Coagulation Testing Gone Awry; Effect of Direct Oral Anticoagulant (DOAC) Removal on Lupus Anticoagulant Assays

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S11-S11
Author(s):  
Daniel Casa ◽  
Morayma Reyes Gil
Keyword(s):  
Lupus Anticoagulant ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Plasma Concentrations ◽  
False Negative ◽  
Plasma Samples ◽  
Negative Results ◽  
False Negative Results ◽  
Increased Risk ◽  
Before And After

Abstract Background Direct oral anticoagulants (DOACs) such as apixaban and rivaroxaban are widely used to treat those with or at risk for thromboembolic disease. However, DOACs have been shown to interfere with coagulation assays making their interpretations challenging. Importantly, lupus anticoagulant (LA) assays using the dilute Russell Viper Venom Time (dRVVT) to screen for patients at increased risk of thrombosis are particularly affected by DOACs leading to inaccurate results. DOAC removal agents are available to improve dRVVT specificity for LA and eliminate assay interferences. Aims To evaluate the performance of DOAC-Remove to accurately measure LA in patient plasma. Methods 10 LA positive and 10 LA negative samples without DOAC as well as normal pool plasma (NPP) were used as controls. We assessed 64 patient plasma samples including 39 patients on apixaban and 25 patients on rivaroxaban (anticoagulation was confirmed by chart review). LA testing by dRVVT was performed using Staclot® DRVV Screen and Staclot® DRVV Confirm reagents on STA R Max analyzer. DRVVT testing was performed before and after DOAC removal (DOAC-Remove, Aniara). DOAC plasma concentrations were measured using STA Liquid Anti-Xa assay. Acceptable DOAC removal was defined as an anti Xa level <0.03 IU/mL. Positive LA was defined as a screen ratio and mix ratio greater than 1.15. Results Positive and negative samples without DOAC remained the same after DOAC removal treatment. Factor levels in NPP were not affected by DOAC removal treatment. DOAC removal resulted in shortening of the dRVVT in 91% of the samples. Surprisingly, 6 cases showed prolongation in the dRVVT after DOAC removal. Before DOAC removal, 47 cases (24 apixaban and 23 rivaroxaban) tested positive and 17 tested negative (15 apixaban and 2 rivaroxaban). Following DOAC removal, 28 cases tested positive and 36 tested negative. As expected, many samples of patients on DOAC were found to be falsely positive (27/64; 15 on apixaban and 12 on rivaroxaban). Interestingly, 8 of 64 tests were found to be falsely negative. Of the 8 samples that were falsely negative, 7 were on apixaban and 1 on rivaroxaban. 9 samples that were negative before DOAC removal remained negative after DOAC removal, and 20 tests that were positive before DOAC removal remained positive after DOAC removal for a total of 29 results (45%) that remained unchanged. It was found that DOACs caused inaccurate results in 55% of cases. Conclusions Our study was able to demonstrate the effectiveness of DOAC-Remove to eliminate DOACs from patient plasma and provide accurate LA results. DOAC interference on LA assays predictably creates many false positive results, however, presence of DOACs can produce false negative results as well, underlying the importance of pretest screening for presence of anticoagulants in plasma samples.

scholarly journals The Effect of Direct Oral Anticoagulants on Antithrombin Activity Testing Is Abolished by DOAC-Stop in Venous Thromboembolism Patients

2020 ◽  
Vol 145 (1) ◽  
pp. 99-104
Author(s):  
Michał Ząbczyk ◽  
Joanna Natorska ◽  
Magdalena Kopytek ◽  
Krzysztof P. Malinowski ◽  
Anetta Undas
Keyword(s):  
Venous Thromboembolism ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
False Negative ◽  
Interquartile Range ◽  
Antithrombin Activity ◽  
Negative Results ◽  
False Negative Results ◽  
At Deficiency ◽  
Deficiency Screening

