Case report: Complex evaluation of coagulation, fibrinolysis and inflammatory cytokines in a SARS-CoV-2 infected pregnant woman with fetal loss.

Background: SARS-CoV-2 infection during pregnancy increases the risk of severe obstetrical complications. Detailed evaluation of COVID-19-associated coagulopathy in a pregnancy with stillbirth hasn't been described so far. Besides knowledge gaps in the pathomechanism leading to stillbirth in COVID-19 pregnancies, currently, no prognostic biomarker is available to identify pregnant patients who are at imminent risk of COVID-19-associated maternal and fetal complications, requiring immediate medical attention. Case: Here we report the case of a 28-year-old SARS-CoV-2 infected pregnant patient, admitted to our hospital at 28 weeks of gestation with intrauterine fetal loss. The presence of SARS-CoV-2 placentitis was confirmed by immunohistological evaluation of the placenta. She had only mild upper respiratory symptoms and her vital signs were within reference throughout labor and postpartum. The stillborn infant was delivered per vias naturales. Fibrinogen concentrate was administered before and after labor due to markedly decreased fibrinogen levels (1.49 g/l) at admission and excessive bleeding during and after delivery. Although coagulation screening tests were not alarming at admission, the balance of hemostasis was strikingly distorted in the patient. As compared to healthy age- and gestational age-matched pregnant controls, increased D-dimer, low FVIII activity, low FXIII level, marked hypocoagulability as demonstrated by the thrombin generation assay, together with shortened clot lysis and decreased levels of fibrinolytic proteins were observed. These alterations most likely have contributed to the increased bleeding observed during labor and in the early postpartum period. Interestingly, at the same time, only moderately altered inflammatory cytokine levels were found at admission. Serum ACE2 activity did not differ in the patient from that of age- and gestational age-matched healthy controls, suggesting that despite previous speculations in the literature, ACE2 may not be used as a potential biomarker for the prediction of COVID-19 placentitis and threatening fetal loss in SARS-CoV-2-infected pregnancies. Conclusions: Although based on this case report no prognostic biomarker could be identified for use in pregnant patients with imminent risk of fetal loss associated with COVID-19 placentitis, the above-described hemostasis alterations warrant awareness of postpartum hemorrhagic complications and could be helpful to identify patients requiring intensified medical attention.

Low factor XIII levels and altered fibrinolysis in patients with multiple myeloma.

BACKGROUND: Acquired factor FXIII (FXIII) deficiency can be immune- or non-immune mediated and may cause severe bleeding symptoms. The incidence of acquired FXIII deficiency and its etiology in patients with multiple myeloma (MM) are poorly understood. OBJECTIVES: To assess FXIII levels and the balance of fibrinolysis in newly diagnosed, untreated MM and monoclonal gammopathy of undetermined significance (MGUS) patients. METHODS: FXIII activity, mixing studies, FXIII-A2B2 antigen, total FXIII-B antigen were measured in platelet-poor plasma from 17 untreated MM patients, 33 untreated MGUS patients, and 30 age and sex-matched healthy controls. Besides routine laboratory measurements, the balance of coagulation and fibrinolysis was evaluated using quantitative fibrin monomer (FM) test, thrombin-antithrombin assay, α2-antiplasmin activity, plasmin-α2-antiplasmin (PAP) complex, D-dimer, plasmin generation assay, clot lysis assay, and ClotPro-TPA test. RESULTS: FXIII-A2B2 levels were significantly lower in MM patients compared to controls [median (IQR):14.6 (11.2-19.4) vs. 21.8 (17.1-26.4) mg/L, p = 0.0015], whereas total FXIII-B did not differ between groups. Decrease in FXIII activity was parallel to the decrease in FXIII-A2B2. An immune-mediated inhibitory mechanism was ruled out. Free/total FXIII-B was significantly higher in MM patients compared to MGUS and healthy controls, suggesting an etiology of FXIII-A consumption. In MM and MGUS patients, FM, D-dimer, and PAP complex were significantly elevated compared to controls, indicating hypercoagulability and ongoing fibrinolysis. CONCLUSIONS: Low FXIII levels due to consumption were observed in MM patients at diagnosis. Hypercoagulability and ongoing fibrinolysis were detected in MM and MGUS, indicating that a disturbed hemostasis balance is already present in the latter benign condition.

Effect of anti-SARS-CoV-2 BNT162b2 mRNA vaccination on thrombin generation in children with inflammatory bowel disease.

