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Medical Hypotheses Sep 2020Currently, our world is facing the 2019 Novel Coronavirus (COVID-19) outbreak and tremendous efforts are made for developing drugs to treat and vaccines to prevent the...
The old but new: Can unfractioned heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV2 by inhibition of host cell proteases?
Currently, our world is facing the 2019 Novel Coronavirus (COVID-19) outbreak and tremendous efforts are made for developing drugs to treat and vaccines to prevent the disease. At present, there is no specific antiviral drug or vaccine for COVID-19. The pathogenic infectivity of the virus requires the S1 subunit of the spike (S) protein to bind the host cell receptor, angiontensin converting enzyme (ACE2). While the binding to host cell receptor is the first step of infection, the entrance of the virus into the cell needs the cleavage of S1-S2 subunits to expose S2 for fusion to cell membrane via host proteases including cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, trypsin and factor Xa. Previous in vitro studies have shown that factor Xa inhibition can decrease viral infectivity. We suppose that host cell proteases including furin (as expressed highly in lungs), factor Xa and cathepsin are possible targets to decrease viral burden, therefore unfractioned heparin and low molecular weight heparin-LMWH (specifically dalteparin and tinzaparin for their anti inflammatory action) can be potential inhibitors of multiple endoproteases involved in virus infectivity. Our hypothesis needs to be tested in in vitro and clinical studies, however as we are in an urgent situation as the burden of SARS-CoV2 is increasing all around the world, we recommend the usage of unfractioned heparin or LMWH in intensive care unit (ICU) and non-ICU hospitalized patients with the risk-benefit judgement of the clinician. Whether our hypothesis is clinically applicable and successful in decreasing viral infection will be evaluated for further studies.
Topics: Betacoronavirus; COVID-19; Coronavirus Infections; Drug Administration Schedule; Factor Xa; Heparin; Heparin, Low-Molecular-Weight; Humans; Models, Theoretical; Pandemics; Pneumonia, Viral; Protease Inhibitors; Protein Binding; SARS-CoV-2; Spike Glycoprotein, Coronavirus; COVID-19 Drug Treatment
PubMed: 32335456
DOI: 10.1016/j.mehy.2020.109743 -
Thrombosis Research Jun 2020
Topics: Aged; Antibodies, Antiphospholipid; Anticoagulants; Betacoronavirus; Blood Coagulation; COVID-19; Coronavirus Infections; Dalteparin; Endothelium; Factor VIII; Fibrin Fibrinogen Degradation Products; Heparin; Humans; Immunoglobulin M; Intensive Care Units; Male; Pandemics; Pneumonia, Viral; SARS-CoV-2; von Willebrand Factor
PubMed: 32305740
DOI: 10.1016/j.thromres.2020.04.014 -
World Neurosurgery Jul 2020The chronic subdural hematoma (cSDH)-Drain trial compared recurrence rates and clinical outcome associated with the use of subperiosteal drain (SPD) and subdural drain... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
The chronic subdural hematoma (cSDH)-Drain trial compared recurrence rates and clinical outcome associated with the use of subperiosteal drain (SPD) and subdural drain (SDD) after burr-hole drainage for cSDH. This subgroup analysis aimed to determine whether one drain type is preferable for patients treated with platelet inhibitors (PI) or anticoagulants (AC).
METHODS
This subanalysis included 133 patients treated with PI/AC of the 220 patients from the preceding cSDH-Drain trial. For these patients the association between the drain type used and recurrence rates, mortality, as well as clinical outcome at 6 weeks and 12 months follow-up were analyzed using a logistic regression analysis model. Additionally, recurrence rates, clinical outcome, and mortality were assessed for each PI or AC type separately.
RESULTS
The insertion of SPD was associated with 7.35% recurrence rates compared to 13.85% with SDD in patients treated with PI or AC (OR 0.41, 95% CI 0.06-2.65, P = 0.36). Outcome measurements and mortality did not differ significantly between both groups at 6-week and 12-month follow-up. In addition, there was no statistically significant association between drain type and recurrence rate or mortality when comparing data for each PI or AC type. At 24 hours postoperatively, significantly more patients under phenprocoumon and natrium-dalteparin had a Glasgow Coma Scale score between 13 and 15 in the SDD group compared with the SPD group (P = 0.006), whereaas at 6-week follow-up significantly more patients in the SDD group treated with ASA had a good modified Rankin scale score (P = 0.01). At 12 months, no significant difference in outcome measurements was seen for all PI and AC types.
