cyclophosphamide

I know it's been a while, but we've been fighting on some new fronts. Just to bring everyone up to speed, Kimberly has chronic ITP. She is 32 years old and been fighting this for eleven years now. Kimberly is also a NICU nurse and the little sister of a big Brother who didn't survive ITP.
After a failed splenectomy five years ago, she became hyper coagulative, requiring numerous procedures to restore blood flow and treat numerous emergency events spanning the five years, all the while trying to maintain a healthy platelet count. She has since developed esophageal veracies requiring three banding procedures to date with two more to go.
By the way she and her HEMO have tried every drug you can think of and even some out of the box like Gizyva.
Recently after a severe drop in her counts <6000, she received two doses of IVIG. She had received IVIG a couple of times in years past, with no noticeable side effects. This time would be different. Three days after the second dose. Kimberly had a major brain bleed caused by clotting in the venus sinus veins. This caused a major seizure. After three weeks of treatment she was able to come home with to date no permanent side effects. The migraine type head aches have subsided after 45 days out of the hospital, which allowed for the third banding procedure.
All along Kimberly's platelet counts are up one week and down the next. They don't seem to be able to get her to a continued stable count of >30,000 for any period of time due to the counter fear of clotting and need for blood thinners.
All this being said brings me to this question at hand. Cyclophosphamide, Cytoxan. It seems every time they have tried some new approach, their has been a major down side effect, that giver the knowledge before hand would have prevented taking that approach in the first place.
She is currently taking prednisone, nplate ( don't think this is doing anything other than enhancing the potential of clotting and giving her headaches )and countless other drugs. High dose prednisone is her rescue drug, but at times even that hasn't worked, ie. the IVIG treatment recently.
So community, help us out, if anyone knows of any reason, given her situation and unique problem why she shouldn't go this chemo route, please let us know.

Thanks
Dad

Your daughter has had a horribly tough time with this. I'm so sorry. This would be a very hard decision. I consider Cytoxin to be a treatment of last resort and I see that you are at that point. The downside to this treatment is that I have rarely seen it work and there can be permanent side effects, the main one being neuropathy. Neuropathy can be a very painful thing to live with.

I can't tell you what to do, but I hope you find peace with whatever decision you make. Please keep us updated.

Is it possible that Rituxan might be used again but at a much lower dosage? You did not say what kind of reaction Kimberly had. Studies have shown that Rituxan is equally effective at a much lower dose, but some reactions are not dose-dependant.

Since Rituxan worked well, but caused a reaction (possibly to the mouse DNA) you might consider the off-label use of Ofatumumab, which like rituximab is an anti-CD20 monoclonal antibody, but is fully human and contains no mouse protein. Here is a discussion from this forum three years ago:
www.pdsa.org/forum-sp-534/7-treatment-general/27608-alternative-to-rituximab-ofatumumab.html#35871
The discussion mentioned Dr. James Bussell. He is a PDSA medical advisor and is at Cornell University.

The following 2016 article includes a discussion of the potential of cyclophosphamide to induce thrombosis, but with the caveat that the reported cases only appear in a cancer treatment setting, and may not apply to autoimmunities.

www.thieme-connect.com/products/ejournals/html/10.1055/s-0036-1579642
Thrombosis in Autoimmune Diseases: A Role for Immunosuppressive Treatments?
...
In 2006, a review by Haddad and Greeno[144] focused on the possible link between chemotherapeutic agents and thromboembolism. Cyclophosphamide is used in various chemotherapy regimens, and in the last decades, its use has been reported to be associated with an increased risk of VTE.[145] [146] [147] [148] [149] Notably, it is difficult to determine the mechanism of this increase. However, cyclophosphamide was found to have a procoagulant activity in animal studies. Actually, thrombin generation is increased when acrolein, a cytochrome P metabolite, impairs the phosphatidylserine exposure and tissue factor activity. In the same study, mice treated with cyclophosphamide and acrolein had elevated plasma thrombin/antithrombin complex levels, whereas anticoagulant protein C levels remained low.[150] This drug is able to modify the microvascular architecture causing endothelial damage,[151] as shown in an experimental model on liver specimens, resulting in blood stasis and thrombosis.[152]

In human studies, cardiotoxicity has been reported in patients treated with cyclophosphamide, and the association with methotrexate and fluorouracil chemotherapy may cause protein C and protein S deficiency along with enhanced PAI-1 levels.[153]

However, the majority of studies that found a prothrombotic activity of cyclophosphamide are based on subjects with oncohematological diseases, often in combination with other immunosuppressive drugs and with other prothombotic risk factors.

Cyclophosphamide is a milestone in the treatment of autoimmune diseases and several case reports found that it might be useful in the prevention of recurrent thrombotic events in these patients.[154] [155] [156] [157] [158]