Effects of melagatran on activated partial thromboplastin time and on ecarin clotting time in cord versus adult plasma.

Melagatran is the active form of the oral direct thrombin inhibitor ximelagatran. Melagatran does not require antithrombin as a cofactor. Its administration is therefore of special interest in neonatal patients, whose plasma is relatively deficient in antithrombin. We investigated the effects of increasing amounts of melagatran (0.05-1 micromol/l) on the activated partial thromboplastin time (APTT) and ecarin clotting time (ECT) in cord versus adult plasma. Both the APTT and ECT were dose-dependently prolonged in the presence of increasing amounts of melagatran. Furthermore, the ECT revealed a higher susceptibility of cord plasma to addition of melagatran than adult plasma. Whereas similar amounts of melagatran were required in cord and adult plasma samples to double the APTT (IC(50), 0.47 vs 0.46 micromol/l), significantly less melagatran was required in cord versus adult plasma to double the ECT (IC(50), 0.26 vs 0.56 micromol/l). Based on APTT measurements, similar plasma levels of melagatran might be required in neonates and in adults to treat thromboembolic complications. The APTT, however, is relatively insensitive to plasma melagatran concentrations. When the sensitive indicator ECT is used, results suggest that lower amounts of melagatran might be required in neonates than in adults. This has to be scrutinized in future clinical studies.     

Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety

Dietary vitamin K is known to influence the anticoagulation response to warfarin. It is possible that dietary vitamin K availability also influences the pharmacological activity of other oral anticoagulants, which target the vitamin-K dependent clotting proteins in the coagulation cascade. This study examined whether vitamin K insufficiency affected anticoagulation response to the direct thrombin inhibitor, ximelagatran. Anticoagulation response to ximelagatran and warfarin in rats on a normal diet was compared to those on a vitamin K deficient diet. Ximelagatran and warfarin increased prothrombin time (PT) by 1.4- and 1.3-fold, activated partial thromboplastin time (APTT) by 1.8- and 1.4-fold and ecarin clotting time (ECT) by 6.8- and 1.2-fold, respectively, in rats on normal diet. Vitamin K deficient diet alone caused modest increases in PT, APTT and ECT. The anticoagulant activity of both ximelagatran and warfarin was significantly greater in rats on vitamin K deficient diet (6.1- and 12.3-fold for PT, 2.6- and 5.1-fold for APTT and 2.9- and 1.6-fold for ECT, respectively) compared to those on normal diet. Factor II activity was reduced by both ximelagatran (58%) and warfarin (44%) in rats on normal diet. However, factor II activity was virtually abolished (<0.1%) by both drugs in rats on vitamin K deficient diet. The results suggest that oral anticoagulant drugs, whose primary site of action is not within the vitamin K cycle, may also exhibit variability in clinical response due to dietary variation as the established coumarin drugs such as warfarin.     

Pharmacokinetics and pharmacodynamics of ximelagatran

Oral anticoagulant therapy with vitamin K antagonists (VKAs) such as warfarin has proven benefits in the treatment and prevention of thromboembolic disorders but has important limitations that result in substantial underuse. In particular, the VKAs have variable and unpredictable pharmacokinetics and pharmacodynamics and a narrow separation between antithrombotic and hemorrhagic effects that necessitates careful dose adjustment based on frequent coagulation monitoring. In contrast, the oral direct thrombin inhibitor ximelagatran has a predictable and reproducible pharmacokinetic/pharmacodynamic profile that allows treatment using fixed-dose regimens without coagulation monitoring. The bioavailability of melagatran, the active form of ximelagatran, after oral administration of ximelagatran is approximately 20% with low inter- and intra-individual variability. Peak plasma melagatran concentrations are reached approximately 2 hours after oral dosing of ximelagatran to healthy volunteers, and melagatran is eliminated with a half-life of approximately 3 hours with clearance predominantly by renal excretion. Hence, a higher melagatran exposure is seen in patients with renal failure; ximelagatran is currently not recommended for patients with severe renal impairment (creatinine clearance of <30 mL/min) as these patients were not included in the clinical trial program. Exposure to melagatran increases linearly with the ximelagatran dose. The pharmacokinetic/pharmacodynamic profile is consistent across a broad range of different patient populations and is unaffected by gender, age, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Any differences in melagatran pharmacokinetics associated with these factors are attributable to differences in renal function.     

