Abnormal clotting of the intrinsic/contact pathway in Alzheimer disease patients is related to cognitive ability by Georgette L. Suidan, Pradeep K. Singh,

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Abnormal clotting of the intrinsic/contact pathway in Alzheimer disease patients is related to cognitive ability by Georgette L. Suidan, Pradeep K. Singh, Sunita Patel-Hett, Zu-Lin Chen, Dmitri Volfson, Hitomi Yamamoto-Imoto, Erin H. Norris, Robert D. Bell, and Sidney Strickland BloodAdv Volume 2(9):954-963 May 8, 2018 © 2018 by The American Society of Hematology

Georgette L. Suidan et al. Blood Adv 2018;2:954-963 © 2018 by The American Society of Hematology

Intrinsic clotting profile is altered in AD patient plasma. Intrinsic clotting profile is altered in AD patient plasma. Intrinsic clotting in ND and AD plasma was assessed by TEG and microtiter plate–based aPTT. (A) TEG trace from normal plasma indicates the origin of the graphed metrics. (B) Representative TEG traces from ND and AD plasma (red = 1 ND donor, blue = 3 AD donors). (C) Tmax. (D) R2. (E) Rate of clot formation (alpha). (F) Representative spectra of ND and AD plasma in the aPTT assay. (G) Clotting start time. (H) Clotting rate (Vmax) in ND and AD plasma assessed in the aPTT assay. All scatter graphs are the mean with SD. *P < .05, **P < .01, ***P < .001. The unpaired Student t test was used to determine statistical significance in panels C-E and G-H. Georgette L. Suidan et al. Blood Adv 2018;2:954-963 © 2018 by The American Society of Hematology

Intrinsic clotting abnormality is more profound in younger AD patient plasma and correlated inversely with MMSE score. Intrinsic clotting abnormality is more profound in younger AD patient plasma and correlated inversely with MMSE score. ND and AD plasma samples were separated into a “young” group (50-65 years) and an “old” group (66-80 years), and different TEG parameters were analyzed. Tmax (A), R2 (B), and alpha (C) graphed by age group. (D) Correlation of Tmax and MMSE score. (E) Correlation of R2 and MMSE score. (F) Correlation of alpha V and MMSE score. (G) Correlation of Vmax (from aPTT assay) and MMSE score. In panels D-G, red dots represent ND samples, and blue squares represent AD samples. In panels A-C, 2-way analysis of variance (ANOVA) revealed that age category and group, but not their interaction, were significantly different. In panels D-G, correlations were assessed for all subjects and within the AD group only via Pearson’s method. r = Pearson’s correlation coefficient. *P < .05, **P < .01, ***P < .001. Georgette L. Suidan et al. Blood Adv 2018;2:954-963 © 2018 by The American Society of Hematology

Coagulation assay end points correlate with CSF NF-L levels. Coagulation assay end points correlate with CSF NF-L levels. (A) Trend toward a positive correlation between R2 and NF-L. (B) Trend toward a negative correlation between alpha (rate of clot formation) and NF-L. (C) Significant positive correlation between clot start time and NF-L. (D) Significant negative correlation between Vmax and NF-L. Correlations were assessed for all subjects via Pearson’s method. r = Pearson’s correlation coefficient. Georgette L. Suidan et al. Blood Adv 2018;2:954-963 © 2018 by The American Society of Hematology

FXII and FXI functional inhibitor(s) are likely to be responsible for coagulopathy in AD samples. FXII and FXI functional inhibitor(s) are likely to be responsible for coagulopathy in AD samples. (A) Clotting start time of NPP and NPP mixed with ND or AD plasma was assessed via aPTT. (B) Plasma deficient in FIX, FX, FXI, or FXII was mixed with ND or AD plasma (9:1), and clotting start time was assessed via aPTT. Data are represented as the fold change over the average of the ND sample mixed with each factor-depleted plasma. Plasma protein levels of FXI (C) and FXII (D). For NPP-mixing experiments, 1-way ANOVA was performed with Tukey’s post hoc analysis. For each factor-depleted plasma experiment, the unpaired Student t test was performed between ND and AD with Welch’s correction. *P < .05, **P < .01, ***P < .001. Georgette L. Suidan et al. Blood Adv 2018;2:954-963 © 2018 by The American Society of Hematology

Clotting time is delayed in Tg6799 mice compared with WT littermates in an age-dependent manner. Clotting time is delayed in Tg6799 mice compared with WT littermates in an age-dependent manner. Clotting start time was assessed by aPTT in Tg6799 and age-matched littermate WT animals. Data are represented as a fold change compared with the average WT clotting time for each age group. *P < .05, **P < .01, unpaired Student t test. Georgette L. Suidan et al. Blood Adv 2018;2:954-963 © 2018 by The American Society of Hematology