ITP "lifer" New Here and Seeking Treatment Advice

So,

Since I've been soliciting all kinds of advice here I thought I'd give you all an update on my appointment with my hematologist today.

My counts have dropped to 52K (72 last Thursday and 84 last Monday). Since I'm tapering off the prednisone this was not a surprise. I'm going to continue to taper off and go for weekly counts to see where I am. Going forward we talked about options and I told her where I thought I wanted to go in the future based on the risks that I am comfortable with. We have started the approval process for Promacta with my insurance and will see how long that takes.

She would like me to treat with small doses of steroids (she's fine with me trying 5mg or 10mg) if my counts go below 30K while we wait for medication approval. The side effects of the steroids are much less debilitating at the smaller doses, so I'll resort to that if needed, but I'm going back down to zero for the moment.

Since Promacta will be introducing clotting considerations I'm going to be doing absolutely nothing on the gynecological side (all of my biopsies, tests, etc. came back negative, no fibroids or other sources of bleeding, just the ITP triggering excessive monthly bleeding). She ordered the test to check for Antiphospholipid Antibodies, liver function, and a few other things that are required prior to starting treatment with Promacta.

Our goal will be to get me anywhere between 30-50, and she is completely comfortable with the 30s, which seems like a number I can feel comfortable with to hopefully mitigate some clotting risk. This was the first time that I had a substantial conversation with her after arming myself with knowledge and it was really great. I'm quite pleased with this doctor and think that we can work together for the long haul since it looks like I'm just one of those ITP cases that needs more management at this phase in my life (or perhaps going forward indefinitely).

Thanks for the continued support, and while my counts are currently tanking, I have some optimism for managing this in a way that I'm comfortable with in the future and to reclaim a higher quality of life.

Glad to hear things went so well with your MD! Just a few points to consider: 1) don't worry or obsess about "the numbers;" whether you are at 10K or 100K really doesn't matter at all if you are not having symptoms. When I first started on Promacta, I actually started cutting pills so that I could "titrate" my dosage to get me in the 50 K range! Looking back, I realize that, not only was that time consuming, but it really did not impact my numbers significantly, so I gave up on trying to match the 50K mentioned in the literature for Promacta. If you don't have symptoms at 20K, be thankful and happy that you can live with it. Secondly, I'm not sure what you mean by the statement "since Promacta will be introducing clotting considerations." I have read extensively about this and other drugs, and have seen nothing that indicates that there is an significant increase of clotting risks. What I have read is that new platelets--which TPO's like Promacta help produce--are "stickier" than older ones, so that you actually need less of them to do the same job--hence back to point 1 re: don't seat the numbers. Also, I have not seen anywhere in the literature that the tests you mentioned are required or advised--e.g. Antiphospholid...etc. before taking Promacta. Yes, liver function is important for the black box warnings with this and other potent meds,but as I mentioned earlier, I have never had a red flag on this issue, nor have I seen anything in the literature raising this as a significant risk. Further, given the discussion of "sticky" new platelets and your expressed concern over possible clots, you want to stay on the low side of the platelet numbers when on TPO's (just based on common sense, and not anything that has been shown in the literature). Finally, although steroids seem to have worked for you at some level, nearly every post I have read on this site over the years points out the evils of long term use of steroids, so I agree with you completely that if you can transition off of them completely, you are headed in the right direction. Good luck and let us know how your symptoms are impacted by the changes!

My opinion differs a bit from Luca. I think your doctor is spot on and I think the plan is perfect. We have had several people here have clots on the TPO's and there are articles that state other risk factors for those with ITP as well. Clotting risks include prior splenectomy, APS and some medications (ie birth control and TPO's). ITP itself is considered to be a thrombic disorder as well as a bleeding disorder due to large platelets and platelet microparticles. Sometimes the risks can be identified and sometimes they cannot. Limiting the risks can never be a bad idea.

Quite agree Sandi..my platelets are now at 90 on 0.2ml of N Plate a week. If they go any higher I shall drop down to 0.15ml for the next dose and see what happens. I am only aiming to keep count at >50 until I retire then to be honest unless I have symptoms worse than bruising I'm not too worried how low they go.

Sandi: I'm interested in your comments about blood clots and TPO's as I have researched this issue and have seen nothing more than the slightly increased risk numbers posted in the literature. Other than the anecdotal reports of "several people here" do you have anything I can look at that gives further data? I am particularly interested in any correlated factors that increase blood clot risks (e.g. certain physical activities, other diagnoses, other meds etc.) as I think this would be very important for all of us to have in front of us! Tx!