Hypothermia and blood coagulation: dissociation between enzyme activity and clotting factor levels

Previous studies of hypothermia and blood coagulation have focused on alterations in the levels of blood clotting elements using coagulation tests performed under normothermic conditions. However, because of the enzymatic nature of activated clotting factors, hypothermia should also be expected to affect clotting factor activities. Multiple determinations of activated partial thromboplastin times (APTT), prothrombin times (PT), and thrombin times (TT) were performed on commercially available normal human plasma at assay temperatures similar to those encountered clinically (25-37 degrees C). Both the APTT and the PT were significantly prolonged at temperatures below 35 degrees C (P less than 0.05). Clotting time correlated significantly with assay temperature in a negative exponential fashion for all three tests (r = -0.97 for APTT, -0.93 for PT, -0.71 for TT, P less than 0.001 for all regressions). Clotting time prolongation appears proportional to the number of enzymatic steps involved. These data indicate that the coagulopathy observed during hypothermia is, in part, independent of clotting factor levels.     

Inhibitory effect of a new synthetic protease inhibitor (FUT-175) on the coagulation system

The inhibitory effects of 6-amidino-2-naphthyl-4-guanidinobenzoate X dimethanesulfonate (FUT-175) on the human Hageman factor fragment (HFf), factor Xa, thrombin, plasma kallikrein, and plasmin were studied. FUT-175 inhibited plasma kallikrein most (IC50 = 3.0 X 10(-9) M), followed by HFf (IC50 = 3.3 X 10(-7) M). FUT-175 was found to have an anticoagulant effect in the APTT and PT assay systems of human plasma. The concentration of FUT-175 for twofold increase in the clotting time in the APTT assay system was 5 X 10(-7) M.     

Effects of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and dalteparin on the endogenous thrombin potential in venous blood from healthy male subjects.

The effect of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran, on thrombin generation was investigated in vitro and ex vivo using a thrombin generation assay. In-vitro thrombin generation was triggered in human platelet-poor plasma by the addition of tissue factor, and the endogenous thrombin potential (ETP) was measured. The ETP IC(50) values for melagatran and the low-molecular-weight heparin dalteparin were 0.44 micromol/l and 0.06 IU/ml, respectively. In contrast to dalteparin, melagatran increased the time-to-thrombin peak in a concentration-dependent manner. ETP was also studied ex vivo in platelet-poor plasma collected from healthy male subjects (n = 54) at pre-dose and 2 h post-dose, with ximelagatran (60 mg) orally, dalteparin (120 IU/kg) subcutaneously, or control (water) orally. After ximelagatran or dalteparin administration, the time-to-thrombin peak was prolonged by 41 and 95%, and the ETP was decreased by 61 and 77%, respectively. Thus, melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, efficiently delays and inhibits the generation of thrombin in plasma both in vitro and ex vivo.     

Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong anticoagulant and antiplatelet actions in human blood.

In an in vitro study, anticoagulant and antiplatelet effects of the synthetic, direct factor Xa inhibitor DX-9065a, (+)-2S-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-a midino-2-naphthyl]propanoic acid hydrochloride pentahydrate, which shows a high affinity and selectivity towards the enzyme, were investigated. Anticoagulant actions of DX-9065a were studied in human plasma using global clotting assays [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and Heptest]. The effect on thrombin generation was measured in whole blood by determining the plasma concentration of prothrombin fragment F1.2. The influence on agonist-induced platelet activation in whole blood was studied using flow cytometric analysis. DX-9065a caused a concentration-dependent prolongation of clotting times in the PT and APTT assay, whereas Heptest was less affected and TT was not influenced. Furthermore, DX-9065a strongly inhibited the generation of thrombin without and after coagulation activation. The factor Xa inhibitor did not affect platelet activation mediated by either thrombin receptor activating peptide, arachidonic acid or y-thrombin, but prevented tissue factor- and factor Xa-induced activation of platelets in a concentration-dependent manner. Inactivation of factor Xa by a highly effective and selective inhibitor, and the resulting inhibition of thrombin generation leads to strong anticoagulant and antiplatelet actions. The interference with the coagulation system at the early level of factor Xa is expected to be an effective approach for a successful anticoagulant/antithrombotic therapy.     

