Chromogenic anti-Xa test: the ratio between heparin activity units and concentration of apixaban and rivaroxaban

Introduction. The direct oral anticoagulants (DOC) therapy does not require alaboratory control; however, it may be required to determine the anticoagulationlevel to choose a treatment strategy if alarge bleeding is developing or emergency surgery is needed.The objective of this experimental study was to investigate the relationship between the residual factor Xa (FXa) activity, anti-Xa activity units oflow molecular weight heparins (LMWH), and the apixaban and rivaroxaban plasma concentrations in a chromogenic anti-Xa assay.Material and methods. Concentrated DOC solutions were prepared by extracting apixaban and rivaroxaban from crushed tablets using methanol and dimethyl sulfoxide, respectively. The resulting solutions were added to the donor plasma pool until final inhibitor concentrations are achieved in the range from 10 to 100 ng/ml plasma. Anti-Xa activity was determined using an STA-compact analyser and the Liquid anti-Xa reagent kit, an analysis protocol, and calibrators designed to control the LMWH therapy. The effect on the thrombin formation dynamics was investigated using the thrombin generation test (TGT) and the PPR reagent as a trigger (final concentrations of tissue factor are 5 pM, and those of phospholipids are 4 μM). TGT curves were analysed using the Thrombinoscope program.Results. It was shown that in the anti-Xa activity test version designed to control the LMWH therapy, there is a high correlation (R2 > 0.98) between thelogarithm of the residual factor Xa activity and the content of apixaban and rivaroxaban in the range from 10 to 80 ng/ml. Rivaroxaban shows about 1.5 times more anti-Xa activity than apixaban at equal concentrations. It was also shown that apixaban and rivaroxaban at doses equal both in concentration and in anti-Xa activity differ in their effect on the thrombin formation dynamics and thrombin inactivation in the TGT.Conclusion. In the LMWH anti-Xa activity test version, the measured range of apixaban and rivaroxaban includes 30 ng/ml and 50 ng/ ml concentrations taken as “cut-off points” to determine the treatment tactics in emergency cases. However, thelack of certified DOC calibratorslimits the use of this test in clinical practice.

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Viscoelastometry for detecting oral anticoagulants

Thrombosis Journal ◽

10.1186/s12959-021-00267-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Philipp Groene ◽

Daniela Wagner ◽

Tobias Kammerer ◽

Lars Kellert ◽

Andreas Giebl ◽

...

Keyword(s):

Healthy Volunteers ◽

Prospective Observational Study ◽

Oral Anticoagulants ◽

Plasma Concentrations ◽

Factor Xa ◽

Clotting Time ◽

Emergency Situations ◽

Tissue Plasminogen ◽

The Impact

Abstract Background Determination of anticoagulant therapy is of pronounced interest in emergency situations. However, routine tests do not provide sufficient insight. This study was performed to investigate the impact of anticoagulants on the results of viscoelastometric assays using the ClotPro device. Methods This prospective, observational study was conducted in patients receiving dabigatran, factor Xa (FXa)-inhibitors, phenprocoumon, low molecular weight heparin (LMWH) or unfractionated heparin (UFH) (local ethics committee approval number: 17–525-4). Healthy volunteers served as controls. Viscoelastometric assays were performed, including the extrinsic test (EX-test), intrinsic test (IN-test) Russel’s viper venom test (RVV-test), ecarin test (ECA-test), and the tissue plasminogen activator test (TPA-test). Results 70 patients and 10 healthy volunteers were recruited. Clotting time in the EX-test (CTEX-test) was significantly prolonged versus controls by dabigatran, FXa inhibitors and phenprocoumon. CTIN-test was prolonged by dabigatran, FXa inhibitors and UFH. Dabigatran, FXa inhibitors and UFH significantly prolonged CTRVV-test in comparison with controls (median 200, 207 and 289 vs 63 s, respectively; all p < 0.0005). Only dabigatran elicited a significant increase in CTECA-test compared to controls (median 307 vs 73 s; p < 0.0001). CTECA-test correlated strongly with dabigatran plasma concentration (measured by anti-IIa activity; r = 0.9970; p < 0.0001) and provided 100% sensitivity and 100% specificity for detecting dabigatran. Plasma concentrations (anti-XA activity) of FXa inhibitors correlated with CTRVV-test (r = 0.7998; p < 0.0001), and CTRVV-test provided 83% sensitivity and 64% specificity for detecting FXa inhibitors. Conclusions In emergency situations, ClotPro viscoelastometric assessment of whole-blood samples may help towards determining the presence and type of anticoagulant class that a patient is taking. Trial registration German clinical trials database ID: DRKS00015302.

