Hydroxyethyl starches and dextran during hip replacement surgery: effects on blood volume and coagulation

Background: Colloid fluids influence the coagulation system by diluting the plasma and, potentially, by exerting other effects that are unique for each fluid product. We hypothesised that changes in the coagulation measured at the end of surgery would be mainly governed by differences in half‐life between the colloid fluids. Methods: Eighty‐four patients were randomised to receive one of four colloids: HES 130/0.42/6 : 1 (Venofundin^®), 130/0.4/9 : 1 (Voluven^®), 200/0.5/5 : 1 (Haes‐steril^®) and 6% dextran 70 (Macrodex^®). Blood samples were taken just before and after a preoperative 500 ml bolus, and also after subsequent elective hip replacement surgery. Volume expansion was estimated from the blood dilution and coagulation assessed by ROTEM, activated partial thromboplastin time, prothrombin international normalised ratio (PT‐INR), D‐dimer and thrombin–antithrombin complex (TAT). Results: The blood volume expansion amounted to approximately 600 ml for all four colloids directly after infusion. Voluven^® and Haes‐steril^® prolonged the aPT time and Venofundin^® increased TAT. Although all colloids increased PT‐INR and D‐dimer, the ROTEM analyses showed that they consistently shortened the clotting time and weakened the clot strength. These effects were mainly unchanged after surgery, during which the haemorrhage averaged 500–600 ml. Macrodex^® produced a stronger volume support at the end of the surgery (91% of infused volume; P<0.001) than the three starch solutions (42–60%). Conclusions: All tested colloid fluids induced a mild hypercoagulable state with faster clotting, but with weaker clot strength. The additive influence of surgery was relatively small, and postoperative changes in coagulation were mainly due to differences in the half‐life of each colloid.     

Low- and medium-molecular-weight hydroxyethyl starches: comparison of their effect on blood coagulation

BACKGROUND: High-molecular-weight hydroxyethyl starch (HES) compromises blood coagulation more than medium-molecular-weight HES. The authors compared medium molecular weight HES (200 kd [HES200]) and low-molecular-weight HES (70 kd [HES70]). METHODS: In a prospective, double-blind, randomized-sequence crossover study, 22 male volunteers received 15 ml/kg HES200 and HES70. Blood samples were taken before and 5 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after infusion. The following parameters were analyzed at all time points: prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, antigenetic and functional von Willebrand factor, platelets, Thrombelastograph analysis parameters (reaction time, coagulation time, maximum amplitude, angle alpha, and clot lysis 30 and 60 min after maximum amplitude), ionized calcium, hematocrit, HES plasma concentration, molecular weight (weight average and number average), molar substitution, and polydispersity (weight average/number average). Repeated-measures analysis of variance (P < 0.05) was used to compare the response of the aforementioned parameters to the infusion of HES70 and HES200. RESULTS: Both HES solutions had a significant impact on all parameters. A slightly greater compromise with HES200 was found in activated partial thromboplastin time (P = 0.010), factor VIII (P = 0.009), antigenetic von Willebrand factor (P = 0.041), functional von Willebrand factor (P = 0.026), maximum amplitude (P = 0.008), and angle alpha (P = 0.003). No difference was established with the other parameters. HES concentration (P < 0.001), weight average (P < 0.001), number average (P < 0.001), and polydispersity (P < 0.001) were higher with HES200. There was no difference with molar substitution (P = 0.091). CONCLUSIONS: Low-molecular-weight hydroxyethyl starch (70 kd) compromises blood coagulation slightly less than HES200, but it is unclear whether this is clinically relevant.     