Low potential for interactions between melagatran/ximelagatran and other drugs, food, or alcohol

Vitamin K antagonists including warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly bleeding. In contrast, ximelagatran has a low potential for pharmacokinetic drug:drug and food interactions. There is no significant metabolism of melagatran, and the main route of elimination of melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly, cytochrome P450 isoenzymes that mediate many drug:drug interactions are not involved in the biotransformation of ximelagatran to melagatran. No significant pharmacokinetic interactions have been observed when oral ximelagatran is administered with a range of agents, including diclofenac, diazepam, nifedipine, digoxin, atorvastatin, or amiodarone. The low potential for drug:drug interactions with ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with atrial fibrillation receiving long-term treatment with oral ximelagatran. Increases of mean melagatran area under the curve and maximum plasma concentration ( Cmax) of up to approximately 80% have been observed when ximelagatran is co-administered with the macrolide antibiotics erythromycin or azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of melagatran is not altered by co-administration with food or alcohol. The melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of thrombin inhibition, is not altered by other drugs [including digoxin, atorvastatin, acetylsalicylic acid (ASA), and amiodarone], food, or alcohol. The effect of melagatran on capillary bleeding time, which is prolonged as a result of the inhibition of thrombin-induced platelet aggregation, is relatively low and additive to the platelet-inhibitory effect of ASA.     

Drotrecogin alfa activated (recombinant human activated protein C) in combination with heparin or melagatran: effects on prothrombin time and activated partial thromboplastin time.

Recombinant human activated protein C (rhAPC) has recently been demonstrated to be a promising candidate to improve the outcome for patients with severe sepsis. Plasma-derived activated protein C and unfractionated heparin (UH) exert anticoagulant synergy due to mechanisms that simultaneously decrease thrombin generation. Melagatran, a new direct thrombin inhibitor, does not bind to plasma proteins or requires antithrombin as a cofactor. The latter is often consumed in patients with severe sepsis. We investigated the anticoagulant efficiency in combined administration of rhAPC and UH or melagatran in terms of prolongation of the standard clotting assays activated partial thromboplastin time (aPTT) and prothrombin time (PT) in pooled plasma samples in vitro. RhAPC dose-dependently prolonged the aPTT but not the PT. The ability of UH and melagatran to prolong the aPTT was significantly enhanced in combination with rhAPC. The combined administration of rhAPC and melagatran, but not UH, resulted in additive prolongation of the PT. In control measurements the capability of rhAPC to suppress prothrombin fragment 1.2 generation dose-dependently increased in combination with heparin and melagatran. Our study demonstrates the respective effects of rhAPC, UH, melagatran and further different additive effects in combined administration of rhAPC and UH or melagatran on the prolongation of the aPTT and PT clotting assays usually used to monitor anticoagulant treatment.     

Effects of α-tocopherol on platelets and the coagulation system

Vitamin E is one of the most widely used antioxidants in cryopreservation and preservation technology. The objective of this study is to examine the effect of vitamin E on platelets and the coagulation system. Vitamin E was added at different concentrations in the range between 0.25 and 5 mM to donor plasma. Using a STA/STA Compact coagulation analyzer the following clotting tests were performed: prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT). The control clotting times PT (13.80 - 0.4 s), APTT (27.4 - 2.4 s) and TT (17.6 - 0.4 s) remained unchanged in the presence of vitamin E. The effect of vitamin E on platelets was assessed by platelet-induced clot retraction (PICR) and aggregation by thrombin. PICR was unaffected by vitamin E. Platelet aggregation, however, was profoundly inhibited by vitamin E. We found that inhibition of platelet aggregation by vitamin E was concentration dependent: increasing with increasing vitamin E concentration. This inhibitory effect, however, was widely reversible upon dilution of vitamin E with autologus platelet-poor plasma.     

