• Factor XII can contribute to thrombus formation in human and nonhuman primate blood.• An antibody that blocks factor XII activation (15H8) produces an antithrombotic effect in a primate thrombosis model.The plasma zymogens factor XII (fXII) and factor XI (fXI) contribute to thrombosis in a variety of mouse models. These proteins serve a limited role in hemostasis, suggesting that antithrombotic therapies targeting them may be associated with low bleeding risks.Although there is substantial epidemiologic evidence supporting a role for fXI in human thrombosis, the situation is not as clear for fXII. We generated monoclonal antibodies (9A2 and 15H8) against the human fXII heavy chain that interfere with fXII conversion to the protease factor XIIa (fXIIa). The anti-fXII antibodies were tested in models in which anti-fXI antibodies are known to have antithrombotic effects. Both anti-fXII antibodies reduced fibrin formation in human blood perfused through collagen-coated tubes. fXII-deficient mice are resistant to ferric chloride-induced arterial thrombosis, and this resistance can be reversed by infusion of human fXII. 9A2 partially blocks, and 15H8 completely blocks, the prothrombotic effect of fXII in this model. 15H8 prolonged the activated partial thromboplastin time of baboon and human plasmas. 15H8 reduced fibrin formation in collagen-coated vascular grafts inserted into arteriovenous shunts in baboons, and reduced fibrin and platelet accumulation downstream of the graft. These findings support a role for fXII in

Objective To describe the clinical data from the first 108 patients seen in the Mayo Clinic post–COVID-19 care clinic (PCOCC). Methods After Institutional Review Board approval, we reviewed the charts of the first 108 patients seen between January 19, 2021, and April 29, 2021, in the PCOCC and abstracted from the electronic medical record into a standardized database to facilitate analysis. Patients were grouped into phenotypes by expert review. Results Most of the patients seen in our clinic were female (75%; 81/108), and the median age at presentation was 46 years (interquartile range, 37 to 55 years). All had post-acute sequelae of SARS-CoV-2 infection, with 6 clinical phenotypes being identified: fatigue predominant (n=69), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women, and the dyspnea-predominant phenotype was more common in men. Interleukin 6 (IL-6) was elevated in 61% of patients (69% of women; P =.0046), which was more common than elevation in C-reactive protein and erythrocyte sedimentation rate, identified in 17% and 20% of cases, respectively. Conclusion In our PCOCC, we observed several distinct clinical phenotypes. Fatigue predominance was the most common presentation and was associated with elevated IL-6 levels and female sex. Dyspnea predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were more likely than erythrocyte sedimentation rate and C-reactive protein to be elevated in patients with post-acute sequelae of SARS-CoV-2 infection.

Objective To develop and implement criteria for description of post COVID syndrome based on analysis of patients presenting for evaluation at Mayo Clinic Rochester between November 2019 and August 2020. Methods A total of 465 patients with a history of testing positive for COVID-19 were identified and their medical records reviewed. After a thorough review, utilizing the DELPHI methods by an expert panel, 42 (9%) cases were identified with persistent central sensitization (CS) symptoms persisting after the resolution of acute COVID-19, herein referred to as Post COVID syndrome (PoCoS). In this report we describe the baseline characteristics of these PoCoS patients. Results Among these 42 PoCoS patients, the mean age was 46.2 years (median age was 46.5 years). Pain (90%), fatigue (74%), dyspnea (43%), and orthostatic intolerance (38%) were the most common symptoms. The characteristics of an initial 14 patients were utilized for the development of clinical criteria via a modified Delphi Method by a panel of experts in central sensitization disorders. These criteria were subsequently applied in the identification of 28 additional cases of suspected PoCoS. A 2-reviewer system was used to analyze agreement with using the criteria, with all 28 cases determined to be either probable or possible cases by the reviewers. Inter-reviewer agreement using these proposed defining criteria was high with a Cohen’s alpha of .88. Conclusions Here we present what we believe to be the first definitional criteria for Post COVID syndrome. These may be useful in clinical phenotyping of these patients for targeted treatment and future research.

