Tinzaparin sodium for thrombosis treatment and prevention during pregnancy

OBJECTIVE: This study was undertaken to assess the pharmacodynamic profile, safety, and efficacy of tinzaparin during pregnancy. STUDY DESIGN: Fifty-four pregnant women, 12 for treatment of thrombosis and 42 for thromboprophylaxis, received tinzaparin by once daily injection. Four-hour postdose anti-Xa results were analyzed by use of repeated measures statistical methods. RESULTS: One woman (3.4%) on the 175 anti-Xa U/kg dose and three women (20%) on the 50 anti-Xa U/kg dose required a dose increase during the initial dose titration phase to achieve target anti-Xa activity. No thrombotic events occurred. CONCLUSION: The 175 anti-Xa U/kg dose is appropriate for treatment and for high-risk thromboprophylaxis throughout pregnancy. In pregnant women at moderate risk of thrombosis, a higher tinzaparin dose is required than in the nonpregnant state and 75 anti-Xa U/kg appears to be appropriate. The majority of women do not need a dose increase with advancing gestation.     

Low molecular weight heparins: the optimal treatment for venous thromboembolism

SUMMARY

Venous thromboembolism (VTE) is a common vascular complication that requires immediate as well as long-term treatment.

Recent trials evaluated the efficacy and safety of LMWH therapy as an alternative to vitamin K antagonists in long-term VTE secondary prophylaxis for all patients and in specific subgroups.

In this brief overview, we consider the potential advantages of treatment with LMWH in patients with VTE.     

Thromboelastography (TEG®) demonstrates that tinzaparin 4500 international units has no detectable anticoagulant activity after caesarean section

BackgroundLow molecular weight heparin is routinely used for thromboprophylaxis in pregnancy and the puerperium. Consensus guidelines recommend waiting 10–12 h after administration of a thromboprophylactic dose of low molecular weight heparin before performing a neuraxial block or removing an epidural catheter. Thromboelastography (TEG®) has been reported to be sensitive to the effects of enoxaparin 4 h after administration. The purpose of this study was to use TEG to examine coagulation changes in the first 10 h after a thromboprophylactic dose of tinzaparin in an attempt to ratify the current consensus guidelines about timing of neuraxial blockade and epidural catheter removal.MethodsTwenty-four women who had undergone caesarean delivery and were classified as low or intermediate risk of thrombosis were recruited. Blood samples were taken before subcutaneous administration of tinzaparin 4500 IU, and at 4, 8 and 10 h post-dose. Standard TEG analyses were performed using plain and heparinase cuvettes and samples were also sent for laboratory anti-Xa assay. Thromboelastograph profiles were analysed for a low molecular weight heparin effect.ResultsAnalysis revealed no significant differences in R time, K time, alpha angle or maximum amplitude between plain and heparinase samples at any time point. Apart from a small statistically significant (P=0.033) decrease in maximum amplitude of 2.8% (95% CI 0.3 to 5.4%) at 4 h, there were no significant changes in coagulation for any TEG parameter. Anti-Xa levels were virtually undetectable in all patients over the 10 h period (median 0.00 U/mL; range 0.00–0.13 U/mL).ConclusionA thromboprophylactic dose of tinzaparin 4500 IU had little detectable effect on coagulation as assessed by TEG and anti-Xa assay. These findings support consensus guidelines which state that it is acceptable to perform neuraxial blockade or remove an epidural catheter 10–12 h after a thromboprophylactic dose of tinzaparin. Rather than suggesting a lack of anticoagulant activity, the findings indicate that TEG may not have the sensitivity to detect a tinzaparin effect when this dose is used in this patient group.     

Treatment of Pulmonary Embolism in an Extremely Obese Patient

Low-molecular-weight heparins are effective as initial therapy for pulmonary embolism (PE) in a weight-based dosing regimen up to known body weights of 160 kg. The present case reports an extremely obese man of 252 kg (body mass index (BMI) 74 kg/m²) with PE who was treated with tinzaparin, dosed on a body weight of 160 kg. Morbid obesity defined as a BMI higher than 40 kg/m² is becoming more common in general practice, but there are no evidence-based drug dosing strategies for these patients. This case demonstrates the successful use of a maximum dose of 28,000 anti-Xa international units of tinzaparin for an extremely obese patient with proven PE, instead of the accepted doses of 175 IU/kg, as bridge therapy to a coumarin.     

