Proper attention to 𝗮𝗹𝗹 aspects of pathology in COVID19, simultaneously, is paramount to proper treatment:

pulmonary endothelium

platelets

Products of platelet-endothelial activation:

thrombi
platelet-derived mediators

SARS-CoV-2 causes a double-whammy state of 𝗽𝗹𝗮𝘁𝗲𝗹𝗲𝘁 𝗮𝗰𝘁𝗶𝘃𝗮𝘁𝗶𝗼𝗻 and 𝗽𝘂𝗹𝗺𝗼𝗻𝗮𝗿𝘆 𝗲𝗻𝗱𝗼𝘁𝗵𝗲𝗹𝗶𝗮𝗹 𝗱𝗲𝘀𝘁𝗮𝗯𝗶𝗹𝗶𝘇𝗮𝘁𝗶𝗼𝗻:

pericyte loss

unstable pulm endothelium

platelet activation

Pericyte loss of the pulmonary endothelium due to SARS-CoV-2 leads to endothelial destabilization, which in turn activates MKs and platelets maturing and residing in the pulmonary capillary spaces.

In addition to endothelial activation by inducing pericyte loss, SARS-CoV-2 attaches to platelets via a number of identified (e.g. CD147, etc) receptors, inducing 𝗲𝘃𝗲𝗻 𝗳𝘂𝗿𝘁𝗵𝗲𝗿 𝗽𝗹𝗮𝘁𝗲𝗹𝗲𝘁 𝗮𝗰𝘁𝗶𝘃𝗮𝘁𝗶𝗼𝗻, independent of its endothelial activation actions.

In addition to this direct viral action on platelets, there are likely other pathways that lead to further delayed platelet activation, including 𝗺𝗶𝗺𝗶𝗰𝗸𝗿𝘆 of host pro-aggregant factors, and 𝗮𝘂𝘁𝗼𝗮𝗻𝘁𝗶𝗯𝗼𝗱𝗶𝗲𝘀 that further activate platelets.

To best approach a severe COVID19 infection, one must recognize the 𝗵𝗮𝗹𝗹𝗺𝗮𝗿𝗸 𝗳𝗲𝗮𝘁𝘂𝗿𝗲𝘀 of COVID19 and potential targets for intervention.

To 𝗺𝗲𝗿𝗲𝗹𝘆 𝘁𝗮𝗿𝗴𝗲𝘁 𝘁𝗵𝗿𝗼𝗺𝗯𝗶 formation by DOACs, and ignore the need to address

(1) endothelial activation
(2) platelet activation
(3) potent 𝗽𝗹𝗮𝘁𝗲𝗹𝗲𝘁 𝗺𝗲𝗱𝗶𝗮𝘁𝗼𝗿𝘀 released during platelet activation

most likely will be 𝗶𝗻𝗮𝗱𝗲𝗾𝘂𝗮𝘁𝗲 therapy

DOAC montherapy reduces the burden of existing and forming thrombi.

But it will *𝗻𝗼𝘁* exert endothelial stabilization effects that would be present with heparin.

𝗣𝗹𝗮𝘁𝗲𝗹𝗲𝘁 𝗺𝗲𝗱𝗶𝗮𝘁𝗼𝗿𝘀 𝗺𝗮𝘆 𝗮𝗰𝗰𝘂𝗺𝘂𝗹𝗮𝘁𝗲, including serotonin and angiogenic factors.

𝗛𝗲𝗽𝗮𝗿𝗶𝗻 products have the added benefit of endothelial stabilization, and thereby, reduce feed-forward platelet activation that would stem from endothelial factors

Avoiding VILI with lung protective ventilation (low TV, avoid overzealous PEEP) further protects endothelium

In certain cases (such as late presenters, or those on DOAC or VKA monotherapy), 𝙥𝙡𝙖𝙩𝙚𝙡𝙚𝙩 𝙢𝙚𝙙𝙞𝙖𝙩𝙤𝙧𝙨 𝙖𝙘𝙘𝙪𝙢𝙪𝙡𝙖𝙩𝙞𝙤𝙣 may be 𝗮𝘀 𝗼𝗿 𝗲𝘃𝗲𝗻 𝗺𝗼𝗿𝗲 𝗽𝗮𝘁𝗵𝗼𝗹𝗼𝗴𝗶𝗰 𝗮𝗻𝗱 𝗱𝗲𝘁𝗿𝗶𝗺𝗲𝗻𝘁𝗮𝗹 as gas exchange abnormalities encountered in COVID19

One such platelet mediator is serotonin. Plasma serotonin is kept at tightly regulated low levels by storing 95% of body's serotonin in platelet granules

Serotonin is uniquely positioned to 𝗮𝗰𝗰𝘂𝗺𝘂𝗹𝗮𝘁𝗲 in COVID19, as it's released copiously and its reuptake is impaired.

There is clear evidence of plasma serotonin 𝗲𝘅𝗰𝗲𝘀𝘀 in COVID19, with this excess being a result of platelet degranulation, combined with the pulmonary vasculopathy and endothelial dysfunction of COVID19, the same endothelium that is responsible for reuptake of serotonin.

It is paramount to understand the signs of serotonin toxicity, and to recognize that there is 𝗼𝘃𝗲𝗿𝗹𝗮𝗽 between ARDS / sepsis and the signs of serotonin toxicity

Distinguishing signs of serotonin toxicity include
- Myoclonus
- Hyperreflexia
- Severe agitation
- Diarrhea

As it pertains to COVID19, the signs of serotonin toxicity that may occur due to *𝙩𝙝𝙚 𝙙𝙞𝙨𝙚𝙖𝙨𝙚 𝙞𝙩𝙨𝙚𝙡𝙛* without presence of culprit meds include the following:

Some of these may also *𝗻𝗼𝘁* be necessarily explained by a run-of-the-mill sepsis or ARDS picture

In cases where specific signs of serotonin toxicity may be present (ankle clonus, severe agitation, diarrhea), 𝘀𝗲𝗿𝗼𝘁𝗼𝗻𝗶𝗻 𝗶𝗻𝗵𝗶𝗯𝗶𝘁𝗶𝗼𝗻 may be necessary.

The answer to such cases is to 𝙩𝙚𝙖𝙨𝙚 𝙤𝙪𝙩 the specific signs of serotonin toxicity and act accordingly

In case serotonin toxicity is suspected and pathognomonic signs are detected, serotonin inhibition can be relatively safely performed with Cyproheptadine

Please remember that patient does *not* necessarily need to have a culprit medication to harbor serotonin toxicity in COVID19

And more important than inhibition of serotonin in a disease such as COVID19 inherently prone to buildup of serotonin, it's best to 𝗮𝘃𝗼𝗶𝗱 it by avoiding the culprits (e.g. Fentanyl, VILI) and instead addressing platelet-endothelial activation beyond just DOACs (e.g. heparin)

It is a 𝗱𝗶𝘀𝘀𝗲𝗿𝘃𝗶𝗰𝗲 to the patients when we attribute signs of unrecognized serotonin toxicity to "it's just COVID"

Unexplainable agitation, hallucination, tachypnea, fever, explosive diarrhea, myoclonus, hyperreflexia 𝗱𝗲𝘀𝗲𝗿𝘃𝗲 a thinking

is to recognize.