Background: Inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC), are associated with higher thrombotic risk and enhanced thrombin generation (TG) in adults. Despite encouraging data reporting vaccine safety and low IBD flare rates in adults with IBD, vaccine hesitancy was demonstrated to be high in families of children with IBD. We aimed to find out whether TG is increased in children with IBD as compared to healthy controls and whether TG parameters show significant changes following SARS-CoV-2 mRNA vaccination. Patients and methods: In this observational case-control study, 38 children with IBD (CD:18, UC: 20) aged 12-18 years and 62 healthy age-and sex-matched children were enrolled. Blood was collected before the first dose and 2-6 weeks after the second dose of BNT162b2 (Pfizer-BioNTech) mRNA vaccine dose. Blood cell counts, fibrinogen, inflammatory markers (hsCRP, ferritin), anti-SARS-CoV-2 antibody levels were investigated, TG assay was carried-out using platelet-poor plasma. Detailed clinical parameters including disease activity scores (PUCAI, PCDAI) were registered pre-and post- vaccination. A guided questionnaire was used to collect data on adverse reactions (AEs) post- vaccination. Results: Baseline TG parameters did not differ between patients and controls. Endogenous thrombin potential showed a significant positive correlation with markers of inflammation and with PCDAI. Inflammatory parameters and TG did not increase in patients and controls post-vaccination. Vaccination significantly increased antibody levels in all three investigated groups, but post-vaccination anti-SARS-CoV-2 S IgG/IgM levels were below the 5th percentile value of healthy children in more than one third of patients. Those receiving TNFα inhibitor therapy presented significantly lower SARS-CoV-2 S IgG/IgM levels as compared to patients on other immunosuppressive regimens. Systemic AEs did not differ between patients and controls while lower rate of local symptoms was found post-vaccination in children with IBD. Only 2 IBD flares were detected 2-6 weeks after the second dose of vaccination. Conclusion: Our study is the first to support the safety and efficacy of anti-SARS-CoV-2 BNT162b2 vaccination in children with IBD with detailed pre-and post-vaccination laboratory data including TG. Results of this study may further increase confidence and reduce vaccine hesitancy in caretakers of pediatric IBD patients.

Antithrombin Deficiency Is Associated with Prothrombotic Plasma Fibrin Clot Phenotype.

BACKGROUND: Deficiency of antithrombin increases risk of venous thromboembolism. We hypothesized that antithrombin deficiency affects fibrin clot structure and function. METHODS: We evaluated 148 patients (age: 38 [32-50] years; 70% women) with genetically confirmed antithrombin deficiency and 50 healthy controls. Fibrin clot permeability (Ks) and clot lysis time (CLT) along with thrombin generation capacity were assessed before and after antithrombin activity normalization in vitro. RESULTS: Antithrombin-deficient patients had lower antithrombin activity (-39%) and antigen levels (-23%) compared with controls (both p < 0.01). Prothrombin fragment 1 + 2 levels were 26.5% higher in patients with antithrombin deficiency than in controls along with 94% increased endogenous thrombin potential (ETP) and 108% higher peak thrombin (all p < 0.01). Antithrombin deficiency was associated with 18% reduced Ks and 35% prolonged CLT (both p < 0.001). Patients with type I (n = 65; 43.9%) compared with type II antithrombin deficiency (n = 83; 56.1%) had 22.5% lower antithrombin activity (p < 0.001) and despite similar fibrinogen levels, 8.4% reduced Ks, 18% prolonged CLT, and 30% higher ETP (all p < 0.01). Reduced Ks was associated with lower antithrombin antigen level (ß = - 6.1, 95% confidence interval [CI]: -1.7 to -10.5), while prolonged CLT was associated with lower antithrombin antigen (ß = - 69.6, 95% CI: -9.6 to -129.7), activity (ß = - 2.4, 95% CI: -0.3 to -4.5), higher PAI-1 (ß = 12.1, 95% CI: 7.7-16.5), and thrombin-activatable fibrinolysis inhibitor levels (ß = 3.8, 95% CI: 1.9-5.7). Addition of exogenous antithrombin reduced ETP (-42%) and peak thrombin (-21%), and improved Ks (+8%) and CLT (-12%; all p < 0.01). CONCLUSION: Our study suggests that enhanced thrombin generation and prothrombotic plasma fibrin clot phenotype can contribute to increased risk of thrombosis in patients with antithrombin deficiency.

Mortality on DOACs Versus on Vitamin K Antagonists in Atrial Fibrillation: Analysis of the Hungarian Health Insurance Fund Database.

