Pharmacokinetics of heparin VII: Effect of pregnancy on the relationship between concentration and anticoagulant action of heparin in rats

The effect of pregnancy on the anticoagulant action of heparin was determined by comparing the slope of the relationship between the natural logarithm of the activated partial thromboplastin time (APTT) and heparin concentration (the heparin slope) in the plasma of pregnant and nonpregnant female inbred Lewis rats. Also determined were the prothrombin time, hematocrit, and the activities of coagulation factors II, VII, VIII, X, XI, and XII. The heparin slope was significantly decreased in pregnant rats at the 20th day of gestation but not in rats at the 10th day of gestation, indicative of a decreased anticoagulant action of heparin in late pregnancy. The hematocrit and prothrombin time were decreased, and the baseline APTT (i.e., the APTT without added heparin) as well as the activities of factors II, VII, and X were increased in pregnant rats at the 20th day of gestation. Both pregnant and nonpregnant animals showed a significant negative correlation between prothrombin time and factor II activity and a significant positive correlation between the activities of factors II and X. The effects of pregnancy in rats on heparin slope, prothrombin time, hematocrit, and factors VII, VIII, X, and XII are qualitatively the same as those in pregnant women in the third trimester. The increases in factor II activity and baseline APTT found in the rats were not observed in humans. Pregnant rats, like pregnant women, are relatively resistant to the anticoagulant action of heparin.     

肠溶阿司匹林和肝素联合抗凝治疗中出现腹膜后血肿

1例69岁冠心病、高血压女性患者服用卡托普利、阿替洛尔、硝酸异山梨酯及硝苯地平治疗2年余.入院后,患者因不稳定心绞痛加用肠溶阿司匹林0.1 g,1次/d和低分子肝素钙5 000 U,1次/12 h 皮下注射.第2天,肠溶阿司匹林增加至0.3 g,1次/d;低分子肝素钙改为肝素钠800～1 500 U/h,静脉泵入.48 h后再次改为低分子肝素钙6 000 U,1次/12 h皮下注射.第5天,患者出现腹膜后血肿,出血量约1 000～1 200 ml.停用肠溶阿司匹林和低分子肝素钙,给予悬浮红细胞、巴曲酶及扩容治疗.入院第28天,CT检查示患者血肿有所吸收,2 d后出院.出院2个月CT复查示出血肿大部分吸收.     

The anticoagulant and antithrombotic mechanisms of heparin

The molecular basis for the anticoagulant action of heparin lies in its ability to bind to and enhance the inhibitory activity of the plasma protein antithrombin against several serine proteases of the coagulation system, most importantly factors IIa (thrombin), Xa and IXa. Two major mechanisms underlie heparin's potentiation of antithrombin. The conformational changes induced by heparin binding cause both expulsion of the reactive loop and exposure of exosites of the surface of antithrombin, which bind directly to the enzyme target; and a template mechanism exists in which both inhibitor and enzyme bind to the same heparin molecule. The relative importance of these two modes of action varies between enzymes. In addition, heparin can act through other serine protease inhibitors such as heparin co-factor II, protein C inhibitor and tissue factor plasminogen inhibitor. The antithrombotic action of heparin in vivo, though dominated by anticoagulant mechanisms, is more complex, and interactions with other plasma proteins and cells play significant roles in the living vasculature.     

Synthetic heparin derivatives as new anticoagulant drugs

The journey towards a detailed mechanistic understanding of the anticoagulant action of heparin has resulted in synthetic mimetics with improved pharmacodynamic profiles. Inspired by the ternary complex formation of heparin with antithrombin III and thrombin, the active pentasaccharide fondaparinux has been succeeded by several clinical candidates, such as SR123781, that have tailor-made factor Xa and thrombin inhibitory activities combined with less aspecific binding (e.g. binding to platelet factor 4 involved in thrombocytopenia). Novel compounds with both antithrombin III-mediated inhibition of factor Xa and direct thrombin inhibition are emerging. Org42675 is one such compound, balancing dual inhibition of factor Xa and thrombin in one anticoagulant drug, with excellent pharmacokinetic properties and strong inhibitory activity toward clot-bound thrombin.     

