Strategies for managing heparin therapy in patients with antiphospholipid antibody syndrome

Antiphospholipid antibody syndrome (APS) is a common acquired thrombophilia. The diagnosis of APS is based on both clinical and laboratory criteria. The clinical criteria include vascular thrombosis or pregnancy morbidity. The laboratory criteria include a positive test for lupus anticoagulant, anticardiolipin antibodies, or anti-β(2)-glycoprotein I (anti-β(2)GPI) antibodies on two or more occasions at least 12 weeks apart. Antiphospholipid antibodies with lupus anticoagulant activity may prolong phospholipid-dependent coagulation tests such as the activated partial thromboplastin time (aPTT) and the activated clotting time (ACT). This prolongation adds a level of complexity to monitoring heparin therapy in patients with APS who have thrombosis. A literature search of the PubMed database was conducted for relevant articles published from 1995-April 2011. The usual management approach in nonsurgical patients with APS is to switch to low-molecular-weight heparin. In patients in whom heparin remains the agent of choice, management options include monitoring heparin antifactor Xa levels, determining an individualized therapeutic aPTT range, targeting an aPTT goal of 2 times the baseline aPTT, or using an aPTT reagent insensitive to lupus anticoagulant. An algorithm for anticoagulation management in nonsurgical patients with APS who require heparin is provided. The strategies to monitor intraoperative heparin in patients undergoing cardiac surgery include measuring heparin concentrations by an automated protamine titration device, targeting twice the baseline ACT, using preoperative in vitro heparin-ACT titration curves, and measuring heparin antifactor Xa levels. The available published case reports on the use of these strategies are reviewed. Each institution should determine an approach to managing heparin in patients with APS that best meets its needs and resources.     

血凝仪-APTT法测定肝素的效价

目的:建立一种基于血液凝固分析仪测定活化部分凝血活酶时间(APTT)的肝素生物测定法(简称血凝仪-APTT法)。方法:将高、中、低浓度的肝素钠标准品和供试品分别与血浆混和,用血液凝固分析仪测定各含药血浆的活化部分凝血活酶时间(APTT),结果进行对数转换后,按量反应平行线3.3法计算供试品的效价。结果:对数凝血时间与肝素钠的浓度在0.7～3 IU.mL-1范围内线性关系良好(r=0.9965);当供试品的测得效价与估计效价的比值在80%～120%范围内时,血凝仪-APTT法的测定结果准确可靠,重复性(RSD=1.45%,n=6)及中间精密度(RSD=1.61%,n=6)良好。以兔全血法、羊血浆法和血凝仪-APTT法分别测定同一批肝素钠供试品的效价(IU.mg-1,n=3),结果依次为207.56±6.87,205.59±3.62,202.79±2.08,无显著性差异(P>0.05);兔全血法和血凝仪-APTT法的可信限率(%,n=3)分别为8.51±0.77和2.63±0.21,具有显著性差异(P<0.01)。使用不同仪器测定样品效价的结果基本一致。结论:血凝仪-APTT法与兔全血法和羊血浆法的效价测定结果一致,可信限率比兔全血法更低。该法操作简便,客观准确,重复性好,精密度高,适用于不同仪器,可以用于肝素钠生物效价的测定。     

A dose-response study in animals to evaluate the anticoagulant effect of the stage 2 unfractionated heparin USP monograph change

The United States Pharmacopeia (USP) monograph for unfractionated heparin (UFH) was revised in October 2009. This revision was anticipated, based upon in vitro tests, to reduce UFH potency by approximately 10%. To study the potential in vivo consequences of the monograph change, we evaluated activated partial thromboplastin time (aPTT) and activated clotting time (ACT) responses in animals. Female mini-pigs and monkeys (n=8/species) were administered intravenously 60, 54, 48, or 42 U/kg and 50, 45, 40, or 35 U/kg "old" (pre-USP revision) UFH, respectively, in a Williams 4×4 crossover design. Blood samples for aPTT and ACT were collected at 15 min after dosing. The same study design was then repeated using "new" (post-USP revision) UFH. Mean "new" UFH aPTT and ACT values were generally lower than those for "old" UFH although individual animal responses varied considerably. The aPTT and ACT response was generally dose-proportional for both "old" and "new" UFH. These studies indicate that the USP monograph alteration for UFH may result in a modest reduction in the anticoagulant response across a population, but the variability in animal responses underscores the importance of individualization of clinical UFH dosing and the importance of anticoagulant test monitoring.     

Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects

STUDY OBJECTIVE: To evaluate and compare the relationship between dosage and coagulation parameters, as well as safety profiles, of ascending bolus and infusion dosages of argatroban versus heparin in three phase I studies. DESIGN: Two randomized, double-blind studies compared argatroban and heparin, and one open-label, dose-escalation study further evaluated argatroban. SETTING: University teaching hospital clinical research unit. PATIENTS: Healthy men (aged 22-62 yrs). INTERVENTION: In the first study, 36 subjects received an argatroban 30-, 60-, 120-, or 240-microg/kg bolus, or a heparin 30-, 60-, 120-, or 240-U/kg bolus for three subjects, then amended to 15, 30, 60, or 120 U/kg. In the second study, 37 subjects received argatroban 1.25, 2.5, 5, or 10 microg/kg/minute with or without a 250-microg/kg bolus, or heparin 0.15, 0.20, 0.25, or 0.30 U/kg/minute with or without a 125-U/kg bolus. In the third study (open-label), nine subjects received an argatroban 250-microg/kg bolus plus an infusion of 15, 20, 30, and 40 microg/kg/minute. MEASUREMENTS AND MAIN RESULTS: When administered as a bolus dose in the first study, argatroban and heparin both produced dose-related increases in activated clotting time (ACT) and activated partial thromboplastin time (aPTT) within 10 minutes of administration. Dissipation of anticoagulant effect was approximately 4-fold faster for argatroban than for heparin. When administered by infusion with or without a bolus in the second study, argatroban, but not heparin, produced predictable dose-related increases in ACT and aPTT that were generally consistent across both effect measures and modes of administration. Effect steady state was attained by five or more subjects per dosing group receiving argatroban (5-9) but typically two or fewer subjects per group receiving heparin (0-7). Furthermore, upon cessation of infusion, anticoagulant effects dissipated faster for argatroban (effect half-life 18-41 min) than for heparin (effect half-life 23-134 min). When argatroban was infused without a bolus, peak and effect steady-state values for ACT and aPTT generally were attained within 1-3 hours. Data from the second and third studies show that for argatroban dosages up to 40 microg/kg/minute, plasma drug concentrations attained at 4 hours of infusion increased linearly with dose, and weight-adjusted plasma clearance was dose independent. In all studies, argatroban and heparin were well tolerated. CONCLUSION: Anticoagulation was more predictable with argatroban than with heparin as measured by ACT and aPTT, with comparable safety profiles.     

Antifactor Xa levels versus activated partial thromboplastin time for monitoring unfractionated heparin

Intravenous unfractionated heparin (UFH) remains an important therapeutic agent, particularly in the inpatient setting, for anticoagulation. Historically, the activated partial thromboplastin time (aPTT) has been the primary laboratory test used to monitor and adjust UFH. The aPTT test has evolved since the 1950s, and the historical goal range of 1.5-2.5 times the control aPTT, which first gained favor in the 1970s, has fallen out of favor due to a high degree of variability in aPTT readings from one laboratory to another, and even from one reagent to another. As a result, it is now recommended that the aPTT goal range be based on a corresponding heparin concentration of 0.2-0.4?unit/ml by protamine titration or 0.3-0.7?unit/ml by antifactor Xa assay. Given that several biologic factors can influence the aPTT independent of the effects of UFH, many institutions have transitioned to monitoring heparin with antifactor Xa levels, rather than the aPTT. Clinical data from the last 10-20?years have begun to show that a conversion from aPTT to antifactor Xa monitoring may offer a smoother dose-response curve, such that levels remain more stable, requiring fewer blood samples and dosage adjustments. Given the minimal increased acquisition cost of the antifactor Xa reagents, it can be argued that the antifactor Xa is a cost-effective method for monitoring UFH. In this review, we discuss the relative advantages and disadvantages of the aPTT, antifactor Xa, and protamine titration tests, and provide a clinical framework to guide practitioners who are seeking to optimize UFH monitoring within their own institutions.     

Monitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time.

STUDY OBJECTIVE: To determine how much more costly it is to monitor unfractionated heparin (UFH) therapy by antifactor Xa heparin activity (HA) than by activated partial thromboplastin time (aPTT). DESIGN: Prospective, randomized, unmasked, cohort, single-center study. SETTING: A 625-bed, adults-only, private teaching hospital. PATIENTS: Two hundred sixty-eight patients with a variety of indications for UFH therapy. INTERVENTIONS: Patients were treated with UFH based on ideal weight (75 U/kg bolus, 20 U/kg initial infusion) and monitored by either HA or aPTT, MEASUREMENTS AND MAIN RESULTS: After adjusting for gender, groups were equivalent in patient characteristics and UFH dosage. The HA group had fewer monitoring tests and dosage changes/24 hours than the aPTT group. These reductions neutralized much of the increased cost of the HA assay itself. CONCLUSION: Monitoring UFH therapy over 96 hours with an HA assay costs $4.37 more than monitoring with aPTT. This modest increase may be acceptable given other advantages of the HA assay.     

Comparative Effects of Heparin and the Sulfatoid GM1474 on Coagulation Parameters in Plasma and Blood from Various Species

• 1.The discovery and development of novel carbohydrate molecules based on heparin biology and pharmacology requires consideration of coagulation effects in evaluating the therapeutic potential of these agents. A novel sulfatoid compound, GM1474, possessing potent antiproliferative and antiangiogenic properties similar to those of heparin, was evaluated for comparative coagulation effects.
• 2.In vitro and in vivo effects of GM1474 on plasma-activated partial prothromboplastin time (aPTT) and whole-blood clotting time (WBCT) were monitored in plasma and blood from various species and compared with those of heparin. GM1474 possessed approximately 21.7% of the in vitro aPTT and 4.3% of the in vitro WBCT effects relative to heparin, utilizing human plasma and blood.
• 3.Similar differences between GM1474 and heparin were observed in plasma and blood from mice, rats, dogs and nonhuman primates. The concentrations of GM1474 producing a two-fold increase in aPTT and WBCT in vitro in the various species ranged from 2.95 to 11.4 times the concentrations of heparin producing similar effects.
• 4.In in vivo evaluations in mice, the intravenous doses of GM1474 producing 50% of the maximal elevation in plasma aPTT and bleeding time (IC50s) were 2.1 and 12.0 mg/kg, respectively. These doses represented approximately 6.4- and 27.9-fold the in vivo IC₅₀ doses of heparin causing elevations in aPTT and bleeding times, respectively.
• 5.The results of this study demonstrate that GM1474 possesses significantly reduced effects on coagulation relative to heparin, as determined by in vitro and in vivo testing.
• 6.Species differences in sensitivity to GM1474 and heparin were also observed in in vitro profiling. The order of species sensitivity to GM1474 and heparin was similar (mice>human beings>rats>nonhuman primates>dogs) and indicates that the mouse may be the most predictive species with respect to coagulation effects in human beings.

     

Developing a model to determine the effects of adverse drug events in hospital inpatients.