Context.— Direct oral anticoagulants (DOACs) may cause false negative results of antithrombin (AT) deficiency screening. Objective.— To evaluate the impact of DOAC-Stop, an agent reversing in vitro effects of DOACs, on AT testing in anticoagulated patients. Design.— We assessed 130 venous thromboembolism patients aged 46.7 ± 13.5 years. Blood samples were collected 2 to 27 hours after DOAC intake from 49 patients on rivaroxaban, 54 on apixaban, and 27 on dabigatran. Antithrombin activity was assessed using the activated factor X (FXa)–based and the activated factor II (FIIa)–based method twice, before and after DOAC-Stop treatment, together with plasma DOAC levels using coagulometric assays. Results.— The use of DOAC-Stop did not influence AT activity measured using the FIIa-based assay, whereas there was a marked decrease in AT activity determined using the FXa-based assay (ΔAT = 16.9%; 95% CI, 12.9%–19.1%). The AT-FIIa assay revealed decreased AT level (<79%) in all 10 (7.7%) genetically confirmed AT-deficient patients treated with rivaroxaban or apixaban (n = 5 each), whereas the AT-FXa assay showed decreased AT activity (<83%) in 2 subjects on rivaroxaban and 1 on apixaban with low plasma DOAC concentrations (<90 ng/mL). After DOAC-Stop median AT-FXa activity lowered from 83.5% (interquartile range, 66%–143%) to 65.5% (interquartile range, 57%–75%; P = .005; ΔAT = 18%) in AT-deficient patients, without any false negative results. The ΔAT in the FXa-based assay correlated with rivaroxaban and apixaban concentrations in the AT-deficient patients (r = 0.99, P < .001). Conclusions.— Application of DOAC-Stop enables reliable evaluation of AT deficiency screening in patients taking rivaroxaban or apixaban and tested using the FXa-based method.

scholarly journals Helicobacter pylori: From Infection to Cure

1996 ◽  
Vol 10 (3) ◽  
pp. 167-172
Author(s):  
ABR Thomson
Keyword(s):  
Helicobacter Pylori ◽  
False Negative ◽  
Eradication Therapy ◽  
Erosive Esophagitis ◽  
Gastric Body ◽  
Negative Results ◽  
False Negative Results ◽  
Increased Risk ◽  
Major Interest ◽  
H Pylori

Over 380 abstracts, presentations and posters of recent advances were highlighted at the European and InternationalHelicobacter pylorimeeting held July 7 to 9, 1995 in Edinburgh, Scotland. New advances abound, with major interest focusing on the simple, safe, inexpensive new `gold standard’ forH pylorieradication therapy: a single week of tid omeprazole 20 mg, metronidazole 400 mg and clarithromycin 250 mg, or omeprazole 20 mg, amoxicillin 1000 mg and clarithromycin 500 mg. To avoid false negative results, two biopsies must be taken from the antrum and two from the gastric body at least four weeks after completion of eradication therapy, and ideally should be supplemented with at least one furtherH pyloritest such as a biopsy for urease activity or culture, or a urea breath test. While most patients with a gastric or duodenal ulcer (DU) who do not consume nonsteroidal anti-inflammatory drugs are infected withH pylori, the association is much less apparent in those with a DU who present with an upper gastrointestinal hemorrhage.H pylorieradication for nonulcer dyspepsia is not widely recommended, and the patient with a DU given effectiveH pylorieradication who presents with dyspepsia likely has erosive esophagitis rather than recurrent DU orH pylori. Gastroenterologists are at increased risk ofH pyloriinfection, particularly older gastroenterologists who are very busy endoscopists.

Effects of direct oral anticoagulants on lupus anticoagulant assays in a real-life setting

2017 ◽  
Vol 117 (09) ◽  
pp. 1700-1704 ◽  
Author(s):  
Aleksandra Antovic ◽  
Eva-Marie Norberg ◽  
Maria Berndtsson ◽  
Agnes Rasmuson ◽  
Rickard E. Malmström ◽  
...  
Keyword(s):  
Lupus Anticoagulant ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Plasma Concentrations ◽  
Real Life ◽  
Laboratory Diagnosis ◽  
Real Life Setting ◽  
Confirmatory Tests ◽  
Coagulation Assay