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Heparin is more effective than apixaban in inhibiting in vitro contact activated coagulation

European Heart Journal ◽

10.1093/ehjci/ehaa946.3776 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M.M Engelen ◽

C Van Laer ◽

M Jacquemin ◽

C Vandenbriele ◽

K Peerlinck ◽

...

Keyword(s):

Thrombin Generation ◽

Heart Valves ◽

Thrombus Formation ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Factor ◽

Mechanical Heart Valves ◽

Contact Activation

Abstract Introduction Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors. Purpose To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation. Methods Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed. Results With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH. Conclusion UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway. Thrombin generation curves Funding Acknowledgement Type of funding source: None

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Influence of Direct Oral Anticoagulants on Anti–Factor Xa Measurements Utilized for Monitoring Heparin

Annals of Pharmacotherapy ◽

10.1177/1060028017729481 ◽

2017 ◽

Vol 52 (2) ◽

pp. 154-159 ◽

Cited By ~ 8

Author(s):

Kelly A. Macedo ◽

Peter Tatarian ◽

Kenneth R. Eugenio

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa

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Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

Critical Care Research and Practice ◽

10.1155/2018/4907164 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Alok Dabi ◽

Aristides P. Koutrouvelis

Keyword(s):

Side Effects ◽

Intracranial Hemorrhage ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Cascade ◽

Reversal Agents ◽

United States Food ◽

Life Threatening

Direct oral anticoagulants (DOACs) are a new class of anticoagulants that directly inhibit either thrombin or factor Xa in the coagulation cascade. They are being increasingly used instead of warfarin or other vitamin K antagonists (VKAs). Adverse side effects of DOACs may result in hemorrhagic complications, including life-threatening intracranial hemorrhage (ICH), though to a much lesser degree than VKAs. Currently there are relatively limited indications for DOACS but their usage is certain to expand with the availability of their respective specific reversal agents. Currently, only idarucizumab (antidote for dabigatran) has been United States Food and Drug Administration- (FDA-) approved, but others (andexanet-α and ciraparantag) may be approved in near future, and the development and availability of such reversal agents have the potential to dramatically change the current anticoagulant use by providing reversal of multiple oral anticoagulants. Until all the DOACs have FDA-approved reversal agents, the treatment of the dreaded side effects of bleeding is challenging. This article is an attempt to provide an overview of the management of hemorrhage, especially ICH, related to DOAC use.

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Evaluation of the Use of Low-Dose 4-Factor Prothrombin Complex Concentrate in the Reversal of Direct Oral Anticoagulants in Bleeding Patients

Journal of Intensive Care Medicine ◽

10.1177/0885066618800657 ◽

2018 ◽

Vol 35 (9) ◽

pp. 903-908 ◽

Cited By ~ 11

Author(s):

Teresa A. Allison ◽

Pei Jen Lin ◽

Jennifer A. Gass ◽

Kenneth Chong ◽

Samuel J. Prater ◽

...

Keyword(s):

Computed Tomography ◽

Prothrombin Complex Concentrate ◽

Low Dose ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Final Analysis ◽

Factor Xa Inhibitor ◽

Direct Factor

Objective: This study investigated the percentage of patients who achieved hemostasis with 4-factor prothrombin complex concentrate (4-factor PCC) 35 U/kg. The primary end point was to determine the effect of 4-factor PCC 35 U/kg on bleeding progression, assessed using computed tomography. Methods: This was a retrospective, observational, single-center study conducted in patients with a major bleed admitted to a level 1 trauma center from May 1, 2013, to June 15, 2015, who received 4-factor PCC 35 U/kg for reversal of a direct factor Xa inhibitor taken prior to admission. Results: Thirty-three patients were included in the study, with 31 patients in the final analysis. The mean (standard deviation) age was 73 (14.8) years; 54.5% of patients were female. Of the 33 patients, 13 presented with a traumatic brain injury, 9 with an aneurysmal subarachnoid hemorrhage, 8 with an intracerebral hemorrhage, 1 with a gastrointestinal bleed, 1 with a hematoma with active extravasation, and 1 with an intra-abdominal bleed. The most frequently used direct factor Xa inhibitor was rivaroxaban (81.8%). Overall, 83.8% of patients achieved hemostasis with 4-factor PCC 35 U/kg. Progression of hemorrhage was observed in 4 patients on repeat computed tomography scan and 1 patient had continued surgical bleeding. No thromboembolic events were reported. Conclusions: Low-dose, 4-factor PCC 35 U/kg appeared to produce hemostasis in a majority of the patients. This may be an effective dosing regimen for anticoagulant reversal of factor Xa inhibitors in clinically bleeding patients.