PURPOSE: A study was conducted to develop a model to identify adverse drug events (ADEs) and quantify their effect on quality and cost in a large tertiary care hospital. METHODS: The drug-ADE relationship between unfractionated heparin and heparin-induced bleeding was studied for all inpatients receiving heparin infusions at the hospital between January 1 and December 31, 2004. Activated partial thromboplastin time (aPTT) values were used to help determine if the patients received blood products in response to excessive anticoagulation with heparin. The number of aPTT values of > or =150 seconds and the last aPTT value before discharge were evaluated. The key outcome measures were length of stay, cost per admission, and mortality. Of the 1455 admissions to the hospital, 122 patients received blood products before receiving heparin infusion only, 264 received blood products after receiving the drug only, 221 received blood products both before and after, and 848 who received the drug never received blood products. RESULTS: Differences in full cost and length of stay between the group receiving heparin infusion only and the groups receiving both blood products were significant. Differences in mortality between the group only receiving heparin infusion and the groups receiving both heparin infusion and blood products were also significant. CONCLUSION: Using the model developed to study the effect of heparin-induced bleeding, we found that the cost per patient day was highest for patients receiving blood products after heparin infusion treatment. There was a positive correlation between one or more aPTT values of > or =150 seconds and undesirable patient outcomes.     

Challenge and rechallenge: drotrecogin alfa (activated)-induced prolongation of activated partial thromboplastin time in a patient with severe sepsis

An 81-year-old woman with ischemic bowel underwent laparotomy with small-bowel resection and developed septic shock. She required broadspectrum antibiotics, norepinephrine, and mechanical ventilation. The patient received drotrecogin alfa (activated) 24 microg/kg/hour for a total of 67.5 hours. Coagulation parameters were monitored during her therapy. Significant increases in activated partial thromboplastin time (aPTT) during infusion led to two temporary discontinuations of the drug. Coagulation parameters decreased when the drug was held and increased with each rechallenge. The patient survived the episode and was discharged on postoperative day 27. Medical records of 26 other patients who received drotrecogin alfa (activated) at our institution from November 2001-August 2003 were reviewed retrospectively for coagulation parameters and bleeding rate. Of the 26 patients, nine (35%) were treatment compliant (>90% of the 96-hr course). Coagulopathy and bleeding resulted in early discontinuation in four (15%) and six (23%) patients, respectively. An increase in aPTT from baseline to during infusion of drotrecogin alfa (activated) was noted in 14 patients with complete data (p=0.56). A decrease in median platelet count from baseline to during infusion was noted in the six patients who bled during therapy (p=0.01). Two of these patients had platelet counts less than 30x10(3)/mm3 during administration. Drotrecogin alfa (activated) should be considered an anticoagulant. In postmarketing reports, clinically significant bleeding occurred more frequently than was noted in a large, randomized, multicenter trial. Patients receiving drotrecogin alfa (activated) should be closely monitored for prolongation of coagulation parameters. Temporary discontinuation of the drug should be considered when international normalized ratio is greater than 3.0, platelet count is less than 15x10(3)/mm3, and aPTT is greater than 100 seconds.     

Evaluation of Bleeding Rates in Renal Transplant Patients on Therapeutic Intravenous Heparin

Background:

It is unknown whether coagulation properties differ between renal transplant and nontransplant patients.

Objective:

To assess whether renal transplant patients on intravenous (IV) heparin, titrated to therapeutic activated partial thromboplastin times (aPPT; 56-93 seconds), experienced a higher rate of bleeding compared to nontransplant patients.

Methods:

Twenty-nine renal transplant and 29 nontransplant patients receiving IV heparin for a deep vein thrombosis, pulmonary embolism, atrial fibrillation, or acute coronary syndrome were randomly identified through a retrospective chart review.

Results:

Renal transplant patients had higher bleeding rates on IV heparin therapy compared to nontransplant patients (31% vs 6.9%, respectively; P = .041). Renal transplant patients experienced a drop in hemoglobin of at least 1 g/dL or the need for a transfusion more often then nontransplant patients (69% vs 45%, respectively; P = .111), although the difference was not statistically significant.

