2) This series is supported by educational grants from Bayer & AstraZeneca & is intended for healthcare professionals. Faculty disclosures & statement of accreditation at https://t.co/gvXca4G9Xm. Earlier programs, still available for credit, are at https://t.co/U6Mo1oSwIh.
— cardio-met (@cardiomet_CE) September 8, 2022
4) … cascade is actually two pathways in one? There is the intrinsic pathway triggered by contact activation, and the extrinsic pathway, triggered by tissue injury. They come together in the common pathway, which–along with activated platelets–results in a clot. pic.twitter.com/4BcMoEe89q
— cardio-met (@cardiomet_CE) September 8, 2022
6) We can even specifically measure activity in the 2 pathways above the common PW, & as a football fan & dog owner I have always remembered PITT & PET; the Intrinsic PW is measured by PTT, & the Extrinsic PW by PT. This short video is a nice refresher: https://t.co/5y5IW50eIQ
— cardio-met (@cardiomet_CE) September 8, 2022
8) We always think of anticoagulant use–whether for #thromboprophlaxis or for full #anticoagulation–as being of necessity encumbered by an ⬆️risk of bleeding . . . because they have their impact way down in the cascade, where they effect both thrombosis AND hemostasis.
— cardio-met (@cardiomet_CE) September 8, 2022
10) Enter inhibition of Factor XI/XIa. FXIa contributes to coagulation by promoting thrombin-mediated fibrin generation, & FXI can be reciprocally activated by thrombin. In vivo hemostasis is primarily dependent on the extrinsic coagulation PW, with the intrinsic …
— cardio-met (@cardiomet_CE) September 8, 2022
12) … (as in ECMO or bypass) and in reactive states, such as surgery or sepsis, or–maybe–#COVID19. More on that second part later. For now, it’s instructive to note that humans with congenital FXI deficiency (#hemophilia_C) usually have only a mild bleeding diathesis …
— cardio-met (@cardiomet_CE) September 8, 2022
14) … venous and arterial thromboembolism compared to those w/normal FXI levels. pic.twitter.com/PF3rRNa84h
— cardio-met (@cardiomet_CE) September 8, 2022
16) a) inhibitors of hepatic biosynthesis of FXI (antisense oligonucleotides [#ASOs])
— cardio-met (@cardiomet_CE) September 8, 2022
b) monoclonal antibodies that block FXI activation or FXIa activity
c) aptamers that bind FXI/FXIa, and
d) small molecules that block the active site of FXIa
or cause allosteric modulation.
18) Small molecule FXIa inhibitors (BAY 2433334, JNJ-70033093, & ONO-5450598) may be given PO & have fast onset/offset so would be dosed BID or even QD, but must overcome some CYP450 metabolism and renal elimination. See https://t.co/KK09UNpK9s for a review.
— cardio-met (@cardiomet_CE) September 8, 2022
20) So many mechanisms of action, so many efforts to solve the FXIa inhibition puzzle! The poll? All but warfarin. Courtesy of Drs Fredenburgh and Weitz (Hämostaseologie 2021;41:104–110), here are the studies to date (now to be updated post-#ESCCongress) : pic.twitter.com/AKY04pGtS9
— cardio-met (@cardiomet_CE) September 8, 2022
21b) … also included mandatory #venography for efficacy. Major or clinically relevant non-major bleeding was seen in up to 4.7% of pts on osocimab, 5.9% on enox, & 2% on apixa. Bleeds were limited to the surgical site; no ICH or other critical site bleeds.
— cardio-met (@cardiomet_CE) September 8, 2022
22) Ososcimab is now being studied vs placebo in
— cardio-met (@cardiomet_CE) September 8, 2022
patients with #ESRD undergoing #hemodialysis (NCT04523220)–a high bleeding risk population in which safety of #antithrombotic therapy is paramount.
23b) The primary efficacy outcome was #VTE, detected by mandatory venography of the ipsilat or objective confirmation of symptomatic events.