羟乙基淀粉对血液流变学及凝血功能的影响

目的 观察输注6％羟乙基淀粉（HES200／0．5）对病人血液流变学及凝血功能的影响。方法 30例硬膜外阻滞下手术病人,在硬膜外阻滞前输注贺斯12ml/kg。输液前后分别抽取静脉血测定：（1）全血低切、中切、高切粘度,红细胞比容,全血低切、中切、高切还原粘度,血沉,红细胞聚集指数、刚性指数、变形指数。（2）血小板计数（PLC）,血小板粘附率（PAD）,血小板1分钟聚集率（PAG1）、3分钟聚集率（PAG3）和最大聚集率（PAGM）。（3）凝血酶原时间（PT）,凝血酶时间（TT）,部分凝血活酶时间（APTT）和纤维蛋白原浓度（Fib)。结果 输液后全血粘度高切变率、中切变率明显下降,全血还原粘度高切变率、血沉、红细胞刚性指数在输液后显著降低,血小板粘附及聚集功能、TT、APTT及Fib输液后差异无显著意义,只有PT显著延长。结论 静注500－1000ml6%HES,可改善血液流变性,对凝血功能无影响。     

Lidocaine and bupivacaine exert differential effects on whole blood coagulation.

STUDY OBJECTIVES: To compare bupivacaine to lidocaine's effects on blood clotting at two concentrations, and to characterize and determine relative effects of two equianalgesic bupivacaine and lidocaine concentrations. DESIGN: Prospective, dual-controlled, whole blood equal volume admixture thrombelastographic (TEG) study. SETTING: University of Pennsylvania Medical Center operating rooms. PATIENTS: 20 ASA physical status I and II patients' blood comprised control groups and anesthetic groups. INTERVENTIONS: Analysis of whole blood clotting used six TEG channels for untreated and saline controls and four final concentrations (1.0% lidocaine, 0.5% lidocaine, 0.25% bupivacaine, and 0.125% bupivacaine) of local anesthetics. Saline control and the local anesthetic-treated specimens underwent 8.3% hemodilution. MEASUREMENTS AND MAIN RESULTS: Blood was studied. Saline control or four anesthetic solutions (30 microliters) were added in random order two 5 TEG cuvettes. Whole blood (330 microliters) was mixed ex vivo at 37 degrees C. A sixth channel with untreated whole blood (360 microliters) acted as an undiluted control. Data for four TEG parameters [reaction time (r), angle (alpha), maximum amplitude (MA), and percent decrease in TEG amplitude from MA 30 minutes after MA acquisition (Lysis 30)] for undiluted control and saline volumetric controls were compared to each other using Student's t-test for paired observations. Lidocaine and bupivacaine groups' TEGs were compared to the paired saline control analysis of variance for repeated measures. A p-value less than 0.05 was considered significant. There was no difference between whole blood and saline control TEGs. All local anesthetics produced significant hypocoagulable changes from control. Angle alpha and MA were significantly decreased in all local anesthetic groups. Ther time was prolonged only in the high lidocaine-treated blood. Lysis was a feature of the low lidocaine and bupivacaine solutions. Equianalgesic lidocaine produced more profound hypocoagulable effects than did bupivacaine. CONCLUSIONS: Lidocaine and bupivacaine both significantly impaired TEG coagulation in a concentration-dependent manner. Lidocaine was significantly more hypocoagulable than bupivacaine at two similarly analgesic concentrations.     

The effects of a one unit blood donation on auto-haemodilution and coagulation

The effect of haemodilution on coagulation has been extensively investigated. We investigated auto-haemodilution following a 10% blood loss (480 ml) and its effect on coagulation. Ten healthy, unstarved volunteers were enrolled. One unit of blood was taken from each volunteer. Concurrently blood was taken from the opposite arm prior to and immediately after the blood donation, and at 1, 2, 4 and 6 hours. It was tested for thrombelastography, haematocrit and endorphins. There was a significant decrease in r-time from the control sample to the sample taken immediately post blood donation. This value returned to baseline at 1 hour post donation and did not change again. There were no other significant changes in thromboelastographic parameters. Fractional plasma noradrenaline changes were significantly raised at 1 hour post donation (P = 0.048), returning to baseline by 2 hours post donation. The haematocrit showed a rapid (approximately 4%) fall during donation followed by a slow, but progressive decrease over six hours, falling by a mean of 8.3% from pre-donation values. A state of relative hypercoagulability is found immediately after a rapid 10% loss in circulating blood volume. This may be related to the rapid immediate haemodilution. It is unlikely that the sympathetic response to blood loss plays a role. However, after the initial drop, slow restoration of circulating blood volume by autodilution takes six to eight hours, and is not associated with enhanced coagulation. Of interest is that a 10% blood loss in a healthy person does not require volume replacement.     