Oral direct thrombin inhibitors in clinical development

Thrombin has long been a target for development of oral anticoagulants but it has been difficult to find synthetic inhibitors with a desirable combination of pharmacodynamic and pharmacokinetic properties. However, there are now two oral direct thrombin inhibitors (DTIs) in clinical development, ximelagatran (ExantaTM) and BIBR 1048. Both are prodrugs with two protecting groups that are eliminated after absorption from the gastrointestinal tract. Their main active substances, melagatran and BIBR 953, are both potent and selective DTIs. In experimental models of thrombosis, melagatran has been shown to have a shallower dose-response curve than warfarin and, therefore, a better separation between efficacy and bleeding. Oral bioavailability, measured as the plasma concentration of the active metabolite, seems to be higher for ximelagatran (20%) than for BIBR 1048 (estimated to 5%). BIBR 953 has a longer half-life (about 12 h) than does melagatran (3-5 h) after oral administration of BIBR 1048 and ximelagatran, respectively. Both melagatran and BIBR 953 are mainly eliminated via the renal route. The variability of the plasma concentration of melagatran after oral administration of ximelagatran is low. There are no clinically relevant interactions with food or cytochrome P450 metabolized drugs and ximelagatran. In clinical studies, ximelagatran has been administered in a twice-daily fixed-dose regimen without coagulation monitoring. Results of published clinical studies are encouraging, both with regard to efficacy and bleeding. Major indications in Phase III studies with ximelagatran are the prevention of venous thromboembolism (VTE) in hip and knee replacement surgery, treatment and long-term secondary prevention of VTE and prevention of stroke in patients with nonvalvular atrial fibrillation. It is anticipated that with a favourable outcome of the Phase III clinical studies new oral DTIs, with the oral fixed-dose regimen without routine coagulation monitoring, will ease the use of today's anticoagulant therapy.     

高龄心房颤动患者抗血小板与抗凝策略的临床观察

目的 观察高龄心房颤动(房颤)患者抗血小板治疗与抗凝治疗现状及有效性和安全性. 方法 根据高龄房颤患者住院时的治疗情况分为华法林抗凝组(15例)和阿司匹林(或氯吡格雷)抗血小板组(52例)进行分析.每组分别测定用药前后的凝血酶原时间(PT)、活化凝血时间(ACT)、国际标准化比值(INR)、部分活化凝血活酶时间(APTT)、纤维蛋白原(FIB)、凝血酶时间(TT)、凝血因子(Ⅱ、Ⅴ、Ⅶ、Ⅷ、Ⅸ、Ⅹ)活性、纤维蛋白降解产物(FDP)和D-二聚体. 结果抗血小板组平均治疗时间(44.2±37.5)个月.抗凝组平均治疗时间(39.0±61.5)个月.抗血小板组有6例发生缺血性脑卒中,1例发生急性右下肢动脉栓塞,3例发生消化道出血.抗血小板组用药前后PT、ACT、INR、APTT、FIB、TT、凝血因子(Ⅱ、Ⅴ、Ⅶ、Ⅷ、Ⅸ、Ⅹ)活性比较、差异均无统计学意义.抗凝组共发生2例消化道出血及2例致死性出血性脑卒中.抗凝组华法林用药后PT延长(8.4±7.5)s,ACT下降(0.49±0.22)s.INR升高0.93±0.83,凝血因子Ⅱ、Ⅶ、Ⅸ及Ⅹ活性均较用药前有显著降低(均P<0.05). 结论 抗凝治疗能够有效预防高龄房颤患者的缺血性脑卒中发生,但出血事件发生率可能增多,总体不良事件发生并未显著减少.     

联合输注新鲜冰冻血浆和冷沉淀凝血因子的止血效果观察

目的:探讨联合输注新鲜冰冻血浆(FFP)和冷沉淀凝血因子用于肝肿瘤术后凝血功能异常患者的止血效果。方法:将120例肝肿瘤术后凝血功能异常患者随机分为3组:FFP单独输注组、冷沉淀凝血因子单独输注组及FFP和冷沉淀凝血因子联合输注组,每组各40例。所有患者住院期间均行肝肿瘤切除术,术后进行常规治疗,联合或单独输注FFP和冷沉淀凝血因子,3组分别于输注前1h及输注后24h静脉采血,检测输注前后凝血酶原时间(PT)、部分凝血活酶时间(APTT)、凝血酶时间(TT)和纤维蛋白原(FIB)。结果:3组输注后PT、APTT、TT、FIB和输注前1h比较均差异有统计学意义(均P0.01);与2个单独输注组比较,联合输注组PT、APTT、TT数值均差异有统计学意义(均P0.05),FIB数值与FFP单独输注组比较也有明显提高(P0.05)。结论:联合或单独给肝肿瘤术后凝血功能异常患者进行输注均能改善患者的凝血功能,联合输注的止血效果要好于单独输注一种成分。     

Lipoprotein-associated coagulation inhibitor (LACI) is a cofactor for heparin: synergistic anticoagulant action between LACI and sulfated polysaccharides.