Sandy, I really commend you for bringing out the possibility of serum sickness with Rituxan and the different side affects. Five years ago when I was going to go on the trial at USC on a medication similar to Rituxan--just a smaller dose--I was a bit worried (especially since the success rate was so low, especially for people over 60).

My Hemo uses a lot of Rituxan and they push for it quite a bit. I really appreciate the fact that you have made so many of us aware of how toxic it can be for some people. And, most likely, I would be one of the people who reacted to it since I do react to everything out there in one way or another.

Thank you so much. So far, I am still in remission and do not have to think about what to use just yet.

Okay, Luca. Here we go! I've never said that physical activities can induce or cause blood clots, so that is not included in this response. The information is out there and I have seen plenty of articles that connect ITP and thrombosis in a number of ways. I think the anecdotal stories on here play a big part in the overall picture whether they are officially documented or not. I've seen enough over the years to know that even without the TPO's, blood clots can and do occur in ITP patients for a variety of reasons. I personally know a woman (since 1998) who had several serious clots even with low platelets. She'd had a prior splenectomy and no one could really find a reason for it. Years later, it was discovered that she had the Lupus Anticoagulant, but that hadn't shown up on prior tests. Anyway, she was the first one that brought this to my attention and I've been researching it since. The TPO's have raised the number of thrombotic cases that I've seen, enough so that I am concerned about misuse of those drugs, especially when other risk factors may be present.

In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% (31/955) treated with Promacta experienced a thrombotic event compared with 1% (5/484) on placebo. The majority of events were of the portal venous system (1% in patients treated with Promacta versus less than 1% for placebo).

Thrombotic/thromboembolic complications may result from increases in platelet counts with Promacta. Reported thrombotic/thromboembolic complications included both venous and arterial events and were observed at low and at normal platelet counts.

Consider the potential for an increased risk of thromboembolism when administering Promacta to patients with known risk factors for thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, chronic liver disease). To minimize the risk for thrombotic/thromboembolic complications, do not use Promacta in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet counts.

In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in patients treated with 75 mg of Promacta once daily. Seven thrombotic complications (six patients) were reported in the group that received Promacta and three thrombotic complications were reported in the placebo group (two patients). All of the thrombotic complications reported in the group that received Promacta were portal vein thrombosis (PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the six patients in the group that received Promacta experienced a thrombotic complication within 30 days of completing treatment with Promacta and at a platelet count above 200 x 109/L. The risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver disease treated with 75 mg of Promacta once daily for 2 weeks in preparation for invasive procedures.

I know this article is mainly about chronic liver disease and thrombosis, but the area that is in bold is the part that stands out to me. Many people are unaware of those potential risks if they have never been tested. Most are not.

www.drugs.com/pro/promacta.html

In the RAISE study [Cheng et al. 2011b], three patients (2%) receiving eltrombopag reported on-therapy thromboembolic events (two with pulmonary embolism, one had deep vein thrombosis) compared with none in the placebo group. All three patients had risk factors for venous thrombosis and the platelet counts were less than 50,000/µl around the time of the thrombotic events. In the EXTEND study [Saleh et al. 2011], 18 patients (6%) experienced 25 confirmed or suspected thromboembolic events with an incidence rate of 3.02/100 patient years. Deep vein thrombosis (n =10) and cerebral vascular events (n = 7) were the most common thromboembolic events. The majority of these patients (15/18) experienced thromboembolic events at a platelet count within the normal range and lower than the maximum platelet count achieved during eltrombopag treatment. All 18 patients had at least one thromboembolic risk factor such as hypertension, smoking, or obesity. The frequency of thromboembolic events in patients treated with eltrombopag in the EXTEND study is similar to that reported for the ITP patient population [Sarpatwari et al. 2010]. The data so far do not suggest an increased risk of thromboembolism with eltrombopag treatment. However, in patients with underlying risk factors of thrombosis, eltrombopag should be used with caution, perhaps starting at a lower dose, monitoring the platelet counts very carefully, and aiming at the minimal platelet counts adequate to reduce bleeding symptoms.[/i]

www.ncbi.nlm.nih.gov/pmc/articles/PMC3573439/

Initial studies with recombinant TPO in patients with ITP were encouraging, and novel compounds designed to stimulate the TPO receptor and resultant pathways have been shown in randomized trials to be effective in raising the platelet count and sustaining it at safe levels. Adverse effects of these agents have been relatively mild, although rare serious events including increased bone marrow reticulin deposition, increased numbers of circulating blasts and thrombosis have occurred, and theoretic risks of stimulation of megakaryocytopoiesis and platelet activation remain a concern.

asheducationbook.hematologylibrary.org/content/2008/1/219


Risk of thrombosis.