PURPOSE: Limited real-world data are available on the survival of patients treated with vitamin K antagonists (VKAs) versus with direct oral anticoagulants (DOACs) for nonvalvular atrial fibrillation (AF). In this nationwide registry, we analyzed the mortality risk of patients with nonvalvular AF taking DOACs versus VKAs, with a special attention to the early treatment period. METHODS: The Hungarian National Health Insurance Fund (NHIF) database was searched to identify patients treated with VKA or DOAC as a thromboembolic prophylaxis for nonvalvular AF between 2011 and 2016. The overall and the early (0-3, 4-6, and 7-12 months) mortality risks with the 2 types of anticoagulation were compared. A total of 144,394 patients with AF treated with either a VKA (n = 129,925) or a DOAC (n = 14,469) were enrolled. FINDINGS: A 28% improvement in 3-year survival with DOAC treatment compared with VKA treatment was shown. Mortality reduction with DOACs was consistent across different subgroups. However, younger patients (30-59 years old) initiated on DOAC therapy had the greatest RRR (53%) in mortality. Furthermore, DOAC treatment also yielded a benefit of greater magnitude (HR = 0.55; 95% CI, 0.40-0.77, P = 0.001) in the lower (0-1) CHA2DS2-VASc score segment and in those with fewer (0-1) bleeding risk factors (HR = 0.50, CI 0.34-0.73, P = 0.001). The RRR in mortality with DOACs was 33% within the first 3 months, and 6% in the second year. IMPLICATIONS: Thromboembolic prophylaxis with DOACs in this study yielded significantly lower mortality compared with VKA treatment in patients with nonvalvular AF. The largest benefit was shown in the early period after treatment initiation, as well as in younger patients, those with a lower CHA2DS2-VASc score, and those with fewer bleeding risk factors.

Elevated Blood Alcohol Concentration Is Associated with Improved Clinical Outcomes of Intravenous Thrombolysis Treatment in Acute Ischemic Stroke Patients-A Retrospective Study.

BACKGROUND: Intravenous thrombolysis (IVT) improves acute ischemic stroke (AIS) outcomes, but with limited success. In addition, ethanol potentiates the effect of r-tPA in ischemia models. METHODS: The effect of acute alcohol consumption on IVT outcomes was investigated in a retrospective cohort study. AIS patients with detectable blood alcohol concentration (BAC) during IVT were included (alcohol group; n = 60). For each case, 3 control subjects who underwent IVT but denied alcohol consumption were matched in terms of age, sex, affected brain area, and stroke severity. Outcomes were determined using the NIHSS at 7 days and the modified Rankin scale (mRS) at 90 days. RESULTS: Patients were younger and had a less severe stroke than in a standard stroke study. Favorable long-term outcomes (mRS 0-2) occurred significantly more frequently in the alcohol group compared to controls (90% vs. 63%, p < 0.001). However, the rates of hemorrhagic transformation were similar. Multiple logistic regression models identified elevated BAC as a significant protective factor against unfavorable short-term (OR: 0.091, 95% CI: 0.036-0.227, p < 0.001) and long-term outcomes (OR: 0.187, 95% CI: 0.066-0.535, p = 0.002). In patients with BAC > 0.2%, significantly lower NIHSS was observed at 3 and 7 days after IVT vs. in those with 0.01-0.2% ethanol levels. CONCLUSION: Elevated BAC is associated with improved outcomes in IVT-treated AIS without affecting safety.

Patients with multiple myeloma and monoclonal gammopathy of undetermined significance have variably increased thrombin generation and different sensitivity to the anticoagulant effect of activated protein C.

BACKGROUND: Patients with multiple myeloma (MM) are at high risk of thrombosis especially when receiving immunomodulatory therapy. Thrombotic risk in patients with monoclonal gammopathy of undetermined significance (MGUS) may also be increased. Although activated protein C (APC) resistance has been linked to an increased risk of thrombosis in MM, little is known about how APC influences thrombotic risk in MGUS. We compared thrombin generation (TG) in MM and MGUS patients to that of healthy controls (HCs) and investigated the exogenous effect of APC on TG in these groups. METHODS: Hemostasis tests including factor VIII (FVIII) and von Willebrand factor (vWF) levels were measured in platelet-poor plasma in 14 untreated MM patients, 34 MGUS patients, and 30 age and sex-matched HCs. TG assay was performed with or without the addition of APC. RESULTS: Peak thrombin and velocity index were significantly higher in MM and MGUS patients compared to HCs, while MM patients also had elevated endogenous thrombin potential (ETP). In MGUS cases, ETP and peak thrombin values significantly correlated with FVIII and vWF levels. In the presence of APC, peak thrombin and ETP were reduced in MGUS and control plasmas whereas lagtime and time to peak were significantly prolonged. In contrast, adding APC to MM plasma had no effect on any TG parameters. CONCLUSIONS: Hypercoagulability was observed in MM and even in MGUS cases with very low monoclonal protein concentration. In MM patients, APC had no effect on TG, but it attenuated TG in MGUS patients.

