Factor XIII Deficiency in Patients with Acute Leukemia: One out of Three Is Presenting with Deficiency

Abstract Introduction: Factor XIII (FXIII) is a coagulation factor, playing an important role in the coagulation process by keeping the hemostatic clot and allowing tissue repair. The incidence of FXIII deficiency in acute leukemia is not well characterized. FXIII deficiency is known to have a high bleeding risk and cannot be detected by lab evaluation of aPTT and/or INR levels. In combination with thrombocytopenia in patients (pts) presenting with acute leukemia, FXIII deficiency increases bleeding risk (for example in invasive procedures or for intracranial hemorrhage). In 2013 a study was conducted in 9 pediatric pts (6 acute leukemias, 1 burkitt, and 2 solid tumors) in whom FXIII deficiency was found. These pts had bleeding complications that were resolved by FXIII concentrate substitution (Wiegering. V. et al. Haematologica, June, 10, 2013).Patients affected from AML and ALL could easily be screened at diagnosis regarding FXIII level. In the setting of newly diagnosed acute leukemia pts in whom thrombocytopenia is frequently occurring, a preemptive substitution of FXIII could be considered in order to reduce the risk of bleeding complications. Methods: In this retrospective analysis (Jan. 2009 to June 2014) we identified a total of 103 ptspresentingwithnewly diagnosed acute leukemia in whom we assessed FXIII level. In 95 pts FXIII level was available at initial diagnosis of acute leukemia and during treatment. Substitution of FXIII concentrate have been used in case of factor’s deficiency below 70% (normal range 70%-130%). Results: Patients presented withAML (64 primary AML and 20 secondary AML), or ALL (10), or 1 AUL. Median age was 67 years (range: 25-95). Thirty-four pts (35.8%) were younger than 60 years, 61 pts (64.2 %) were older than 60 years. FXIII deficiency was found in 35/95 pts (36.8%) with a median level of 49% (range: 21%-68%). Of those 35 pts with FXIII deficiency 33 had AML (1 AML M0, 9 AML M1, 2 AML M1/2, 5 AML M2, 6 AML M4, 5 AML M5). All pts (5/95) with AML M3 showed a deficiency with a median level of 28%. A level below 70% could be found in 7 out of 13 FLT3-ITD positive pts (53.8%) and in 7 out of 24 NPM1 positive pts (29.2 %). Median FXIII level was 34% for FLT3-ITD positive pts, respectively 30% for NPM1. FXIII substitution in deficient pts was well tolerated and effective. No patient showed intracranial hemorrhage. In addition, invasive procedures like bone marrow biopsy and central line insertion were possible without clinically relevant bleeding complications. In responding pts achieving remission following chemotherapy, a trend towards higher concentration of factor XIII during treatment was observed. Conclusions: Patients affected by AML or ALL are presenting usually with thrombocytopenia and have a high bleeding risk. In case of FXIII deficiency, risk of bleeding is increased potentially leading to a higher leukemia-related morbidity and mortality. Detection of FXIII deficiency is an established method and routinely available. Substitution of FXIII decreases the risk of bleeding and can reduce leukemia associated morbidity and mortality. In our study FXIII deficiency occurred in more than a third of our pts, including all AML M3 patients. We found a trend for more FXIII deficiency in FLT3-ITD high risk group patients. We suggest screening at diagnosis and during treatment of all acute leukemia pts and FXIII substitution in case of deficiency. To evaluate further the role of FXIII assessment and substitution in case of FXIII deficiency in acute leukemia, a prospective trial should be considered. Disclosures No relevant conflicts of interest to declare.