Lipoprotein-associated coagulation inhibitor (LACI) is a plasma-derived protein that inhibits tissue factor (TF)/factor VIIa-induced coagulation in a factor Xa-dependent manner. The roles of endogenous plasma LACI and exogenously added LACI and heparin, in the regulation of coagulation, initiated via the intrinsic and extrinsic pathways, were studied using the activated partial thromboplastin time (APTT) and the modified prothrombin time (PT) assays, respectively. Both LACI-depleted plasma and normal plasma have identical APTTs and similar prolongations of the APTT in response to heparin; both are fully anticoagulated (arbitrarily defined as clotting times of greater than 1 hour) at similar concentrations of heparin. These results indicate that heparin is an effective anticoagulant when coagulation is initiated by the intrinsic pathway and that endogenous LACI is not significantly involved in the regulation of this pathway. The PT of normal plasma is only marginally longer than that of LACI-depleted plasma in the absence of heparin, suggesting that endogenous plasma LACI has a very limited capacity to inhibit TF-induced clotting. However, in the presence of heparin, the PTs of LACI-depleted plasma and normal plasma are different. Prolongation of the PT occurred only moderately and linearly with increasing concentrations of heparin in LACI-depleted plasma. In contrast, normal plasma showed a greater extent of PT prolongation in response to heparin and the plasma became fully anticoagulated at a certain threshold concentration of heparin. These results suggest that LACI serves as a cofactor for heparin and thus greatly enhances the inhibition of TF-induced coagulation. LACI-depleted plasma was supplemented with purified recombinant LACI and/or heparin and the effects on TF-induced clotting were studied. A combination of LACI and heparin greatly enhanced anticoagulation compared with LACI or heparin alone. Many sulfated polysaccharides were also found to enhance the LACI-dependent inhibition of TF-induced clotting. By weight, the relative potencies of these compounds are: low molecular weight heparin (mean Mr, 5,100) greater than unfractionated heparin greater than low molecular weight heparin (mean Mr, 3,700) greater than pentosan polysulfate greater than dermatan sulfate greater than dextran sulfate greater than heparan sulfate. Based on the above results, it is concluded that LACI is a cofactor for heparin in the inhibition of TF-induced clotting and that LACI and sulfated polysaccharides act synergistically in whole plasma.     

老年肺心病急性发作期凝血功能检测的临床意义

目的探讨凝血功能和血液流变学检测对老年肺心病患者的临床意义。方法检测30例老年肺心病急性加重期患者凝血功能(PT,APTT,TT,FBG),D-二聚体以及血液流变学指标,包括红细胞压积、全血粘度、血浆粘度(高切、低切),并同肺心病缓解期和正常健康老人相比较。结果慢性肺心病急性发作期与其缓解期以及对照组相比,PT,APTT,TT缩短,FBG,D-二聚体上升,且差异有显著性;红细胞压积、血浆粘度、全血粘度升高,且差异有显著性。结论血浆D-二聚体,FBG,血液流变学,凝血功能监测对评估疾病程度及其预后以及疗效观察提供有力的依据。     

肝硬化患者凝血功能检测分析

目的分析肝硬化患者凝血指标随肝功能损害程度的变化,并探讨其临床意义。方法测定肝硬化组（50例）和对照组（40例）血浆凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、凝血酶时间（TT）和纤维蛋白原（FIB）。结果肝硬化组凝血指标与对照组比较,PT、APTT、TT均明显延长,差异有显著统计学意义（P〈0.01）,FIB明显下降,差异有统计学意义（P〈0.05）。肝硬化失代偿组PT、APTT、TT及FIB与代偿组比较,差异有显著统计学意义（P〈0.01）。结论凝血指标可以客观准确的评价肝硬化患者的凝血功能,能够发现早期肝病造成的凝血机制障碍,对肝硬化出血患者的抢救和治疗具有重要意义。     

Alteration in the laboratory profile of a lupus anticoagulant in a patient with non‐Hodgkin's lymphoma

