Targeting thromboinflammation in antiphospholipid syndrome

[pattismith]

@SWAlexander​

Although I don't have personnally APSyndrome, I do find useful to take the drugs suggested in this paper (Colchicine, Rapamycin, Ubiquinol). I also take Piroxicam (thromboxan inhibitor)

​

Targeting thromboinflammation in antiphospholipid syndrome​

2022 Netherland
https://www.jthjournal.org/article/S1538-7836(22)12803-5/fulltext

Abstract​

Antiphospholipid syndrome (APS) is a systemic autoimmune disease, where persistent presence of antiphospholipid antibodies (aPL) leads to thrombotic and obstetric complications.

APS is a paradigmatic thromboinflammatory disease. Thromboinflammation is a pathophysiological mechanism coupling inflammation and thrombosis, which contributes to the pathophysiology of cardiovascular disease.

APS can serve as a model to unravel mechanisms of thromboinflammation and the relationship between innate immune cells and thrombosis. Monocytes are activated by aPL into a proinflammatory and procoagulant phenotype, producing proinflammatory cytokines such as tumor necrosis factor α, interleukin 6, as well as tissue factor.

Important cellular signaling pathways involved are the NF-κB-pathway, mammalian target of rapamycin (mTOR) signaling, and the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome.

All of these may serve as future therapeutic targets.

Neutrophils produce neutrophil extracellular traps in response to aPL, and this leads to thrombosis.

Thrombosis in APS also stems from increased interaction of neutrophils with endothelial cells through P-selectin glycoprotein ligand-1. NETosis can be targeted not only with several experimental therapeutics, such as DNase, but also through the redirection of current therapies such as defibrotide and the antiplatelet agent dipyridamole.

Activation of platelets by aPL leads to a procoagulant phenotype.

Platelet-leukocyte interactions are increased, possibly mediated by increased levels of soluble P-selectin and soluble CD40-ligand. Platelet-directed future treatment options involve the inhibition of several platelet receptors activated by aPL, as well as mTOR inhibition. This review discusses mechanisms underlying thromboinflammation in APS that present targetable therapeutic options, some of which may be generalizable to other thromboinflammatory diseases.

 

[SWAlexander]

Although I don't have personnally APSyndrome, I do find useful to take the drugs suggested in this paper (Colchicine, Rapamycin, Ubiquinol). I also take Piroxicam (thromboxan inhibitor)

Thank you very much for this valuable information.

I will start with Piroxicam as soon as I can get a prescription. First I must lower inflammation. I have to test carefully every medication.

Just a few days ago I gathered some information on:

Reactive oxygen species (ROS) the principle of oxidative stress​

https://swaresearch.blogspot.com/2023/12/reactive-oxygen-species-ros-principle.html​

 

[SWAlexander]

Thank you pattismith
On my second day on Piroxicam. I feel energetic without the ever-nagging inflammation and pain.

 

[pattismith]

Thank you pattismith
On my second day on Piroxicam. I feel energetic without the ever-nagging inflammation and pain.

keep in mind that it's an NSAID with toxicity to the stomach and kidney.

Try to take the lower dosage, always with food, and drink a lot

 

[SWAlexander]

Try to take the lower dosage, always with food, and drink a lot

Grateful for your reminder. My pharmacist already reminded me about not going over 20mg.

 

[pattismith]

Grateful for your reminder. My pharmacist already reminded me about not going over 20mg.

I consider 20 mg a big dose. 5 or 10 mg would be safer and still working.

 

[SWAlexander]

I started with 10mg on the first day. Not even 3 hours later the symptoms were back. Today I tried 10mg in the morning and 10 mg at noon.
If I don't have any physical challenges I may try a lower dose.
Thanks for caring.

 

[pattismith]

I started with 10mg on the first day. Not even 3 hours later the symptoms were back. Today I tried 10mg in the morning and 10 mg at noon.
If I don't have any physical challenges I may try a lower dose.
Thanks for caring.

I do care about trials we may experiment.

I also try to check any drug association before starting;

For example in this paper they suggest Colchicine and Rapamycin, but I do not advise to do an association of these drugs, because it can produce muscle toxicity.

Increased autophagy accelerates colchicine-induced muscle toxicity​

Abstract​

Colchicine treatment is associated with an autophagic vacuolar myopathy in human patients.

presumed mechanism of colchicine-induced myotoxicity is the destabilization of the microtubule system that leads to impaired autophagosome-lysosome fusion and the accumulation of autophagic vacuoles.

Using the MTOR inhibitor rapamycin we augmented colchicine’s myotoxic effect by increasing the autophagic flux; this resulted in an acute myopathy with muscle necrosis.

In contrast to myonecrosis induced by cardiotoxin, myonecrosis induced by a combination of rapamycin and colchicine was associated with accumulation of autophagic substrates such as LC3-II and SQSTM1; as a result, autophagic vacuoles accumulated in the center of myofibers, where LC3-positive autophagosomes failed to colocalize with the lysosomal protein marker LAMP2.

A similar pattern of central LC3 accumulation and myonecrosis is seen in human patients with colchicine myopathy, many of whom have been treated with statins (HMGCR/HMG-CoA reductase inhibitors) in addition to colchicine.

In mice, cotreatment with colchicine and simvastatin also led to muscle necrosis and LC3 accumulation, suggesting that, like rapamycin, simvastatin activates autophagy.

Consistent with this, treatment of mice with four different statin medications enhanced autophagic flux in skeletal muscle in vivo.

Polypharmacy is a known risk factor for toxic myopathies; our data suggest that some medication combinations may simultaneously activate upstream autophagy signaling pathways while inhibiting the degradation of these newly synthesized autophagosomes, resulting in myotoxicity.

https://www.tandfonline.com/doi/full/10.4161/auto.26150

 

[SWAlexander]

For example in this paper they suggest Colchicine and Rapamycin, but I do not advise to do an association of these drugs, because it can produce muscle toxicity.

Thank you.
This Part is very important: "Polypharmacy is a known risk factor for toxic myopathies; our data suggest that some medication combinations may simultaneously activate upstream autophagy signaling pathways while inhibiting the degradation of these newly synthesized autophagosomes, resulting in myotoxicity."

Just yesterday a friend's husband was pre-diagnosed with myasthenia gravis after taking Amlodipine and aspirin in the last 4 years. Further tests are needed to confirm but Parkinson's was ruled out. However, his eyelid on the right side and facial muscles are slightly drooping, pointing in the direction of MG.

 

[SWAlexander]

Try to take the lower dosage, always with food, and drink a lot

I had to stop taking Piroxicam.
The inflammation went down, and my energy was better - BUT I started the same kind of vaginal bleeding (without having a uterus), I had last year when I was on Methotrexate.

It makes no sense and I cannot find any combination except, that both Methotrexate and Piroxicam reduce inflammation.
Maybe it is my antiphospholipid syndrome (APS) or Lupus that is reacting.