CONCLUSIONS
In patients treated with PI or AC, the insertion of SPD after burr-hole drainage of cSDH showed comparable recurrence, mortality, and long term outcome rates when compared with SDD.
Topics: Aged; Aged, 80 and over; Anticoagulants; Drainage; Female; Hematoma, Subdural, Chronic; Humans; Male; Periosteum; Platelet Aggregation Inhibitors; Recurrence; Subdural Space; Treatment Outcome; Trephining
PubMed: 32247794
DOI: 10.1016/j.wneu.2020.03.134 -
Taiwanese Journal of Obstetrics &... Mar 2020Due to the morbidity and mortality of mothers and fetuses developed by preeclampsia, preventive approaches have always been taken into account in high risk individuals....
Due to the morbidity and mortality of mothers and fetuses developed by preeclampsia, preventive approaches have always been taken into account in high risk individuals. Systematic review studies contribute to make a better decision about the results of such studies. Accordingly, this study strived to systematically study the factors effective in the prevention of preeclampsia. The MEDLINE, ISI Web of Science, PubMed, Scopus, Google Scholar, and Proquest databases were systematically reviewed between January 2000 and May 2019. The quality of the studies was analyzed using the CONSORT checklist. A study was conducted on 29 quality interventional studies; 28 of which were RCT type, and on various factors such as anticoagulants (heparin, enoxaparin, Dalteparin and Nadroparin), aspirin, paravastatin, nitric oxide, yoga, micronutrients Such as l-Arginine, Folic Acid, Vitamin E and C, Phytonutrient, Lycopene and Vitamin D alone or in combination with Calcium. The results of this study showed that low molecular weight heparin, enoxaparin, PETN, yoga, L arginine, folic acid, vitamin D prevented preeclampsia alone or combined with calcium.
Topics: Arginine; Calcium; Drug Therapy, Combination; Enoxaparin; Female; Folic Acid; Heparin, Low-Molecular-Weight; Humans; Pentaerythritol Tetranitrate; Pre-Eclampsia; Pregnancy; Prenatal Care; Vitamin D; Yoga
PubMed: 32127134
DOI: 10.1016/j.tjog.2020.01.002 -
Journal of Thrombosis and Haemostasis :... Apr 2020The Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D) trial demonstrated reduction in recurrent venous... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism (SELECT-D) trial demonstrated reduction in recurrent venous thromboembolism (VTE) but increased bleeding with rivaroxaban compared with dalteparin for treatment of acute VTE in cancer patients, at 6 months. Uncertainty remains around optimal duration of anticoagulation.
OBJECTIVES
To assess VTE recurrence and bleeding, with anticoagulation or not, beyond 6 months.
PATIENTS/METHODS
In SELECT-D, after 6 months of trial treatment for VTE, patients with active cancer and residual deep vein thrombosis (RDVT) or index pulmonary embolism (PE) were eligible for randomization to a further 6 months of rivaroxaban or placebo. Patients with no RDVT stopped anticoagulation. Primary outcome was VTE recurrence at 12 months. The second randomization closed prematurely because of low recruitment when 92 of the planned 300 patients were recruited.
RESULTS
Ninety-two of 136 eligible patients were randomized to rivaroxaban or placebo. The cumulative VTE recurrence after 6 months from the second randomization was 14% with placebo and 4% with rivaroxaban (hazard ratio, 0.32; 95% confidence interval [CI], 0.06-1.58). The major and clinically relevant non-major bleeding rates were 0% and 0% with placebo; and 5% (95% CI, 1-18) and 4% (95% CI, 1-17) with rivaroxaban. In an exploratory analysis, 7 (15%) of 46 placebo patients with RDVT or an index PE experienced recurrent VTE compared to none in the 35 patients in the RDVT-negative cohort (P = .03).
CONCLUSION
The SELECT-D trial was underpowered to detect a statistically significant reduction in recurrent VTE with extended anticoagulation. The absence of RDVT and/or index PE, defined a population at low risk of recurrence.