Conclusions:

Further research is necessary to identify the factors contributing to increased rates of bleeding in renal transplant patients on IV heparin and to determine the ideal aPTT to appropriately balance anticoagulation in renal transplant patients.In patients who need anticoagulation, it is a challenge to provide the optimal balance between enough anticoagulant to prevent the formation of a thrombus and too much, which may cause a bleeding event.¹ As many as 10% of adult patients experience thrombotic events following renal transplantation.² Most thrombotic events occur in the initial 48 hours after surgery, but they can occur up to 14 days after renal transplantation.² It is especially important in this population to achieve that balance in anticoagulation therapy, because immediate graft loss may occur if patients experience thrombosis of the renal artery or vein.² Heparin may be used in the perioperative phase in an attempt to prevent thrombotic events, especially in patients with hypercoagulable states.^3-5In the general population, major bleeding occurs in up to 7% of patients who receive therapeutic intravenous (IV) heparin.^1,6 Because one of the risk factors for heparin-induced bleeding is recent surgery, it would be expected that there would be increased bleeding risk in the early postoperative transplantation period.⁶Patients with chronic renal failure may have impaired hemostasis. Platelet production may be disturbed due to the accumulation of protein biodegradation products. Bleeding tendencies may be further increased due to clotting factor deficiencies and vascular defects. Conversely, in uremic patients, clotting factors VII and XIII and fibrinogen may be increased, leading to an increased thrombosis risk. The clotting inhibitors protein C and S, antithrombin III, and heparin cofactor II activity may also be impaired. Unfortunately, complete improvement in hemostasis does not occur after successful renal transplantation.⁷A previous study by Mathis et al² evaluated bleeding events due to therapeutic IV heparin in renal transplant patients to prevent perioperative thrombosis. They found no link between the immunosuppressive agents used in the study (primary agents: cyclosporine, mycophenolate, prednisone; alternatives: tacrolimus and rapamycin) and risk of bleeding. However, there was a trend toward increased rates of bleeding in patients who received antibiotic prophylaxis for surgery for longer periods of time (P = .053); cefotetan was used more frequently in patients who experienced bleeding (P = .091).A literature search regarding bleeding rates in renal transplant patients found trials in the early postoperative transplantation period, with bleeding occurring in 60% to 64.3% of patients.^2,5,8 No literature was found regarding bleeding rates in renal transplant patients who were receiving therapeutic IV heparin at any time beyond the early transplantation period. The perceived increase in susceptibility to bleeding in renal transplant patients receiving IV heparin (any time after transplantation) led to our assessment of renal transplant patients’ bleeding rates on IV heparin, titrated to a therapeutic activated partial thromboplastin time (aPTT; 56-93 seconds; 1.5 to 2 times normal, institution specific) compared to nontransplant patients.     

Evaluation of a rapid monitoring system to study heparin pharmacokinetics and pharmacodynamics

The pharmacokinetic and pharmacodynamic characteristics of heparin were studied in 10 healthy volunteers using the Hepcon/System B-10. This coagulation-monitoring system uses each patient's body weight, height, baseline activated clotting time (ACT), and heparin dose response values to determine initial heparin doses. We administered a calculated mean +/- SD heparin doses of 85 +/- 14 U/kg to 10 subjects to achieve a mean +/- SD target ACT of 364 +/- 29 seconds. This dose produced a mean +/- SD measured peak ACT of 337 +/- 53 seconds from a mean +/- SD baseline of 121 +/- 10 seconds. The measured peak ACT values resulting from the individualized heparin doses were within 20% of the desired peak in 9 (90%) of the subjects. Using the ACT values, the average mean residence time for heparin effect was 1.2 hours and half-life was 0.8 +/- 0.2 hours, with all the subjects' values returning to within 10% of baseline by 4 hours after the dose. Using the protamine-derived heparin concentrations, heparin total-body clearance ranged from 43 to 99 ml/hr/kg (mean +/- SD 73.3 +/- 14.5 ml/hr/kg). A linear relationship was found between heparin concentration and change in ACT that was described by delta ACT = 16.85 + 136.7.(heparin concentration). We conclude that this method is easy to perform and accurate for determining initial heparin dosage requirements, and could be an important improvement over existing approaches. In addition, it is a valuable research tool for studying heparin pharmacodynamics and pharmacokinetics.     