Use of the low-molecular-weight heparin nadroparin during pregnancy. A review

Antithrombotic therapy is often used during pregnancy for the treatment and prevention of venous thromboembolism, the prevention of systemic embolism in patients with heart valve prostheses and the prevention of foetal loss in patients with antiphospholipid syndrome. Low-molecular-weight heparins (LMWHs), including nadroparin, have largely replaced unfractionated heparin as the anticoagulant of choice. The use of the LMWH nadroparin in pregnant women at an increased risk of thromboembolism or foetal loss is discussed in this review. Deep vein thrombosis can be effectively treated or prevented with nadroparin without any serious adverse events. Nadroparin 0.1 ml/10 kg s.c. once daily prevents thromboembolic complications in pregnant women with heart valve prostheses. Nadroparin is also effective in preventing foetal loss, through contributing to normal placental development and in decreasing the risk of premature delivery in pregnant women with antiphospholipid syndrome or women with herpes and antiphospholipid syndrome. These results demonstrate nadroparin is effective, easy to administer and associated with a low incidence of foetal and maternal complications. The use of nadroparin at a prophylactic dose of 0.3 ml (2850 IU AXa, 95 IU/kg) (for high-risk patients, 0.3-0.6 ml) s.c. once daily, and a therapeutic dose of 0.1 ml/10 kg (95 IU/kg) s.c. twice daily, is in line with the latest international guidelines of the American College of Chest Physicans.     

Use of the low-molecular-weight heparin nadroparin during pregnancy. A review

Summary

Antithrombotic therapy is often used during pregnancy for the treatment and prevention of venous thromboembolism, the prevention of systemic embolism in patients with heart valve prostheses and the prevention of foetal loss in patients with antiphospholipid syndrome. Low-molecular-weight heparins (LMWHs), including nadroparin, have largely replaced unfractionated heparin as the anticoagulant of choice. The use of the LMWH nadroparin in pregnant women at an increased risk of thromboembolism or foetal loss is discussed in this review. Deep vein thrombosis can be effectively treated or prevented with nadroparin without any serious adverse events. Nadroparin 0.1?ml/10?kg sc once daily prevents thromboembolic complications in pregnant women with heart valve prostheses. Nadroparin is also effective in preventing foetal loss, through contributing to normal placental development and in decreasing the risk of premature delivery in pregnant women with antiphospholipid syndrome or women with herpes and antiphospholipid syndrome. These results demonstrate nadroparin is effective, easy to administer and associated with a low incidence of foetal and maternal complications. The use of nadroparin at a prophylactic dose of 0.3?ml (2850IU AXa, 95?IU/kg) (for high-risk patients, 0.3–0.6?ml) sc once daily, and a therapeutic dose of 0.1?ml/10kg (95?IU/kg) sc twice daily, is in line with the latest international guidelines of the American College of Chest Physicians.     