There is no consensus whether ITP is intrinsically a procoagulant disorder,121 especially during rapid platelet response, manifested by platelet activation, and release of platelet microparticles. As discussed, the literature is conflicting whether coexisting APLAs predispose to thrombosis. Absent compelling data, these concerns mitigate in favor of treating to attain a hemostatic, but not a normal, platelet count in most patients and to consider use of aspirin in patients at risk for thrombosis who attain stable counts more than 50 000/μL (50 × 109/L).

www.bloodjournal.org/content/113/26/6511

Thirty-one patients (37.8%) were APA positive at diagnosis. No statistically significant differences were found between the APA-positive and APA-negative groups regarding gender, initial platelet counts, or response to methylprednisolone therapy. After 5 years of follow-up, cumulative thrombosis-free survival of APA-positive (n = 31) and APA-negative (n = 51) ITP patients was 39% and 97.7%, respectively. A significant difference was found between these groups by log-rank test (P = .0004). In addition, LA was an important risk marker for the development of thrombosis in ITP patients. After a median follow-up of 38 months, 14 ITP patients (45%) who had APA positivity developed clinical features (thrombosis or fetal losses) of antiphospholipid syndrome (APS). There were no differences between the APA-positive patients with and without APS regarding the initial platelet counts, response to the therapy, or ACA positivity. The positivity rate for LA was significantly higher in those patients with ITP who developed APS (χ2: P = .0036; relative risk 7.15; 95% confidence interval, 1.7-47). In conclusion, this study indicates that a significant proportion of patients initially presenting with ITP and APA positivity developed APS. In patients with ITP, the persistent presence of APAs is an important risk factor for the development of APS.

In conclusion, we propose that measurement of APAs, especially LA, in patients with an initial diagnosis of ITP may identify a subgroup of patients with a high risk of developing APS features (ie, thrombosis or fetal loss). The episodic nature of the clinical complications of APS, compared with the gradual development of other autoimmune diseases such as SLE, warrants a need for a serologic workup rather than clinical follow-up. A prophylactic drug regimen may avoid the potential complications of APS in patients with ITP and positive LA, considering the high correlation between LA positivity and thrombosis. Future research may determine other markers, including genetic factors, that may help to identify high-risk patients.

www.bloodjournal.org/content/98/6/1760?variant=full-text&sso-checked=1

Having immune thrombocytopenia purpura (ITP) appears to increase the risk of thrombosis, a British researcher said here.
The finding -- derived from a large British database -- "confirms clinical suspicion" that the disease is linked to clotting, according to Ameet Sarpatwari, M.Phil., of the University of Cambridge. The risk appears to be primarily associated with venous thromboembolic events, he said at the American Society of Hematology meeting. Overall, the researchers found, the rate of such events among the ITP patients without a known prior history of thromboembolism was 6.7%, compared with 5.7% for the non-ITP controls.

The researchers found an adjusted hazard ratio of 1.58 for venous thrombosis, with a 95% confidence interval from 0.98 to 2.53. The ratio for arterial events was 1.02, with a 95% confidence interval from 0.65 to 1.59, while the combined hazard ratio was 1.17, with a 95% confidence interval from 0.82 to 1.66.

The finding may appear paradoxical, because the main characteristic of ITP is a low platelet count, said David Kuter, M.D., D.Phil., of Massachusetts General Hospital in Boston, who was not part of the study.

But there are probably two reasons, he said. In the first place, in ITP patients, platelets are younger and thus more active. Secondly, in ITP, an antibody reaction shatters the platelets, but the fragments are highly thrombogenic, Dr. Kuter said.

Physicians should be aware of the risk of thrombosis and take care not to let the platelet count rise too high, Dr. Kuter said. "You shouldn't try to normalize the platelet count," he said. They should also be aware of underlying cardiovascular disease and increase the platelet count in such patients "very gingerly," he said.

www.medpagetoday.com/MeetingCoverage/ASHHematology/12103

After splenectomy, patients with ITP have a higher risk of venous thrombosis and sepsis than patients with ITP who do not undergo splenectomy.