Thrombin generation as a predictor of outcomes in patients with non-traumatic intracerebral hemorrhage.

Background: Non-traumatic intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes and leads to a higher rate of mortality as compared to ischemic strokes. We aimed to find out whether the thrombin generation assay (TGA) could predict outcomes in patients with ICH. Patients and methods: In this prospective, observational study, 87 consecutive patients with ICH and 164 healthy controls were included. Computed tomography (CT), detailed clinical investigation, and laboratory investigations were performed from patients on admission. TGA was performed using stored platelet poor plasma obtained on admission. Lag time, endogen thrombin potential (ETP), peak thrombin, and time to peak parameters were calculated. Short- and long-term outcomes of ICH were defined at 14 days and 3 months post-event according to the NIHSS and the modified Rankin Scale (mRS), respectively. Results: Peak thrombin was significantly higher in patients as compared to controls (397.2 ± 93.9 vs. 306 ± 85.3 nM, p < 0.0001). Lag time, ETP, and time to peak parameters showed a significant positive correlation with CRP in both groups. In patients with worse long-term functional outcomes, peak thrombin was significantly higher as compared to those with favorable outcomes [mRS 2-6 median: 402.5 (IQR:344.8-473.8) vs. mRS 0-1: 326.4 (294.2-416.1) nM, p = 0.0096]. Based on the statistically optimal threshold of 339.1 nM peak thrombin, the sensitivity and specificity of this parameter to determine mRS 2-6 as an outcome were 80.8 and 64.7%, respectively. In a binary logistic regression model including age, sex, BMI, smoking status, NIHSS on admission, D-dimer, and peak thrombin (>339.1 nM), only NIHSS and the peak thrombin parameters remained in the model as significant, independent predictors of poor outcome. Lag time and time to peak showed a modest, significant negative correlation with intracerebral bleeding volume on admission (r = -0.2603, p = 0.0231 and r = -0.3698, p = 0.0010, respectively). During the follow-up of patients, estimated hemorrhage volumes on day 90 showed significant positive association with the ETP and peak thrombin parameters (r = 0.3838, p = 0.0363 and r = 0.5383, p = 0.0021, respectively). Conclusion: In patients with ICH, TG was increased as compared to healthy controls, which might be explained by the presence of higher inflammatory parameters in patients. Peak thrombin measured on admission might be a useful tool to predict outcomes in patients with ICH.

Low α2-Plasmin Inhibitor Antigen Levels on Admission Are Associated With More Severe Stroke and Unfavorable Outcomes in Acute Ischemic Stroke Patients Treated With Intravenous Thrombolysis.

Background: Intravenous administration of recombinant tissue plasminogen activator (rt-PA) fails to succeed in a subset of acute ischemic stroke (AIS) patients, while in approximately 6-8% of cases intracerebral hemorrhage (ICH) occurs as side effect. Objective: Here, we aimed to investigate α2-plasmin inhibitor (α2-PI) levels during thrombolysis and to find out whether they predict therapy outcomes in AIS patients. Patients/Methods: In this prospective, observational study, blood samples of 421 AIS patients, all undergoing i.v. thrombolysis by rt-PA within 4.5 h of their symptom onset, were taken before and 24 h after thrombolysis. In a subset of patients (n = 131), blood was also obtained immediately post-lysis. α2-PI activity and antigen levels were measured by chromogenic assay and an in-house ELISA detecting all forms of α2-PI. α2-PI Arg6Trp polymorphism was identified in all patients. Stroke severity was determined by NIHSS on admission and day 7. Therapy-associated ICH was classified according to ECASSII. Long-term outcomes were defined at 3 months post-event by the modified Rankin Scale (mRS). Results: Median α2-PI activity and antigen levels showed a significant drop immediately post-lysis and increased to subnormal levels at 24 h post-event. Admission α2-PI levels showed a significant negative stepwise association with stroke severity. Patients with favorable long-term outcomes (mRS 0-1) had significantly higher admission α2-PI antigen levels (median:61.6 [IQR:55.9-70.5] mg/L) as compared to patients with poor outcomes (mRS 2-5: median:59.7 [IQR:54.5-69.1] and mRS 6: median:56.0 [IQR:48.5-61.0] mg/L, p < 0.001). In a Kaplan-Meier survival analysis, patients with an α2-PI antigen in the highest quartile on admission showed significantly better long-term survival as compared to those with α2-PI antigen in the lowest quartile (HR: 4.54; 95%CI:1.92-10.8, p < 0.001); however, in a multivariate analysis, a low admission α2-PI antigen did not prove to be an independent risk factor of poor long-term outcomes. In patients with therapy-related ICH (n = 34), admission α2-PI antigen levels were significantly, but only marginally, lower as compared to those without hemorrhage. Conclusions: Low α2-PI antigen levels on admission were associated with more severe strokes and poor long-term outcomes in this cohort. Our results suggest that in case of more severe strokes, α2-PI may be involved in the limited efficacy of rt-PA thrombolysis.