An institution-specific heparin titration nomogram: development, validation, and assessment of compliance

STUDY OBJECTIVE: To develop, validate, and assess compliance with a heparin titration nomogram. DESIGN: Prospective, open-label trial. SETTING: University teaching hospital. SUBJECTS: Patients admitted with heart failure who required therapy with intravenous unfractionated heparin. Intervention. An in vitro concentration-response was determined by measuring activated partial thromboplastin times (aPTTs) on normal pooled plasma containing known concentrations of heparin. The therapeutic aPTT range was determined from the concentration-response by using the therapeutic heparin concentration range of 0.2-0.4 U/ml (protamine neutralization). Patients were consecutively enrolled, and therapy was managed by using the heparin titration nomogram. Paired aPTT-heparin concentrations were obtained, and nomogram validation was performed by comparing the in vitro and the ex vivo concentration-responses with use of linear regression. Nomogram compliance also was assessed. MEASUREMENTS AND MAIN RESULTS: The therapeutic aPTT ranges based on in vitro and ex vivo data were determined to be 45-72 seconds and 47-61 seconds, respectively. The ranges were significantly different (p<0.001). Overall compliance with the nomogram was 88%. CONCLUSION: These results confirm that, even in a relatively homogeneous disease-state patient population, in vitro data do not accurately predict ex vivo data. If in vitro data are used to develop an institution-specific nomogram, a validation procedure should be used to ensure accuracy. Although 100% compliance to a nomogram may not be attainable, it should be expected. Therefore, a compliance rate of 88% is concerning and suggests a need for increased nursing and physician education.     

Heparin responsiveness during off-pump coronary artery bypass graft surgery: predictors and clinical implications

Aim:To evaluate the clinical impact of reduced heparin responsiveness (HR(reduced)) on the incidence of myocardial infarction (MI) following off-pump coronary artery bypass graft surgery (OPCAB), and to identify the predictors of HR(reduced).Methods:A total of 199 patients scheduled for elective OPCAB were prospectively enrolled. During anastomosis, 150 U/kg of heparin was injected to achieve an activated clotting time (ACT) of ≥ 300 s, and the heparin sensitivity index (HSI) was calculated. HSIs below 1.0 were considered reduced (HR(reduced)). The relationships between the HSI and postoperative MI, cardiac enzyme levels and preoperative risk factors of HR(reduced) were investigated.Results:There was no significant relationship between the HSI and cardiac enzyme levels after OPCAB. The incidence of MI after OPCAB was not higher in HR(reduced) patients. HR(reduced) occurred more frequently in patients with low plasma albumin concentrations and high platelet counts.Conclusion:HR(reduced) was not associated with adverse ischemic outcomes during the perioperative period in OPCAB patients, which seemed to be attributable to a tight prospective protocol for obtaining a target ACT regardless of the presence of HR(reduced).     