低分子量肝素核磁共振鉴别方法的研究

目的:建立核磁共振一维碳谱定性鉴别低分子肝素类型的方法。方法:一维13C-NMR实验在装配5 mm BBO探头的Bruker Ascend-500核磁共振谱仪上采集。采样时间1.1s;弛豫时间1s;测量温度40℃;谱宽δ(ppm)236。结果:比较不同类型低分子量肝素标准品的碳谱精细结构信息发现,不同类型的低分子量肝素都有其特征的碳谱信号,因此可以通过碳谱特征信号对低分子量肝素进行区分。结论:核磁共振一维碳谱定性鉴别低分子肝素的方法专属性强,简单方便,是鉴别低分子量肝素较好的方法。     

Long term administration of LMWH - pharmacodynamic parameters under therapeutic or prophylactic regimen of enoxaparin or tinzaparin in neurological rehabilitation patients

We investigated anti-FXa- and anti-FIIa-activity, thrombin generation (ETP), tissue factor pathway inhibitor (TFPI) - and D-dimer in patients exhibiting high bleeding risk in early neurological rehabilitation over 2 months in an observational study. Blood of 64 patients under LMWH administration due to therapeutic (cohort 1 [tinzaparin 90 IE/kg BID, N = 18] and 2 [enoxaparin 100 IE/kg BID; N = 15]) or prophylactic (cohort 3 [tinzaparin 4500 IE; N = 16] and 4 [enoxaparin 4000 IE; N = 15]) indication was drawn before and 4h after injection on day 7 (V1) and 2 months (follow up [V2]).Although the dose in cohort 1 and 2 was similar (median 7000 IE BID), a-FXa-activity was significantly larger under enoxaparin than under tinzaparin (e.g. median at V2: 0.70 IU/ml vs. 0.33 IU/ml). Also, prophylactic enoxaparin exhibited larger a-FXa-activity than tinzaparin (e.g. median at V2: 0.37 IU/ml vs. 0.22 IU/ml). The a-FXa/a-FIIa-ratio in plasma samples at 4h p.a. was about 4 (tinzaparin) and 8 (enoxaparin), respectively. No differences were seen for TFPI and ETP between cohort 1 and 2 or between cohort 3 and 4. D-dimer levels decreased significantly between V1 (e.g. cohort 4 median 1940 ng/ml) and V2 (median 652 ng/ml). Minimal bleeding events occurred in 6 patients (2 under tinzaparin, 4 under enoxaparin) and were associated with significantly higher anti-FXa-activity.In conclusion, although marked differences between tinzaparin and enoxaparin based on anti-FXa-activity were seen, markers of in vivo biological activity such as TFPI and D-dimer were not different. Furthermore, BID tinzaparin is a feasible option for therapeutic anticoagulation in patients with high bleeding risk.     

Home Therapy of Venous Thrombosis with Long-term LMWH versus Usual Care: Patient Satisfaction and Post-thrombotic Syndrome

Purpose

Home-LITE compared long-term treatment at home with tinzaparin or usual care in terms of efficacy, safety, patients' treatment satisfaction, incidence of post-thrombotic syndrome, and associated venous leg ulcers.

Methods

This multicenter, randomized, controlled trial enrolled 480 patients with documented, acute, proximal deep vein thrombosis. Patients received tinzaparin 175 IU/kg subcutaneously once daily for 12 weeks, or tinzaparin for ≥5 days plus oral warfarin, commenced on day 1, international normalized ratio-adjusted, and continued for ≥12 weeks (“usual care”). Patients received 1 in-clinic injection, then home treatment.

Results

The rate of recurrent venous thromboembolism at 12 weeks was 3.3% in both groups (absolute difference 0%; 95% confidence interval −3.2-3.2), and at 1 year was 10.4%/8.3% in the tinzaparin/usual-care groups, respectively (difference 2.1%; 95% confidence interval −3.1-7.3). There were no between-group differences in deaths at 12 weeks or 1 year, or bleeding at 12 weeks. Patients in the tinzaparin group expressed significantly greater treatment satisfaction (P = .0024), particularly regarding freedom from the inconvenience of blood monitoring; were less likely to report signs/symptoms of post-thrombotic syndrome (individual odds ratios 0.66 to 0.91, overall odds ratio 0.77, P = .001); and reported fewer leg ulcers at 12 weeks: 1 (0.5%) versus 8 (4.1%) (P = .02) with usual care.

Conclusions

Long-term home treatment with tinzaparin or usual care resulted in similar rates of recurrent venous thromboembolism, death, and bleeding. The significantly lower incidence of post-thrombotic syndrome and leg ulcers observed in the tinzaparin group is a potentially important benefit and deserves further study.     

The Low Molecular Weight Heparin,Tinzaparin, in Thrombosis and Beyond

Standard unfractionated heparin (UFH) has been in clinical use for over 50 years. The commercial use of low molecular weight heparins (LMWHs) began in the mid 1980s for hemodialysis and the prophylaxis of deep vein thrombosis (DVT). Initially, the clinical development of LMWHs was concentrated on the European continent. Subsequently, LMWHs were introduced in North America as well. In the initial stages of development of these drugs only nadroparin, dalteparin and enoxaparin were used. Subsequently, several other LMWHs such as ardeparin, tinzaparin, reviparin and parnaparin were introduced. LMWHs constitute a group of important medications with total sales reaching nearly 2.5 billion dollars with expanded indications reaching far beyond the initial indications for the prophylaxis of post‐surgical DVT. This review highlights the pharmacology of tinzaparin. Unlike other LMWHs, tinzaparin is prepared by enzymatic hydrolysis with heparinase, while various chemical depolymerization methods are used for the synthesis of other LMWHs. As compared with the standard heparin, LMWHs have different pharmacodynamic, and pharmacokinetic properties; they also differ in clinical benefits.