EHA Guidelines on Management of Antithrombotic Treatments in Thrombocytopenic Patients With Cancer.

In cancer patients, thrombocytopenia can result from bone marrow infiltration or from anticancer medications and represents an important limitation for the use of antithrombotic treatments, including anticoagulant, antiplatelet, and fibrinolytic agents. These drugs are often required for prevention or treatment of cancer-associated thrombosis or for cardioembolic prevention in atrial fibrillation in an increasingly older cancer population. Data indicate that cancer remains an independent risk factor for thrombosis even in case of thrombocytopenia, since mild-to-moderate thrombocytopenia does not protect against arterial or venous thrombosis. In addition, cancer patients are at increased risk of antithrombotic drug-associated bleeding, further complicated by thrombocytopenia and acquired hemostatic defects. Furthermore, some anticancer treatments are associated with increased thrombotic risk and may generate interactions affecting the effectiveness or safety of antithrombotic drugs. In this complex scenario, the European Hematology Association in collaboration with the European Society of Cardiology has produced this scientific document to provide a clinical practice guideline to help clinicians in the management of patients with cancer and thrombocytopenia. The Guidelines focus on adult patients with active cancer and a clear indication for anticoagulation, single or dual antiplatelet therapy, their combination, or reperfusion therapy, who have concurrent thrombocytopenia because of either malignancy or anticancer medications. The level of evidence and the strength of the recommendations were discussed according to a Delphi procedure and graded according to the Oxford Centre for Evidence-Based Medicine.

High Neutrophil-Lymphocyte Ratio and Low Lymphocyte-Monocyte Ratio Combination after Thrombolysis Is a Potential Predictor of Poor Functional Outcome of Acute Ischemic Stroke.

(1) Background: Ischemic stroke is one of the leading causes of death and disability. An inflammatory response is observed in multiple stages of cerebral ischemia, particularly in the acute phase. Recent publications revealed that the neutrophil−lymphocyte ratio (NLR) and lymphocyte−monocyte ratio (LMR) may be used to predict long-term prognosis in acute ischemic stroke (AIS) after thrombolysis. To test whether there is a relationship between the combination of these parameters and long-term prognosis, we analyzed the NLR−LMR combination in AIS patients treated with intravenous recombinant tissue plasminogen activator (rtPA); (2) Methods: The study included 285 adults with a diagnosis of AIS and rtPA treatment within a 4.5 h time window. Blood samples were obtained at admission and 24 h after thrombolysis to calculate pre- and post-thrombolysis NLR and LMR. Clinical data, including NIHSS was registered on admission and day 1. The long-term outcome was defined 90 days post-event by the modified Rankin Scale (mRS). Therapy-associated intracranial hemorrhage (ICH) was classified according to ECASS II. Receiver operating characteristic curve (ROC) analysis was performed to determine optimal cutoffs of NLR and LMR as predictors of therapy outcomes; (3) Results: Patients were stratified by cutoffs of 5.73 for NLR and 2.08 for LMR. The multivariate logistic regression model, including all possible confounders, displayed no significant association between NLR or LMR with 3-months functional prognosis. The combination of high NLR−low LMR vs. low NRL−high LMR as obtained 24 h after thrombolysis was found to be an independent predictor of poor 3-months functional outcome (mRS ≥ 2; OR 3.407, 95% CI 1.449 to 8.011, p = 0.005). The proportion of patients between low NLR−high LMR and high NLR−low LMR groups from admission to day 1 showed no significant change in the good outcome group. On the other hand, in the poor outcome group (mRS ≥ 2), low NLR−high LMR and high NLR−low LMR groups displayed a significant shift in patient proportions from 67% and 21% at admission (p = 0.001) to 36% and 49% at 24 h after thrombolysis (p < 0.001), respectively; (4) Conclusions: Our study demonstrated for the first time that a high NLR−low LMR combination as observed at 24 h after thrombolysis can serve as an independent predictor of 3-months poor outcome in AIS patients. This simple and readily available data may help clinicians to improve the prognostic estimation of patients and may provide guidance in selecting patients for personalized and intensified care post-thrombolysis.

