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Journal of Hematology and Transfusion

Management of Bleeding Complications in Patients on New Oral Anticoagulants

Mini Review | Open Access

  • 1. Division of Hematology, Department of Internal Medicine, Mayo Clinic, USA
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Corresponding Authors
Patnaik M, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester MN, USA 55905, Tel: 507-266-0792
Abstract

Until recently, the Vitamin K antagonist (VKA) warfarin was the only oral anticoagulant available for clinical use. However, with the US FDA approval of new oral anticoagulants (NOAs) such as dabigatran, rivaroxaban and apixaban, there currently exist several choices. With any anticoagulant, bleeding complications are anticipated and require well defined management guidelines. Unlike warfarin, the NOAs present a clinical challenge in the management of bleeding issues due to their lack of specific antidotes/reversal agents. Given the increasing use of NOAs and anticipated challenges associated with bleeding complications, we provide a management overview for physicians based on current evidence based practices.

Citation

Gonsalves WI, Gupta V, Patnaik MM (2014) Management of Bleeding Complications in Patients on New Oral Anticoagulants. J Hematol Transfus 2(1): 1015.

Keywords

•    New oral anticoagulants
•    Bleeding
•    Reversal
•    Dabigatran
•    Apixaban and Rivaroxaban

INTRODUCTION

The vitamin K antagonist, warfarin, remains the gold standard for oral anticoagulation for more than half a century. However its narrow therapeutic index, multiple food and drug interactions and need for frequent coagulation monitoring negatively impacts its efficacy, safety and compliance [1]. These limitations prompted the development of new oral anticoagulants (NOAs) with improved efficacy and safety profiles that do not require coagulation monitoring. The NOAs currently approved in the US include dabigatran (Pradaxa®, Boehringer Ingelheim), rivaroxaban (Xarelto®, Bayer, J&J) and apixaban (Eliquis®, Pfizer and Bristol-Myers Squibb) [2]. These agents have been approved for short-term thromboprophylaxis after hip and knee arthroplasty [3-10], treatment of venous thromboembolism (VTE) [11,12] and prevention of VTE in atrial fibrillation (AF) [13-15]. Edoxaban (Lixiana®, Daiichi Sankyo) is another NOA approved for clinical use only in Japan for the prevention of VTE after major orthopedic surgery. The characteristics of these NOAs are summarized in Table 1.

Apart from the aforementioned indications, several clinical studies are being conducted to extend the approved indications for these NOAs, thus a wider use is expected in the future [16-18]. Bleeding complications secondary to anticoagulant use is common and is associated with significant morbidity and mortality [19]. Physicians have become familiar with the management of such issues in patients on conventional anticoagulants such as warfarin, heparin or low molecular weight heparin (LMWH). However, there remains a lack of experience in managing patients treated with NOAs. A recent study indicated that majority (>90%) of non-malignant hematology physician members of the Hemostasis and Thrombosis Research Society (HTRS) and US hemophilia center directors remain concerned about their ability to manage bleeding complications secondary to NOAs due to the lack of established management protocols and experience [20]. Thus, this review provides an evidence based overview to clinicians to help them deal with this pressing issue.

Challenges in managing bleeding complications due to NOAs

Unlike warfarin, managing bleeding complications in patients on NOAs poses several different challenges. First, there are no specific antidotes for reversing the anticoagulant effects of NOAs [21]. Second, conventional coagulation monitoring assays such as the activated partial thromboplastin time (aPTT), prothrombin time (PT) and thrombin time (TT) are unable to accurately measure the degree of anticoagulation, making it difficult to gauge the severity [22]. Finally, there is increasing use of NOAs for patients with AF and those requiring VTE prophylaxis after knee and hip arthroplasty. This patient group tends to be elderly with multiple comorbidities sometimes requiring concurrent antiplatelet therapies, further complicating bleeding issues [23,24].

Measuring the anticoagulation effect of NOAs during bleeding complications

Though traditional coagulation assays are incapable of accurately measuring the anticoagulant effect of NOAs, rapid assessment of the degree of anticoagulation is still required when assessing bleeding complications. The prothrombin time (PT) is relatively insensitive at therapeutic levels of dabigatran compared to rivaroxaban and apixaban; whereas the activated partial thromboplastin time (aPTT) is more sensitive to dabigatran[25,26]. Unfortunately, different aPTT and PT reagents used amongst different laboratories have different responsiveness to these NOAs making it difficult to standardize results [22].