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Periprocedural Interruption of Anticoagulation in Patients with Cancer-Associated VTE: An Analysis of Thrombotic and Bleeding Outcomes

Blood ◽

10.1182/blood-2018-99-117715 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1235-1235

Author(s):

Joseph R. Shaw ◽

James Douketis ◽

Gregoire Le Gal ◽

Marc Carrier

Keyword(s):

Major Bleeding ◽

Patient Population ◽

Research Funding ◽

Bleeding Risk ◽

Advisory Board ◽

Bleeding Complications ◽

Invasive Procedures ◽

Patients With Cancer ◽

High Bleeding Risk ◽

Active Cancer

Abstract Background: Approximately 10-20% of patients with venous thromboembolic events (VTE) have underlying malignancy. VTE is considered the second leading cause of death in patients with cancer, and patients with cancer-associated VTE are at higher risk of anticoagulant-related bleeding. Although patients with cancer often undergo diagnostic or therapeutic invasive procedures, there is a paucity of data on adverse outcomes following the periprocedural interruption of anticoagulation in this patient population. Methods: We did a single-center, retrospective chart review of consecutive patients with cancer-associated VTE who had periprocedural interruption of anticoagulation for invasive procedures between November 2015 and March 2018. Perioperative interruption of warfarin/low-molecular-weight heparin was done as per CHEST guidelines (Douketis et al. Chest 141(2 Suppl). Heparin bridging anticoagulation was used only for patients with recent (< 3 months) VTE. Perioperative interruption of direct oral anticoagulants (DOACs) was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Active cancer was defined as per the HOKUSAI VTE CANCER trial (Raskob et al. NEJM 378(7)). Primary outcomes were 30-day post-operative rates of VTE and major bleeding. Secondary outcomes were 30-day post-operative rates of clinically relevant non-major bleeding (CRNMB) and mortality. Major bleeding and CRNMB were defined according to ISTH definitions. Data are reported on a per-interruption basis. Herein, we present an interim analysis of results. Results: To date, 82 perioperative interruptions are included, of whom 69.5% were receiving a DOAC. Mean age of the cohort was 65.8 years, 62.2% were male, 92.6% had active cancer and 41.5% had metastatic cancer. Thrombocytopenia (platelet count < 100 x 106/L) was present in 12.2% of interruptions. Procedures were stratified as high bleeding risk in 65.9% of cases. The 30-day rates of thromboembolism and major bleeding were both 3.70 % (95% confidence interval [CI] 1.25 to 10.2%), as was the 30-day rate of CRNMB. There were no deaths during the 30-day follow-up period. Conclusions: The periprocedural interruption of anticoagulation in patients with cancer-associated VTE appears to be associated with high rates of post-operative thrombotic and bleeding complications. Prospective studies are required to better quantify the risks of periprocedural anticoagulation interruption in this patient population. Disclosures Shaw: Portola Pharmaceuticals: Research Funding. Douketis:BMS: Other: Advisory Board; Janssen: Consultancy; Bayer: Other: Advisory Board; Pfizer: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Portola: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Biotie: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board. Carrier:Pfizer: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

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Antiplatelet therapy after PCI in patients with high risk of bleeding

Pharmacia ◽

10.3897/pharmacia.67.e52737 ◽

2020 ◽

Vol 67 (3) ◽

pp. 135-143

Author(s):

Ivayla Zheleva-Kyuchukova ◽

Valeri Gelev

Keyword(s):

Bleeding Risk ◽

Bleeding Complications ◽

Percutaneous Coronary Interventions ◽

Everyday Clinical Practice ◽

Risk Of Bleeding ◽

Coronary Interventions ◽

Complex Patient ◽

Percutaneous Coronary ◽

Drug Eluting ◽

High Bleeding Risk

The progress of percutaneous coronary interventions (PCI) over the last few decades facilitated treatment of increasingly complex patient populations. The introduction of drug-eluting stents (DESs) led to need of stronger and prolonged inhibition of platelets which in turn increased the incidence of bleeding complications. The identification and management of patients at high bleeding risk (HBR) during and after percutaneous coronary interventions (PCI) is still problematic in everyday clinical practice.

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Antithrombotic therapy according to baseline bleeding risk in patients with atrial fibrillation undergoing percutaneous coronary intervention: applying the PRECISE-DAPT score in RE-DUAL PCI

European Heart Journal - Cardiovascular Pharmacotherapy ◽

10.1093/ehjcvp/pvaa135 ◽

2020 ◽

Author(s):

Francesco Costa ◽

Marco Valgimigli ◽

Philippe Gabriel Steg ◽

Deepak L Bhatt ◽

Stefan H Hohnloser ◽

...

