The prognostic impact of non-driver gene mutations and variant allele frequency in primary myelofibrosis.

Prognostic impact of non-MPN driver gene mutations in primary myelofibrosis. MIPSS70: Mutation-Enhanced International Prognostic Score System.

Genomic classification and outcomes of young patients with polycythemia vera and essential thrombocythemia according to the presence of splanchnic vein thrombosis and its chronology.

To elucidate the role of splanchnic vein thrombosis (SVT) and genomic characteristics in prognosis and survival, we compared patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting SVT at diagnosis (n = 69, median age 43 years) or during follow-up (n = 21, median age 46 years) to a sex- and age-matched control group of PV/ET without SVT (n = 165, median age 48 years). The majority of patients presenting with SVT at diagnosis were classified as myeloproliferative neoplasm with heterozygous JAK2 mutation (87% of cases vs. 69% in PV/ET control group, p < 0.05), characterized by low JAK2 allele burden and no high-risk mutations. Despite this lower molecular complexity, patients presenting with SVT showed a higher risk of death (HR 3.0, 95% CI 1.5-6.0, p = 0.003) and lower event-free survival (HR 3.0, 95% CI 1.9-4.8, p < 0.001) than age- and sex-matched PV/ET controls. In patients presenting with SVT, molecular high-risk was associated with increased risk of venous re-thrombosis (HR 5.8, 95% CI 1.4-24.0, p = 0.01). Patients developing SVT during follow-up were more frequently allocated in molecular high-risk than those with SVT at diagnosis (52% versus 13%, p < 0.05). In the whole cohort of patients, molecular classification identified PV/ET patients at higher risk of disease progression whereas DNMT3A/TET2/ASXL1 mutations were associated with higher risk of arterial thrombosis. In conclusion, clinical and molecular characteristics are different in PV/ET patients with SVT, depending on whether it occurs at diagnosis or at follow-up. Molecular characterization by NGS is useful for assessing the risk of thrombosis and disease progression in young patients with PV/ET.

Clinical Characteristics and Outcomes of Patients with Primary and Secondary Myelofibrosis According to the Genomic Classification Using Targeted Next-Generation Sequencing.

Myelofibrosis (MF) is a heterogeneous disease regarding its mutational landscape, clinical presentation, and outcomes. The aim of our work is to evaluate the genomic classification of MF considering whether it is primary or secondary. One-hundred seventy-five patients, 81 with primary MF (PMF) and 94 with secondary MF (SMF) were hierarchically allocated into eight molecular groups. We found that TP53 disruption/aneuploidy (n = 16, 9%) was more frequent (12% versus 6%) and showed higher allele burden (57% versus 15%, p = 0.01) in SMF than in PMF, and was associated with shorter survival (median 3.5 years). Mutations in chromatin/spliceosome genes (n = 72, 41%) represented the most frequent genomic group in PMF. Homozygous JAK2 mutation (n = 40, 23%) was enriched with old patients with SMF after long-standing polycythemia vera, whereas MF with heterozygous JAK2 mutation (n = 22, 13%) was similarly distributed among PMF and SMF. MF with CALR mutation (n = 19, 11%) predominated in post-essential thrombocythemia MF. The remaining genomic groups were infrequent. TP53 disruption, chromatin/spliceosome mutation, and homozygous JAK2 mutation were associated with significantly shorter survival and higher risk of progression. In conclusion, genomic classification reveals different pathogenic pathways between PMF and SMF and provides relevant information regarding disease phenotype and outcomes.

Application of IPSET-thrombosis in 1366 Patients Prospectively Followed From the Spanish Registry of Essential Thrombocythemia.

The International Prognostic Score of thrombosis in Essential Thrombocythemia (IPSET-thrombosis) and its revised version have been proposed to guide thrombosis prevention strategies. We evaluated both classifications to prognosticate thrombosis in 1366 contemporary essential thrombocythemia (ET) patients prospectively followed from the Spanish Registry of ET. The cumulative incidence of thrombosis at 10 years, taking death as a competing risk, was 11.4%. The risk of thrombosis was significantly higher in the high-risk IPSET-thrombosis and high-risk revised IPSET-thrombosis, but no differences were observed among the lower risk categories. Patients allocated in high-risk IPSET-thrombosis (subdistribution hazard ratios [SHR], 3.7 [95% confidence interval, CI, 1.6-8.7]) and high-risk revised IPSET-thrombosis (SHR, 3.2 [95% CI, 1.4-7.45]) showed an increased risk of arterial thrombosis, whereas both scoring systems failed to predict venous thrombosis. The incidence rate of thrombosis in intermediate risk revised IPSET-thrombosis (aged >60 years, JAK2-negative, and no history of thrombosis) was very low regardless of the treatment administered (0.9% and 0% per year with and without cytoreduction, respectively). Dynamic application of the revised IPSET-thrombosis showed a low rate of thrombosis when patients without history of prior thrombosis switched to a higher risk category after reaching 60 years of age. In conclusion, IPSET-thrombosis scores are useful for identifying patients at high risk of arterial thrombosis, whereas they fail to predict venous thrombosis. Controlled studies are needed to determine the appropriate treatment of ET patients assigned to the non-high-risk categories.