Illustrated State-of-the-Art Capsules of the ISTH 2022 Congress.

The ISTH London 2022 Congress is the first held (mostly) face-to-face again since the COVID-19 pandemic took the world by surprise in 2020. For 2 years we met virtually, but this year's in-person format will allow the ever-so-important and quintessential creativity and networking to flow again. What a pleasure and joy to be able to see everyone! Importantly, all conference proceedings are also streamed (and available recorded) online for those unable to travel on this occasion. This ensures no one misses out. The 2022 scientific program highlights new developments in hemophilia and its treatment, acquired and other inherited bleeding disorders, thromboinflammation, platelets and coagulation, clot structure and composition, fibrinolysis, vascular biology, venous thromboembolism, women's health, arterial thrombosis, pediatrics, COVID-related thrombosis, vaccine-induced thrombocytopenia with thrombosis, and omics and diagnostics. These areas are elegantly reviewed in this Illustrated Review article. The Illustrated Review is a highlight of the ISTH Congress. The format lends itself very well to explaining the science, and the collection of beautiful graphical summaries of recent developments in the field are stunning and self-explanatory. This clever and effective way to communicate research is revolutionary and different from traditional formats. We hope you enjoy this article and will be inspired by its content to generate new research ideas.

Neurophysiological Examinations as Adjunctive Tool to Imaging Techniques in Spontaneous Intracerebral Hemorrhage: IRONHEART Study.

Introduction: Intracerebral hemorrhage (ICH) is a devastating disease, which may lead to severe disability or even death. Although many factors may influence the outcome, neurophysiological examinations might also play a role in its course. Our aim was to examine whether the findings of electroencephalography (EEG) and transcranial magnetic stimulation (TMS) can predict the prognosis of these patients. Methods: Between June 1 2017 and June 15 2021, 116 consecutive patients with ICH were enrolled prospectively in our observational study. Clinical examinations and non-Contrast computed tomography (NCCT) scan were done on admission for ICH; follow-up NCCT scans were taken at 14 ± 2 days and at 3 months ± 7 days after stroke onset. EEG and TMS examinations were also carried out. Results: Of the patients in the study, 65.5% were male, and the mean age of the study population was 70 years. Most patients had a history of hypertension, 50.8% of whom had been untreated. In almost 20% of the cases, excessive hypertension was measured on admission, accompanied with >10 mmol/L blood glucose level, whereas their Glasgow Coma Scale was 12 on average. Presence of blood in the ventricles or subarachnoid space and high blood and perihematomal volumes meant poor prognosis. Pathological EEG was prognostic of a worse outcome. With TMS examination at 14 days, it might be possible to estimate outcome in a univariate model and the absence, or reduction of the amplitude of the motor evoked potentials was associated with poor prognosis. Conclusion: Together with the clinical symptoms, the volume of bleeding, perihematomal edema (or their combined volume), and neurophysiological examinations like EEG and TMS play an important role in the neurological outcome of patients with ICH. This might affect the patients' rehabilitation plans in the future, since with the help of the examinations the subset of patients with potential for recovery could be identified.

Decreased clot burden is associated with factor XIII Val34Leu polymorphism and better functional outcomes in acute ischemic stroke patients treated with intravenous thrombolysis.

BACKGROUND: Intravenous thrombolysis using recombinant tissue plasminogen activator remains the mainstay treatment of acute ischemic stroke (AIS), although endovascular treatment is becoming standard of care in case of large vessel occlusions (LVO). To quantify the thrombus burden in LVO, a semiquantitative CT angiography (CTA) grading system, the clot burden score (CBS) can be used. Here we aimed to study the association between CBS and various hemostasis parameters, and to evaluate which parameters are major determinants of thrombolysis outcome. METHODS: In this single-centered prospective observational case-control study, 200 anterior circulation AIS patients receiving intravenous thrombolysis treatment without thrombectomy were enrolled: 100 AIS patients with LVO (CBS 0-9) and 100 age- and sex-matched AIS patients without LVO (CBS 10). Fibrinogen, α2-plasmin inhibitor, plasminogen, factor XIII and D-dimer were assessed from blood samples taken before and 24 h after thrombolysis, and FXIII-A Val34Leu was genotyped. CBS was calculated using admission CTA. Short-term outcomes were defined based on the change in NIHSS by day 7, long-term outcomes were assessed according to the modified Rankin scale at 3 months post-event. RESULTS: Poor outcomes were significantly more frequent in the CBS 0-9 group. Plasminogen activity on admission was significantly higher in the CBS 0-9 group. In a univariate analysis, significant protective effect of the Leu34 allele against developing larger clots (CBS 0-9) could be demonstrated (OR:0.519; 95%CI:0.298-0.922, p = 0.0227). Multivariate regression analysis revealed that CBS is an independent predictor of short- and long-term functional outcomes, while such effect of the studied hemostasis parameters could not be demonstrated. CONCLUSIONS: CBS was found to be a significant independent predictor of thrombolysis outcomes. FXIII-A Leu34 carrier status was associated with smaller thrombus burden, which is consistent with the in vitro described whole blood clot mass reducing effects of the allele, but the polymorphism had no effect on thrombolysis outcomes.

