factor Xa) across diverse methodologies. Design.—Samples with different concentrations of fondaparinux (0, 0.4, 0.8, and 2.0 μg/mL) were sent to laboratories participating in the College of American Pathologists Comprehensive Coagulation proficiency survey (N = 898). Laboratory-specific methods were used to assay coagulation parameters. Results.—Prophylactic or therapeutic fondaparinux prolonged the prothrombin time by approximately 1 second and the activated partial thromboplastin time by 4 to 5 seconds, and reduced factor VIII from 119% to 107% and 102%, respectively. Supratherapeutic fondaparinux reduced factor VIII to 85%. The activated partial thromboplastin time was prolonged in 19%, 29%, and 52% of laboratories with prophylactic, therapeutic, and supratherapeutic fondaparinux levels, respectively. Fibrinogen, antithrombin, and thrombin time assays did not show clinically significant changes. When measuring fondaparinux concentration using an anti-factor Xa assay, the most accurate results were obtained when fondaparinux was used as the calibrator. Conclusions.—Fondaparinux, even in prophylactic doses, slightly prolongs the prothrombin time and activated partial thromboplastin time and can interfere with factor VIII assays, but it has no clinically relevant effect on fibrinogen, antithrombin, or thrombin time. A fondaparinux standard curve should be used for reporting fondaparinux levels using an anti-factor Xa assay. [ABSTRACT FROM AUTHOR]