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis.

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification.

Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish Registry of Myelofibrosis.

Available data have proved insufficient to develop consensus recommendations on the prevention of thrombosis and bleeding in myelofibrosis (MF). We evaluated the incidence and risk factors of vascular complications in 1613 patients from the Spanish Myelofibrosis Registry. Over a total of 6981 patient-years at risk, 6.4% of the study population had at least one thrombotic event after MF diagnosis, amounting to an incidence rate of 1.65 per 100 patient-years. Prior history of thrombosis, the JAK2 mutation, and the intermediate-2/high-risk International Prognostic Scoring System (IPSS) categories conferred an increased thrombotic risk after adjustment for the risk-modifying effect of anti-thrombotic and cytoreductive treatments. History of thrombosis and the JAK2 mutation allowed us to pinpoint a group of patients at higher risk of early thrombosis. No decreased incidence of thrombosis was observed while patients were on anti-thrombotic or cytoreductive treatment. An increased risk of venous thrombosis was found during treatment with immunomodulatory agents. A total of 5.3% of patients had at least one episode of major bleeding, resulting in an incidence rate of 1.5 events per 100 patient-years. Patients in the intermediate-2/high-risk IPSS categories treated with anti-coagulants had an almost sevenfold increased risk of major bleeding. These findings should prove useful for guiding decision-making in clinical practice.

Real-world analysis of main clinical outcomes in patients with polycythemia vera treated with ruxolitinib or best available therapy after developing resistance/intolerance to hydroxyurea.

BACKGROUND: Ruxolitinib is approved for patients with polycythemia vera (PV) who are resistant/intolerant to hydroxyurea, but its impact on preventing thrombosis or disease-progression is unknown. METHODS: A retrospective, real-world analysis was performed on the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to subsequent treatment with ruxolitinib (n = 105) or the best available therapy (BAT; n = 272). Survival probabilities and rates of thrombosis, hemorrhage, acute myeloid leukemia, myelofibrosis, and second primary cancers were calculated according to treatment. To minimize biases in treatment allocation, all results were adjusted by a propensity score for receiving ruxolitinib or BAT. RESULTS: Patients receiving ruxolitinib had a significantly lower rate of arterial thrombosis than those on BAT (0.4% vs 2.3% per year; P = .03), and this persisted as a trend after adjustment for the propensity to have received the drug (incidence rate ratio, 0.18; 95% confidence interval, 0.02-1.3; P = .09). There were no significant differences in the rates of venous thrombosis (0.8% and 1.1% for ruxolitinib and BAT, respectively; P = .7) and major bleeding (0.8% and 0.9%, respectively; P = .9). Ruxolitinib exposure was not associated with a higher rate of second primary cancers, including all types of neoplasia, noncutaneous cancers, and nonmelanoma skin cancers. After a median follow-up of 3.5 years, there were no differences in survival or progression to acute leukemia or myelofibrosis between the 2 groups. CONCLUSIONS: The results suggest that ruxolitinib treatment for PV patients with resistance/intolerance to hydroxyurea may reduce the incidence of arterial thrombosis. LAY SUMMARY: Ruxolitinib is better than other available therapies in achieving hematocrit control and symptom relief in patients with polycythemia vera who are resistant/intolerant to hydroxyurea, but we still do not know whether ruxolitinib provides an additional benefit in preventing thrombosis or disease progression. We retrospectively studied the outcomes of 377 patients with resistance/intolerance to hydroxyurea from the Spanish Registry of Polycythemia Vera according to whether they subsequently received ruxolitinib (n = 105) or the best available therapy (n = 272). Our findings suggest that ruxolitinib could reduce the incidence of arterial thrombosis, but a disease-modifying effect could not be demonstrated for ruxolitinib in this patient population.

Patients' perceptions with dabigatran in patients with atrial fibrillation previously treated with vitamin K antagonists.