A modified in vitro clot lysis assay predicts outcomes and safety in acute ischemic stroke patients undergoing intravenous thrombolysis.

The outcome of intravenous thrombolysis using recombinant tissue plasminogen activator (rt-PA) is only favorable in ≈ 40% of acute ischemic stroke (AIS) patients. Moreover, in ≈ 6-8% of cases, intracerebral hemorrhage (ICH) develops. We tested whether a modification of clot lysis assay (CLA), might predict therapy outcomes and safety. In this prospective observational study, blood samples of 231 AIS patients, all receiving intravenous rt-PA, were taken before thrombolysis. Cell-free DNA (cfDNA), CLA and CLA supplemented with cfDNA and histones (mCLA) were determined from the blood samples. Stroke severity was determined by NIHSS on admission. ICH was classified according to ECASSII. Short- and long-term outcomes were defined at 7 and 90 days post-event according to ΔNIHSS and by the modified Rankin Scale, respectively. Stroke severity demonstrated a step-wise positive association with cfDNA levels, while a negative association was found with the time to reach 50% lysis (50%CLT) parameter of CLA and mCLA. ROC analysis showed improved diagnostic performance of the mCLA. Logistic regression analysis proved that 50%CLT is a predictor of short-term therapy failure, while the AUC parameter predicts ICH occurrence. A modified CLA, supplemented with cfDNA and histones, might be a promising tool to predict short-term AIS outcomes and post-lysis ICH.

Multimodal hyperspectroscopy ­ the use of digital technology in cervical cancer screening / Multimodális hiperspektroszkópia - elorelépés a digitális technológia felé a méhnyakszurésben.

Összefoglaló. Bevezetés: Bevezetés: A citológiai alapú méhnyakrákszurés átmeneti kategóriáinak optimális menedzselése a humán papillomavírus (HPV) szurése és tipizálása ellenére jelenleg is kihívás. Vizsgálatunk célja a modern cervixspektroszkópiának (multimodális hiperspektroszkópia - MHS), egy azonnali eredményt nyújtó, digitális technológiára épülo módszernek a vizsgálata volt a citológiai alapú méhnyakszurés találati biztonságának javítására. Betegek és módszer: Vizsgálatainkat 208, 18 és 75 év közötti nobeteg bevonásával végeztük, akiknél már indikálásra került valamely, a méhnyakon végzendo mutét, citológiai eredményük rendelkezésre állt (a HPV-tesztet, amennyiben nem történt meg, elvégeztük), valamint valamennyi betegnél elvégeztük a mutét elott az MHS-vizsgálatot. A szövettani mintavétel 166 betegnél történt meg. Eredmények: A citológiai vizsgálatot (az összes betegre tekintve) magas álpozitív arány jellemezte (69,28%), amely megfigyelések mindenképpen utalnak az újabb komponens alkalmazásának igényére a triázsban. Az összes citológiai kategóriára nézve az MHS-eredmények közül kiemelendo az álnegatív leletek rendkívül alacsony aránya (3/166 = 1,8%), mely a HPV-teszt esetén ennél magasabb volt (11/165 = 6,66%). A spektroszkópiás vizsgálat álpozitív aránya ugyanakkor kedvezotlenebbnek bizonyult (91/166 = 54,81%) a HPV-vizsgálat álpozitív arányánál (40/165 = 24,24%). Az atípusos laphámsejt (ASC-US/ASC-H) citológiai kategória esetén a spektroszkópia álnegatív eredményeinek aránya (3/126 = 2,38%) szintén kedvezobb volt, mint a HPV-vizsgálaté (9/126 = 7,14%). A cervicalis intraepithelialis neoplasia-2 vagy súlyosabb fokozatú hámelváltozások azonosításában a spektroszkópia szenzitivitása 94% (95% CI = 0,84-0,99), specificitása 22% (95% CI = 0,15-0,31), negatív prediktív értéke 90% (95% CI = 0,73-0,98), pozitív prediktív értéke 34% (95% CI = 0,26-0,43) volt (p = 0,00130). Következtetés: Az MHS fejlett innovatív technológián alapuló, azonnali eredményt adó vizsgálóeljárás, amely kiemelkedoen alacsony álnegatív eredménye miatt nagy segítséget nyújt a citológiai eltéréssel rendelkezo betegek további vizsgálatában. Orv Hetil. 2021; 162(20): 790-799. INTRODUCTION: Despite the use of human papillomavirus (HPV) testing, the management of the transitional categories of cytology-based screening still remains a challenge. The modern multimodal hyperspectroscopy (MHS) of the cervix is a novel digital technology based on artificial intelligence, providing an instant result in the assessment of cytology-based screening abnormalities. PATIENTS AND METHODS: 208 women (age 18-75) were enrolled. The patients already had cytology results and an operation on the cervix indicated at the time of inclusion. HPV and the hyperspectroscopy examination was performed pre-operatively. The pre-indicated operation was performed on 166 patients. RESULTS: Cytology-based screening alone (in the category of all patients) resulted in a high false-positive rate (69.28%). In this category, the MHS had an outstanding false-negative rate (3/166 = 1.80%) compared to the HPV (11/165 = 6.66%). The false-positive rate of the spectroscopy examination (91/166 = 54.81%) was higher than that of the HPV testing (40/165 = 24.24%). In the atypical squamous cell (ASC-US/ASC-H) category, the false-negative rate of the spectroscopy (3/126 = 2.38%) was also lower than that of the HPV test (9/126 = 7.14%). In the detection of high-grade abnormalities (cervical intraepithelial neoplasia 2 and worse), the spectroscopy had a 94% sensitivity (95% CI = 0.84-0.99), with a 22% specificity (95% CI = 0.15-0.31), an 90% negative predictive value (95% CI = 0.73-0.98), and a 34% positive predictive value (95% CI = 0.26-0.43) (p = 0.00130). CONCLUSION: In the case of cytological abnormality, the MHS provides an immediate result based on advanced digital technology, and because of its outstanding false negative rate it is a great aid and should be considered in the triage of such patients. Orv Hetil. 2021; 162(20): 790-799.

