The Dangers of Nplate (Romiplostim) include Death

I wanted to share this information with the public in the hopes it can help save lives. Nplate (Romiplostim) killed my wife in 2016. She was in her mid-30’s, perfectly healthy save her ITP and Hashimoto's, and had been wrestling with ITP since she was 18. In late 2015 her platelets were constantly dropping (<15) and unlike the past she was not recovering. By this time she was making regular trips to the ER to get prednisone injections. Because of this continued problem, we met with an ITP specialist who presented both Rituxan and Nplate as treatments. We did the research and avoided Rituxan due to the side effects and questionable impact and found Nplate to be the “safest” option with “no side effects” except for excessive platelet production.

She started Nplate in January of 2016.

By the beginning of March 2016 she began to exhibit signs we didn’t think was anything more than common cold symptoms. Note her platelets did stabilize (~150k). But as the weeks passed in March she began to feel worse and worse, even going to the doctor to be told she had a sinus infection.

On a Sunday she woke up at 4am and had trouble breathing. I rushed her to the hospital and she was diagnosed with atypical pneumonia and acute renal failure (kidney failure). The doctors were perplexed. For the following days she continued to degrade; her behavior changed and she was completely out of it (seemed confused, etc.). The hospital said it was due to the numerous medications they were giving to address her pain and anxiety and "nothing to be alarmed about".

Her kidneys continued to fail (and was getting so bad dialysis was going to be required) and she was getting worse. The doctors were perplexed. They thought she might have Wegener’s Syndrome. They ran every test they could think of and were now administering pain killers due to how miserable she was.

The Thursday following her Sunday admittance she went down for a kidney biopsy and went into code blue respiratory arrest. Little did we know at that time she suffered eight ( watershed strokes. She was essentially rendered a vegetable. The doctors were stunned; they couldn’t believe nor explain what or how this happened.

A few days after her strokes, I received a random call from somebody at Amgen asking “how she was”. I was so distraught I didn’t think about what the call meant or even how they got the information. The call was short and I can’t remember the details, but it was strange.

For weeks, I attempted to do everything I could to save her; but the brain damage was too severe and the doctors still had no idea what was wrong – at all. She became the medical mystery of the area; and she was still getting worse, receiving daily dialysis now.

Finally, it was agreed to put her on palliative care. Her body collapsed upon itself and she passed away due to “Acute Respiratory Failure, Acute Renal Failure, and Unknown Etiology.”

Even though I asked numerous times during her sickness if Nplate could be the cause, all doctors said “no” because there was no documentation for such and her platelets never got high enough to cause issues (they were ~150k).

An autopsy was performed only after I battled for it (people may be unaware that hospitals no longer perform routine autopsies because of costs). Her brain was sent to one of the top universities in the country and the pathologist was very thorough.

They found her lungs and kidneys were in perfect health except for the “recent trauma” which was unidentifiable. The pathologist found nothing strange or unusual. Her organs were perfectly healthy (overall). Note this is somebody who was receiving dialysis sometimes daily with acute renal failure.

Her brain pathology was the telling sign; she developed microclots and strange crystalline formations in her tissue – not only in her brain, but her heart tissue as well. These developments were unprecedented and would never have shown up on any sort of screening (or CAT scan). The neuro-pathologist (one of the top in the country) had to confirm his findings with his colleagues because they said his findings were “nearly impossible”. Yet, they were confirmed.

The final assessment from the neuro pathologist was: “Nplate caused this. I’m not sure how, but I’m confident it did.”

Our guess is my wife had some undiagnosed auto-immune condition that catalyzed with the Nplate which caused the microclots and some sort of cellular breakdown. Antiphospholipid Syndrome (AFS) was mentioned (or something similar), but it was never confirmed.

Regardless, all of this happened after she started taking Nplate. She didn't start any other medications.

I did talk with lawfirms in the US who specialize in these sorts of cases and they said there just wasn’t enough data to support action against Amgen because they couldn’t find similar deaths tied to Nplate (the law requires multiple victims in order to pursue remedy of this kind). Here’s the kicker – as I mentioned above, autopsies are no longer performed routinely. As a matter of fact I believe autopsies are only performed if a patient dies within 72 hours of arriving at the hospital. So, it’s possible many others are dying from Nplate but it’s taking weeks (or longer) and we’re never hearing about it because autopsies are not performed. I only got mine because I pushed at the highest levels of the hospital -- they were going to deny it!

Regardless, my wife was healthy except for her ITP. And she was young; only in her 30’s. She died due to undocumented side effects tied to Nplate.

