Low molecular weight heparins dosing and anti-factor Xa activity in patients with novel coronavirus infection COVID-19.

2020 ◽  
Author(s):  
Е.В. Ройтман ◽  
А.Ю. Буланов ◽  
В.М. Печенников
Keyword(s):  
Molecular Weight ◽  
Cluster Analysis ◽  
Body Weight ◽  
Discriminant Analysis ◽  
Dose Adjustment ◽  
Roc Analysis ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Low Molecular Weight Heparins

Низкомолекулярные гепарины (НМГ) рекомендованы всем госпитализированным пациентам с COVID-19. Однако эффективная доза НМГ неизвестна, и эскалация дозы НМГ представляется уместной для лечения COVID-19-ассоциированной коагулопатии. Цель исследования: анализ дозирования НМГ для лечения COVID-19-ассоциированной коагулопатии, а также индикаторов, указывающих на необходимость коррекции доз этих препаратов. Материалы и методы. В период апрель-июнь 2020 г. обследовано 49 человек с диагнозом COVID-19. НМГ получили 43 пациента: 25 человек — эноксапарин натрия, 18 — далтепарин натрия. При лабораторном обследовании определяли С-реактивный белок, количество тромбоцитов, активированное частичное тромбопластиновое время, тромбиновое время, концентрацию фибриногена, активность антитромбина III, протромбиновое время, концентрацию Д-димера и анти-фактор Ха активность (анти- Ха активность). Данные были представлены как медиана (Me), нижний (LQ) и верхний (UQ) квартили. Статистический анализ включал в себя проверку на нормальность распределения по критерию Шапиро–Уилка, сравнение независимых групп по критерию Манна–Уитни при уровне значимости < 0,05, корреляционный анализ с применением критерия Спирмена, регрессионный анализ с использованием F-критерия. Многомерный поэтапный анализ результатов исследования проводили методами кластерного, дискриминантного и ROC-анализа. Результаты. Установлено, что воспалительный ответ у мужчин и у женщин протекает с различающимися акцентами в рамках системы гемостаза. Если анти- Ха активность была ниже 0,4 МЕ / мл, то выбранная доза НМГ никак не влияла ни на процессы тромбообразования и воспаления, ни на течение заболевания в целом. При анти- Ха активности в диапазоне 0,4–0,6 МЕ / мл воспалительный ответ также преодолевал эффект НМГ. Только при анти- Ха активности > 0,6 МЕ / мл была выявлена достоверная корреляция между анти- Ха активностью и суточной дозой НМГ (r = 0,493; p = 0,031). Выявление в этой группе такой связи означает, что часть поступившего в организм НМГ уже была «потрачена» на противовоспалительные цели, а оставшаяся проявила эффект, направленный на другую цель назначения НМГ, т. е. собственно антитромботический. При этом ROC-анализ не подтвердил значимость концентрации фибриногена в прогнозе достижения антитромботической эффективности НМГ. Кластерный анализ достоверно разделил исходную выборку в точке анти- Ха активность = 0,6 ЕД / мл. Из 43 пациентов, получивших НМГ, только у 15 (34,9%) выбранная доза НМГ анти- Ха активность > 0,6 ЕД / мл, тогда как у оставшихся анти- Ха активность оказалась ниже данного значения, несмотря на большую вариацию полученного НМГ: AUC = 0,482 (95% ДИ = 0,298–0,665) со статистической значимостью p = 0,848. Дискриминантный анализ показал, а ROC-анализ подтвердил, что для до- стижения антитромботического эффекта требуется коррекция дозы с учетом веса тела пациента, а целевым значением анти- Ха активности является 0,65 ME / мл. Заключение. Антитромботический эффект как искомый результат применения НМГ достижим только при дозировании с учетом массы тела пациента, независимо от того, снижена она, нормальная