Topics: Anticoagulants; Humans; Neoplasms; Random Allocation; Rivaroxaban; Treatment Outcome; Venous Thromboembolism
PubMed: 31995662
DOI: 10.1111/jth.14752 -
Biology of Reproduction Apr 2020Preeclampsia is a serious hypertensive disorder of pregnancy, which is only cured with delivery of the placenta, thereby commonly necessitating preterm birth of the...
Preeclampsia is a serious hypertensive disorder of pregnancy, which is only cured with delivery of the placenta, thereby commonly necessitating preterm birth of the fetus. Low-molecular-weight heparin (LMWH) has demonstrated potential to reduce the incidence of preeclampsia in high-risk pregnant women, although the underlying mechanism by which LMWH protects against preeclampsia is unknown. Given the complex structure and biologic actions of heparin, we tested the hypothesis that heparin can mediate preeclampsia prevention via nonanticoagulant pathways. We compared the effects of a nonanticoagulant, glycol-split LMWH (gsHep)-rendered nonanticoagulant through disruption of the antithrombin binding regions-with the LMWH dalteparin in the rat reduced uterine perfusion pressure (RUPP) surgical model of preeclampsia. Although RUPP animals exhibit significantly elevated blood pressure and reduced plasma levels of placental growth factor (PGF) compared to sham, neither dalteparin nor gsHep treatment significantly impacted these parameters. However, the observed positive correlation between PGF levels and number of viable fetuses in RUPP-induced animals suggests that reduced PGF levels were predominately due to placental loss. Daily subcutaneous injections of low-dose dalteparin but not gsHep significantly restored fetal growth that was impaired by RUPP surgery. Placentas from RUPP animals exhibited an abnormal labyrinth structure, characterized by expanded sinusoidal blood spaces, relative to sham-operated animals. Morphometric analysis demonstrated that dalteparin but not gsHep treatment normalized development of the labyrinth in RUPP-exposed conceptuses. These data suggest that the antithrombin-binding regions of LMWH are required to confer its protective effects on fetal growth and placental development.
Topics: Animals; Anticoagulants; Dalteparin; Female; Fetal Development; Gene Expression Regulation; Heparin; Hypertension; Placenta Diseases; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Rats; Rats, Sprague-Dawley
PubMed: 31950133
DOI: 10.1093/biolre/ioaa006 -
The Netherlands Journal of Medicine Dec 2019Monitoring low-molecular-weight heparins is generally not required. However, guidelines advise to monitor anti-Xa levels in patients with renal insufficiency or a BMI...
BACKGROUND
Monitoring low-molecular-weight heparins is generally not required. However, guidelines advise to monitor anti-Xa levels in patients with renal insufficiency or a BMI above 50, and in pregnancy. Measuring anti-Xa levels is a complex challenge since sampling should be performed three to five hours after subcutaneous injection and after steady state concentrations have been reached. Strict compliance is pivotal for justified dose adjustments.
OBJECTIVES
We questioned compliance to our protocol and performed this study to explore that.
METHODS
This retrospective cohort study included patients ≥ 18 years receiving therapeutic dalteparin in a Dutch academic medical centre. Patients with a first anti-Xa level measured between February 23rd and December 30th, 2017 were selected. According to our local guideline, monitoring anti-Xa activity is indicated in patients on therapeutic doses of dalteparin who are pregnant, morbidly obese (BMI > 50), or have renal insufficiency (clearance < 60 ml/min). Accurate sampling was defined as measuring levels after at least three injections (after which a patient may reach steady state) and then four hours after the injection with dalteparin. The frequency of compliance to our protocol was assessed.
RESULTS
We included 158 patients with 396 anti-Xa levels, of which 41% (65/158) of all first anti-Xa levels were drawn without appropriate indication. Almost half, 48% (211/396), were sampled incorrectly and 25% of these (53/211) were followed by a dose adjustment. In total, 74% (293/396) of the samples were not indicated or were taken at the wrong time.
CONCLUSIONS
Monitoring anti-Xa levels is a complex clinical challenge. This study showed that non-compliance with recommendations for anti-Xa monitoring was high, often resulting in unjustified dose adjustments.