Use of fondaparinux as an anticoagulant during hemodialysis: a preliminary study

OBJECTIVE: To study the effect of fondaparinux, a new antithrombotic agent, as an anticoagulant during a 4-hour conventional hemodialysis session. materials and methods: Fondaparinux was administered as an anticoagulant to 16 chronic hemodialysis patients during a single 4-hour hemodialysis session at an intravenous bolus dose of 2.5 mg. Eight patients were using high-flux polyester polymer alloy (PEPA) dialyzers (Group A) and the remainder low-flux polysulfone dialyzers (Group B), whilst all had received conventional doses of tinzaparin sodium as an anticoagulant during the previous month. The dialyzers were primed with 1 l of normal saline containing 5,000 IU of unfractionated heparin. Blood samples for the measurement of INR, APTT (activated partial thromboplastin time) and anti-Xa levels were taken before the study dialysis session (pre), 5 min postdialysis (post), and before the next dialysis session (next). Mean fibrin/clot formation in the extracorporeal circuit and dialyzer was assessed macroscopically by visual inspection and was graded using a 4-point scale. RESULTS: Predialysis anti-Xa levels were 0.04 A+/- 0.03 IU/ml in Group A, and 0.025 A+/- 0.025 IU/ml in Group B (p = NS). Postdialysis anti-Xa levels were significantly higher than predialysis levels in both groups (Group A = 0.16 A+/- 0.04 IU/ml, Group B = 0.46 A+/- 0.12 IU/ml, p < 0.02 for both) and significantly higher in Group B compared to Group A (p < 0.025). Anti-Xa levels before the next dialysis session were 0.06 A+/- 0.04 IU/ml in Group A and 0.25 A+/- 0.06 IU/ml in Group B (p < 0.0001 between Groups A and B). APTT values were significantly higher in postdialysis than predialysis samples for both groups (higher by 27.0 A+/- 26.0% in Group A and 24.3 A+/- 31.9% in Group B). No significant differences were found when comparing APTT values in pre, post and next samples between Groups A and B. No differences were also found between pre, post and next samples for INR values, either within or between groups. Mean fibrin/ clot formation score in the extracorporeal circuit at the end of the study dialysis session was significantly higher in patients of Group A than those of Group B (p < 0.05). Dialysis had to be terminated before the completion of 4 hours in 2 patients of Group A because of the presence of extensive fibrin/clots in the circuit and dialyzer. CONCLUSIONS: Our findings indicate that fondaparinux sodium at an intravenous dose of 2.5 mg can be used successfully as an anticoagulant during a 4-hour conventional hemodialysis session in patients dialyzed with low-flux polysulfone dialyzers, but not in those dialyzed with high-flux dialyzers. However, anti-Xa levels in the former patients were still increased before the next dialysis session, potentially exposing the patients to an increased risk of bleeding.     

The anticoagulant activity of heparin: measurement and relationship to chemical structure

For many years the anticoagulant activity of heparin has been estimated by coagulation assays, in which the prolongation of clotting times by heparin is measured under various conditions. More recently, assays have been developed which measure the inhibitory action of heparin on isolated coagulation enzymes, notably Factor Xa and thrombin, using specific amidolytic peptide substrates. The anticoagulant activity of heparin arises primarily from its ability to bind to antithrombin III (AT III), altering the conformation and enhancing the activity of this major protease inhibitor. Passage of heparin through an immobilised AT III column yields two fractions: a high affinity fraction with 300-350 iu mg-1 anticoagulant activity, comprising one-third of the total, and a low affinity fraction with an activity of less than 10 iu mg-1, comprising the remaining two-thirds. Studies in several laboratories have demonstrated that a specific pentasaccharide sequence is required for AT III binding. The authors have shown that the presence or absence of this sequence can be detected by high-field proton NMR, thus providing a semi-quantitative method for a functionally important group. A second major influence on anticoagulant activity is molecular weight distribution. Studies in the authors' laboratory on a series of fractions of 5000-35,000 showed that whereas anticoagulant activity in APTT clotting assays decreased with decreasing molecular weight (Mr), activity in anti-Xa assays was maintained or increased in the low Mr fractions. However, in vivo studies showed that high affinity fragments with anti-Xa activity only were poor antithrombotic agents. It appears that the presence of the AT III binding site alone is not sufficient for full antithrombotic activity; an extra length of polysaccharide chain of at least 15 residues is required. Molecular weight distribution is readily assessed by HPLC, although the lack of suitable reference materials hampers assignment of absolute molecular weights. Important determinants of anticoagulant activity can now be assessed by physicochemical techniques but, at present, these techniques are not precise enough to replace anticoagulant assays as predictors of in vivo behaviour.     

Aspirin and heparin in pregnancy

Introduction: A pro-coagulant state during pregnancy can be involved in the occurrence of gestational vascular complications (GVCs) and venous thromboembolism (VTE).

Areas covered: Antithrombotic drugs are used to prevent GVCs and VTE. Aspirin is not efficacious to prevent recurrences in women with previous early loss, while it can prevent pre-eclampsia in some groups of women. Heparins are not effective in the prevention of early recurrent loss and there is uncertainty about their efficacy in women carrying inherited thrombophilias. They could be efficacious in the prevention of GVCs in carriers of inherited thrombophilias, as GVCs have heterogeneous causes, and future studies have to focus on more homogeneous groups of patients. Not enough data are available regarding prophylaxis with heparins to prevent pregnancy-related VTE, but an accurate risk stratification of women during pregnancy and puerperium is crucial for administering prophylaxis in moderate-/high-risk women. Aspirin does not improve live births after assisted reproductive technologies, while heparins increase the number of clinical pregnancies and live births.