или повышена. Развитие антитромботического эффекта должно выявляться, а его стабильность подтверждаться на основе определения анти- Ха активности, которая должна быть не менее 0,65 МЕ/мл. Анти- Ха активность ниже данного значения может служить указанием на необходимость коррекции дозы НМГ у пациентов с COVID-19-ассоциированной коагулопатией. Background. Low molecular weight heparins (LMWH) are guided for all in-hospital patients with COVID-19. However LMWH effective dose is still unknown. Escalating the LMWH dose seems appropriate for the treatment of COVID-19-associated coagulopathy. Objectives: to explore the LMWHs doses effects in the treatment of COVID-19-associated coagulopathy, and to fi nd indicators signaling the need to adjust the LMWH dose. Patients / Methods. From April to June 2020, 49 patients with COVID-19 were examined. LMWH were given to 43 patients: 25 of them received enoxaparin sodium, 18 — dalteparin sodium. Lab testing included C-reactive protein, platelet count, activated partial thromboplastin time, thrombin time, fibrinogen, antithrombin III, prothrombin time, D-dimer, and anti-factor Xa activity (anti- Xa activity). The data were presented as median (Me), lower (LQ) and upper (UQ) quartiles. Statistical analysis included the check of the distribution normality by Shapiro–Wilk test, comparing independent groups with Mann- Whitney test for p < 0.05, correlation analysis with Spearman test, and regression analysis with the F-test. Multivariate step-by-step analysis of data was performed using cluster analysis, discriminant analysis and ROC-analysis. Results. It was found that the inflammatory response reflects differently for hemostatic system in men and women. When anti-Xa activity was < 0.4 IU / ml, the LMWH selected dose did not affect either the processes of thrombosis and inflammation, or the course of the disease as a whole. When anti- Xa activity was within 0.4–0.6 IU / ml, the inflammation overcame the LMWH effect as well. A significant correlation between anti- Xa activity and the LMWH daily dose (r = 0.493; p = 0.031) was found only for anti-Xa activity > 0.6 IU / ml. That does mean that part of the administered LMWH was already “spent” for anti-inflammatory purposes, and the remaining part was enough to develop an antithrombotic effect. Other result was that ROC-analysis did not confirm the fibrinogen value for the forecast of LMWH antithrombotic effectiveness. Cluster analysis divided significantly the initial sample at the point with anti- Xa activity = 0.6 IU / ml. Of the 43 patients received LMWH, the selected LMWH dose provided anti- Xa activity > 0.6 IU / ml in 15 (34.9%) only, while in other patients the anti- Xa activity was lower despite a wide variation in the LMWH doses: AUC = 0.482 (95% CI = 0.298–0.665; p = 0.848). Discriminant analysis showed, and then ROC-analysis confirmed, that to an antithrombotic effect, LMWH dose adjustment is required taking into account the patient’s body weight, and the target value of anti- Xa activity is 0.65 IU / ml. Conclusions. The antithrombotic effect as the desired result of the LMWH use is achievable only under dosing with the patient’s body weight regardless of whether it is reduced, normal or increased. The LMWH antithrombotic effect should be detected and then its stability confirmed by testing the anti- Xa activity which should be at least 0.65 IU / ml. Lower anti- Xa activity may indicate the need for LMWH dose adjustment in patients with COVID-19-associated coagulopathy.