A Modified in vitro Clot Lysis Assay Predicts Outcomes in Non-traumatic Intracerebral Hemorrhage Stroke Patients-The IRONHEART Study.

Background: Non-traumatic intracerebral hemorrhage (ICH) accounts for 10-15% of all strokes and results in a higher rate of mortality as compared to ischemic strokes. In the IRONHEART study, we aimed to find out whether a modified in vitro clot lysis assay method, that includes the effect of neutrophil extracellular traps (NETs) might predict ICH outcomes. Patients and Methods: In this prospective, observational study, 89 consecutive non-traumatic ICH patients were enrolled. Exclusion criteria included aneurysm rupture, cancer, liver- or kidney failure or hemorrhagic diathesis. On admission, detailed clinical and laboratory investigations were performed. ICH volume was estimated based on CT performed on admission, day 14 and 90. A conventional in vitro clot lysis assay (CLA) and a modified CLA (mCLA) including cell-free-DNA and histones were performed from stored platelet-free plasma taken on admission. Clot formation and lysis in case of both assays were defined using the following variables calculated from the turbidimetric curves: maximum absorbance, time to maximum absorbance, clot lysis times (CLT) and area under the curve (CLA AUC). Long-term ICH outcomes were defined 90 days post-event by the modified Rankin Scale (mRS). All patients or relatives provided written informed consent. Results: Patients with more severe stroke (NIHSS>10) presented significantly shorter clot lysis times of the mCLA in the presence of DNA and histone as compared to patients with milder stroke [10%CLT: NIHSS 0-10: median 31.5 (IQR: 21.0-40.0) min vs. NIHSS>10: 24 (18-31.0) min, p = 0.032]. Shorter clot lysis times of the mCLA showed significant association with non-survival by day 14 and with unfavorable long-term outcomes [mRS 0-1: 36.0 (22.5.0-51.0) min; mRS 2-5: 23.5 (18.0-36.0) min and mRS 6: 22.5 (18.0-30.5) min, p = 0.027]. Estimated ICH volume showed significant negative correlation with mCLA parameters, including 10%CLT (r = -0.3050, p = 0.009). ROC analysis proved good diagnostic performance of mCLA for predicting poor long-term outcomes [AUC: 0.73 (0.57-0.89)]. In a Kaplan-Meier survival analysis, those patients who presented with an mCLA 10%CLT result of >38.5 min on admission showed significantly better survival as compared to those with shorter clot lysis results (p=0.010). Conclusion: Parameters of mCLA correlate with ICH bleeding volume and might be useful to predict ICH outcomes.