ANTI-COAGULATION
Animportant paper appeared in the Journal of the American College ofCardiology on August 26. It came out of Mt Sinai, which happens to be thelead hospital in the Mesoblast EAP and phase 3 trial of remestemcel-Lin C-19 ARDS. So, I'm re-activating this thread to make somecomments. The paper's title is:
Anticoagulation,Mortality, Bleeding and Pathology Among Patients Hospitalized withCOVID-19: A Single Health System Study
Referencelink is below, apologies if it's been discussed elsewhere. In anutshell it provides evidence that anti-coagulating C-19 patientsleads to significantly better results in terms of progression tointubation and mortality (“a50 percent higher chance of survival, and roughly a 30 percent lowerchance of intubation, than those not on anticoagulants”). Both low dose and full dose (therapeutic) anti-coagulation (AC) didbetter than no dose. However, full dose AC came with a higher risk ofserious bleeding as a side effect; low dose did not increase thebaseline risk seen in non-anti-coagulated controls.
Theretrospective study (which is weaker than a prospective study) analyzed 4,389 patients admitted to 5 NYChospitals between March 1 and April 30, which overlaps with patientsof the EAP and the control groups used to compare the EAP. I suspectmany in both the EAP and the control group received at least low dose AC and no doubtthere's overlap even of some control patients. Surprisingly, 42% ofpatients who went to autopsy in this study were found to haveunsuspectedblood clots in one or more major organs – and in 27% of those casesthe clots occurred in spite of full anti-coagulation. Wow. Part ofthe reason C-19 is such a bad disease.
Whatare we to make of the study in relation to rem-L? First, there are no great surpriseshere, rather confirmations. If one looks at the Petrilli paper (citedin Mesoblast's April 24 announcement of EAP results), which summarizesthe EAP control group from March-April, one finds this statement:“Someemerging case reports suggest that patients with critical Covid-19disease are developingcomplications from hyper-coagulability, includingboth pulmonary emboliandmicro-thrombi”. They reference a paper by Tang et al suggestinganti-coagulation would lower mortality in C-19. They noted thatcritical patients had over 60% higher d-dimer levels thannon-critical. So,precise numbers would be nice, but no doubt many of the patients inthe EAP AND in the historical NYC control group received some form of AC,especially low-dose heparin which is common in the ICU where patientsare at high risk of “thrombo-embolic events”, ie abnormal bloodclots. The burning question: Is there a better way to deal with theproblem in C-19 patients? Remestemcel-L, for example.
Second,As with other medicines that may be tried with the phase 3 patients (likeremdesivir, dexamethasone and convalescent plasma), anti-coagulationwill randomize to both arms of the phase 3 trial and should NOTtarnish the results. We discussed it earlier on this thread, Ibelieve, and that point was confirmed by Dr. Grossman during the CC.
Third,the paper provides further proof that C-19 is primarily a disease ofsmall blood vessels throughout the body not just the lungs. It adds support to pursuing all-cause mortality as a primary end point. Specifically the virus causes an endotheliitis, an inflammation of thecells that line the inside of blood vessels. That's the linkingfactor in many of the manifestations of the illness. Again, this isconfirmation and not a big surprise. Endotheliitis can lead to bloodclots. Anti-coagulation helps prevent clots, but comes with the riskof bleeding and it doesn't prevent all clots. ie there's lots of roomfor a better therapeutic. We know from the early work of Dr. Caplanthat MSC's can function as pericytes and home to areas of vascularinflammation and damage inside of blood vessels. In fact, that'sprobably their primary natural function in the interstitial spaces ofthe bone marrow from whence they come. Perhaps that's why theyappear to be particularly effective in C-19, just like a trip backhome.
Fourth,@CavATHXbull's, @bio's and other “downrampers” observation thatMSC's “clog the pulmonary vascular bed” may rather be evidence oftheir therapeutic effect. To my knowledge there has been no evidencethat an infusion of MSC's leads to right heart EKG abnormalities, V/Qmismatch or PAH (things that would be expected if they significantlyblocked blood flow to the lungs). These are not rigid BB's, rather cells that can flatten and transform. There is evidence that they home to areas ofinflammation, here in the lungs and probably to other organs wherethey cling to inner vessel walls and do their repair work. In part,that's probably due to the surface markers and receptors they carry,among them TNFR1 that was discussed during the ODAC hearing. Bycontrast, the MAPC's of Athersys are smaller in diameter and areknown to pass through the lungs to accumulate in the spleen in highpercentage. We are told they interact with host immune cells in thespleen which indirectly leads to a reduction in inflammation ortissue damage from infarct (stroke) or trauma. Of course, thatremains to be seen. Their effectiveness has not yet been proven inany phase 3 study. And I would point out that the spleen where theycongregate happens to be the organ dedicated to removing senescentand no-longer-needed cells from the circulation and destroying them. Does that rhyme with the billions needed per dose? In other words weneed to see more than just scan evidence that injected cellsaccumulate in the spleen to draw any conclusion as to theireffectiveness. Meanwhile, the paper out of Mt. Sinai documentsdiffuse blood vessel disease and unsuspected blood clots. Is it better totreat with cells that home to areas of blood vessel inflammation orwith cells that get taken out of circulation by the spleen? Place your investment. Time and trials will ultimately tell.
Finally,the study results suggest that the move to anti-coagulating C-19patients is going to continue, even increase. The phase 3 trial mayshed light on whether MSC's work in synergy with the anti-coagulant / allow safer dosing ofthe anti-coagulant / allow the anti-coagulant to be stopped sooner aspatients convalesce. On the other hand, this evidence ofinflammation inside vessels and the trend to anti-coagulation doesn'tbode well for PSTI using multiple IM injections – even if PLX cells are eventually proven to “work”. All things equal ICU docs will choose an IValternative if available, imo. Let's scratch our collective head for a second. To treat diffuse disease on the insideof blood vessels does it make sense to inject the cells into a bloodvessel so that they can circulate, or is it better to create a remotedepot of cells outside the blood vessels and far away in the butt ordeltoid? Again, trials will tell but color me skeptical on thelatter approach. Not to mention the danger of giving IM injectionsto patients fully anti-coagulated (900 of the patients in this study= 20%, so no small number). It's a bizarre approach in the ICUsetting. Let's see how it plays out in large studies, but givingcells by 15 to 30 IM injections to anti-coagulated, unconscious,chemically paralyzed, hypo-perfusing ICU patients on ventilators whohave to be proned periodically may go down in the annals of medicineas one of the great follies of all time. Ranking up there with bloodletting, internal mammary artery ligation and frontal lobotomy. Why? An anti-coagulated patient can lose large quantities of bloodundetected into the thigh/buttock, especially if unconscious and obese. Generally, even 1 IM injection is contraindicated in a fullyanti-coagulated patient unless there's no good alternative andprecautions are taken. Not to mention 15 of them. #Dangerous #Ouch.
Alink to the Mt Sinai announcement is here and inside there's a linkto the JACC paper. https://www.mountsinai.org/about/newsroom/2020/mount-sinai-team-offers-additional-data-on-efficacy-of-blood-thinners-for-covid19-and-insight-on-best-potential-regimens-pr
Allstatements are IMO. Sorry about the formatting. Awaiting the interim readout which will helpfurther with interpreting papers like this. glta
(20min delay)