Aim: To analyze the perception of anticoagulation with dabigatran in patients with nonvalvular atrial fibrillation previously treated with vitamin K antagonists over a 6-month period. Materials & methods: This is a prospective, noninterventional, noncontrolled, multicenter study. To assess patients' perceptions, PACT-Q2 questionnaire was completed. Results: Six hundred and fifty nine patients (73.1 ± 9.4 years, CHA2DS2-VASc 3.6 ± 1.6) were included. At baseline, the convenience and satisfaction scores were 60.9 ± 24.9 and 49.9 ± 17.7, respectively. The scores significantly increased along the study. Convenience score was higher in males and in patients with low-moderate thromboembolic risk. Satisfaction score was higher in females. Only 8.0% of patients discontinued dabigatran (3.7% due to side effects). Conclusion: Convenience and satisfaction scores for nonvalvular atrial fibrillation patients treated with dabigatran at 6 months were significantly better than with previous vitamin K antagonists.

Natural history of polycythemia vera and essential thrombocythemia presenting with splanchnic vein thrombosis.

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) presenting with splanchnic vein thrombosis (SVT) might have a specific clinico-biological profile. To investigate this hypothesis, 3705 PV/ET patients from three national registers, 118 of them presenting with SVT, were reviewed. After correction for age and sex, PV/ET patients with SVT showed an increased risk of death (HR 2.47, 95% CI 1.5-4.01, p < 0.001), venous thrombosis (IRR 3.4, 95%CI 2.1-5.5, p < 0.001), major bleeding (IRR 3.6, 95%CI 2.3-5.5, p < 0.001), and second cancer (IRR 2.37, 95%CI 1.4-4.1, p = 0.002). No case of acute leukemia was documented among patients with PV/ET presenting with SVT and seven of them (6%) progressed to myelofibrosis. SVT was not associated with lower risk of MF after correction by age and sex. Patients with SVT more frequently died from complications related to hepatic disease, major bleeding, or second cancer, resulting in a 5-year reduction of age- and sex-adjusted median survival. In conclusion, PV and ET patients presenting with SVT have shorter survival than patients with PV and ET of the same age and sex. This excess mortality is related to liver disease, major bleeding, and second cancer rather than to the natural evolution of the MPN.

Idarucizumab, but not procoagulant concentrates, fully restores dabigatran-altered platelet and fibrin components of hemostasis.

BACKGROUND: Comparative studies on the restoration of hemostasis with different reversal agents after dabigatran therapy have not been performed. We compared the efficacy and prothrombotic potential of the specific antidote idarucizumab with that of previously recommended non-specific procoagulant concentrates. STUDY DESIGN AND METHODS: We explored the in vitro effects of dabigatran (184 ng/mL) on fibrin and platelet-aggregate formation onto a damaged vessel under flow conditions (600 s-1 ). The reversal mechanisms and efficacy of idarucizumab (0.3-3 mg/mL) were compared with that of the non-specific procoagulant concentrates aPCC (25-75 U/Kg), PCC (70 U/Kg), or rFVIIa (120 µg/Kg). Generation of thrombin and prothrombin fragment (F1 + 2), and thromboelastometry parameters of clot formation were measured. RESULTS: Dabigatran caused pronounced reductions in fibrin (87%) and platelet interactions (36%) with damaged vessels (p < 0.01) and significantly impaired thrombin generation and thromboelastometric parameters (delayed dynamics and reduced firmness). Idarucizumab completely normalized rates of fibrin and platelet coverage to baseline values in flow studies; and reversed the alterations in thrombin generation, F1 + 2 and thromboelastometry parameters produced by dabigatran. In comparison, aPCC and PCC only partially compensated for the dabigatran-induced alterations in fibrin deposition, but were unable to fully restore them to baseline values. Reversal with aPCC or PCC improved the majority of alterations in coagulation-related tests, but tended to overcompensate thrombin generation kinetics and significantly increased F1 + 2 levels. CONCLUSION: Idarucizumab antagonizes alterations of direct and indirect biomarkers of hemostasis caused by dabigatran. In our studies, idarucizumab was clearly more efficacious than strategies with non-specific procoagulant concentrates and devoid of the excessive procoagulant tendency observed with the latter.

Essential thrombocythaemia with mutation in MPL: clinicopathological correlation and comparison with JAK2V617F-mutated and CALR-mutated genotypes.