Keyword(s):

Atrial Fibrillation ◽

Antithrombotic Therapy ◽

Bleeding Risk ◽

Coronary Intervention ◽

Bleeding Complications ◽

Event Analysis ◽

Increased Risk ◽

Safety Endpoint ◽

High Bleeding Risk ◽

The Impact

Abstract Aims Patients with atrial fibrillation undergoing coronary intervention are at higher bleeding risk due to the concomitant need for oral anticoagulation and antiplatelet therapy. The RE-DUAL PCI trial demonstrated better safety with dual antithrombotic therapy (DAT: dabigatran 110 or 150 mg b.i.d., clopidogrel or ticagrelor) compared to triple antithrombotic therapy (TAT: warfarin, clopidogrel or ticagrelor, and aspirin). We explored the impact of baseline bleeding risk based on the PRECISE-DAPT score for decision-making regarding DAT vs. TAT. Methods and results A score ≥25 points qualified high bleeding risk (HBR). Comparisons were made for the primary safety endpoint International Society of Thrombosis and Haemostasis major or clinically relevant non-major bleeding, and the composite efficacy endpoint of death, thrombo-embolic events, or unplanned revascularization, analysed by time-to-event analysis. PRECISE-DAPT was available in 2336/2725 patients, and 37.9% were HBR. Compared to TAT, DAT with dabigatran 110 mg reduced bleeding risk both in non-HBR [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.31–0.57] and HBR (HR 0.70, 95% CI 0.52–0.94), with a greater magnitude of benefit among non-HBR (Pint = 0.02). Dual antithrombotic therapy with dabigatran 150 mg vs. TAT reduced bleeding in non-HBR (HR 0.60, 95% CI 0.45–0.80), with a trend toward less benefit in HBR patients (HR 0.92, 95% CI 0.63–1.34; Pint = 0.08). The risk of ischaemic events was similar on DAT with dabigatran (both 110 and 150 mg) vs. TAT in non-HBR and HBR patients (Pint = 0.45 and Pint = 0.56, respectively). Conclusions PRECISE-DAPT score appeared useful to identify AF patients undergoing PCI at further increased risk of bleeding complications and may help clinicians identifying the antithrombotic regimen intensity with the best benefit–risk ratio in an individual patient.

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Thrombopoietin Receptor Agonists in Patients with Chronic Liver Disease

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0040-1715451 ◽

2020 ◽

Vol 46 (06) ◽

pp. 682-692

Author(s):

Saro Khemichian ◽

Norah A. Terrault

Keyword(s):

Liver Disease ◽

Chronic Liver Disease ◽

Invasive Procedure ◽

Bleeding Risk ◽

Chronic Liver ◽

Bleeding Complications ◽

Invasive Procedures ◽

Platelet Counts ◽

Receptor Agonists ◽

Platelet Transfusions

AbstractThrombocytopenia is one of the most common hematologic complications in cirrhosis. Despite limited data linking platelet count and bleeding risk in patients with cirrhosis, the use of platelets transfusions for invasive procedures has been a common practice. Recently, thrombopoietin (TPO) receptor agonists have been approved for use in patients with chronic liver disease (CLD) undergoing invasive procedures. The aim of this study was to review current literature on bleeding risk in patients with cirrhosis and the use of platelet transfusions and TPO receptor agonists in the context of invasive procedures. PubMed search was conducted to find articles relating to cirrhosis, thrombocytopenia, and new novel treatments for this condition. Search terms included CLD, cirrhosis, thrombocytopenia, bleeding, thrombosis, coagulopathy, hemostasis, and TPO receptor agonists. Romiplostim, eltrombopag, avatrombopag, and lusutrombopag are approved TPO receptor agonists, with avatrombopag and lusutrombopag specifically approved for use in patients with CLD undergoing invasive procedures. In patients with platelet counts < 50,000/mm3, avatrombopag and lusutrombopag increased the platelet counts above this threshold in the majority of treated patients and reduced the frequency of platelet transfusions. At the approved doses, incidence of thrombosis was not increased and therapies were well tolerated. Studies were not powered to assess whether risk of bleeding complications was reduced and the fundamental question of whether correction of thrombocytopenia is warranted in patients undergoing invasive procedures remains unanswered. The use of TPO receptor agonists has resulted in less requirement for platelet transfusions. In patients with cirrhosis undergoing invasive procedures for whom platelet transfusion is planned, TPO receptor agonists are an alternative and avoid the risks associated with transfusions. However, there is need for a thoughtful approach to manage bleeding risk in patients with cirrhosis undergoing procedures, with the consideration of a comprehensive hemostatic profile, the severity of portal hypertension, and the complexity of the invasive procedure to guide decisions regarding transfusions or use of TPO receptor agonists.