Patients with immune thrombocytopenia (ITP) who relapse after an initial trial of corticosteroid treatment present a therapeutic challenge. Current guidelines recommend consideration of splenectomy, despite the known risks associated with surgery and the postsplenectomy state. To better define these risks, we identified a cohort of 9976 patients with ITP, 1762 of whom underwent splenectomy. The cumulative incidence of abdominal venous thromboembolism (AbVTE) was 1.6% compared with 1% in patients who did not undergo splenectomy; venous thromboembolism (VTE) (deep venous thrombosis and pulmonary embolus) after splenectomy was 4.3% compared with 1.7% in patients who did not undergo splenectomy. There was increased risk of AbVTE early (<90 days; hazard ratio [HR] 5.4 [confidence interval (CI), 2.3-12.5]), but not late (≥90 days; HR 1.5 [CI, 0.9-2.6]) after splenectomy. There was increased risk of VTE both early (HR 5.2 [CI, 3.2-8.5]) and late (HR 2.7 [CI, 1.9-3.8]) after splenectomy. The cumulative incidence of sepsis was 11.1% among the ITP patients who underwent splenectomy and 10.1% among the patients who did not. Splenectomy was associated with a higher adjusted risk of sepsis, both early (HR 3.3 [CI, 2.4-4.6]) and late (HR 1.6 or 3.1, depending on comorbidities). We conclude that ITP patients post splenectomy are at increased risk for AbVTE, VTE, and sepsis.

www.bloodjournal.org/content/121/23/4782.abstract?sso-checked=true

People who have APS also are at higher risk for thrombocytopenia (THROM-bo-si-to-PE-ne-ah). This is a condition in which your blood has a lower than normal number of blood cell fragments called platelets (PLATE-lets). Antibodies destroy the platelets, or they’re used up during the clotting process. Mild to serious bleeding can occur with thrombocytopenia.

APS can be fatal. Death may occur as a result of large blood clots or blood clots in the heart, lungs, or brain.

www.nhlbi.nih.gov/health/health-topics/topics/aps/

Background: Splenectomy is frequently employed for therapeutic and diagnostic purposes in various clinical disorders. However its long-term safety is not well elucidated. Although risk of infection by encapsulated organisms is widely recognized, less well-known are risks of thrombosis and cardiovascular disease. Methods: We investigated levels of cell-derived microparticles (C-MP) in 23 splenectomized ITP (ITP-S) and 53 unsplenectomized ITP patients (ITP-nS). Assay of C-MP derived from platelets (PMP), leukocytes (LMP), red cells (RMP) and endothelial cells (EMP) were performed by flow cytometry. Coagulation parameters included PT, aPTT and activities of FVIII, IX and XI. Results of all measures were compared between the two groups, ITP-S vs ITP-nS. Results: Levels of all C-MP were higher in ITP-S than ITP-nS but only RMP and LMP reached statistical significance (p=0.0035 and p<0.0001, respectively). The aPTT was significantly shorter in ITP-S (p=0.029). Interestingly, correlation analysis revealed that RMP, but not other C-MP, were associated with shortening of aPTT (p=0.024) as well as with increased activities of factors VIII (p=0.023), IX (p=0.021) and XI (p=0.0089). Conclusions: RMP and LMP were significantly elevated in splenectomized compared to non-splenectomized ITP patients. This suggests that the spleen functions to clear procoagulant C-MP, and that elevation of C-MP might contribute to increased risk of thrombosis, progression of atherosclerosis and cardiovascular disease following splenectomy.

www.thrombosisresearch.com/article/S0049-3848%2808%2900002-9/abstract?cc=y=

Chronic ITP was associated with increased levels of RMP and PMP. FVIII, FIX and FXI were increased in ITP patients but showed a negative correlation with platelet count. Splenectomy was associated with increased levels of RMP and lower levels of FIX and F XI. The high level of microparticles in ITP might point towards a prothrombotic tendency.

www.thrombosisresearch.com/article/S0049-3848%2812%2900842-0/abstract

Video:

www.onclive.com/insights/immune-thrombocytopenia/Risk-of-Thrombosis-in-Patients-With-ITP

This was a thread that discussed the issue and had many articles cited. Rather than post them all individually, here is the whole thread:

pdsa.org/forum-sp-534/6-general-itp-discussion/28768-interesting-video-re-itp-and-thrombosis.html#49905

And then there is this latest post from a member:

pdsa.org/forum-sp-534/7-treatment-general/28982-promacta-and-pulmonary-embolism.html

Sandy, thank you for all this information!! I am definitely going to save it in a ITP file!

DeeDee:

I'm so glad that your remission is holding and I hope it continues. I think that Rituxan has its place in the treatment line-up, but it should be seriously investigated first. I literately jumped into it too quickly without considering the possible consequences. That was a long time ago and I was so intent on getting my counts up without steroids that I didn't give it any real thought. I didn't have enough respect for the toxicity of medications and possible harms. I sure do now!