Oral Delivery of New Heparin Derivatives in Rats

Purpose. In this study, conjugates of heparin and deoxycholic acid were synthesized in order to enhance the heparin absorption in the GI tract. Oral delivery of heparin is a preferred therapy in the treatment of patients who are at high risk of deep vein thrombosis and pulmonary embolism. Methods. Several different kinds of heparin derivatives were synthesized, and their absorption in the GI tract was determined by activated partial thromboplastin time (aPTT) and factor Xa (FXa) assay. Any histological changes caused by heparin derivatives were examined by hematoxylin and eosin (H&E) stain and transmission electron microscopy (TEM). Results. After administering heparin-DOCA orally, the clotting time in aPTT assay was increased with the increase of the coupled DOCA amount. The maximum clotting time of heparin-DOCA was 136±33 sec at 200 mg/kg of oral dose. This value was 7 times higher than the baseline. The absorption of heparin-cholesterol, heparin-palmitic acid, and heparin-lauric acid conjugates in the GI tract was lower than that of heparin-DOCA. Histological examination of the GI tract indicated that heparin derivatives did not cause any damage to the microvilli and the cell layer. Conclusions. DOCA coupled with heparin greatly enhanced absorption of heparin in the GI tract, and this enhancing effect was induced without changing the tissue structure of the GI wall.     

Two instruments to determine activated partial thromboplastin time: implications for heparin monitoring

STUDY OBJECTIVE: To measure the difference in therapeutic ranges of activated partial thromboplastin time (APTT) between two laboratory devices. DESIGN: Prospective, controlled laboratory study. SETTING: University-affiliated hospital. PATIENTS: Thirty inpatients receiving intravenous unfractionated heparin for treatment of myocardial infarction, unstable angina, deep venous thrombosis, or pulmonary embolism. INTERVENTIONS: Therapeutic APTT ranges were determined by a portable (whole blood assay) and a central laboratory device (plasma assay) based on heparin serum concentrations. They were compared with APTT ranges equivalent to 1.5-2.5 times the mean normal determination. MEASUREMENTS AND MAIN RESULTS: The central laboratory and portable devices produced therapeutic ranges of 61-93 and 56-73 seconds, respectively. Both differed from conventional therapeutic ratios of 1.5-2.5 times the mean normal (41-68 sec). Mean absolute APTT differences between instruments were statistically significant (12 +/- 20 sec, p<0.006), and 58% of paired APTT values differed by more than 10 seconds. CONCLUSION: A fixed APTT ratio as a goal for monitoring unfractionated heparin may result in significant underanticoagulation. Individual therapeutic APTT ranges must be reported for each instrument if more than one is used for heparin monitoring.     

用血栓弹力图评价肝素浓度变化对凝血系统的影响

目的通过血栓弹力图(thrombelastograph,TEG)研究不同肝素浓度下凝血系统的变化。方法对60名健康志愿者行枸橼酸真空抗凝管肘静脉抽血。用同种肝素钠注射液,使待测血样中肝素浓度分别为0、1、2、3、4、5、6 ku.L-1。用血栓弹力图测定凝血因子水平(reaction time,R)、纤维蛋白原时间(kinetics of clot development,K)、最大血块强度(maximum amplitude,MA)、凝血综合指数(coagulation index,CI)和最大血块形成时间(time to maximum amplitude,TMA),共5项参数。结果肝素浓度与凝血因子和血小板聚集功能的抑制程度成正比。当肝素浓度到达3 ku.L-1以上时,R和MA与对照组比较具有统计学意义。当肝素浓度到达4 ku.L-1以上时,R、MA、CI和TMA与对照组比较具有统计学意义。K值变化与肝素浓度变化无关。结论血栓弹力图可以全面检测肝素对血液的抗凝作用。研究认为,肝素可直接抑制凝血酶生成从而抑制凝血因子和血小板的促凝功能,使血液的综合凝血状态降低,血块形成时间延长。肝素用量多少和血液低凝状态存在线性关系,这对今后肝素使用、监测、出血风险等情况具有很好的临床预警价值。在管理肝素使用以及常规凝血风险管理中具有重要作用。     