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Current Concepts on Antiplatelet Therapy: Focus on the Novel Thienopyridine and Non-Thienopyridine Agents

Advances in Hematology ◽

10.1155/2010/595934 ◽

2010 ◽

Vol 2010 ◽

pp. 1-7 ◽

Cited By ~ 7

Author(s):

L. Testa ◽

G. G. L. Biondi Zoccai ◽

M. Valgimigli ◽

R. A. Latini ◽

S. Pizzocri ◽

...

Keyword(s):

Myocardial Infarction ◽

Clinical Practice ◽

Drug Targeting ◽

Bleeding Risk ◽

Daily Practice ◽

Adenosine Diphosphate ◽

Bleeding Complications ◽

The Novel ◽

Platelet Activity ◽

Risk Of Bleeding

Thienopyridines are a class of drug targeting the platelet adenosine diphosphate (ADP) 2 receptor. They significantly reduce platelet activity and are therefore clinically beneficial in settings where platelet activation is a key pathophysiological feature, particularly myocardial infarction. Ticlopidine, the first of the class introduced to clinical practice, was soon challenged and almost completely replaced by clopidogrel for its better tolerability. More recently, prasugrel and ticagrelor have been shown to provide a more powerful antiplatelet action compared to clopidogrel but at a cost of higher risk of bleeding complications. Cangrelor, a molecule very similar to ticagrelor, is currently being evaluated against clopidogrel. Considering the key balance of ischemic protection and bleeding risk, this paper discusses the background to the development of prasugrel, ticagrelor, and cangrelor and aims to characterise their risk-benefit profile and possible implementation in daily practice.

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Modified regional citrate anticoagulation is optimal for hemodialysis in patients at high risk of bleeding: a prospective randomized study of three anticoagulation strategies

BMC Nephrology ◽

10.1186/s12882-019-1661-y ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Ting Lin ◽

Li Song ◽

Renwei Huang ◽

Ying Huang ◽

Shuifu Tang ◽

...

Keyword(s):