SummaryLaboratory diagnosis of lupus anticoagulant (LA) is based on prolongation in at least one coagulation assay (diluted Russell’s viper venom time – dRVVT or activated partial thromboplastin time – aPTT), which normalises after addition of phospholipids. Both assays may be influenced by anticoagulants and therefore LA should not be tested during warfarin or heparin treatment. It has been shown (primarily in vitro) that direct oral anticoagulants (DOACs – dabigatran [DAB], rivaroxaban [RIV] and apixaban [API]) may also influence LA testing. We tested the effects of DOACs on assays routinely used for the diagnosis of LA in patients treated with these drugs in a real-life setting. Plasma from patients with atrial fibrillation treated with DAB (n=30), RIV (n=20) and API (n=17) and not known to have LA were tested using dRVVT (LA-screen and LA-confirm, Life Diagnostics) and aPTT (PTT-LA, Diagnostica Stago and aPTT Actin FS, Siemens Healthcare Diagnostics) assays. According to the diagnostics algorithm, dRVVT and aPTT ratios of <1.2 were considered negative, ratios of >1.4 positive, while if the ratios were 1.2–1.4 LA could not be ruled out. Plasma concentrations varied between 8–172 µg/l for DAB, 8–437 µg/l for RIV and 36–178 µg/l for API. LA diagnosis was negative in only eight (27 %) plasma samples from patients treated with DAB, and in five (25 %) and four samples (24 %) from patients treated with RIV and API, respectively. LA Positivity (dRVVT and aPTT ratios >1.4) was found in 5 cases (17 %) among patients treated with DAB, in 10 cases (50 %) treated with RIV and in 7 cases (41 %) treated with API. A concentration-dependent effect of DOACs on dRVVT-based parameters was observed, particularly as regards DAB. At lower concentrations, RIV and API had only minor effects on the confirmatory tests (below 100 µg/l and 70 µg/l, respectively). Our results suggest that a risk of overestimation of LA detection is present in samples from patients treated with DOACs. Therefore, LA testing should not be performed during treatment with DOACs. Prolongation in confirmatory assays may be helpful for the recognition of false positivity, especially as regards DAB.

Consultative Interpretation for Lupus Anticoagulant by Expert Pathologist Reduces False-Positive Rates in the Era of Direct Oral Anticoagulants

2019 ◽  
Vol 5 (1) ◽  
pp. 73-82
Author(s):  
Angelica Vivero ◽  
Sumire Kitahara ◽  
Alice Runge ◽  
Oksana Volod
Keyword(s):  
False Positive ◽  
Lupus Anticoagulant ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Before And After ◽  
Expert Pathologist ◽  
Testing Algorithm ◽  
The Impact ◽  
Order Set

Abstract Background The diagnosis of antiphospholipid syndrome requires detection of antiphospholipid antibodies (aPL). A retrospective review of our testing practices revealed that societal recommendations for lupus anticoagulant (LA) testing as part of aPL testing are largely not followed by clinicians, and there was a high proportion of positive LA results. Increasing direct oral anticoagulant (DOAC) usage creates additional challenges in identifying LA. This prompted us to establish an order set with pathologist consultation (“LA panel”) and testing algorithm to reduce false-positive LA and to ensure optimal LA identification and best practices for interpretation and follow-up. Methods The laboratory database was reviewed to determine the number of LA tests ordered and rate of LA positivity before and after the LA panel was instituted. We assessed the impact of pathologist consultation to minimize false-positive findings and on following diagnostic guidelines. Results LA panels were ordered for 1146 patients. LA was detected in 10% (111 of 1146) by dilute Russel viper venom time (dRVVT) normalized ratio [includes dRVVT screen (dRVVTs) positive/lupus-sensitive partial thromboplastin time (PTT-LA) positive and dRVVTs positive/PTT-LA negative] and 20% (228 of 1146) by Staclot-LA (includes dRVVTs negative/PTT-LA positive and dRVVTs positive/confirm negative). There was a reduction of false-positive LA by Staclot-LA; previously, 48% positive. We saw increased cancellation of LA testing for interfering anticoagulants [6.8% (16 of 236) vs 14.4% (55 of 383); P = 0.0061]. There was also increased adherence to follow-up LA testing [3% (8 of 236) vs 13.8% (53 of 383); P ≤ 0.001]. Conclusions Creating a predetermined order set and testing algorithm with pathologist consultation improved LA testing interpretation and diagnostic follow-up testing.