Oral testosterone-triglyceride conjugate in rabbits: single-dose pharmacokinetics and comparison with oral testosterone undecanoate

Development of a safe and effective oral form of testosterone has been inhibited by the rapid hepatic metabolism of nonalkylated androgens. Since triglycerides are absorbed via lymphatics and bypass the liver, we hypothesized that a testosterone-triglyceride conjugate (TTC) might allow for safe and effective oral testosterone therapy. Therefore, we studied the single-dose pharmacokinetics of oral administration of TTC in rabbits. Female New Zealand rabbits were administered 2, 4, or 8 mg/kg of TTC in sesame oil by gastric lavage. Testosterone undecanoate (TU) by gastric lavage was used as a positive control. Blood was sampled from a catheter in the auricular artery at 0, 15, 30, 60, 90, 120, 180, 240, 360, 480, and 600 minutes after drug administration. Samples were assayed for testosterone by a fluoroimmunoassay. Mean serum testosterone, area under the curve (AUC), and terminal half-life were calculated. Oral TTC administration resulted in rapid and marked increases in serum testosterone. Oral TTC resulted in higher maximum serum testosterone concentrations than oral TU at 8 mg/kg (TTC: 28.6 +/- 7.9 nmol/L vs TU: 11.9 +/- 2.1 nmol/L; P <.001) and 4 mg/kg (TTC: 11.5 +/- 4.2 nmol/L vs TU: 3.6 +/- 1.0 nmol/L; P <.001). In addition, the AUC was 1.8 to 2.6 times greater for TTC than TU at both doses (P <.05). The terminal half-life for both TU and TTC was between 3 and 5 hours and was not significantly different. We conclude that oral TTC is rapidly absorbed from the rabbit intestine and results in elevated concentrations of serum testosterone. The absorption of TTC appears to be superior to that of TU; however, the in vivo persistence of the 2 compounds is similar. TTC may offer an alternative to the use of TU for oral testosterone therapy. Further testing of this compound is warranted.     

The effects of hepatic ischemia on systemic blood coagulation and fibrinolysis in mongrel dogs

In order to elucidate the effects of hepatic ischemia on systemic blood coagulation and fibrinolysis, experimental study was performed. Under the heparinized hydrophilic catheter-bypass between splenic and femoral vein, the hepato-duodenal and hepato-gastric ligaments were ligated to interrupt hepatic blood inflow in 5 dogs, and temporary interruption of hepatic blood inflow for 15, 30, 60, 90 minutes were performed in each 5 dogs. In this experimental study, changes of systemic blood coagulation and fibrinolysis, and histological changes of the liver were investigated periodically. Continuous interruption of hepatic blood inflow decreased blood coagulability gradually. Temporary interruption of hepatic blood inflow for more than 60 minutes caused remarkable decrease of blood coagulability after declamp, and histologically fibrin deposits were found in sinusoid and portal vein of Glisson's area, indicating that apparent DIC occurred in the liver at more than 60 minutes after clamp. One hour after declamp of 90 minutes interruption of hepatic blood inflow, most of fibrin deposits disappeared but severe degeneration of endothelial cell of sinusoid and hepatocyte were observed, indicating the disturbance of hepatic microcirculation which caused acute liver failure and systemic DIC, finally death in shock.     

Ketorolac tromethamine: stereo-specific pharmacokinetics and single-dose use in postoperative infants aged 2-6 months