High Risk ◽

Randomized Study ◽

Bleeding Risk ◽

Saline Group ◽

Regional Citrate Anticoagulation ◽

Expansion Chamber ◽

Citrate Anticoagulation ◽

Risk Of Bleeding ◽

Group 4 ◽

High Bleeding Risk

Abstract Background Recommended regular saline flushing presents clinical ineffectiveness for hemodialysis (HD) patients at high risk of bleeding with heparin contraindication. Regional citrate anticoagulation (RCA) has previously been used with a Ca2+ containing dialysate with prefiltered citrate in one arm (RCA-one). However, anticoagulation is not always achievable and up to 40% results in serious clotting in the venous expansion chamber. In this study, we have transferred one-quarter of the TSC from the prefiltered to the post filter based on RCA-one, which we have called RCA-two. The objective of this study was to compare the efficacy and safety of RCA-two with either saline flushing or RCA-one in HD patients with a high bleeding risk. Method In this investigator-initiated, multicenter, controlled, prospective, randomized clinical trial, 52 HD patients (77 sessions) were randomized to the RCA-2 and RCA-one group in part one of the trial, and 45 patients (64 sessions) were randomized to the RCA-2 and saline group in part two of the trial. Serious clotting events, adverse events and blood analyses were recorded. Results Serious clotting events in the RCA-two group were significantly lower compared with the RCA-one and saline group (7.89% vs. 30.77%, P = 0.011; 3.03% vs. 54.84%, P < 0.001, respectively). The median circuit survival time was 240 min (IQR 240 to 240) in the RCA-two group, was significantly longer than 230 min (IQR 155 to 240, P < 0.001) in the RCA-one group and 210 min (IQR 135 to 240, P = 0.003) in the saline group. The majority of the AEs were hypotension, hypoglycemia and chest tightness, most of which were mild in intensity. Eight patients (20.51%) in the RCA-one group, 4 patients (12.90%) in the saline group and 10 patients (26.31%) in the RCA-two group, P > 0.05. Conclusions Our data demonstrated that the modified anticoagulation protocol was more effective and feasible during hemodialysis therapy for patients at high risk of bleeding. Trial registration GDREC, GDREC2017250H. Registered February 2, 2018; retrospectively registered.

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Bleeding Complications with Drotrecogin Alfa Activated (Xigris®): A Retrospective Review of 31 Operative and 68 Non-Operative Patients with Severe Sepsis

The American Surgeon ◽

10.1177/000313480807401003 ◽

2008 ◽

Vol 74 (10) ◽

pp. 898-901

Author(s):

Benedict J.W. Taylor ◽

Sarah J. Lee ◽

Kenneth Waxman

Keyword(s):

Severe Sepsis ◽

Intracranial Hemorrhage ◽

Drotrecogin Alfa ◽

Surgical Patients ◽

Bleeding Complications ◽

Serious Adverse Event ◽

Risk Of Bleeding ◽

Drotrecogin Alfa Activated ◽

Significant Difference ◽

Nonsurgical Patients

We reviewed 100 consecutive patients who received Drotrecogin alfa (activated) (DAA) (Xigris®, Eli Lilly, Indianapolis, IN) for the treatment of severe sepsis and compared the incidence of bleeding complications in surgical (n = 30) and nonsurgical cohorts (n = 70). Thirty patients who received DAA therapy for severe sepsis underwent one or more contemporaneous surgical procedures. These were compared with 70 DAA patients who did not undergo surgery. During the course of DAA administration, transfusion of greater than three units of blood, an intracranial hemorrhage, or other bleeding serious adverse event were qualified as bleeding complications. Overall, we identified seven patients who fulfilled the designated bleeding complication criteria, four in the surgical cohort, and three in the nonsurgical cohort. There was no significant difference in the rate of bleeding complications between surgical and nonsurgical cohorts (P = 0.1063). Moreover, there were no mortalities ascribed to bleeding and there were no intracranial hemorrhage events. All bleeding complications were due to a drop in hemoglobin or platelets only, and were treated with transfusion. Our experience demonstrates that there is an equivalent risk of bleeding for surgical patients treated with DAA compared with nonsurgical patients. Additionally, all bleeding complications were amenable to simple transfusion.

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Long-term outcomes in high-bleeding risk patients undergoing PCI for acute coronary syndromes: results from a large single-center pci registry

European Heart Journal ◽

10.1093/ehjci/ehaa946.2563 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

J Nicolas ◽

D Cao ◽

B Claessen ◽

S Sartori ◽

R Chandiramani ◽

...

Keyword(s):