scholarly journals Case Report: Three's a crowd: a case report examining the diagnostic and pharmacokinetic challenges in HIV-tuberculous meningitis-malaria co-infection

2018 ◽  
Vol 3 ◽  
pp. 111
Author(s):  
Jayne Ellis ◽  
Prosperity C. Eneh ◽  
Kenneth Ssebambulidde ◽  
Morris K. Rutakingirwa ◽  
Mohammed Lamorde ◽  
...  
Keyword(s):  
Case Report ◽  
Treatment Guidelines ◽  
Plasma Concentrations ◽  
False Negative ◽  
Peripheral Blood Smear ◽  
Pharmacokinetic Studies ◽  
Global Public Health ◽  
Cytochrome P450 Enzymes ◽  
Negative Results ◽  
False Negative Results

In 2016, 10.4 million cases of tuberculosis (TB) were reported globally. Malaria also continues to be a global public health threat. Due to marked epidemiological overlap in the global burden of TB and malaria, co-infection does occur. An HIV-infected, 32-year-old male presented with a two-week history of headache with fevers to Mulago National Referral Hospital, Uganda. Five months prior, he was diagnosed with pulmonary TB. He endorsed poor adherence to anti-tuberculous medications. Mycobacterium tuberculosis in CSF was confirmed on Xpert MTB/RIF Ultra. On day 2, he was initiated on dexamethasone at 0.4mg/kg/day and induction TB-medications were re-commenced (rifampicin, isoniazid, ethambutol, pyrazinamide) for TBM. He continued to spike high-grade fevers, a peripheral blood smear showed P. falciparum parasites despite a negative malaria rapid diagnostic test (RDT). He received three doses of IV artesunate and then completed 3 days of oral artemether/lumefantrine. To our knowledge this is the first published case of HIV-TBM-malaria co-infection. TBM/malaria co-infection poses a number of management challenges. Due to potential overlap in symptoms between TBM and malaria, it is important to remain vigilant for co-infection. Access to accurate parasitological diagnostics is essential, as RDT use continues to expand, it is essential that clinicians are aware of the potential for false negative results. Anti-malarial therapeutic options are limited due to important drug-drug interactions (DDIs). Rifampicin is a potent enzyme inducer of several hepatic cytochrome P450 enzymes, this induction results in reduced plasma concentrations of several anti-malarial medications. Despite recognition of potential DDIs between rifampicin and artemisinin compounds, and rifampicin and quinine, no treatment guidelines currently exist for managing patients with co-infection. There is both an urgent need for the development of new anti-malarial drugs which do not interact with rifampicin and for pharmacokinetic studies to guide dose modification of existing anti-malarial drugs to inform clinical practice guidelines.

Danger of false negative (exclusion) or false positive (diagnosis) for ‘congenital thrombophilia’ in the age of anticoagulants

2019 ◽  
Vol 57 (6) ◽  
pp. 873-882 ◽  
Author(s):  
Emmanuel J. Favaloro
Keyword(s):  
False Positive ◽  
Ex Vivo ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
False Negative ◽  
Factor V Leiden ◽  
Protein S ◽  
Factor V ◽  
Increased Risk

Abstract Background Most guidelines and experts recommend against performance of thrombophilia testing in general, and specifically against testing patients on pharmacological anticoagulants, due to substantially increased risk of false positive identification. For example, vitamin K antagonist (VKA) therapy affects protein C (PC) and protein S (PS), as well as some clotting assays (e.g. as used to investigate activated PC resistance [APCR]). Although heparin may also affect clotting assays, most commercial methods contain neutralisers to make them ‘insensitive’ to therapeutic levels. Direct oral anticoagulants (DOACs) also affect a wide variety of thrombophilia assays, although most reported data has employed artificial in vitro spiked samples. Methods In the current report, data from our facility for the past 2.5 years has been assessed for all ‘congenital thrombophilia’ related tests, as evaluated against patient anticoagulant status. We processed 10,571 ‘thrombophilia’ related test requests, including antithrombin (AT; n=3470), PC (n=3569), PS (n=3585), APCR (n=2359), factor V Leiden (FVL; n=2659), and prothrombin gene mutation (PGM; n=2103). Results As expected, VKA therapy affected PC and PS, and despite manufacturer claims, also APCR. Most assays, as suggested by manufacturers, were largely resistant to heparin therapy. DOACs’ use was associated with falsely low APCR ratios (i.e. FVL-like effect) and somewhat unexpectedly, anti-Xa agents apixaban and rivaroxaban were also associated with lower AT and higher PS values. Conclusions It is concluded that ex-vivo data appears to confirm the potential for both false positive and false negative ‘thrombophilia’ events in patients on anticoagulant (including DOAC) treatment.

