My thoughts on COVID-19
1) Reason for ACE inhibitor use as risk for severe COVID-19, due to
2) Microvascular thrombosis in severe COVID-19
3) Possible Role for tPA / heparin / DEFIBROTIDE to treat late-stage severe COVID-19, possible PVOD
4) Possible role for prophylaxis against this thrombotic cascade of MILD cases discharged from ER with anti-platelets for 14 days ??
5) A pathway proposed via PAI-1 surge resulting in thrombosis from ACEI cessation and COVID-19 cytokine storm
This is a possible pathway that could explain role of HTN, ACE inhibitors being associated with severe COVID-19, and the potential role for tPA in COVID-19 treatment. Please be patient and read my thoughts and let know what your thoughts are.
1) A common thread in the fatality of COVID-19 has been the well described, VERY SUDDEN, development of cardiomyopathy and idiopathic AKI and need for CRRT. To think that ARDS or septic shock is causing fatality is not accurate, as most reports clearly mention patient even coming off the vent, coming off vasopressors, even almost ready for downgrade from ICU, and suddenly crashing with low EF, AKI, and death within 2 days. To think the virus somehow has not affected the heart and kidneys until day 11 of severe illness is also not too convincing. There has to be a sudden event, such as thrombosis.
2) In several reports and autopsies by Italian and Chinese, MICROTHROMBI have been identified in cardiac tissue and renal tissue of severe fatal COVID-19. Even massive PEs and large arterial thrombosis were noted in young healthy people with severe COVID-19.
3) We do know that some infections are PRO-THROMBOTIC, as in DIC with thrombosis, such as Dengue fever. Elevated PAI-1 levels are associated with significantly worse outcomes in Dengue.
4) We also have some anecdotal evidence that patients with HTN (inevitably a lot on chronic ACE inhibitors) possibly have higher incidence of severe illness from COVID-19.
5) Fact: ACE inhibitor REDUCES PAI-1 production.
6) Fact: PAI-1 inhibits tPA, thereby causing thrombosis, as described in MI literature. PAI-1 antigen levels are higher in men, and higher with advancing age, among many other factors.
7) Fact: Dengue, as an example, causes elevated PAI-1, described in literature, and Dengue is pro-thrombotic.
8) IL-6, and other cytokines increase PAI-1 release/production during acute inflammatory response.
9) Could it be that ACE inhibitor depletes PAI-1 levels in the serum --> COVID-19 causes a relative surge in PAI-1 level (just as in Dengue due to IL-6 and other cytokine release) --> Sudden surge in PAI-1 levels (particularly if PAI-1 already depleted due to ACE inhibitor use or due to well described genetic polymorphisms) lead to a very large thrombotic surge (by inhibiting tPA) --> lead to vast micro-thrombosis and sudden collapse with microvascular thrombi causing sudden cardiomyopathy and AKI as seen in fatal COVID-19 cases?
10) Could there be a role for tPA infusion or anticoagulation in severe cases of COVID-19? Yes, tocilizumab will stop the IL-6 from wreaking more havoc, but what if the cat is out of the hat, and the thrombotic cascade has begun due to PAI-1 surge (as well evidenced by continuous rise in D-dimer despite its short half-life compared to ALL other inflammatory markers with longer half-life (ferritin, CRP) coming DOWN, even pressors and oxygen requirements coming down). Perhaps a role for tPA even in moderate cases to prevent the fatal thrombotic outcome that has been seen on autopsies in the fatal cardiomyopathy that occurs, in the AKI that occurs?
OR DIRECT PAI-1 inhibitors: tiplaxtinin? Other novel compounds reported and not in use?
Or high-dose STATINS? There is established association with statin use and decrease in PAI-1.
11) Could this explain why HTN (inevitably a lot on ACE inhibitors) has been somewhat anecdotally associated with worse outcomes? A lower PAI-1 state in hemostasis with tPA in the body due to chronic ACE inhibitor use, followed by a sudden huge surge of PAI-1 due to the prothrombotic (via PAI-1) nature of COVID-19 (and a sudden surge in PAI-1 due to holding ACE inhibitors that we naturally hold in sepsis) causing microvascular thrombosis and fatality?
12) Could a plausible explanation in worse outcomes in patients on ACE inhibitor be that, as patient inevitably goes to septic shock, ACE inhibitor is held --> leads to rebound elevation in PAI-1 naturally --> this elevation works synergistically with PAI-1 elevation from the inflammatory cascade that COVID-19 causes (as documented in Dengue) --> leads to a large surge in PAI-1 --> thrombotic cascade and death.
13) If you have a case with CRP improving, Ferritin improving, sepsis improving, IL-6 improving, but D-dimer rising and patient not improving, would it not make sense that the discordant D-dimer rise (which has the shortest half-life of all three and should technically be falling if it were only due to acute inflammation) is due a thrombotic cascade? Perhaps consider treating this subset first to see if fatal outcomes can be prevented?
14) Could it be that some of the mild cases discharged will go to cytokine storm, microvascular thrombosis, and show up late-stage with hypoxia without any significant lung auscultation findings (as has been reported), because of this process? And succumb to a quick death in this late stage?
15) Should we risk stratify mild cases based on IL-6 level and D-dimer level before discharging a seemingly mild case? Should we prophylaxis everyone we send out with some sort of agent to avoid thrombosis if we cannot tell exactly who gets it and who doesn't?
16) Should we across the board just assume every case's "thrombotic" tendency from cytokine storm is at the same intensity? I understand from this study that prophylaxis dose of LMWH was used and is being used in US. Could there be cases that need a therapeutic dose in someone with a higher thrombotic propensity depending on their cytokine storm, depending on their IL-6 level? What about those cases that roll into ER without prior care at late stage, very elevated D-dimer, discordant findings? Is a prophylactic dose of Lovenox SC enough to stem the thrombotic cascade? Could they need a higher dose? Could some late presenters need tPA?
17) Could PVOD be the reason we are hearing reports that patients in ARDS turn course and behave more like a "cardiogenic" pulmonary edema without LV issues noted on echo, which is essentially a post-arterial outflow issue, as that could happen in PVOD. And if this worsening in A-a gradient is associated with rise in D-dimer (and small vessel PE is not found on CT), then PVOD is a possibility as with other thrombosis elsewhere. If having ACUTE thrombosis causing PVOD-like picture, then perhaps treatment with anticoagulant, tPA, or Defibrotide (as in hepatic VOD) may help.
18) Can Italian, Chinese, or WA/NY doctors tell the rest of us how well did patients do that were NOT on ACEI/ARB but on chronic ASA/Plavix or anticoagulation? If they did the best, then the writing is on the wall regarding this thrombotic cascade.
Thoughts?
Disclaimer: I'm your average not too bright GI doctor 10 years out from any biochemistry. Smarter people need to chime in. Maybe run this by the smartest physician in your facility and see if it makes any sense to try this please. Please don't try this based alone on this thread. Although Chinese and Italian doctors are recommending anticoagulation per many reports.
Disclaimer #2: Please don't stop your ACE inhibitors based on this. These are just theoretical possibilities. I'm NOT recommending any change in meds or practice for anyone. These are just food for thought and for smarter people to analyze.
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