Given these limitations, modified or novel assays have been developed to help accurately measure the degree of anticoagulation in patients on NOAs though none are standardized or routinely available [27]. The ecarin clotting time (ECT) is a TTlike assay that uses a metalloprotease derived from the venom of the Echis carinatus snake that generates meizothrombin from prothrombin, which then converts fibrinogen to fibrin, leading to clot formation[28]. Direct thrombin inhibitors like dabigatran can inactivate meizothrombin prolonging the clotting time, thus making it useful as a monitoring assay [28]. Newer chromogenic based ECT assays prevent influence of results by the levels of fibrinogen and prothrombin [29].

The HEMOCLOT direct thrombin inhibitor assay (HYPHEN BioMed, Neuville Sur Oise, France) is a dilute thrombin time assay that provides accurate, reproducible measures of dabigatran anticoagulant activity and plasma concentrations. It shows linear effects with dabigatran plasma concentrations but no activity to rivaroxaban or apixaban [30]. It is licensed for commercial use in Europe and Canada but not the US. For factor Xa inhibitors such as rivaroxaban and apixaban, commercially available chromogenic anti-factor Xa assays can be used to measure their serum levels based on their respective calibration curves, thus making them sensitive and specific [31-33].

Management of bleeding complications or overdoses in patients on NOAs

Patients bleeding due to NOA use need to undergo rapid clinical assessment in order to confirm hemodynamic stability, identify the bleeding source and evaluate the severity of blood loss (Figure 1) [34]. If hemodynamically unstable, patients should receive life supporting therapies in an intensive care setting such as volume replacement, vasopressors or mechanical ventilation [35]. Packed red blood cells (PRBCs) and platelets can be transfused in response to severe anemia and impaired platelet function secondary to anti-platelet therapies respectively. Hemostasis of the bleeding source for minor bleeding e.g. epistaxis, can be obtained by addressing the potential anatomical defects e.g. cauterization or nasal packing [36]. However, more severe bleeding may necessitate referrals for procedural and surgical hemostasis [36]. Finally, further NOA exposure must be held based on the co-morbidities and assessment of risks of drug discontinuation. For moderate to severe bleeding, given the relatively short half-lives of the NOAs, most of the anticoagulant effect should dissipate within 48 hours [37]. Adjunctive medications such as antiplatelet drugs that may exacerbate the bleeding events should also be held.

Other supportive measures that can be employed to manage bleeding complications are described in Table 2 and include the following:

Activated charcoal: Though this method has not been evaluated prospectively in clinical trials, in vitro experiments have shown that activated charcoal can absorb 99.9% of dabigatran suspended in acidic water [38]. Thus, it can be used to decrease the absorption of recently ingested dabigatran within a couple hours of presentation [39] and may be especially useful in cases of intoxication. Though there is no data regarding the use of activated charcoal to reverse the anticoagulant effect of rivaroxaban, there is preliminary data with apixaban. A study evaluated 18 healthy subjects in a randomized, crossover study of single-dose apixaban (20 mg) administered alone and with activated charcoal given at 2 or 6 hours post-dose to healthy subjects [40]. The area under the concentration-time curve for apixaban without activated charcoal decreased by 50% and 28 %, respectively, when charcoal was administered at 2 and 6 hours post-dose. Furthermore, the mean half-life for apixaban alone which is about 10 to 14 hours decreased to around 5 hours when activated charcoal was administered at 2 or 6 hours post dose [40]. Thus, activated charcoal may be useful in cases of intoxication with apixaban and potentially with rivaroxaban.

Hemodialysis: Given that only 35% of dabigatran is bound to plasma proteins, hemodialysis should be considered, especially in patients with impaired renal function [41,42]. In an open-label, single-center phase I study, four hour hemodialysis sessions rapidly eliminated a substantial amount of dabigatran with a concomitant marked reduction in its anticoagulant activity [43]. These results suggest that hemodialysis is a suitable approach to eliminate dabigatran in emergency situations. However, this method is limited by the need for placing a central dialysis catheter in a patient who is fully or excessively anticoagulated placing the patient at risk for further bleeding. Although there are no data, dialysis is unlikely to be effective for rivaroxaban and apixaban as they are over 85-90% protein-bound.