Objective: We determined the postoperative pharmacokinetics (PK), safety, and analgesic effects of ketorolac in 14 infants (aged <6 months) receiving a single intravenous (IV) administration of racemic ketorolac or placebo. Background: Information on the PK of ketorolac in infants is limited. Unblinded studies suggest ketorolac may be useful in infants. Methods: This double‐blinded, placebo‐controlled study enrolled 14 infants (aged <6 months) postoperatively. At 6–18 h after surgery, infants were randomized to receive placebo, 0.5 mg·kg^?1, or 1 mg·kg^?1 ketorolac IV. All infants received morphine sulfate as needed for pain control. Blood was collected up to 12‐h postdosing. Analysis used noncompartmental and compartmental population modeling methods. Results: In addition to noncompartmental and empirical Bayes PK modeling, data were integrated with a previously studied data set comprising 25 infants and toddlers (aged 6–18 months). A two‐compartmental model described the comprehensive data set. The population estimates of the R (+) isomer were (%CV): central volume of distribution 1130 (10%) ml, peripheral volume of distribution 626 (25%) ml, and clearance from the central compartment 7.40 (8%) ml·min^?1. Those of the S (?) isomer were 1930 (15%) ml, 319 (58%) ml, and 39.5 (13%) ml·min^?1. Typical elimination half‐lives were 191 and 33 min, respectively. There was a trend for increased clearance and central volume with increasing age and weight. The base model suggested that clearance of the S (?) isomer was weakly related to age; however, when body size adjustment was added to the model, no covariates were significant. Safety assessment showed no changes in renal or hepatic function tests, surgical drain output, or continuous oximetry between groups. Cumulative morphine administration showed large inter‐patient variability and was not different between groups. Conclusion: Stereo‐isomer‐specific clearance of ketorolac in infants (aged 2–6 months) shows rapid elimination of the analgesic S (?) isomer as reported in infants aged 6–18 months. No adverse effects were seen after a single IV ketorolac dose.     

Different effects of enoxaparin and unfractionated heparin on extrinsic blood coagulation during haemodialysis: a prospective study.

BACKGROUND: Heparin inhibits prothrombotic tissue factor (TF) and releases its inhibitor, tissue factor pathway inhibitor (TFPI), from the endothelium, but repeated administration of heparin depletes vascular stores of TFPI. We studied the anticoagulant effects of unfractionated heparin (UFH) vs low-molecular-weight enoxaparin-used for thrice-weekly maintenance haemodialysis (HD)-on plasma levels of total TF and TFPI and on those of an activated coagulation marker prothrombin fragment 1+2 (PF 1+2). METHODS: Twenty-five patients dialysed using a single injection of enoxaparin (at a mean dose of 0.68 mg/kg) were randomly assigned to either receive UFH administered as a mean bolus of 42.1 IU/kg and continuous infusion of 57.8 IU/kg (n=12) or to be maintained on enoxaparin (n=13), and were followed prospectively for 12 weeks. Plasma immunoreactive TF, TFPI and PF 1+2 were measured at the start and after 10 and 180 min of HD, and compared with values in 15 healthy controls. RESULTS: Pre-dialysis TF, TFPI and PF 1+2 were higher than normal (all P<0.0001). TF and PF 1+2 did not change, while TFPI levels, compared with baseline, increased at each interval in enoxaparin-anticoagulated HD patients (all P<0.0001). TFPI increments correlated inversely with pre-dialysis TFPI (both P<0.0007). In patients switched to UFH, TF levels remained unchanged compared with pre-randomization values, TFPI increased at each interval of HD sessions (all P<0.035) and PF 1+2 increased pre-dialysis (P=0.015). The over-dialysis effects of UFH resembled those of enoxaparin. In contrast, baseline TFPI and its 10-min rise correlated inversely with the UFH loading dose (both P<0.040). Pre-dialysis PF 1+2 was inversely associated with TFPI increments (both P<0.034), and directly with pre-dialysis TFPI (P=0.018) and the UFH loading dose (P=0.045). CONCLUSIONS: Depletion of heparin-releasable stores of TFPI is an untoward effect of repeated anticoagulation during maintenance HD therapy. The traditional UFH regimen is more prothrombotic than single enoxaparin injections, with high loading doses of UFH being involved in TFPI exhaustion and subsequent hypercoagulability.     