Does Amgen know about this? I would be surprised if they don’t. Why is there no documentation on these potential side effects? I find it hard to believe my wife is the ONLY person who has died due to side effects of Nplate. Statistically it’s possible, but highly improbable.

The danger with this is all of the doctors who were “educated” with Nplate made it very clear that Nplate could NOT be the cause of her condition; but only after her death did one of the top neuro pathologist in the country confirm it was Nplate.

My wife died at a very young age because of Nplate. Others who are considering this drug need to be aware it’s not totally safe, and anyone who is on Nplate and develops strange symptoms (outlined here) needs to take action immediately – although even now after all of the research, I’m not sure how one could prevent the strokes and cellular breakdown issues (we’re talking microbiology at this level).

My late wife would want me to share this with everyone in the hopes it can save lives. I certainly hope it does. Be warned. Nplate is not completely safe and it can cause death.

Thank you for taking the time to write this detailed account of your wife's experience. I'm sure it wasn't easy for you. I'm truly sorry for everything you've been through. I can't even imagine.

It is important for all of us to realize that these treatments can have very serious side effects. There is no such thing as a 'side effect free' treatment. While many, many people do well with them, there are some who do not. In the constant quest to have 'normal' counts, there is a risk that can be greater than the risk of lower counts. That should always be taken into consideration when making treatment choices. I have seen patients over-medicated when the need for that clearly wasn't there, and I have seen medications used improperly by the same doctors who are supposed to know and understand the proper protocols. All patients need to be aware of this and question if something does not seem right.

Yes, thank you. I agree completely with Sandi, that you are performing a valuable service by reminding us that even the safest treatments have terrible risks associated with them.

You wrote, "Our guess is my wife had some undiagnosed auto-immune condition that catalyzed with the Nplate which caused the microclots and some sort of cellular breakdown. Antiphospholipid Syndrome (AFS) was mentioned (or something similar), but it was never confirmed."

Given the possibility of catastrophic antiphospholipid syndrome with either Nplate or Promacta, as well as the possibility of less catastrophic clotting, I believe that all Nplate and Promacta patients should be screened for antiphospholipid antibodies (APA) prior to treatment. I don't think that this testing is mentioned in the product literature, and in my opinion it should be required.

Rob16 wrote: Given the possibility of catastrophic antiphospholipid syndrome with either Nplate or Promacta, as well as the possibility of less catastrophic clotting, I believe that all Nplate and Promacta patients should be screened for antiphospholipid antibodies (APA) prior to treatment. I don't think that this testing is mentioned in the product literature, and in my opinion it should be required.

What I find interesting is people in this forum seem to be familiar with "catastrophic APS" tied to Nplate yet the doctors seem to know nothing about this and Amgen is silent.

Note the clotting she experienced was microclotting; not platelet clotting - so it was something completely different than the one side effect they document for Nplate. They actually don't know what caused the microclots but they know it wasn't platelet related.

The fact people in this forum know about APS and APA screening as it related to Nplate yet there's nothing from Amgen shows there's something going on here that needs to be addressed...

A few of us are familiar with APS, Catastrophic APS, TTP, and other clotting disorders/problems that can go along with ITP. I have tried to educate others over the years without seeming like an alarmist; not easy. I have not seen much in literature over the years regarding APS and N-Plate causing problems, but common sense has made me cautious about the possibility. It is not widely discussed in the medical community and in fact, most articles state that testing for clotting disorders is not required prior to TPO use. I do agree with Rob that it should be standard testing, but there isn't much we can do about it. I had to beg my Hemo to get tested for APS. I asked several times and he flat out refused. Years later, a Rheumtologist agreed and I did have elevated antibody levels. I was advised to take an aspirin daily and I believe that this knowledge should definitely affect treatment decisions.

I have not heard of any incidents similar to that of your wife, but we wouldn't have known if you had not alerted us. I have heard quite a few stories about thrombisis/strokes during N-Plate use, even in very young patients (20's). I get personal e-mails from people from time to time and it has happened enough for there to be concern not only about this treatment, but all treatments including splenectomy. It is known by top ITP experts that thrombosis risks exist in ITP patients, even in patients with low platelets. Too many doctors do not know this, or do not take it seriously. I am always concerned when a patient is using N-Plate and has counts above the recommended 50 to 100k. All I can do is mention the risk and hope that everything goes well.