Objective Persistent post-COVID symptoms are estimated to occur in up to 10% of patients who have had COVID-19. These lingering symptoms may persist for weeks to months after resolution of the acute illness. This study aimed to add insight into our understanding of certain post-acute conditions and clinical findings. The primary purpose was to determine the persistent post COVID impairments prevalence and characteristics by collecting post COVID illness data utilizing Patient-Reported Outcomes Measurement Information System (PROMIS®). The resulting measures were used to assess surveyed patients physical, mental, and social health status. Methods A cross-sectional study and 6-months Mayo Clinic COVID recovered registry data were used to evaluate continuing symptoms severity among the 817 positive tested patients surveyed between March and September 2020. The resulting PROMIS® data set was used to analyze patients post 30 days health status. The e-mailed questionnaires focused on fatigue, sleep, ability to participate in social roles, physical function, and pain. Results The large sample size (n = 817) represented post hospitalized and other managed outpatients. Persistent post COVID impairments prevalence and characteristics were determined to be demographically young (44 years), white (87%), and female (61%). Dysfunction as measured by the PROMIS® scales in patients recovered from acute COVID-19 was reported as significant in the following domains: ability to participate in social roles (43.2%), pain (17.8%), and fatigue (16.2%). Conclusion Patient response on the PROMIS® scales was similar to that seen in multiple other studies which used patient reported symptoms. As a result of this experience, we recommend utilizing standardized scales such as the PROMIS® to obtain comparable data across the patients’ clinical course and define the disease trajectory. This would further allow for effective comparison of data across studies to better define the disease process, risk factors, and assess the impact of future treatments.

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Objective: To describe the clinical data from the first 107 patients seen in the Mayo Clinic Post COVID-19 Care Clinic (PCOCC). Patients and Methods: After IRB approval, we reviewed the charts of 107 patients seen between January 19, 2021 and April 29, 2021 in the Mayo Clinic Post COVID Care Clinic (PCOCC) in order to describe the first 107 patients treated through the Mayo Clinic PCOCC. Data was abstracted from the electronic medical record into a standardized database to facilitate analysis. Phenotypes of patients seen in the PCOCC clinic were identified by expert review of predominant symptom clusters. Results: The majority of patients seen in our clinic were female (75%, 80/107), and the median age at presentation was 47 years (interquartile range [IQR] 37, 55). All had Post Acute Sequelae of SARS-CoV-2 infection (PASC) with six clinical phenotypes being identified: fatigue predominant (n=68), dyspnea predominant (n=23), myalgia predominant (n=6), orthostasis predominant (n=6), chest pain predominant (n=3), and headache predominant (n=1). The fatigue-predominant phenotype was more common in women (84%, p=0.006) and the dyspnea-predominant phenotype was more common in men (52%, p=0.002). IL-6 was elevated in 61% of patients (69% of women, p=0.0046) which was statistically discordant with elevation in CRP and ESR which was identified in 17% and 20% of cases respectively (p<0.001). Four PASC phenotypes (fatigue-predominant, myalgia-predominant, orthostasis predominant, and headache-predominant) were associated with central sensitization (CS), and higher IL-6 levels than those phenotypes not associated with CS (p=0.013). Patients with CS phenotypes after COVID-19 infection (post COVID syndrome) were predominantly female (80%, p=0.0085). Conclusion: In our post COVID clinic, we observed several distinct clinical phenotypes. Fatigue-predominance was the most common presentation and was associated with elevated IL-6 levels and female gender. Dyspnea-predominance was more common in men and was not associated with elevated IL-6 levels. IL-6 levels were significantly elevated in patients with PASC and discordant with ESR and CRP, particularly in those with central sensitization phenotypes.