EXPERIMENTAL THROMBUS FORMATION AND HAEMOSTASIS OF DIFFERENT LOW MOLECULAR WEIGHT HEPARINS AND DOSAGES

1987 ◽  
Author(s):  
R A Zimmerman ◽  
C T Rieger ◽  
K Hübner ◽  
C W Harenber ◽  
W Kübler
Keyword(s):  
Molecular Weight ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Bleeding Complications ◽  
Maximum Effect ◽  
Low Molecular Weight ◽  
Antithrombotic Effect ◽  
Low Molecular Weight Heparins ◽  
Antithrombotic Activity ◽  
Thrombosis Model

Low molecular weight heparin induces a higher anti factor Xa (a-Xa) and a lower antithrombin activity in plasma in comparison to conventional heparin. From this constellation a more pronounced antithrombotic effect and a minor incidence of bleeding Complications has been suggested.Therefore the antithrombotic activity of heparins was studied in a standardized experimental thrombosis model in rabbits. Three low molecular weight heparins with a mean molecular weight of 4.200 (heparin I),4.000 (heparin II),4.600 Dalton (heparin III) and standard heparin were tested at different dosages in 120 experiments. In the first series the dose of 60 anti Xa units (a-Xa U) given initially and 60 a-Xa U/kg/h induced a reduction of the thrombus size by 40 % (heparin I),37 % (heparin II) and 53 % (heparin III) and a prolongation of the aPTT to 45 (heparin I),66 (heparin II) and 79 sec (heparin III). The a-Xa activity was minor than 0.1 U/ml. In the second series heparins were given to aim at an a-Xa activity of 0.2-0.3 U/ml. Thereby the thrombus formation could be reduced by 84 % (heparin I), 62 % (heparin II) and 39 % (heparin III). aPTT and a-Xa activity were measured at 65.5 sec and 0.22 a-Xa U/ml (heparin I),67.3 sec and 0.3 a-Xa U/ml (heparin II) and 67.5 and 0.31 a-Xa U/ml (heparin III),respectively. In the third series the increase of the a-Xa activity to more than 0.3 U/ml showed no further reduction of the thrombus formation by heparin I, while heparins II and III already at this level reachedthe antithrombotic activity of heparin I.Our data on three different low molecular weight heparins demonstrate that already a heparin level ranging at a minimal a-Xa activity induces a clear and statistically significant antithrombotic effect. A higher heparin dosage with higher a-Xa activity increases the antithrombitic effect. At a level of 0.2-0.3 a-Xa U/ml an obvious and maximum effect could be reached, but the further elevation of the a-Xa activity produced no further antithrombotic action.

scholarly journals The anti-factor Xa range for low molecular weight heparin thromboprophylaxis

2015 ◽  
Vol 7 (4) ◽  
Author(s):  
Matthew Y. Wei ◽  
Salena M. Ward
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Dose Adjustment ◽  
Factor Xa ◽  
Research Data ◽  
Target Range ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins ◽  
Therapeutic Doses ◽  
Venous Thromboses

Low molecular weight heparins (LMWHs) are now the mainstay option in the prevention and treatment of venous thromboembolism. In some patients receiving therapeutic doses of LMWH, activity can be measured by quantifying the presence of Anti-factor Xa (AFXa) for dose adjustment. However, currently there are no guidelines for LMWH monitoring in patients on thromboprophylactic, doses, despite certain patient populations may be at risk of suboptimal dosing. This review found that while the AFXa ranges for therapeutic levels of LMWHs are relatively well defined in the literature, prophylactic ranges are much less clear, thus making it difficult to interpret current research data. From the studies published to date, we concluded that a reasonable AFXa target range for LMWH deep venous thromboses prophylaxis might be 0.2-0.5 IU/mL.

scholarly journals Modern low-molecular-weight heparins in the prevention and treatment of venous thromboembolic complications in oncourologic patients

2018 ◽  
pp. 106-112
Author(s):  
N. V. Vorobyev ◽  
S. V. Popov
Keyword(s):  
Molecular Weight ◽  
Impaired Renal Function ◽  
Low Molecular Weight Heparin ◽  
Low Molecular Weight ◽  
Efficacy And Safety ◽  
Thromboembolic Complications ◽  
Antithrombotic Effect ◽  
Low Molecular Weight Heparins ◽  
Prevention And Treatment ◽  
Venous Thromboembolic

Oncourologic diseases are accompanied by a risk for subsequent venous thromboembolic complications, which are rated the most dangerous in terms of thrombogenic effect. The article presents a review of the clinical studies of efficacy and safety, and the experience in using of modern low-molecular-weight heparins in clinical practice - drugs of choice for the prevention of venous thromboembolic complications in cancer patients. Particular attention is paid to Bemiparin - a new second-generation low-molecular-weight heparin with a significant antithrombotic effect and improved pharmacological parameters that allow it to be successfully used in patients with impaired renal function in oncourological practice.