Expert opinion: Aspirin is efficacious in the prevention of GVCs in women at risk for pre-eclampsia and in those with antiphospholipid antibodies syndrome. Heparins could give benefit to women at risk for GVCs and/or pregnancy-related VTE.     

Intersubject variability in the anticoagulant response to heparin in vitro

Summary The significance of baseline coagulation times and plasma concentrations of serine protease inhibitors as determinants of the relationship between heparin activity and its anticoagulant effect has been investigated in vitro. Citrated plasma was prepared from blood obtained from 20 normal subjects, and heparin added to yield concentrations ranging from 0.05 to 1.5 units/ml. The anticoagulant effect was determined by the activated partial thromboplastin time (APTT) and thrombin time (TT). An excellent linear relationship was observed between the natural logarithms (ln) of the coagulation times and heparin activity. Baseline APTT values ranged from 28.4 to 59.7 s and the slope values for the ln APTT vs heparin curves ranged from 1.488 to 3.427 ml/unit. Similar range was observed in the slope values for the ln TT vs heparin curves. There was a highly significant positive correlation between the ln APTT vs heparin slope values and the baseline APTT values (r: 0.905; p<0.001). There was also a weak but statistically significant positive correlation between plasma concentrations of ₂ macroglobulin and baseline APTT values (0.02>p>0.01) and slope values of the ln APTT vs heparin curves (0.02>p>0.01). Furthermore, there was a statistically significant positive correlation between plasma concentrations of ₁ antitrypsin and baseline TT values (0.05>p>0.02) and slope values of the ln TT vs heparin curves (0.02>p>0.01). Neither baseline APTT and TT values nor slope values of the ln APTT and TT vs heparin curves were statistically significantly related to plasma concentrations of antithrombin III, fibrinogen, or ₁ acid glycoprotein. This study has demonstrated that baseline APTT is a major determinant of the anticoagulant response to heparin in vitro, as determined by that same coagulation test, and it illustrates that there is a wide intersubject variation in the anticoagulant response to heparin in vitro.     

Low molecular weight heparin and pregnancy

(1) Low molecular weight heparins (LMWH) are increasingly used during pregnancy. (2) Clinical data on the use of LMWH during pregnancy are limited. They are drawn mainly from heterogeneous case series, most of which were non comparative and involved prophylaxis rather than therapy. They provide no clear conclusions as to the efficacy and adverse effects of LMWH compared with unfractionated heparin, or the optimal dose regimen during the different phases of pregnancy. (3) No risk of malformations has been reported with LMWH preparations available in France, but data are insufficient to rule out a risk of obstetric, fetal or neonatal problems. (4) Cases of intraspinal haematoma have occurred after epidural anaesthesia. (5) Unfractionated heparin remains the reference treatment during pregnancy.     

Possible effect of thyroid function on anticoagulant response to unfractionated heparin

Many factors are known to influence the unfractionated heparin (UFH) dosage required to achieve therapeutic anticoagulation, including weight, sex, age, tobacco smoking, and diabetes mellitus. However, no interaction between thyroid function and UFH has been documented. An 83-year-old Caucasian woman had active hyperthyroidism that appeared to significantly increase her dosage requirements for UFH. The patient had atrial fibrillation secondary to the hyperthyroidism. She had no known factors that would increase UFH requirements. A UHF dosage of 1400 U/hour was needed to achieve a therapeutic level of anticoagulation (activated partial thromboplastin time 62 sec). After she was treated for hyperthyroidism, her atrial fibrillation resolved and UFH was discontinued. On day 9 of her hospital admission, atrial fibrillation resumed, and the patient's thyroid function began to normalize. Unfractionated heparin was restarted, and this time therapeutic anticoagulation was achieved with only 800 U/hour. This patient's experience suggests a previously undocumented and clinically significant relationship between active hyperthyroidism and altered dosage requirements for UFH. Recognition of this potential interaction may shorten the time required for patients with hyperthyroidism to achieve therapeutic anticoagulation, thereby preventing complications associated with subtherapeutic anticoagulation.     