Pro-haemostatic agents: Recombinant activated factor VIIa (rFVIIa) activates Factor X leading to thrombin generation and was developed for the treatment of bleeding episodes in hemophiliac patients with Factor VIII and IX inhibitors. It has been used off-label in clinical practice to help reverse life-threatening bleeds caused by NOAs. It decreases the bleeding time in animal models but does not reverse the anticoagulation effect on most other laboratory coagulation tests [44,45]. Other than anecdotal case reports [46,47], there are no randomized controlled studies confirming its benefit in these situations. Furthermore, one must keep in mind, potential serious side effects of rVIIa, including disseminated intravascular coagulation and systemic thrombosis.

Activated 4-factor prothrombin complex concentrate (aPCC) (Factor eight inhibitor bypass activity, FEIBA NF) is a coagulation concentrate that contains activated factor VII and inactive factors II, IX and X. It corrects the anticoagulant effect in animal models48 as well as plasma from healthy volunteers treated with NOAs [47,49]. Our recommendations for reversing the anticoagulant effects of dabigatran or other Factor Xa inhibitors with aPCC are, an initial dose of 50 units/kg of actual body weight with an additional 50 units/kg being administered every 6-12 hours (up to 200 units/kg/day) until the bleeding ceases. Patients should be monitored closely for disseminated intravascular coagulation

Coagulation factor replacements: There are no studies evaluating the use of fresh frozen plasma (FFP) in patients with bleeding complications secondary to NOAs. Given that FFP carries risks of volume overload, infusion reactions (including TRALI) and infections, its use is generally not recommended. On the other hand, prothrombin complex concentrates (PCC) seem to be attractive option. The 3-factor PCCs (Bebulin, Baxter and Profilnine SD, Grifols) have relatively similar concentrations of non-activated factors II, IX, and X, with low concentrations of non-activated factor VII. Similarly, 4-factor PCCs (Beriplex) contains large amounts of four non-active vitamin K dependent procoagulant factors (factors II, VII, IX and X) that stimulate thrombin formation.

In a randomized, double-blind, placebo-controlled study, 6 healthy volunteers received rivaroxaban 20 mg twice daily and another 6 volunteers received dabigatran 150 mg twice daily for two and a half days followed by either a single bolus of 50 IU/kg 4-factor PCC or a similar volume of saline [50]. After a washout period, this procedure was repeated with the other anticoagulant treatment. The thrombin formation and prothrombin time was inhibited by rivaroxaban but normalized with the administration of PCC whereas saline infusions had no effect [50]. On the contrary, even though dabigatran increased the activated partial thromboplastin time, ecarin clotting time (ECT), and thrombin time, the administration of PCC did not restore these coagulation tests to their normal values [50].

The use of either 3 or 4 factor PCC may increase the risk of thrombosis, with the 3-factor PCC being less likely to do so [51]. In spite of the pre-clinical and human volunteer data on the ability of PCCs to reverse the effects of Factor Xa inhibitors, there are no randomized controlled trials evaluating the various PCCs in human patients with clinically relevant bleeding. Furthermore, there are variations in the amount of factors II, VII, IX and X, and antithrombotic proteins (proteins C and S) contained in the different PCCs making it likely that the different PCCs are not all equivalent in their reversal effects. Nevertheless, it is reasonable to use either 3-factor or 4-factor PCCs in the setting of serious bleeding related to Factor Xa inhibitors. We recommend based on our practice that in order to reverse the anticoagulant effects of rivaroxaban or apixaban, 3-factor PCCs such as Bebulin can be used with an initial dose of 25 units/kg of actual body weight for moderate bleeding not requiring massive transfusion or 50 units/kg if the bleeding is severe enough requiring massive transfusion. This concentrate can be re-dosed every 12 hours for ongoing hemorrhage but patients should be monitored closely for disseminated intravascular coagulation and thrombosis.

Table 1: Comparative properties of the NOAs dabigatran, rivaroxaban, apixaban and edoxaban.

Characteristic Dabigatran Rivaroxaban Apixaban Edoxaban*
Target Factor IIa (Free and clot -bound thrombin) Factor Xa Factor Xa Factor Xa
Half-life (t ½) 14 –17 hours 5 –9 hours 
9-13 hours (elderly)
10 – 14 hours 9 – 11 hours
Elimination 80% renal 
20% fecal
66% renal 
33% fecal
27% renal
63% fecal
33% renal
66% fecal
Monitoring Not needed Not needed Not needed Not needed
Peak effect 2 hours 2 - 4 hours 3 – 4 hours 1 – 2 hours
Antidote None None None None

* Approved only in Japan

Table 2: Choice of interventions available for the reversal of anticoagulation based on the type of NOA causing the clinical bleeding.