Effects of an Enzymatically Depolymerized Heparin as Compared with Conventional Heparin in Healthy Volunteers

1987 ◽  
Vol 57 (01) ◽  
pp. 097-101 ◽  
Author(s):  
Thomas Mätzsch ◽  
David Bergqvist ◽  
Ulla Hedner ◽  
Per Østergaard
Keyword(s):  
Molecular Weight ◽  
Body Weight ◽  
Healthy Volunteers ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Normal Range ◽  
Factor Xa Inhibition ◽  
At Iii ◽  
Mean Molecular Weight ◽  
Enzymatic Depolymerization

SummaryA low molecular weight heparin (LMW-heparin) with a mean molecular weight of 4900 dalton was prepared by controlled enzymatic depolymerization of conventional porcine mucosal heparin. The effects of 2,500, 5,000 and 10,000 U (Xal; 29,58 and 116 mg) on factor Xa inhibition (Xal), factor Ila inhibition (Hal), APTT, AT III and platelet count were compared to those of 5,000 U (Xal; 26 mg) of conventional heparin given s. c. to 6 healthy volunteers. 5,000 U (Xal; 58 mg) of LMW-heparin was given i. v. A dose related response with regard to the Xal and the Ila-inhibitory activities with peak values at 4 hours after the s. c. injections was obtained. An increase of the Xal/IIal ratio over the time after injection was seen only after i. v. administration of the LMW-heparin. The APTT was only slightly prolonged and remained within normal range after s. c. injection. AT III and platelet counts were unaffected. The biological half life of the LMW-heparin was 111 minutes if assayed by Xa inhibition, 76 minutes if assayed by Ila inhibition and 40 minutes if assayed by APTT. A strong correlation between the Xal activities obtained and body weight was seen, indicating that LMW-heparin should be administered individually according to body weight.

PHARMACOLOGIC INEQUIVALENCE OF LOW MOLECULAR WEIGHT HEPARINS

1987 ◽  
Author(s):  
J Fareed ◽  
J M Walenga ◽  
D Hoppensteadt ◽  
R N Emanuele ◽  
A Racanell
Keyword(s):  
Molecular Weight ◽  
Animal Models ◽  
Comparative Study ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Low Molecular Weight Heparins ◽  
In Vivo Test ◽  
In Vitro Effects

Compared to unfractionated heparin, low molecular weight heparins (LMWHs) have been found to exhibit marked variations in in vitro effects due to variations in molecular weight and structure. Moreover, when the in vitro potency of these agents is equally adjusted bypharmacopeial assay (current and proposed) wide variations in the in vivo responses have been noted. These variations were strongly dependent on the route of administration. Utilizing defined animal models, a systematic comparative study of the in vivo responses of seven commercial LMWHs was undertaken. Choay Fraxiparine (CY 216} Choay CY 222, NovoLHN, Kabi Fragmin, Opocrin 2123 (OP), Hepar RD 11885 (RD), Pharmuka Enoxaparin (PK) and Choay porcine mucosal heparin (PMH) were tested in identical settings at equigravimetric dosages. The graded results are given in the following.Wide variations in the in vivo pharmacologic and toxicity responseswere noted suggesting that different LMWHs are not bioequivalent at equigravimetric levels. When these responses were expressed in anti-factor Xa or pharmacopeial potency, these differences were further magnified. The clinically reported dosimetric and safety problems may be minimized by profiling LMWHs in defined in vivo test systems to optimize their safety/efficacy ratio.