1106 The plasma protease factor XIIa (FXIIa) contributes to vascular occlusion in murine thrombosis models, at least partly through activation of factor XI (FXI). While there is good correlation between plasma FXI levels and thrombotic events in humans, the situation is not as clear for FXII (the precursor of FXIIa), suggesting fundamental differences in thrombus formation in mice and humans. To facilitate studies on the effects of FXII/XIIa on thrombus formation, we developed novel inhibitory antibodies to human FXII, designated 9A2 and 15H8, by immunizing FXII-deficient mice with human FXII. Using recombinant human FXII molecules that lack various domains, and chimeras in which specific domains in FXII are replaced with those from the related protein hepatocyte growth factor activator, we determined that 9A2 and 15H8 bind to the FXII/XIIa non-catalytic heavy chain at different sites. 9A2 binds on or near the EGF2 domain, while 15H8 binds to the fibronectin type I and/or kringle domain. These areas have been implicated in FXII binding to polyanionic surfaces. Saturating concentrations of 9A2 or 15H8 reduced FXII activity by 50% and 90%, respectively, in an aPTT assay using normal plasma, while combining the antibodies resulted in >95% inhibition. However, in assays in which clot formation was triggered by adding FXIIa directly to plasma, preincubation of FXIIa with either antibody did not prolong the clotting time. Furthermore, neither antibody had a strong effect in a chromogenic assay of FXI activation by FXIIa, indicating the antibodies interfere with the aPTT assay primarily by inhibiting FXII activation. FXII activation in the aPTT assay is initiated by addition of a polyanion such as silica to the plasma to induce contact activation. In vivo, polymers of inorganic phosphate (polyP) may serve a similar function. Contact activation is triggered in plasma when FXII bound to the polyanion is activated, probably by trace amounts of FXIIa or another protease present in the plasma. Once formed, FXIIa converts the zymogens prekallikrein and FXI to the proteases kallikrein and FXIa, both of which can activate additional FXIIa to amplify the process. In the presence of 9A2 or 15H8, activation of pure FXII in the presence of either silica or polyP was significantly reduced. Interestingly, the antibodies actually potentiated FXII activation by kallikrein or FXIa in the absence of a polyanion. Taken as a whole, these results suggest that binding of 9A2 or 15H8 to FXII results in conformational changes that make FXII a better substrate for kallikrein and FXIa, possibly by mimicking the effect of FXII binding to a polyanion, but that prevent activation of FXII by FXIIa (autoactivation), blunting the overall rate of activation. We tested the effects of 9A2 and 15H8 in a mouse model in which thrombotic occlusion of the carotid artery is induced by exposing the vessel to a 3.5% solution of ferric chloride. Wild type C57Bl/6 mice develop arterial occlusion within 5 to 10 minutes, while FXII-deficient mice are resistant to arterial occlusion. Infusion of human FXII into FXII-deficient mice restores the wild type phenotype. 15H8 prevented thrombus formation in mice reconstituted with human FXII, while 9A2 reduced the rate of thrombotic occlusion by 50%. In an ex vivo flow model, perfusion of human blood through collagen-coated tubes at a shear rate of 300 sec−1 results in tube occlusion by platelet and fibrin rich clot in ∼15 minutes. 15H8 effectively blocked fibrin formation and reduced platelet accumulation, preventing tube occlusion. 9A2 was also effective at preventing clot formation, but there was evidence of some fibrin accumulation over time. In summary, the monoclonal anti-human FXII IgGs 9A2 and 15H8 prevent thrombus formation in whole blood in vivo and ex vivo by interfering with FXII activation. Our data support the hypothesis that pharmacologic inhibition of FXII activation may have therapeutic utility in disorders that are driven or aggravated by the blood contact system. Disclosures: No relevant conflicts of interest to declare.

The post-COVID syndrome is estimated to occur in up to 10% of patients who have had COVID-19. This condition manifests as lingering symptoms which persist for weeks to months after resolution of the acute illness. The syndrome is poorly understood and efforts are just beginning to appropriately characterize the symptoms expressed by this population. We present a population of patients with persistent symptoms as measured by a select number of PROMIS surveys (i.e. fatigue, sleep, pain, physical functioning, and social roles). We believe this to be the first use of the PROMIS survey data collected in this population and one of the first to attempt to measure social dysfunction secondary to the post-COVID syndrome. Our patient population is notably younger (30.9% were between 40-59 years of age), with a majority being female (60.5%). They also reported deficits in social roles (34.5%), and greater fatigue (14.7%), and pain (15.9%); along with a variety of disease severity ranging from asymptomatic to requiring admission. Despite this increased heterogeneity of population, the symptomatology of the post-COVID syndrome is preserved. These findings differ significantly from previously published data that demonstrated that outpatients can have duration of post-COVID syndrome similar to those who were hospitalized.