Choosing an atypical antipsychotic

The atypical antipsychotics vary in terms of their pharmacological profiles, particularly in relation to their tolerability, effects on safety parameters and patient acceptability. Olanzapine, risperidone and ziprasidone are associated with extrapyramidal symptoms (EPS) in a dose-dependent manner, whereas quetiapine has been shown to produce a significantly lower incidence of substantial EPS effects than haloperidol, and less EPS requiring treatment than risperidone. Similarly, unlike risperidone and haloperidol, quetiapine treatment has been associated with a significant reduction in serum prolactin levels, and has normalized raised prolactin levels after discontinuation of previous treatment. Weight gain is also one of the major unwanted adverse effects of treatment with many antipsychotic drugs but, in contrast, quetiapine has demonstrated a neutral or 'normalizing' effect on body weight. In comparison with other antipsychotics, quetiapine has been shown to possess a favourable safety profile, with no requirement for routine blood, thyroid, or liver monitoring during treatment. Overall, quetiapine therapy has produced high levels of patient satisfaction and compliance and this, coupled with its efficacy in reducing psychoses of various origins, has made it an attractive treatment option in both patients at increased risk of EPS, and the general population.     

Effect of etatsizin on blood coagulability and the anticoagulant effect of heparin

Etacyzine, a new antiarrhythmic drug of the phenothiazine series, injected intravenously (1 mg/kg) does not change the blood coagulation balance of rabbits. The effect of heparin (100 Units/kg i.v.) reduces after preinjection of etacyzine (1 mg/kg). Etacyzine lowers the concentration of heparin in an aqueous medium and blood plasma.     

肝素抗凝血浆用于生化检验的可行性分析

目的：通过观察两种对血液处理方式的生化检验,分析肝素抗凝血浆在生化检验中是否可行,为奠定肝素抗凝血浆在检验科的地位做好准备。方法将随机并自愿受试的、生理情况正常的120例做生化检验的患者选出,所有患者均接受采血6 mL,分别注入两种颜色（标签颜色分红、蓝两组颜色,红色为真空普通试管,蓝色为真空肝素抗凝血浆试管）不同的试管,分别进行生化分析,仪器型号为西门子2400,生化分析完毕后将两组所测定值进行统计学处理。结果通过观察,两组分别得到了测定值,血清组和血浆组组间比较,存在差异的（P〈0.05）指标有K＋、Na＋、GLU 、LDH、CO2,而相比之下所剩下的其他指标则差异不大（P〉0.05）,如：Cl-、CR、BUN、AST、UA、B-AMY、CK、CK-MB、LPS。结论分析结果证实了肝素抗凝血浆在生化中的可行性,为检验科今后应该继续使用该技术做了更为确定性的表达,血液凝固过程延长、标本分离时间缩短、血液互溶情况减少等都是肝素抗凝血浆在生化中应用的特异性优点,该技术推广可以更为清晰准确的测量出指标的浓度,关于钾离子测量的微小差异也能因此而得到纠正,故在临床中反应出患者最真实的病情,这一点是十分有意义的。     

血栓弹力图指导血液净化治疗肝素抗凝的应用

目的探讨血栓弹力图指导连续性血液净化治疗肝素抗凝的应用效果。方法选取2017年8月～2018年8月在我院行连续性血液净化治疗的42例患者作为研究对象,采用随机数字表法将其分为研究组和参照组,每组21例。参照组患者常规应用部分凝血酶原时间(APTT)指导血液净化监测凝血功能调整肝素用量,研究组患者则采用血栓弹力图(rTEG)联合APTT进行监测凝血功能指导肝素应用。比较两组患者的滤器使用时间、肝素用量,并观察两组治疗过程中的出血发生情况。结果研究组患者滤器使用时间为(22.9±3.7)h,长于参照组的滤器使用时间(18.3±3.1)h,差异有统计学意义(P 0.05)。研究组和参照组的肝素用量分别为(17625.6±3084.7)、(17782.9±3097.8)U,两组比较差异无统计学意义(P 0.05)。参照组的出血发生率为34.38%高于研究组的12.50%,差异有统计学意义(P 0.05)。结论应用血栓弹力图指导血液净化治疗肝素抗凝的应用,能更准确的调整肝素用量,从而延长滤器使用寿命,降低患者出血风险,是一种实用、有效的抗凝监测手段。