A NEW ONE STAGE CLOTTING ASSAY FOR HEPARIN AND LOW MOLECULAR WEIGHT HEPARINS

1987 ◽  
Author(s):  
Ch Giese ◽  
A Knodler ◽  
R Zimmermann ◽  
J Harenberg
Keyword(s):  
Molecular Weight ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Chromogenic Substrate ◽  
Clotting Time ◽  
Low Molecular Weight Heparins ◽  
One Stage ◽  
High Preference ◽  
Coagulation Tests ◽  
Plasma Assay

Heparin and its low molecular weight (LMW) derivatives are usually measured by chromogenic or fluorogenic synthetic substrate assays and by coagulation tests. Since the activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) are insensitive to LMW heparins, we report here of data obtained with heptest, a new one stage modification of the original heparin in plasma assay of Yin. The assay was compared with the antifactor Xa chromogenic substrate S2222 method, the TCT and aPTT tests in 100 patients receiving unfractionated pig intestinal mucosa heparin and 100 patients treated with low molecular weight heparin Kabi 2165. The results indicate a high correlation between the heptest and the anti Xa chromogenic substrate method, whereas the correlations were lower for the aPTT and TCT. correlations with LMW heparinThe lowest detection limit of the heptest is 0,005 heparin units per ml plasma. The test is very sensitive, simple, highly reproducable and reliable clotting assay for unfractionated and low molecular weight heparins in human plasma. The test detects with high preference the inhibition on factor Xa but also the other anticoagulant effects on die coagulation tractors.

Biological Activity of Low-Molecular-Weight Heparin Increases Over 9 Days in Patients Treated for Acute Venous Thromboembolism.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4176-4176
Author(s):  
Job Harenberg ◽  
Kai Bauer ◽  
Claudia Abletshauser
Keyword(s):  
Molecular Weight ◽  
Body Weight ◽  
Venous Thromboembolism ◽  
Low Molecular Weight Heparin ◽  
Factor Xa ◽  
The Body ◽  
Bleeding Complications ◽  
Fixed Dose ◽  
Low Molecular Weight ◽  
Acute Venous Thromboembolism

Abstract Abstract 4176 Subcutaneous (s.c.) body-weight adjusted as well as fixed dose low-molecular-weight heparin (LMWH) for treatment of acute venous thromboembolism (VTE) has been proven to be at least as effective and safe as intravenous unfractionated heparin (UFH). We hypothesized that the anticoagulant effects of LMWH may accumulate during a 9 days fixed dose therapy in patients with acute VTE. Ten patients received 8,000 IU LMWH certoparin bid s.c. for 9±1 days after having given written informed consent. The local ethics committee accepted the study protocol. Serial blood and urine were collected at days 2 and 9 and daily before and after the morning administration of the anticoagulant. The pharmacodynamic parameters were analysed on the anti-factor Xa S2222 method (aXa), heptest, thrombin generation inhibition assay (TGIA), and tissue factor pathway inhibitor activity (TFPI). The area under the activity time curves (AUC) of the parameters was compared at days 2 and 9. LMWH reached steady state levels of the S2222 and heptest assay within 24 hrs. aXa, heptest, TGIA and TFPI were 22%, 38%, 13% and 22% higher at day 9 compared to day 2. The elimination half-lives of aXa and heptest and the aXa excreted into the urine did not differ between days 2 and 9, respectively. The AUC of the aXa did not correlate with the body weight of the patients. Fixed dose, body weight-independent subcutaneous LMWH accumulated to some extend after 9 days of treatment in patients with acute VTE. However, the results of the clinical trials with the LMWH certoparin did not show more bleeding complications compared to UFH. Therapy with LMWH for more than 10 days may require dose reduction. Disclosures: Harenberg: Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Aventis: Consultancy, Honoraria; Roche Diagnostics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bayer Health Care: Consultancy, Honoraria. Abletshauser:Novartis: Employment.

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