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The Severity of Intracranial Hemorrhages Measured by Free Hemoglobin in the Brain Depends on the Anticoagulant Class: Experimental Data

Stroke Research and Treatment ◽

10.1155/2017/6516401 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Kyle M. Ware ◽

Douglas L. Feinstein ◽

Israel Rubinstein ◽

Prudhvi Battula ◽

Jose Otero ◽

...

Keyword(s):

Vitamin K ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Hemoglobin Concentration ◽

Thrombin Inhibitor ◽

Free Hemoglobin ◽

Intracranial Hemorrhages ◽

The Brain

Background and Purpose. Anticoagulant therapy is broadly used to prevent thromboembolic events. Intracranial hemorrhages are serious complications of anticoagulation, especially with warfarin. Direct oral anticoagulants reduce but do not eliminate the risk of intracranial hemorrhages. The aim of this study is to determine the degree of intracranial hemorrhage after application of anticoagulants without additional triggers. Methods. Rats were treated with different anticoagulant classes (vitamin K antagonists, heparin, direct thrombin inhibitor, and factor Xa inhibitor). Brain hemorrhages were assessed by the free hemoglobin concentration in the brain parenchyma. Results. Vitamin K antagonists (warfarin and brodifacoum) significantly increased free hemoglobin in the brain. Among direct oral anticoagulants, thrombin inhibitor dabigatran also significantly increased free hemoglobin in the brain, whereas treatment with factor Xa inhibitor rivaroxaban did not have significant effect on the free hemoglobin concentration. Conclusions. Our data indicates that the severity of brain hemorrhages depends on the anticoagulant class and it is more pronounced with vitamin K antagonists.

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Bleeding Risk in Non-Valvular Atrial Fibrillation Patients Receiving Direct Oral Anticoagulants and Warfarin: A Systematic Review and Meta-Analysis of Observational Studies

Blood ◽

10.1182/blood-2019-123870 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3672-3672 ◽

Cited By ~ 1

Author(s):

Yimin Pearl Wang ◽

Rohan Kehar ◽

Alla Iansavitchene ◽

Alejandro Lazo-Langner

Keyword(s):

Major Bleeding ◽

Lower Risk ◽

Observational Studies ◽

Meta Analysis ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Bleeding Risk ◽