Anticoagulation Therapy for Patients with Non-Valvular Atrial Fibrillation

Background: Anticoagulation in patients with atrial fibrillation (AF) is challenging because stroke-risk reduction must be balanced against increased bleeding risk. Objective: We developed a decision model integrating both stroke and bleeding risk schemes to guide optimal use of anticoagulation in AF, and compared model recommendations with warfarin use in a real-world database. Methods: A Markov model based on demographics, CHADS₂ (Congestive Heart Failure, Hypertension, Age of 75 years and greater, Diabetes Mellitus and History of Stroke) stroke and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleed risk scores, and anticoagulation treatment effects from clinical trials simulated health state transitions for recently diagnosed AF patients. The model recommended the treatment with greater quality-adjusted life expectancy. Model recommendations were contrasted with actual warfarin use recorded in the Thomson Reuters MarketScan database (N=64 946). Results: 74.8% (n = 48 548) of the Marketscan AF cohort had CHADS₂ ≥1, of whom 14.3% had moderate/high (≥4) ATRIA bleeding risk. While the model recommended warfarin for almost all patients with CHADS₂ ≥1 who are at low bleeding risk, it recommended warfarin for fewer patients as bleeding risk increased. Of the 44 611 patients recommended warfarin, 63.4% of patients were considered warfarin exposed (concordant with model recommendation), and of the 20 335 patients recommended aspirin (ace-tylsalicylic acid), 59.7% received warfarin (discordant with model recommendations). Actual warfarin use decreased modestly with higher stroke risk (p< 0.0001) and with higher bleeding risk (p< 0.0001). Conclusion: High discordance between actual warfarin use and model recommendations suggests that anticoagulation decisions are not based on systematic evaluation of stroke and bleeding risks. Model-based clinical decision aids may improve oral anticoagulation decisions by more systematically weighing bleed and stroke risk.     

The influence of heparin on the prothrombin time

We studied the effect of known concentrations of heparin on the prothrombin time (PT) in patients receiving warfarin and in controls who were not anticoagulated. Plasma from the subjects and controls was serially diluted with known concentrations of heparin, and PT was measured. Linear regression of heparin concentration versus percentage change in PT resulted in r = 0.86 in the warfarin group and r = 0.72 in the control group. The warfarin group was more sensitive to the effects of heparin than the control group, as manifested by a steeper slope of the regression line (p less than 0.001). Over the therapeutic range of heparin concentration (0.2-0.4 units/ml), the 95% prediction interval of the percentage change in PT was -6-12% at 0.2 units/ml, and 2-20% at 0.4 units/ml in the warfarin group. These results demonstrate a strong relationship between the heparin concentration in plasma and the percentage change in the PT. This effect should be considered when adding warfarin to the regime of patients receiving heparin therapy.     

Cost-effectiveness of Argatroban Versus Heparin Anticoagulation in Adult Extracorporeal Membrane Oxygenation Patients

Purpose: The purpose of this study was to evaluate the cost effectiveness of argatroban compared to heparin during extracorporeal membrane oxygenation (ECMO) therapy. Methods: This was a retrospective study of patients who received argatroban or heparin infusions with ECMO therapy at a community hospital between January 1, 2017 and June 30, 2018. Adult patients who received heparin or argatroban for at least 48 hours while on venovenous (VV) or venoarterial (VA) ECMO were included. Patients with temporary mechanical circulatory assist devices were excluded. Each continuous course of anticoagulant exposure that met the inclusion criteria was evaluated. The primary endpoint was the total cost of anticoagulant therapy for heparin versus argatroban, including all administered study drugs, blood or factor products, and associated laboratory tests. Secondary endpoints included safety and efficacy of anticoagulation with each agent during ECMO. Documentation of bleeding events, circuit clotting, and ischemic events were noted. Partial thromboplastin time (PTT) values were evaluated for time to therapeutic range and percentage of therapeutic PTTs. Results: A total of 11 courses of argatroban and 24 courses of heparin anticoagulation were included in the study. The average cost per course of argatroban was less than the average cost per course of heparin ($7,091.98 vs $15,323.49, respectively; P value = 0.15). Furthermore, argatroban was not associated with an increased incidence of bleeding, thrombotic, or ischemic events. Conclusion: Argatroban may be more cost-effective during ECMO therapy in patients with low antithrombin III levels without increased risk of adverse events.