Major Bleeding ◽

Acute Coronary Syndromes ◽

Bleeding Risk ◽

Bleeding Complications ◽

Major Adverse Cardiovascular Events ◽

Bleeding Events ◽

Increased Risk ◽

Risk Patients ◽

Coronary Syndromes ◽

High Bleeding Risk

Abstract Introduction Current clinical guidelines recommend prolonged dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndromes (ACS). However, an extended DAPT duration in high-bleeding risk (HBR) patients amplifies the risk of post procedural complications. Hence, clinicians often face the dilemma of prolonging DAPT duration to prevent recurrent ischaemic events at the expense of increasing the incidence of bleeding in high-risk patients. The actual incidence of ischaemic and bleeding events in this particular population is not well elucidated. Purpose To evaluate one-year ischemic and bleeding outcomes following PCI for ACS in a real-world HBR population as defined by the Academic Research Consortium (ARC) consensus document. Methods We included all patients who presented with ACS to a high-volume single PCI centre from 2012 to 2017 and underwent PCI with 2nd generation drug-eluting stent implantation. Patients were classified as HBR if they met ≥1 major or ≥2 minor criteria according to the recent ARC-HBR consensus. The outcomes of interest were major adverse cardiovascular events (MACE), a composite of all-cause death, myocardial infarction (MI), and target lesion revascularization (TLR), and major bleeding events, including both peri-procedural and post-discharge bleeding. All outcomes were assessed at 1-year follow-up. The Kaplan-Meier method was used for time-to-event analyses. Results Out of 6,097 ACS patients included in this analysis, 2,717 (44.6%) fulfilled the ARC-HBR definition. Compared to non-HBR group, HBR patients were more frequently female, older, more likely to have cardiovascular risk factors (e.g., diabetes, hypertension, and hyperlipidemia) and complex coronary artery disease (e.g., multi-vessel disease, bifurcation lesions, and calcification). The 1-year incidence of MACE was significantly higher in HBR patients (16.3% vs. 8.1%, HR 2.16, 95% CI [1.81–2.59], p<0.001) (Figure 1A). This finding was driven by higher rates of all-cause death and MI (Figure 1B). The 1-year incidence of major bleeding was also significantly higher in HBR patients compared to non-HBR (11.1% vs. 3.1%, HR: 3.92, 95% CI 3.10–4.95; p<0.001). Conclusions HBR patients undergoing PCI for ACS are not only subject to bleeding complications but are also at an increased risk for ischemic events and all-cause mortality. Figure 1 Funding Acknowledgement Type of funding source: None

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Bleeding Risk Profile in Patients on Oral Anticoagulation Undergoing Percutaneous Coronary Interventions: A Prospective 24 Months Cohort Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.589426 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sara Schukraft ◽

Tibor Huwyler ◽

Cindy Ottiger-Mankaka ◽

Sonja Lehmann ◽

Ezia Cook ◽

...

Keyword(s):

Percutaneous Coronary Intervention ◽

Primary Endpoint ◽

Oral Anticoagulation ◽

Academic Research ◽

Bleeding Risk ◽

Coronary Intervention ◽

Risk Of Bleeding ◽

Percutaneous Coronary ◽

High Bleeding Risk

Background: The Academic Research Consortium has identified a set of major and minor risk factors in order to standardize the definition of a high bleeding risk (ACR-HBR). Oral anticoagulation is a major criterion frequently observed.Aims: The objective of this study is to quantify the risk of bleeding in patients on oral anticoagulation with at least one additional major ACR-HBR criteria in the Cardio-Fribourg Registry.Methods: Between 2015 and 2017, consecutive patients undergoing percutaneous coronary intervention were prospectively included in the Cardio-Fribourg registry. The study population included patients with ongoing long-term oral anticoagulation (OAC) and planned to receive triple antithrombotic therapy. Patients were divided in two groups: patients on OAC with at least one additional major ACR-HBR criteria vs. patients on OAC without additional major ACR-HBR criteria. The primary endpoint was any bleeding during the 24-month follow-up. Secondary bleeding endpoint was defined as Bleeding Academic Research Classification (BARC) ≥3.Results: Follow-up was completed in 142 patients at high bleeding risk on OAC, of which 33 (23%) had at least one additional major ACR-HBR criteria. The rate of the primary endpoint was 55% in patients on OAC with at least one additional ACR-HBR criteria compared with 14% in patients on OAC without additional ACR-HBR criteria (hazard ratio, 3.88; 95%CI, 1.85–8.14; p < 0.01). Patients with additional major ACR-HBR criteria also experienced significantly higher rates of BARC ≥ 3 bleedings (39% at 24 months).Conclusion: The presence of at least one additional ACR-HBR criterion identifies patients on OAC who are at very high risk of bleeding after percutaneous coronary intervention.

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