It would be very helpful to know if your wife had CAPS or TTP and it's a shame that you were not able to obtain that information. Both of those are very sudden, serious disorders that can occur at the onset of an infection or illness. They usually involve micro-clots; not the type of thrombosis that is usually seen with N-Plate. I'm not saying that N-Plate did not contribute to what happened to your wife; I am saying that this is the first time I have heard of a possible connection between N-Plate and micro-clots.

It is important to bring awareness to this subject and again, I thank you for your time.

Researching CAPS ( www.thedoctorwillseeyounow.com/content/arthritis/art1927.html ) this appears to be very close to what happened; my guess is her autopsy results (with the strange mineralization) may have been one of the first post CAPS-related findings, especially given I had to request the neuro-pathologist go back and re-review the brain tissue because the first screening from his team found nothing. He thanked me for pushing him to do go back and look at the tissue again (doing it himself that time) because of what he found.

The only thing she didn't have was the purplish blotches. She also did not have Lupus.

I'm blown away none of the doctors even mentioned CAPS nor any sort of immuno-suppressive treatment. I do think it was her left ventricular heart tissue where the problem was as well (the strange mineralization that was in the muscle). I'd have to confirm.

I am heartbroken for you. I cannot tell you how thankful I am for the information.
I was happily unaware of ITP until last spring. I have since tried repeatedly to learn and do what is best for my body. The ITP did not get better with prednisone either. I was given two options splenectomy or Rituxan. My body struggles with infection due to immuno deficiency and other auto immune disease, I need my spleen to help with that.
I gradually was sent down the path of Rituxan. What I was told is that it is safe, repeatedly.
I was told there would be support through the infusions including the manufacturer.
What I have experienced is that I struggled with sinus infection throughout the infusions and got zero support. It was a small ER doctor out of town, that helped me and took what I was dealing with seriously.
It was not even my own ER, they did not know what Rituxan was, they did not know what off-label meant, and the,y told me I had no business coming to the ER in the middle of the night as I was too complicated.
I had called my hemo repeatedly, I only ever talked to the reception, the message I got back was "if you go on antibiotic you cannot take your infusions".......I emailed my case worker at the drug company too...who told me she would inform my doctor.......
I waited and toughed out the worst sinus infection for three weeks before I could do it no more, and I went to the ER out of town.
I am still struggling with terrible head and face pain, and foggy head and terrible fatigue.
I called last Friday, I have not yet got a call back. What else can I do?
I mention this as to me from the get go there is just not enough information with regard to these drugs and any given auto immune illness. Sometimes auto immune disease takes forever to get a diagnosis. Sometimes they never do, I also have sjogrne's syndrome, diagnosed by lip biopsy after the blood work was done. I also know for sure my Mother had it, only she never knew. I have two sisters who now have been doiagnosed with it.
I also see and have experienced that physicians and drug companies seem to distance themselves with regard to any reported problems from the patient during infusions. I know it made it very tough for me to know which way to turn.....I was told very clearly that this was the treatment I needed and then told to go to an outside clinic on my own to get it done. Clearly the message was "you took Rituxan on your own" knowing the risks".........or do we?
From my own experiance and now this post, I don't think we really "KNOW" anything at a all.
Thanks again so much for the post.

Requnix:
I'm not surprised that they wouldn't have thought of CAPS. It is pretty rare. I know we like to think that doctors will be able to accurately diagnose in an emergency situation, but that is not always the case. I've been misdiagnosed in an ER even though I pointed out an obvious connection with a drug. I was ignored and luckily, the result wasn't fatal. Turned out that I was having a reaction to a medication and I did not have a virus like the ER doctor stated. I didn't find out until I had the same reaction a year later with the same drug. I lost faith in doctors at that point and started to realize the limitations. There are some good ones out there for sure, but just as many bad ones.

CAPS can occur without having Lupus, and we don't even know for sure if your wife had it. TTP is another, similar type of multi-clotting disorder. There may be others.

This is a good article about CAPS:

www.hss.edu/conditions_top-ten-points-for-patients-catastrophic-antiphospholipid-syndrome.asp

One small correction: microclotting (microcoagulation) does involve platelets. What makes it "micro" is that it occurs in small blood vessels rather than arteries or veins.
Here is a concise description from the Antiphospholipid Syndrome Foundation of America:

What is Microclotting? Thomas L. Ortel, MD, PhD www.apsfa.org/docs/APSFAVol4Winter2007.pdf
Simply put, micro-clotting, better referred to as “microvascular thrombosis” describes blood clotting that is occurring in some of the smallest blood vessels in the body.

The product literature does mention the possibility of clotting problems, but not microclotting and without mentioning APS.