We describe a patient with non‐Hodgkin's lymphoma who developed a lupus anticoagulant (LA) detectable by activated partial thromboplastin time (APTT), dilute Russell's viper venom time (DRVVT) and kaolin clotting time (KCT). IgM anticardiolipin antibodies (ACA) were elevated. At a later admission, and following treatment for the lymphoma, routine coagulation screening showed an elevated prothrombin time (PT) without correction in mixing tests using a recombinant thromboplastin. Routine APTT was below the reference range and ACA levels were normal. Raw data for one‐stage factor assays demonstrated the presence of an inhibitor. Analysis for LA was undertaken by DRVVT, KCT, activated seven lupus anticoagulant assay, Taipan snake venom time, platelet neutralisation procedures (PNP), Ecarin time and PT using rabbit brain thromboplastin. The results revealed a LA capable of prolonging the clotting times of the PNPs and PT using recombinant thromboplastin, but that was corrected using Ecarin venom, modified PNP and brain thromboplastin. The antibody also demonstrated the lupus anticoagulant co‐factor effect. The factor VIII : C was markedly raised which may have masked the LA in the APTT. The changing laboratory profile over time demonstrates the effects of LA heterogeneity and variations in sensitivity and specificity of assays for the detection of antiphospholipid antibodies.     

Alteration in the laboratory profile of a lupus anticoagulant in a patient with non-Hodgkin's lymphoma

We describe a patient with non-Hodgkin's lymphoma who developed a lupus anticoagulant (LA) detectable by activated partial thromboplastin time (APTT), dilute Russell's viper venom time (DRVVT) and kaolin clotting time (KCT). IgM anticardiolipin antibodies (ACA) were elevated. At a later admission, and following treatment for the lymphoma, routine coagulation screening showed an elevated prothrombin time (PT) without correction in mixing tests using a recombinant thromboplastin. Routine APTT was below the reference range and ACA levels were normal. Raw data for one-stage factor assays demonstrated the presence of an inhibitor. Analysis for LA was undertaken by DRVVT, KCT, activated seven lupus anticoagulant assay, Taipan snake venom time, platelet neutralisation procedures (PNP), Ecarin time and PT using rabbit brain thromboplastin. The results revealed a LA capable of prolonging the clotting times of the PNPs and PT using recombinant thromboplastin, but that was corrected using Ecarin venom, modified PNP and brain thromboplastin. The antibody also demonstrated the lupus anticoagulant co-factor effect. The factor VIII: C was markedly raised which may have masked the LA in the APTT. The changing laboratory profile over time demonstrates the effects of LA heterogeneity and variations in sensitivity and specificity of assays for the detection of antiphospholipid antibodies.     

Monitoring of anticoagulant effects of direct thrombin inhibitors

Monitoring of direct thrombin inhibitors with the activated partial thromboplastin time (aPTT) is limited by poor linearity and reproducibility. Recently, direct prothrombin activation methods have been developed for coagulation analysis: ecarin clotting time (ECT) and prothrombinase-induced clotting time (PiCT). Laboratory monitoring of the direct thrombin inhibitors lepirudin, argatroban, and melagatran was analyzed and compared with monitoring unfractionated heparin (UFH). Plasma samples of six healthy donors were spiked with lepirudin and argatroban extending to 3000 ng/mL, melagatran extending to 1000 ng/mL, and UFH up to 0.48 IU/mL. Clotting times of aPTT (two reagents), ECT, PiCT, and prothrombin time were determined in a KC 10, a micro instrument. At 3000 ng/mL ECT values were 339.1 +/- 25.0 seconds with lepirudin and 457.5 +/- 29.5 seconds with argatroban. ECT was 586.0 +/- 38.2 seconds with 1000 ng/mL melagatran. The PiCT method provided clotting times of 137.0 +/- 8.4 seconds with UFH, 128.0 +/- 23.4 seconds with lepirudin, and 151 +/- 23.9 seconds with argatroban, and 153.5 +/- 9.9 seconds with melagatran, with the concentrations mentioned. ECT is more sensitive to therapeutic drug concentration ranges than aPTT (prolongations of 3-7 versus 2-3). PiCT yields comparable results with direct thrombin inhibitors and UFH. This method could therefore be suitable for monitoring both drug groups.     

A dyspnea patient with abnormal prolonged prothrombin time and activated partial thromboplstin time, but without bleeding symptoms

A patient with erythrocytosis secondary to chronic obstructive pulmonary disease (COPD) was admitted to hospital because of dyspnea. The coagulation tests revealed abnormal prolonged prothrombin time (PT) and activated partial thromboplstin time (APTT), however, it could not be explained by the patient's medical history or physical signs of coagulation disorder. High hematocrit (Hct), which leads to reduced plasma-to-anticoagulant rate and increased final plasma anticoagulant concentration, was identified as the reason for false prolongation of PT and APTT.