Impact of the C2/C6 ratio of high-molecular-weight hydroxyethyl starch on pharmacokinetics and blood coagulation in pigs

BACKGROUND: High-molecular-weight, low-substituted hydroxyethyl starch (HES) may not affect blood coagulation more than low-molecular-weight, low-substituted HES. The authors assessed in vivo the effect of a lowered C2/C6 ratio on pharmacokinetic characteristics and the impact on blood coagulation of high-molecular-weight, low-substituted HES. METHODS: A prospective, randomized, parallel study in 30 pigs compared HES 650/0.42/2.8 with HES 650/0.42/5.6. Before, during, and after infusion of 30 ml/kg body weight HES, blood samples were collected over 630 min to measure HES concentrations and plasmatic coagulation and to assess blood coagulation in whole blood by Thrombelastography (TEG; Haemoscope Corporation, Niles, IL). Pharmacokinetic parameters were estimated using a two-compartment model. RESULTS: The elimination constant was 0.009 +/- 0.001 min(-1) for HES 650/0.42/2.8 and 0.007 +/- 0.001 min(-1) for HES 650/0.42/5.6 (P < 0.001); the area under the plasma concentration-time curve was 1,374 +/- 340 min x g/l for HES 650/0.42/2.8 and 1,697 +/- 411 min x g/l for HES 650/0.42/5.6 (P = 0.026). The measured plasma HES concentrations were not different between HES 650/0.42/2.8 and HES 650/0.42/5.6. Both HES solutions equally affected blood coagulation: Thrombelastographic coagulation index decreased similarly at the end of infusion of HES 650/0.42/2.8 and at the end of infusion of HES 650/0.42/5.6 (P = 0.293). Also, activated partial thromboplastin and prothrombin times increased similarly for HES 650/0.42/2.8 and HES 650/0.42/5.6 (P = 0.831). CONCLUSION: Reducing the C2/C6 ratio in high-molecular, low-substituted HES solutions results in a slightly faster HES elimination. However, the blood coagulation compromising effect was unaffected.     

脾外伤回收血的变化及其对凝血功能的影响

目的：探讨脾外伤应用自体血回输技术,病人的回收血巾血细胞及其相关指标的变化和其对凝血功能的影响。方法：2008年至2009年收治的24例单纯脾外伤行全脾切除的病人,分别在术前、回收血、回输后2h采集血样,分析其血细胞计数、血红蛋白、凝血功能及血小板激活指标（P-选择素、血小板第4因子）的变化。结果：①回收血中红细胞计数、血小板计数、白细胞计数、血红蛋白、红细胞比容比循环血低;②回收血中P选择素、血小板第4因子增加;凝血因子Ⅶ活性、凝血因子Ⅻ活性降低,凝血酶原片段F1＋2升高,凝血酶原时间、凝血酶时问、活化部分凝血活酶时间延长;纤维蛋白原减低;⑧回收血液中红细胞呈棘状细胞状;洗涤后,部分红细胞恢复至正常双凹圆盘状;④血液回输后与回收血相比,RBC计数及Het明显升高。结论：①回收血与循环血不同,表现为全血细胞数目不同,血小板被激活,循环血中凝血酶原片段F1＋2水平升高,考虑凝血系统被激活;②回收血液并不会使循环血液内的血小板激活：③自体血液回收技术对RBC形态无明显影响。     

Targeting exosites on blood coagulation proteases

The high specificity of blood coagulation proteases has been attributed not only to residues surrounding the active site but also to other surface domains that are involved in recognizing and interacting with macromolecular substrates and inhibitors. Specific blood coagulation inhibitors obtained from exogenous sources such as blood sucking salivary glands and snake venoms have been identified. Some of these inhibitors interact with exosites on coagulation enzymes. Two examples are discussed in this short revision. Bothrojaracin is a snake venom-derived protein that binds to thrombin exosites 1 and 2. Complex formation impairs several exosite-dependent activities of thrombin including fibrinogen cleavage and platelet activation. Bothrojaracin also interacts with proexosite 1 on prothrombin thus decreasing the zymogen activation by the prothrombinase complex (FXa/FVa). Ixolaris is a two Kunitz tick salivary gland inhibitor, that is homologous to tissue factor pathway inhibitor. Recently it was demonstrated that ixolaris binds to heparin-binding exosite of FXa, thus impairing the recognition of prothrombin by the enzyme. In addition, ixolaris interacts with FX possibly through the heparin-binding proexosite. Differently from FX, the ixolaris-FX complex is not recognized as substrate by the intrinsic tenase complex (FIXa/FVIIIa). We conclude that these inhibitors may serve as tools for the study of coagulation exosites as well as prototypes for new anticoagulant drugs.