AIM: To characterise the clinical and histological features of MPL-mutated essential thrombocythaemia (ET). PATIENTS AND METHODS: Bone marrow biopsies of 175 patients with ET were centrally reviewed according to the 2016 WHO classification, including 42 cases with MPL mutation, 98 JAK2V617F-mutated and 35 CALR-mutated. Clinical and histological features were compared among the three genotypes included in the current 2016 WHO classification and among the different types of MPL mutations. RESULTS: Patients with MPL-mutated ET were significantly older than those with the other genotypes. Haematological values at diagnosis were similar among MPL-mutated and CALR-mutated ET, with both genotypes showing higher platelet counts and lower haemoglobin values than ET with JAK2V617F genotype. In the bone marrow, the median number of megakaryocytes was higher in MPL and CALR than in JAK2V617F genotype (16, 19 and 14 megakaryocytes per ×20 power field, respectively, p=0.004). Histological features of prefibrotic myelofibrosis were rarely observed in MPL genotype, whereas sinusoidal hyperplasia, dense clusters of megakaryocytes and reticulin fibrosis were more frequent in CALR-mutated ET, with 11% of such cases fulfilling WHO 2016 histological criteria of prefibrotic myelofibrosis. With a median follow-up of 3.5 years, no significant differences were seen among genotypes regarding survival, vascular complications or myelofibrotic transformation. There were no significant differences in the clinical data or in the histological characteristics depending on the type of MPL mutation. CONCLUSION: MPL and CALR ET genotypes share clinical and histological characteristics. In contrast to CALR genotype, features of prefibrotic myelofibrosis are uncommon in MPL-mutated ET.

Benefit-risk profile of cytoreductive drugs along with antiplatelet and antithrombotic therapy after transient ischemic attack or ischemic stroke in myeloproliferative neoplasms.

We analyzed 597 patients with myeloproliferative neoplasms (MPN) who presented transient ischemic attacks (TIA, n = 270) or ischemic stroke (IS, n = 327). Treatment included aspirin, oral anticoagulants, and cytoreductive drugs. The composite incidence of recurrent TIA and IS, acute myocardial infarction (AMI), and cardiovascular (CV) death was 4.21 and 19.2%, respectively at one and five years after the index event, an estimate unexpectedly lower than reported in the general population. Patients tended to replicate the first clinical manifestation (hazard ratio, HR: 2.41 and 4.41 for recurrent TIA and IS, respectively); additional factors for recurrent TIA were previous TIA (HR: 3.40) and microvascular disturbances (HR: 2.30); for recurrent IS arterial hypertension (HR: 4.24) and IS occurrence after MPN diagnosis (HR: 4.47). CV mortality was predicted by age over 60 years (HR: 3.98), an index IS (HR: 3.61), and the occurrence of index events after MPN diagnosis (HR: 2.62). Cytoreductive therapy was a strong protective factor (HR: 0.24). The rate of major bleeding was similar to the general population (0.90 per 100 patient-years). In conclusion, the long-term clinical outcome after TIA and IS in MPN appears even more favorable than in the general population, suggesting an advantageous benefit-risk profile of antithrombotic and cytoreductive treatment.

Impact of genotype on leukaemic transformation in polycythaemia vera and essential thrombocythaemia.

The influence of driver mutations on leukaemic transformation was analysed in 1747 patients with polycythaemia vera or essential thrombocythaemia. With a median follow-up of 7·2 years, 349 patients died and 62 progressed to acute leukaemia or myelodysplastic syndrome. Taking death as a competing risk, CALR genotype was associated with a lower risk of transformation [subdistribution hazard ratio (SHR): 0·13, 95% confidence interval (CI): 0·2-0·9, P = 0·039], whereas JAK2 V617F showed borderline significance for higher risk (SHR: 2·05, 95% CI: 0·9-4·6, P = 0·09). Myelofibrotic transformation increased leukaemic risk, except in CALR-mutated patients. Next generation sequencing of 51 genes at the time of transformation showed additional mutations (median number: 3; range: 1-5) in 25 out of 29 (86%) assessable cases. Mutations (median: 1; range: 1-3) were detected in 67% of paired samples from the chronic phase. Leukaemia appeared in a JAK2 V617F negative clone in 17 (58%) cases, eleven of them being previously JAK2 V617F-positive. JAK2 V617F-mutated leukaemia was significantly associated with complex karyotype and acquisition of TP53 mutations, whereas EZH2 and RUNX1 mutations were more frequent in JAK2 V617F-negative leukaemia. Survival was longer in JAK2 V617F-unmutated leukaemia (343 days vs. 95 days, P = 0·003). In conclusion, CALR genotype is associated with a lower risk of leukaemic transformation. Leukaemia arising in a JAK2 V617F-negative clone is TP53 independent and shows better survival.

Differential inhibitory action of apixaban on platelet and fibrin components of forming thrombi: Studies with circulating blood and in a platelet-based model of thrombin generation.