Risk Of Bleeding ◽

Significant Difference

Introduction: The standard oral anticoagulant therapy administered to non-valvular AF patients has typically been Vitamin K Antagonists (VKA) particularly warfarin. In recent years, Direct Oral Anticoagulants (DOACs) including Direct Thrombin Inhibitors (DTI) and Direct Factor Xa inhibitors (FXa inhibitors) have become an alternative to warfarin. Randomized trials comparing warfarin and DOACs showed comparable effectiveness without significant additional major bleeding risk. However, bleeding events in RCTs may differ from those in daily use due to the routine exclusion of patients with a higher risk of bleeding from many studies. We aimed to assess bleeding risk between DOACs and warfarin in AF patients in observational studies and we also sought to determine differences between patients that were experienced or naïve to oral anticoagulants. Methods: A systematic literature search was conducted in the OVID MEDLINE® and EMBASE® electronic databases. Observational studies and randomized control trials (RCT) from 1990 to January 2019 were retrieved and examined by two independent reviewers. A pooled effect hazard ratio (HR) was calculated using a random effects model using the generic inverse variance method. Subgroup analyses according to previous exposure to anticoagulants, study type, funding type and DOAC type were conducted. The primary outcome was major bleeding risk. The secondary outcome was clinically relevant non-major bleeding. All studies must have used an established or validated definition of major bleeding. Results: The initial literature search identified 3359 potentially eligible citations. After primary screening, 150 articles were eligible for full text review and there were 35 studies including 2,356,201 patients that met the inclusion criteria. Overall, patients on DOACs were less likely to experience a bleeding event compared to warfarin (HR 0.78, 95%CI 0.71, 0.85, P<0.001). The results were consistent when analyzing patients receiving DTIs or FXa inhibitors (DTI: HR 0.76, 95% CI 0.67,0.87; FXa inhibitors: HR 0.79, 95% CI 0.69,0.89). However, among patients receiving factor Xa inhibitors, there was a significant difference in the risk of bleeding according to individual drug. Among patients receiving rivaroxaban the risk of bleeding was similar to warfarin (HR 0.98, 95%CI 0.91,1.06, p=0.60) whereas in those receiving apixaban there was a 40% reduction in the risk of bleeding compared to warfarin (HR 0.60, 95%CI 0.50,0.71, p<0.001) (Figure 1). Three studies reported information according to previous anticoagulant exposure. The overall pooled hazard ratio was 0.68 (95% CI 0.55, 0.82 p<0.001) in favor of patients on DOACs. In the subgroup analysis of previous anticoagulant use, the risk of bleeding was lower for DOACs compared to warfarin in both the experienced population (HR 0.70, 95%CI 0.51, 0.96) and the naïve population (HR 0.64, 95% CI 0.47,0.87). However, heterogeneity was moderate to high among both subgroups. Conclusion: This review and meta-analysis of observational studies including over 2.3 million patients showed that overall DOACs have a lower risk of major bleeding and clinically relevant non-major bleeding compared to warfarin. Most importantly, although the pooled effect estimate did not differ between DTIs and FXa inhibitors, among patients receiving FXa inhibitors there was a significant difference between individual agents. Patients on apixaban had a significantly lower risk of bleeding compared to warfarin in contrast to patients on rivaroxaban who had a similar risk. Disclosures No relevant conflicts of interest to declare.

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ORAL ANTICOAGULANTS IN THE TREATMENT OF VENOUS THROMBOEMBOLIC COMPLICATIONS: FOCUS ON APIXABAN

Medical Council ◽

10.21518/2079-701x-2017-7-56-62 ◽

2017 ◽

pp. 56-62 ◽

Cited By ~ 1

Author(s):

M. Yu. Gilyarov ◽

E. V. Konstantinova

Keyword(s):

Vitamin K ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Vitamin K Antagonist ◽

Fixed Dose ◽

Vein Thrombosis ◽

Venous Thromboembolic ◽

Deep Vein

Venous thromboembolism (VTE), comprising deep vein thrombosis and pulmonary embolism, is a common condition associated with a significant clinical and economic burden. Anticoagulant therapy is the mainstay of treatment for VTE. Current guidelines recommend the use of either low molecular weight heparins or fondaparinux overlapping with and followed by a vitamin K antagonist for the initial treatment of VTE, with the vitamin K antagonist continued when long-term anticoagulation is required. These traditional anticoagulants have practical limitations that have led to the development of direct oral anticoagulants that directly target either Factor Xa or thrombin and are administered at a fixed dose without the need for routine coagulation monitoring. The paper reviews results of the trials of apixaban application for treatment and/or long-term secondary prevention of VTE. The paper analyses effectiveness and safety of apixaban in different groups of patients, as well as features of apixaban application in every day practice.

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Update on Edoxaban for the Prevention and Treatment of Thromboembolism: Clinical Applications Based on Current Evidence

Advances in Hematology ◽

10.1155/2015/920361 ◽

2015 ◽

Vol 2015 ◽

pp. 1-19 ◽

Cited By ~ 5

Author(s):

Ali Zalpour ◽

Thein Hlaing Oo

Keyword(s):

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Factors ◽

Current Evidence ◽

Thrombin Inhibitor ◽

Prevention And Treatment ◽

Financial Impacts

Vitamin K antagonists (VKA) and heparins have been utilized for the prevention and treatment of thromboembolism (arterial and venous) for decades. Targeting and inhibiting specific coagulation factors have led to new discoveries in the pharmacotherapy of thromboembolism management. These targeted anticoagulants are known as direct oral anticoagulants (DOACs). Two pharmacologically distinct classes of targeted agents are dabigatran etexilate (Direct Thrombin Inhibitor (DTI)) and rivaroxaban, apixaban, and edoxaban (direct oral factor Xa inhibitors (OFXaIs)). Emerging evidence from the clinical trials has shown that DOACs are noninferior to VKA or low-molecular-weight heparins in the prevention and treatment of thromboembolism. This review examines the role of edoxaban, a recently approved OFXaI, in the prevention and treatment of thromboembolism based on the available published literature. The management of edoxaban in the perioperative setting, reversibility in bleeding cases, its role in cancer patients, the relevance of drug-drug interactions, patient satisfaction, financial impacts, and patient education will be discussed.