Sandi: Can I first say Wow!!! and, "you will be sorely missed!" (but I know you won't go too far...). I have read through your wonderful missive, but will need some time to actually read the articles that you sent, so here is my first impression of the studies:

1) Clearly, ITP itself is associated with a higher risk of thrombotic events, primarily because, as Dr. Kuter states: a) the remaining platelets are young and thus "stickier," and b) platelets that are destroyed in ITP can serve as sites for development of a clot;

2) those studies that look at TPO's vs. thrombotic events seem to focus on overmedication with TPO's to get the platelet counts closer to normal (i.e. 100K and above), rather than an inherent risk associated with TPO's themselves. Put another way, it seems the greater the number of new platelets derived from TPO treatment, the higher the likelihood of potential clots, which matches Dr. Kuter's theory that newer platelets are "stickier"; but

3) even at higher platelet counts derived from TPO treatment, the increased risk for thrombosis is less than roughly 5% (hence our oft repeated advice to not treat the numbers, only the symptoms, as well as the TPO guidelines to target 50K as the max while in treatment).

4) Finally, it seems the majority of the studies that associate ITP with Thrombotic events are focused on correlated conditions or diagnoses (e.g. presence of a portal opening, Lupus diagnosis etc.) rather than the use of TPO's.

Obviously, I'm very interested in this issue because I've been on Promacta for 2 years now, and I continue to seek out info on what risks may be associated with this seemingly benign (for me anyway) treatment. As we all know, you don't get something for nothing, but I still haven't enough info on the direct risks of TPO's alone, rather than in combination with other medical factors. Thanks again for your wonderful research and knowledge!!

Sandy,

From Luca: Can I first say Wow!!! and, "you will be sorely missed!" (but I know you won't go too far...)

Are you leaving the forum? Didn't see that you mentioned it before--of course I'm not always following all the time. It wouldn't be a forum without you!

Dee Dee

Luca:

I think one of the main things to always consider is benefit vs risk. Let's look at statistics. In nearly every article, the statistical rate of thrombosis caused by any one of the known mentioned risk factors was usually well over 1%. Most would look at that and not consider 1% much of a risk, at least, not enough to take it seriously.

Yet, the estimated rate of fatal hemorrhage due to low counts is said to be 0.0162 to 0.0389 cases per adult patient-year. That is a very low risk, but many ITP patients experience extreme anxiety when counts are low. They do take that risk seriously. As a consequence, they will do whatever it takes to get counts up and eliminate that risk, even taking on an additional risk as a result.

I don't think that many doctors look at all the pieces of the puzzle. They pick up the ITP piece and since we say, "Fix that, please", they try to fix that. However, ignoring all of the other pieces such as possible APS, microparticles, prior splenectomy, BC pills, and many other risk factors mentioned just leaves an incomplete puzzle. Very few doctors look at the whole, big picture and take the necessary steps to try to identify those additional risks. Many articles even state that all of that testing isn't even necessary. Why? This is your life that we're talking about here. I truly applaud those doctors who realize the potential problems that some of the treatments can cause. As Dyan said, "I would prefer low platelets rather than risk of another clot and being on blood thinners poses a risk of bleeding regardless. Just my opinion but the clot was far worse than any injury or bleed I personally have endured to date."

By themselves, TPO's might have a very low risk of causing a clotting event. In a young, other-wise healthy individual with no known risk factors, they would probably do just fine. But it is obvious to me that anyone, anyone who has even one of those other risk factors should consider their clotting risk to be higher than average and should take precautions. If you've had a prior splenectomy, the risk is higher. If you have APA Antibodies, the risk is higher. If you have a high propensity to develop microparticles (no way to know that), the risk is higher. Any one of those alone can cause thrombosis. Throw in two, the risk goes up. Add TPO's and it goes up even more.

I would not consider TPO's for myself. I have tested positive on and off for the Anticardiolipin Antibody. It can come and go. Testing negative does not mean that you will always be safe. I take a daily aspirin. I also have Lupus which raises the risk of atherosclerosis. Those are two known factors for clotting, heart attacks and strokes. Adding a TPO does not seem like a viable option for me. My choice. I'd rather have low counts.

My main point is that we cannot consider the TPO's to be harmless in regard to clotting and should not be complacent about it. The fact is that clots have occurred at below normal counts in seemingly healthy people. It's impossible to discover all risk factors that might be present. In light of this, keeping counts around the 50k mark seems to be the responsible and safe thing to do.

DeeDee:

Yes, I plan to. I'm just waiting for a replacement. It's in the Social Section.

You will be missed so much I remember you from the original forum; I think I became a member back
in 2006 with my first bout of ITP. It sure will not be the same.

Dee Dee