Thrombotic Events in Patients With Polycythemia Vera and Essential Thrombocythemia

[Manouche]

« Several lines of evidence suggest other factors contribute to the propensity to develop thrombosis in PV and ET aside from elevations in hematologic parameters. For one, patients who harbor a JAK2V617F are at an increased risk of thrombosis even though they lack diagnostic criteria for an overt MPN, so called clonal hematopoiesis of indeterminant potential (31). Multiple groups have also reported that mutated JAK2 is present in the endothelial cells of some MPN patients, which suggests a common lineage between endothelial cells with hematopoietic stem cells (32–34). In particular, endothelial cells lining the splanchnic vascular bed frequently harbor the JAK2V617F mutation in MPN patients (32, 34). Guy et al. developed a murine model where endothelial cells expressed mutated JAK2, but not hematopoietic cells. They documented a thrombotic propensity in these mice despite normal hematologic parameters. Utilizing multiple experimental methods, they elegantly demonstrated that JAK2 mutated endothelial cells promoted leukocyte adhesion and rolling via increased surface expression of P-selectin and von Willebrand Factor (35). Neutrophils harboring the JAK2 mutation have also been shown to be primed to form neutrophil extracellular traps (NETs), which are extracellular strands of decondensed DNA that complex with histones and others neutrophil granular proteins. NETs can ensnare microorganisms and serve as part of the innate immunity (36), but they are also key to the pathogenesis of thrombosis (37). The propensity for JAK2 mutated neutrophils to form NETs further implicates the central role of leukocytes in MPN-related thrombosis »

frontiersin.org/articles/10...

[bordeauxgirl]

Manouche , for a patient with PV +Jak2 variant, I haven't a clue about your statement. I don't think many will understand most of what you are talking about Very confused.

[MCW22 in reply to bordeauxgirl]

Exactly what I was thinking. The majority of us want things explained in simple every day language

[Windy51 in reply to bordeauxgirl]

Me either

[cmc_ufl]

Thanks for posting, this is a very intriguing study! Quite interesting that their mouse model with JAK2 in endothelial cells (and not hematopoietic cells) still experienced thrombotic events.

[hunter5582]

I have seen reference to the JAK2 mutation alteration in interaction between blood cells and vascular endothelium before. Also reference to the surface level of blood cells and endothelial cells being "extra-sticky". I really do think it is ever more clear that it is more about how the blood cells behave than just how many of them there are. Understanding the molecular biology involved in what is going on is vital to finding better ways to manage MPNS.

Thanks for posting this interesting literature review.

[Manouche in reply to hunter5582]

You are right to say that the way the blood cells behave is important. It’s also important to remember that the number of JAK2 mutated cells pave to way to genomic instability and further mutations. That’s why lowering the allele burden seems important for an increasing number of haematologists.

[EmeraldA]

Thank you for posting. The more we learn and come to know the better off we are re. mpns.

[Aldebaran25]

very interesting. So much more to be understood about the far-reaching effects of JAK2+ and other mutations. We concentrate on the bone marrow in our minds, but the periphery is also actively involved. Incidentally it brought to mind the issue of blood cots in covid-19 infection, where I read that it is the endothelial cells that are thought to be affected by the virus and then trigger the clotting process.

[MPNBlog]

Thanks for posting this link Manouche. There is a lot that is not understood about JAK2 mutations. Until the biology is understood I don't think we'll see a cure for our MPNs. More funds are needed for basic research on cures rather than simply treating symptoms, important though that is for our everyday quality of life.

[Manouche in reply to MPNBlog]

I am not sure about a « cure » as such, but an « operational cure » is already achieved for a subset of many MPN sufferers. The idea to control the MPNs on a level of Minimal Residual Disease is quite an interesting concept.

[Lena70 in reply to Manouche]

Hello Manouche. I appreciate your posts. I have a question. Is the operational cure you are referring to Pegasys?

[Manouche in reply to Lena70]

Hi Lena. An operational cure can ideed be obtained with both PegIngtron or Pegasys. This is what the molecular responses look like on good or poor responders :

res.mdpi.com/d_attachment/c...

[Buggerbear]

Thank you for posting this article as it is most interesting. I am going to re-read and try to understand it better. My Oncologist never discusses the way my blood cells behave or anything in detail like I don't need to know this. He is only concerned about keeping hematocrit below 45percent and keeping platelets lowered.

Question: Is the Jak2 mutation in all my blood cells and platelets? I wonder because my blood got so thick and sticky, I had to discontinue having phlebotomies. Also the size has increased.

[Bluetop]

Thanks for posting. Very interesting focus and for someone like me who is lucky enough to be virtually symptom free, it is thrombotic events which are the big issue.

[jmctrek]

The propensity for thrombotic events despite normal hematopoietic presentations in these JAK2+ mice is in alignment with what my MPN specialist has discussed with me. She noted that regardless of my platelet level, harboring the JAK2 mutation (likely b/c it is also expressed in neutrophils and endothelial cells) increases my risk of thrombotic events.

The authors noted that they were

“unable to recommend on cytoreductive therapy over another for primary prevention of thrombosis in MPN patients”. This is a bit disappointing, as it seems to infer that past studies on current MPN meds provide little evidence on their efficacy in reducing thrombotic events, to include aspirin for ET and pegylated and monopegylated interferons for ET and PV. Let’s hope future MPN clinical studies will be designed to consistently measure biomarkers and the therapeutic effects of specific medications on thrombosis. Thank you for sharing this super informative article!

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[Manouche in reply to jmctrek]

The authors are unable to recommend any cytoreductive therapy, but absence of evidence is not evidence of absence. There are some strong reasons to believe that a medication capable to induce a molecular eradication/remission of JAK2 would also have a positive impact on the risk of thrombosis.