— cardio-met (@cardiomet_CE) September 8, 2022
See 🔓https://t.co/u9zQfPeGpc, led by our friend @VerhammePeter.
23d) The 30-mg abelacimab regimen was noninferior to enox & the 75 & 150mg regimens were superior to enox (P<0.001). Bleeding occurred in 2%, 2%, & none of the patients in the 30mg, 75mg, & 150mg abelacimab groups, respectively, & in none of the patients in the enoxaparin group.
— cardio-met (@cardiomet_CE) September 8, 2022
25) We’ll switch mechanisms to talk #ASO, antibodies, & small molecules tomorrow, RIGHT HERE! Please come back and join us, & pick up 🆓CE/#CME!#FOAMed @connors_md @JerroldLevy @GBarnesMD @Clotmaster @pnatarajanmd @NTConnell @MarcCarrier1 @beaverspharmd @ProfMakris @AryaRoopen
— cardio-met (@cardiomet_CE) September 8, 2022
27a) The #ASO IONIS-FXIRx limits #FXI biosynthesis over 3-4wks; restoration of pre-tx levels takes several weeks after dosing ends. In the FXI-ASO TKA trial (🔓https://t.co/TfOKg44LTT), 2 doses ASO were compared w/enox for postop thromboprophylaxis in 300 elective TKA pts.
— cardio-met (@cardiomet_CE) September 9, 2022
28) Antibody AB023 was also studied 2 doses vs placebo in a small Ph 2 ESRD/HD study (NCT03612856). There were no safety concerns & the antibody⬇️dialyzer clotting.
— cardio-met (@cardiomet_CE) September 9, 2022
As per the Table in tweet 20, there are multiple other Ph 2 studies underway in various indications.
30a) The contact system about which we have been talking is also called the plasma #kallikrein-kinin system & consists of 3 serine proteinases: coagulation factors XII & XI, plasma #prekallikrein (PK), & the nonenzymatic cofactor high molecular weight #kininogen (HK).
— cardio-met (@cardiomet_CE) September 9, 2022
31a) Want to have some fun with this? Check out "Acquired Factor XI Deficiency during SARS-CoV-2 Infection: Not Only Thrombosis," at🔓https://t.co/XeJUKL3lYq, in which the authors speculate that the inhibition of FXI could be a means of the immune system to try …
— cardio-met (@cardiomet_CE) September 9, 2022
32) So . . . leaving behind COVID, what are some potential scenarios in which FXI/XIa inhibition could be a particularly useful antithrombotic strategy?
— cardio-met (@cardiomet_CE) September 9, 2022
a. IV small molecules for ECMO
b. FXI antibodies before CV device implantation
c. acute PE treatment with an ASO
d. a & b
33b) … well suited for chronic #anticoagulation in pts with high bleeding risk (#HBR) such as in #ESRD. Because of FXI's lack of impact on TF-mediated local hemostatic responses to tissue injury, it also has potential advantages for #antithrombotic effect when …
— cardio-met (@cardiomet_CE) September 9, 2022
33d) … with a FXI strategy may be a good choice in HBR patients or when anticoagulation is to be added to #SAPT or #DAPT–even better than #DOACs, which are themselves generally safer than #VKA.
— cardio-met (@cardiomet_CE) September 9, 2022
34b) … and agents that block FXa/FIIa will require huge sample sizes that may not be practical. Nonetheless, the allure of an antithrombotic therapy that provides effective clot risk reduction without attendant ⬆️bleeding risk is strong💪… so watch this space for more data!
— cardio-met (@cardiomet_CE) September 9, 2022
35) And that's it! You made it! Claim your 0.5h CE/#CME at https://t.co/jzWDHAO8HV now, and then FOLLOW US for more of the ONLY accredited serialized #tweetorials in #cardiometabolic medicine! #FOAMed @sortoutbleeding @2Scottish @RosovskyRachel @DebSiegal @czuprynska_j
— cardio-met (@cardiomet_CE) September 9, 2022