Thrombotic/Thromboembolic Complications
Thrombotic/thromboembolic complications may result from increases in platelet counts with Nplate® use. Portal vein thrombosis has been reported in patients with chronic liver disease receiving Nplate®.
To minimize the risk for thrombotic/thromboembolic complications, do not use Nplate® in an attempt to normalize platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 x 109/L.

In my view this is wholly inadequate.

I do hope you will report this "adverse event" to the FDA, if it has not already been done. 1-800-FDA-1088

Amgen should have known of the risk of CAPS:

www.ncbi.nlm.nih.gov/pubmed/26329147
Format: Abstract
Semin Arthritis Rheum. 2016 Feb;45(4):e10-2. doi: 10.1016/j.semarthrit.2015.07.008. Epub 2015 Jul 29.
Two cases of thrombosis in patients with antiphospholipid antibodies during treatment of immune thrombocytopenia with romiplostim, a thrombopoietin receptor agonist.
LaMoreaux B, Barbar-Smiley F, Ardoin S, Madhoun H.
Abstract
INTRODUCTION:
Romiplostim is a thrombopeitin-receptor agonist approved for raising platelet counts in patients with immune thrombocytopenia (ITP). Several hematologic adverse effects have been reported including acute myeloid leukemia, myelofibrosis, and thrombosis.
METHODS:
We report two cases, one pediatric and one adult patient, who had antiphospholipid antibodies and received romiplostim for ITP. Additionally, we conducted medline, Food and Drug Administration (FDA) Adverse Events reports website, and manufacturer's adverse events database.
RESULTS:
Both patients developed thrombosis with evidence for catastrophic antiphospholipid syndrome (CAPS) after treatment with romiplostim. No reports or events were found from literature and database searches in regards to thrombosis associated with romiplostim in patients with antiphospholipid syndrome.
CONCLUSION:
These cases illustrate the potential for thrombosis with the administration of romiplostim. The administration of this drug to patients with a history of an autoimmune disease, especially those with positive antiphospholipid antibodies, should be done with caution.

Also, the risk of thrombosis with Promacta (eltrombopag) is even greater that with Nplate/romiplostim

www.ncbi.nlm.nih.gov/pubmed/26338346
Signal for Thrombosis with Eltrombopag and Romiplostim: A Disproportionality Analysis of Spontaneous Reports Within VigiBase®.

Here is a case of fatal coagulation in a patient with APS treated with eltrombopag/Promacta:

journals.sagepub.com/doi/full/10.1177/0961203315608257
Eltrombopag in systemic lupus erythematosus with antiphospholipid syndrome: thrombotic events
C Boulon, M Vircoulon, J Constans
First Published September 23, 2015 editorial
Sir,
Maroun et al. suggested that eltrombopag is useful to treat immune thrombocytopenic purpura (ITP) in systemic lupus erythematosus (SLE) in order to spare steroids, but they conclude that little data is available in patients with antiphospholipid syndrome (APS).1 We would like to focus on the case of a patient with APS who had severe thrombotic events after starting eltrombopag. This patient was 61 years old and had been diagnosed as having APS because of three fetal losses, two pulmonary embolisms and five deep venous thromboses. Antivitamin K treatment was given and no thrombosis occurred for more than 10 years. Lupus anticoagulant was positive and persistent in three samples (in 2000, 2002 and 2006), but there was no anticardiolipin or anti-β2gp1 antibody. ANA were mildly positive (1/250) and no anti-DNA or anti-ENA antibody was found. Anti-gpIIbIIIa antibodies were present. She was treated over 10 years for ITP with steroids, cyclophosphamide, azathioprine, intravenous immunoglobulins and splenectomy. However, she was hospitalized for diffuse petechial eruption with very low platelet count (4000/mm3) in January 2011. Fibrinogen rate was 4 g/l and factor V 100%, so disseminated intravascular coagulation was unlikely. Treatment was started with eltrombopag (50 mg/d) together with intravenous immunoglobulins. One month later, platelet count was 266,000/mm3. On 27 February 2011, she was hospitalized for dyspnoea. The international normalized ratio (INR) was 4.97 and platelet count was 119,000/mm3. Computed tomography (CT) scan showed pulmonary embolism of the proximal left pulmonary artery and lobar and segmental branches. The left adrenal gland was suspected of haemorrhagic necrosis. The day after, she experienced coma and needed nasotracheal intubation. Cerebral CT scan found frontotemporal hematoma, and unfortunately the patient died with brain herniation. This patient had had no thrombosis for more than 10 years, and presented with proximal pulmonary embolism 1 month after starting eltrombopag despite low platelet count and INR above the target. The mechanisms involved are speculative, but APS has been shown to be associated with platelet activation;2 Sperati suggested that reconstitution of circulating platelets leads to a worsening of thrombosis in a setting of platelet activation.3 Furthermore, other events might also be related to thrombosis: adrenal necrosis and cerebral haematoma, which might be an ischaemic vascular accident complicated by haemorrhage. We suggest that eltrombopag should be used with caution in patients with APS.