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Assessing Coagulation by Rotational Thromboelastometry (ROTEM) in Rivaroxaban-Anticoagulated Blood Using Hemostatic Agents

Prehospital and Disaster Medicine ◽

10.1017/s1049023x17006641 ◽

2017 ◽

Vol 32 (5) ◽

pp. 580-587 ◽

Cited By ~ 2

Author(s):

Jonathan Bar ◽

Alexa David ◽

Tarek Khader ◽

Mary Mulcare ◽

Christopher Tedeschi

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Hemostatic Agent ◽

Publication Type ◽

Rotational Thromboelastometry ◽

Coagulation Parameters ◽

Hemostatic Agents ◽

Clotting Cascade ◽

Data Points

AbstractIntroductionThe use of direct oral anticoagulants (DOACs) such as rivaroxaban (Xarelto) is increasingly common. However, therapies for reversing anticoagulation in the event of hemorrhage are limited. This study investigates the ability of hemostatic agents to improve the coagulation of rivaroxaban-anticoagulated blood, as measured by rotational thromboelastometry (ROTEM).Hypothesis/ProblemIf a chitosan-based hemostatic agent (Celox), which works independently of the clotting cascade, is applied to rivaroxaban-anticoagulated blood, it should improve coagulation by decreasing clotting time (CT), decreasing clot formation time (CFT), and increasing maximum clot firmness (MCF). If a kaolin-based hemostatic agent (QuikClot Combat Gauze), which works primarily by augmenting the clotting cascade upstream of factor Xa (FXa), is applied to rivaroxaban-anticoagulated blood, it will not be effective at improving coagulation.MethodsPatients (age >18 years; non-pregnant) on rivaroxaban, presenting to the emergency department (ED) at two large, university-based medical centers, were recruited. Subjects (n=8) had blood drawn and analyzed using ROTEM with and without the presence of a kaolin-based and a chitosan-based hemostatic agent. The percentage of patients whose ROTEM parameters responded to the hemostatic agent and percent changes in coagulation parameters were calculated.ResultsData points analyzed included: CT, CFT, and MCF. Of the samples treated with a kaolin-based hemostatic agent, seven (87.5%) showed reductions in CT, eight (100.0%) showed reductions in CFT, and six (75.0%) showed increases in MCF. The average percent change in CT, CFT, and MCF for all patients was 32.5% (Standard Deviation [SD]: 286; Range:-75.3 to 740.7%); -66.0% (SD:14.4; Range: -91.4 to -44.1%); and 4.70% (SD: 6.10; Range: -4.8 to 15.1%), respectively. The corresponding median percent changes were -68.1%, -64.0%, and 5.2%. Of samples treated with a chitosan-based agent, six (75.0%) showed reductions in CT, three (37.5%) showed reductions in CFT, and five (62.5%) showed increases in MCF. The average percent changes for CT, CFT, and MCF for all patients were 165.0% (SD: 629; Range:-96.9 to 1718.5%); 139.0% (SD: 174; Range: -83.3 to 348.0%); and -8.38% (SD: 32.7; Range:-88.7 to 10.4%), respectively. The corresponding median percent changes were -53.7%, 141.8%, and 3.0%.ConclusionsRotational thromboelastometry detects changes in coagulation parameters caused by hemostatics applied to rivaroxaban-anticoagulated blood. These changes trended in the direction towards improved coagulability, suggesting that kaolin-based and chitosan-based hemostatics may be effective at improving coagulation in these patients.BarJ, DavidA, KhaderT, MulcareM, TedeschiC. Assessing coagulation by rotational thromboelastometry (ROTEM) in rivaroxaban-anticoagulated blood using hemostatic agents. Prehosp Disaster Med. 2017;32(5):580–587.

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