INTRODUCTION: Mechanisms of action of direct oral anticoagulants (DOAC) suggest a potential therapeutic use in the prevention of thrombotic complications in arterial territories. However, effects of DOACs on platelet activation and aggregation have not been explored in detail. We have investigated the effects of apixaban on platelet and fibrin components of thrombus formation under static and flow conditions. METHODS: We assessed the effects of apixaban (10, 40 and 160 ng/mL) on: 1) platelet deposition and fibrin formation onto a thrombogenic surface, with blood circulating at arterial shear-rates; 2) viscoelastic properties of forming clots, and 3) thrombin generation in a cell-model of coagulation primed by platelets. RESULTS: In studies with flowing blood, only the highest concentration of apixaban, equivalent to the therapeutic Cmax, was capable to significantly reduce thrombus formation, fibrin association and platelet-aggregate formation. Apixaban significantly prolonged thromboelastometry parameters, but did not affect clot firmness. Interestingly, results in a platelet-based model of thrombin generation under more static conditions, revealed a dose dependent persistent inhibitory action by apixaban, with concentrations 4 to 16 times below the therapeutic Cmax significantly prolonging kinetic parameters and reducing the total amount of thrombin generated. CONCLUSIONS: Our studies demonstrate the critical impact of rheological conditions on the antithrombotic effects of apixaban. Studies under flow conditions combined with modified thrombin generation assays could help discriminating concentrations of apixaban that prevent excessive platelet accumulation, from those that deeply impair fibrin formation and may unnecessarily compromise hemostasis.

Magnitudes biológicas que tiene interés medir de modo urgente / Biological markers in emergency laboratory

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Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation.

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2(V617F) mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2(V617F)-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2(V617F)-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3-42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2(V617F)-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

Dosing of rivaroxaban by indication: getting the right dose for the patient.

INTRODUCTION: Vitamin K antagonists were the only oral anticoagulants available for several decades, but they require frequent coagulation monitoring and dose adjustment. The direct oral anticoagulants rivaroxaban , dabigatran, apixaban, and, most recently, edoxaban have been approved for the management of specific thromboembolic indications. AREAS COVERED: This review will provide a brief overview of the cell-based coagulation model, the main determinants of arterial and venous thrombosis, and the pharmacological rationale and clinical evidence for the different dosing regimens of rivaroxaban. Published articles indexed on PubMed and Medline covering arterial and venous thrombi pathophysiology, pharmacokinetics, and pharmacodynamics of rivaroxaban, and Phase II and Phase III clinical studies with rivaroxaban as well as real-world evidence were analyzed. EXPERT OPINION: Education on pharmacokinetic/pharmacodynamic characteristics, as well as how to manage adverse events, is needed to increase physician knowledge and confidence in using direct oral anticoagulants, as specifically discussed for rivaroxaban in this article. The continued uptake of direct oral anticoagulants in clinical practice depends on understanding of the clinical evidence and reassurance provided by emerging real-world data.

Coagulation Factor Concentrates Fail to Restore Alterations in Fibrin Formation Caused by Rivaroxaban or Dabigatran in Studies With Flowing Blood From Treated Healthy Volunteers.

We evaluated the hemostatic alterations in blood from healthy individuals treated for 5 days with direct oral anticoagulants (DOACs) rivaroxaban (20 mg/d) or dabigatran (150 mg/12 h) in a single-blind clinical trial with crossover assignment (NCT01478282). We assessed the potential of prothrombin complex concentrates, activated prothrombin complex concentrates, or recombinant activated factor VII, when added ex vivo, to reverse the alterations caused by these DOACs. Blood was drawn at maximum plasma concentration after the last dose of each DOAC, and modifications in coagulation biomarkers were evaluated using a series of tests performed under steady conditions including routine coagulation, thrombin generation, and thromboelastometry assays. Additional studies in standardized flow devices were applied to evaluate alterations on platelet deposition and fibrin formation on damaged vascular surfaces exposed to flowing blood. Both DOACs caused important modifications of all coagulation biomarkers and significantly reduced fibrin formation in flow studies. Alterations in biomarkers observed in steady laboratory tests were normalized and occasionally overcompensated by procoagulant strategies. In contrast, reductions in fibrin formation observed in studies with flowing blood were improved, although never completely restored to baseline levels. Effects of dabigatran in flow studies appeared more resistant to reversal strategies than those of rivaroxaban. Inconsistencies between results of coagulation studies in steady or flowing assays not only raise concerns about the adequacy of the earlier tests to predict the restoration of the coagulopathy induced by DOACs but also suggest limitations of nonspecific procoagulant strategies to control severe coagulopathy in patients inadvertently overexposed these agents.