Topics: Academic Medical Centers; Adult; Anticoagulants; Dalteparin; Factor Xa Inhibitors; Female; Heparin, Low-Molecular-Weight; Humans; Male; Medication Adherence; Middle Aged; Netherlands; Retrospective Studies; Venous Thromboembolism; Young Adult
PubMed: 31880268
DOI: No ID Found -
Journal of Gynecologic Oncology Jan 2020
Topics: Anticoagulants; Dalteparin; Female; Humans; Neoplasm Recurrence, Local; Rivaroxaban; Venous Thromboembolism
PubMed: 31833262
DOI: 10.3802/jgo.2020.31.e40 -
Heparanase as an Additional Tool for Detecting Structural Peculiarities of Heparin Oligosaccharides.Molecules (Basel, Switzerland) Dec 2019Due to the biological properties of heparin and low-molecular-weight heparin (LMWH), continuous advances in elucidation of their microheterogeneous structure and...
Due to the biological properties of heparin and low-molecular-weight heparin (LMWH), continuous advances in elucidation of their microheterogeneous structure and discovery of novel structural peculiarities are crucial. Effective strategies for monitoring manufacturing processes and assessment of more restrictive specifications, as imposed by the current regulatory agencies, need to be developed. Hereby, we apply an efficient heparanase-based strategy to assert the structure of two major isomeric octasaccharides of dalteparin and investigate the tetrasaccharides arising from antithrombin binding region (ATBR) of bovine mucosal heparin. Heparanase, especially when combined with other sample preparation methods (e.g., size exclusion, affinity chromatography, heparinase depolymerization), was shown to be a powerful tool providing relevant information about heparin structural peculiarities. The applied approach provided direct evidence that oligomers bearing glucuronic acid-glucosamine-3--sulfate at their nonreducing end represent an important structural signature of dalteparin. When extended to ATBR-related tetramers of bovine heparin, the heparanase-based approach allowed for elucidation of the structure of minor sequences that have not been reported yet. The obtained results are of high importance in the view of the growing interest of regulatory agencies and manufacturers in the development of low-molecular-weight heparin generics as well as bovine heparin as alternative source.
Topics: Animals; Antithrombins; Binding Sites; Cattle; Chromatography, High Pressure Liquid; Glucuronidase; Heparin; Heparin, Low-Molecular-Weight; Molecular Structure; Oligosaccharides; Polymerization; Protein Binding; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 31810297
DOI: 10.3390/molecules24234403 -
Journal of Gynecologic Oncology Jan 2020Two randomized, controlled studies comparing outcomes in patients treated with direct oral anticoagulants or low-molecular weight heparin for cancer-associated venous... (Comparative Study)
Comparative Study
OBJECTIVES
Two randomized, controlled studies comparing outcomes in patients treated with direct oral anticoagulants or low-molecular weight heparin for cancer-associated venous thromboembolism (VTE) have previously been performed. However, gynecologic cancers accounted for approximately 10% of the study populations. We compared the outcomes of patients with primary gynecological cancers who were treated for cancer-associated VTE with either rivaroxaban or dalteparin.
METHODS
The 162 eligible patients with gynecologic cancers who were treated with either dalteparin (n=60) or rivaroxaban (n=102) were reviewed. The primary outcome was a composite event, which included recurrence or clinically relevant bleeding events during the therapeutic period. Secondary outcomes were recurrence, clinically relevant bleeding events, and mortality.
RESULTS
During the therapeutic period, there were no significant differences between the groups in the proportion of composite events, recurrence, or clinically relevant bleeding. Multivariate analysis using the Cox proportional hazards model also showed no significant difference in the number of composite events and clinically relevant bleeding between the groups. In the rivaroxaban group, 44.0% of patients experienced gastrointestinal bleeding and 24.0% experienced urinary tract bleeding. In the dalteparin group, bleeding was most common in the urinary tract (44.4%) and at the injection site (22.2%).
CONCLUSION
In this study, although there were no significant differences in effectiveness or safety between the rivaroxaban and dalteparin groups, rivaroxaban use was associated with a higher rate of clinically relevant bleeding than dalteparin. Therefore, caution should be taken when prescribing rivaroxaban for gynecologic cancer-associated VTE and bleeding events should be carefully monitored.
Topics: Aged; Dalteparin; Factor Xa Inhibitors; Female; Genital Neoplasms, Female; Hemorrhage; Humans; Middle Aged; Proportional Hazards Models; Republic of Korea; Rivaroxaban; Venous Thromboembolism
PubMed: 31789000
DOI: 10.3802/jgo.2020.31.e10