So how do we get Amgen and Novartis to change their warnings to include testing for antiphospholipid antibodies???

Thank you for the publication references. I'm confident Amgen does know about this and my wife's death could have been prevented.

I think the only way to get them to address this is to sue them; but I can't find any lawfirms willing to pursue such a case (pro bono) because there's not enough 'case study support' that is able to 'prove in a court of law' to meet the current standards without severe financial risk (e.g. loss of investment in case). If somebody was to pay for such a case it'd probably cost between $200-$500k (at least). Who has that sort of money? Learning a lot about how broken and useless our legal system is as I've investigated this. The best thing we can do for now is document this so google searches bring it online to those who conduct their own research.

But with this and other information I've come across, there's no question Amgen is withholding critical information that is leading to the deaths of people who are using Nplate. And doctors are failing to warn patients about the additional life-threatening side effects.

Requnix:
I've worked for law firms and agree, they will not generally take a case that they believe they will not win. They need proof that N-Plate did in fact cause your wife's death and that cannot be proven at this time. Drug companies are very powerful entities to take on. All you can do now is find out the statute of limitations and keep your eyes open.

I think if anything, doctors are not warning patients because they are not aware of other life-threatening side effects. Most should be aware of the clotting risk though and that is fairly well-known among the patients who agree to use N-Plate. We have patients here who are very cautious about trying to keep counts under 50k, and some who are a bit more trusting with higher counts. Most people do fine but there are those who apparently have higher risk factors and are not aware of it. Being an informed patient helps greatly, and that is why discussing this is so important. I'll repeat: Using N-Plate after a splenectomy does raise the risk of thrombosis. This is very important for those considering splenectomy. They may end up back to N-Plate afterwards and if so, the risk goes higher. Also, it wouldn't hurt to start asking doctors to test for APS prior to TPO use.

As for Amgen withholding information, I would hope that isn't the case. We have to be able to trust the drug companies literally, with our lives. Death is an unfortunate listed side effect on their website. www.nplate.com/patient/about-nplate/starting-nplate/?WT.srch=1
I know this doesn't make things any easier for you since your wife had a very different situation with multi-clotting. I'm sorry that we can't be of more help and again, I appreciate your warning to the patients here. If you do come across any additional information in the future, please share.

Requnix wrote: I think the only way to get them to address this is to sue them....
But with this and other information I've come across, there's no question Amgen is withholding critical information that is leading to the deaths of people who are using Nplate. And doctors are failing to warn patients about the additional life-threatening side effects.

I do not believe Amgen and Novartis are withholding information. They have no reason to do so. I just think they haven't connected all of the dots. Negligence, or at least a lack of due diligence, is most likely at fault. A warning to prescreen patients for clotting disorders prior to use would not cut too deep into their sales and profits. In fact, with better prescreening, their product would have a better safety profile, which might in the end improve sales.

I suggest that you contact the lead author, Brian LaMoreaux, in the article, "Two cases of thrombosis in patients with antiphospholipid antibodies...." I previously posted on this thread. If you follow the link, and click on "Author information" you will find his email address. Tell your story, voice your concerns, and ask him to help get the precautions changed. There are other researchers you might also contact, including those who did the original safety studies. You might also want to contact Novartis directly. Let me know if I can help.

Just off hand seems like there should be easier methods than suing. I would think that if someone had died, in a similar manor to your wife, during the FDA's supervised trial of the drug, we would not be having this discussion. The FDA would have required a box warning. Also I suppose further investigation as to probability (likelihood) of it happening in specific and/or general population groups.

To me, it seems more appropriate to forward as much proof as you can to the FDA. Cause them to act. The FDA has lots of lawyers, lots of medical resources, and lots of regulatory authority.

No one wants drugs to cost more, which is what suing does. Folks just want the facts known concerning risks. As I see it, that's the FDA's job.

Over here in the UK we have the 'Yellow Card' scheme yellowcard.mhra.gov.uk patients as well as medical staff can supply information regarding side effects of medications. Is there a similar scheme in the US ?