Point-of-Care Coagulation Tests Monitoring of Direct Oral Anticoagulants and Their Reversal Therapy: State of the Art

2017 ◽  
Vol 43 (04) ◽  
pp. 423-432 ◽  
Author(s):  
Paolo Bianchi ◽  
Marco Ranucci ◽  
Ekaterina Baryshnikova ◽  
Giacomo Iapichino
Keyword(s):  
Point Of Care ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Plasma Concentrations ◽  
Urgent Surgery ◽  
Drug Plasma Concentrations ◽  
Drug Plasma ◽  
Coagulation Tests ◽  
Before And After

AbstractDirect oral anticoagulants (DOACs) exert similar anticoagulant effects to vitamin K antagonists and are increasingly used worldwide. Nevertheless, an evidence-based approach to patients receiving DOACs when any unplanned urgent surgery or bleeding (either spontaneous or traumatic) occurs is still missing. In this review, we investigate the role of point-of-care coagulation tests when other, more specific tests are not available. Indeed, thromboelastography and activated clotting time can detect dabigatran-induced coagulopathy, while their accuracy is limited for apixaban and rivaroxaban, mostly in cases of low drug plasma concentrations. These tests can also be used to guide the reversal of DOAC-induced coagulopathy providing a quick, before-and-after picture in case of therapeutic use of hemostatic compounds.

scholarly journals Heat inactivation of serum interferes with the immunoanalysis of antibodies to SARS-CoV-2

2020 ◽  
Author(s):  
Xiumei Hu ◽  
Taixue An ◽  
Bo Situ ◽  
Yuhai Hu ◽  
Zihao Ou ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
False Negative ◽  
Average Level ◽  
Heat Inactivation ◽  
Serum Antibodies ◽  
Serum Samples ◽  
Negative Results ◽  
False Negative Results ◽  
Before And After ◽  
Quantitative Fluorescence

AbstractThe detection of serum antibodies to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is emerging as a new tool for the coronavirus disease-2019 (COVID-19) diagnosis. Since many coronaviruses are sensitive to heat, heating inactivation of samples at 56 °C prior to testing is considered a possible method to reduce the risk of transmission, but the effect of heating on the measurement of SARS-CoV-2 antibodies is still unclear. By comparing the levels of SARS-CoV-2 antibodies before and after heat inactivation of serum at 56 °C for 30 minutes using a quantitative fluorescence immunochromatographic assay, we shown that heat inactivation significantly interferes with the levels of antibodies to SARS-CoV-2. The IgM levels of all the 34 serum samples (100%) from COVID-19 patients decreased by an average level of 53.56%. The IgG levels were decreased in 22 of 34 samples (64.71%) by an average level of 49.54%. Similar changes can also be observed in the non-COVID-19 diseases group (n=9). Of note, 44.12% of the detected IgM levels were dropped below the cut-off value after heating, suggesting heat inactivation can lead to false-negative results of these samples. Our results indicate that heat inactivation of serum at 56 °C for 30 minutes interferes with the immunoanalysis of antibodies to SARS-CoV-2. Heat inactivation prior to immunoanalysis is not recommended and the possibility of false-negative results should be considered if the sample was pre-inactivated by heating.

scholarly journals Case Report: Three's a crowd: a case report examining the diagnostic and pharmacokinetic challenges in HIV-tuberculous meningitis-malaria co-infection

2019 ◽  
Vol 3 ◽  
pp. 111
Author(s):  
Jayne Ellis ◽  
Prosperity C. Eneh ◽  
Kenneth Ssebambulidde ◽  
Morris K. Rutakingirwa ◽  
Mohammed Lamorde ◽  
...  
Keyword(s):  
Case Report ◽  
Treatment Guidelines ◽  
Plasma Concentrations ◽  
False Negative ◽  
Peripheral Blood Smear ◽  
Pharmacokinetic Studies ◽  
Global Public Health ◽  
Cytochrome P450 Enzymes ◽  
Negative Results ◽  
False Negative Results