Intervention used Type of New Oral Anticoagulant (NOA)
  Dabigatran Rivaroxaban Apixaban
Activated Charcoal If < 2 hours since last dose ingested If < 2 hours since last dose ingested If < 2 hours since last dose ingested
Desmopressin No clinical evidence No clinical evidence No clinical evidence
Hemodialysis Yes, is dialyzable Not dialyzable Not dialyzable
FFP If DIC or dilutional coagulopathy seen If DIC or dilutional coagulopathy seen If DIC or dilutional coagulopathy seen
PRBCs If symptomatic anemia or Hemoglobin < 8 g/dL If symptomatic anemia or Hemoglobin < 8 g/dL If symptomatic anemia or Hemoglobin < 8 g/dL
Platelets If on anti-platelet therapy or if platelet count < 20,000 If on anti-platelet therapy or if platelet count < 20,000 If on anti-platelet therapy or if platelet count < 20,000
Activated Factor VII (Novo Seven) Anecdotal cases; Not preferred Anecdotal cases; Not preferred Anecdotal cases; Not preferred
Non-activated PCCs 
(3 or 4 factor PCCs)
Not preferred 3-factor PCCs (Bebulin) preferred 3-factor PCCs (Bebulin) preferred
Activated PCCs Yes; FEIBA preferred Not preferred Not preferred
Potential agents available in future • aDabi-Fab
• PER977
• PRT4445
• PER977
• PRT4445
• PER977

 

EXPERIMENTAL AGENTS IN THE FUTURE

Several novel antidotes to reverse NOAs are in development and early clinical trials. PRT4445 (Portola Pharmaceuticals) or “Andexanet alfa”, a novel recombinant protein, binds to Factor Xa inhibitors preventing them from inhibiting the activity of the native Factor Xa, but has no in vivo effects on coagulation parameters due to its unique structure [52]. This drug is currently in phase II evaluation as an antidote for the anticoagulant effect of factor Xa inhibitors. Preliminary data released by the company on their phase 2 studies including more than 80 volunteers using andexanet alfa with apixaban or rivaroxaban suggest a dosedependent and well-tolerated short-term or sustained reversal of their anticoagulation activity [53]. A thrombin double mutant, W215A/E217A, is being developed which shortens thrombin inhibitor-associated aPTT prolongation by thrombin generation in vitro [54]. Recently, a dabigatran-specific antidote known as “aDabi-Fab” has been created to mimic the thrombin structure but not function in vitro and binds with a greater affinity for dabigatran than for thrombin [55]. In a rat model, continuous dabigatran infusion prolonged the TT and aPTT over controls. However, the addition of a single bolus injection of “aDabi-Fab” completely reversed the prolonged anticoagulant activity within one minute [55]. Finally, PER977 is a small molecule that is able to bind to various NOAs and reduces clinical bleeding in a rat tail injury model [56]. Development of such antidotes, if shown to be safe and effective in early phase studies, will be evaluated in later-phase clinical trials thus providing additional options for emergency reversal of NOAs.

CONCLUSION

The new oral direct thrombin inhibitor, dabigatran, and the factor Xa inhibitors, rivaroxaban and apixaban have shown favorable safety and efficacy profiles compared to warfarin for the prevention and treatment of VTE. However, like all anticoagulants, there remains an increased risk of bleeding complications. Instilling routine practices to decrease the chance of bleeding complications remains the most effective way of curbing this issue. Some such measures include prescribing the NOAs at their recommended dosages while limiting the duration of treatment to the shortest time for which anticoagulation is needed. Also, frequent monitoring of the renal function and various drug interactions in patients while on NOAs could help determine the need for dose adjustments thus limiting the risk of over anticoagulation. In the future, the emergence of newer laboratory assays as well as the development of specific reversal agents will play a major role in improving our clinical ability to manage bleeding complications due to NOAs.

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Received : 14 Jan 2014
Accepted : 28 Feb 2014
Published : 03 Mar 2014
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JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
TEST Journal of Dentistry
ISSN : 1234-5678
Launched : 2014
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
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