In 2016, 10.4 million cases of tuberculosis (TB) were reported globally. Malaria also continues to be a global public health threat. Due to marked epidemiological overlap in the global burden of TB and malaria, co-infection does occur. An HIV-infected, 32-year-old male presented with a two-week history of headache with fevers to Mulago National Referral Hospital, Uganda. Five months prior, he was diagnosed with pulmonary TB. He endorsed poor adherence to anti-tuberculous medications. Mycobacterium tuberculosis in CSF was confirmed on Xpert MTB/RIF Ultra. On day 2, he was initiated on dexamethasone at 0.4mg/kg/day and induction TB-medications were re-commenced (rifampicin, isoniazid, ethambutol, pyrazinamide) for TBM. He continued to spike high-grade fevers, a peripheral blood smear showed P. falciparum parasites despite a negative malaria rapid diagnostic test (RDT). He received three doses of IV artesunate and then completed 3 days of oral artemether/lumefantrine. To our knowledge this is the first published case of HIV-TBM-malaria co-infection. TBM/malaria co-infection poses a number of management challenges. Due to potential overlap in symptoms between TBM and malaria, it is important to remain vigilant for co-infection. Access to accurate parasitological diagnostics is essential, as RDT use continues to expand, it is essential that clinicians are aware of the potential for false negative results. Anti-malarial therapeutic options are limited due to important drug-drug interactions (DDIs). Rifampicin is a potent enzyme inducer of several hepatic cytochrome P450 enzymes, this induction results in reduced plasma concentrations of several anti-malarial medications. Despite recognition of potential DDIs between rifampicin and artemisinin compounds, and rifampicin and quinine, no treatment guidelines currently exist for managing patients with co-infection. There is both an urgent need for the development of new anti-malarial drugs which do not interact with rifampicin and for pharmacokinetic studies to guide dose modification of existing anti-malarial drugs to inform clinical practice guidelines.

scholarly journals Preserved Thermal Pain in 3xTg-AD Mice With Increased Sensory-Discriminative Pain Sensitivity in Females but Affective-Emotional Dimension in Males as Early Sex-Specific AD-Phenotype Biomarkers

2021 ◽  
Vol 13 ◽  
Author(s):  
Toni Cañete ◽  
Lydia Giménez-Llort
Keyword(s):  
Pain Sensitivity ◽  
False Negative ◽  
Thermal Nociception ◽  
Thermal Pain ◽  
Negative Results ◽  
People With Dementia ◽  
False Negative Results ◽  
Increased Risk ◽  
Withdrawal Reflexes ◽  
Thermal Pain Sensitivity

The increase of the aging population, where quite chronic comorbid conditions are associated with pain, draws growing interest across its investigation and the underlying nociceptive mechanisms. Burn injuries associated problems might be of relevance in the older adult’s daily life, but in people with dementia, exposure to high temperatures and heat sources poses a significantly increased risk of burns. In this brief report, the hind paws and tail pain withdrawal reflexes and the emotional responses to thermal nociception in 3xTg-AD mice were characterized for the first time in the plantar test and compared to their non-transgenic (NTg) counterparts. We studied a cohort of male and female 3xTg-AD mice at asymptomatic (2 months), early (6 months), middle (9 months), and advanced (12 and 15 months) stages of the disease and as compared to sex- and age-matched NTg control mice with normal aging. At 20 and 40W intensities, the sensorial-discriminative thresholds eliciting the withdrawal responses were preserved from asymptomatic to advanced stages of the disease compared to NTg counterparts. Moreover, 3xTg-AD females consistently showed a greater sensory-discriminative sensitivity already at premorbid ages, whereas increased emotionality was shown in males. False-negative results were found in “blind to sex and age” analysis, warning about the need to study sexes independently. The current results and previous report in cold thermal stimulation provide two paradigms unveiling sex-specific early AD-phenotype nociceptive biomarkers to study the mechanistic underpinnings of sex-, age- and AD-disease-dependent thermal pain sensitivity.

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