Interesting video re: ITP and thrombosis

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

I wonder: If splenectomy quadruples the cumulative lifetime risk of thrombosis in general, does it also quadruple the risk of stroke?

I would think the stroke risk would be raised, yes.

I just had an additional thought. There have been studies that indicate that people with ITP can suffer from dementia and TIA's, so I'm sure strokes would be included.

www.ncbi.nlm.nih.gov/pubmed/12565721

www.medscape.com/medline/abstract/24880747

www.sciencedirect.com/science/article/pii/S0037196313000437

www.medscape.com/viewarticle/446805_3

onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2010.08234.x/full

Went a little nuts with the articles.

Strokes are cause by either a clot or a bleed and if studies show that long term effects after having a splenectomy will put you at a higher risk for clotting!

Than it stands to reason it would increase your risk of a stroke, vascular dementia, TIA's, and heart attacks!


This is the reason I refuse to have a splenectomy due to my family history of strokes, heart attacks, and DVT's.

Without exaggeration, Ellen's greatest nightmare is vascular dementia, and similar mentally disabling conditions.

Based on previous information that TPOs increase the risk of thrombotic events, and that migraine headaches are an additional risk factor for TIAs, Ellen and I had eliminated TPOs from consideration (splenectomy was a no-brainer)

In the Science Direct article above, their take on TPOs contradicts what I have read here and elsewhere. They report that TPOs do NOT increase the risk of thrombosis among ITP patients, and that the target counts with TPOs should be in the low-normal to normal range.

One of the studies cited [edit: in the sciencedirect article above] was this one:

onlinelibrary.wiley.com/doi/10.1111/j.1538-7836.2010.03830.x/full
Evaluation of bleeding and thrombotic events during long-term use of romiplostim in patients with chronic immune thrombocytopenia (ITP)
Conclusions: The incidence and severity of bleeding was decreased in chronic ITP patients treated with romiplostim compared with placebo, and the incidence of thrombotic events was not different between the two groups.

Does anyone have any further thoughts on this conflicting information?

Rob I've just checked 2 medicines reference sites in the UK both of which categorically state thrombosis is a risk factor

I seriously don't know where that article came from. It doesn't look like the one I initially posted. :ohmy: TPO's weren't mentioned in the abstract....did you read the full article? I wonder if that article replaced the one I posted? How odd...it's even a bit off topic.

Yes, I'm sure TPO's contribute to clots. That's a known risk.

That's strange. Could the conventional wisdom be changing? Could it be romiplostin vs. eltrombopag ? (they do act differently)

The following study is one of the most recent. It is a large sample size meta-analysis. Provan is second author.
The study shows no increase (actually, a non-significant decrease) in thrombotic events as well as other adverse events when treating ITP patients using romiplostim vs. placebo. This holds true whether or not the patient has been splenectomized, based on rates per 100 patient years.

www.bloodjournal.org/content/124/21/4199.abstract December 6, 2014; Blood: 124 (21)
Pooled Analysis of Safety and Efficacy of Romiplostim in Splenectomized and Nonsplenectomized Patients (pts) with Immune Thrombocytopenia (ITP)
Francesco Rodeghiero1, Andrew Provan, Michael Steurer, MD, Bertrand Godeau, MD, Nancy Carpenter, MSc, and Georg Kreuzbauer, MD
Conclusions: A relatively large number of nonsplenectomized pts have received romiplostim in clinical studies. Safety of romiplostim was comparable in splenectomized and nonsplenectomized patients with no new safety signals observed, and platelet response rates were high and of sustained duration in both groups.

EDIT: This study has been updated.

link.springer.com/article/10.1007/s12185-015-1837-6#page-1
Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim

Different risk????????

www.bloodjournal.org/content/124/21/2170.abstract December 6, 2014; Blood: 124 (21)
Signal for a Different Risk of Thrombosis Between Eltrombopag and Romiplostim
Conclusions: This study suggests a signal for an increased risk of thrombosis with eltrombopag compared to romiplostim, that must be confirmed by population-based pharmacoepidemiological studies.

Sandi wrote: I seriously don't know where that article came from. It doesn't look like the one I initially posted. :ohmy: TPO's weren't mentioned in the abstract....did you read the full article? I wonder if that article replaced the one I posted? How odd...it's even a bit off topic.

Yes, I'm sure TPO's contribute to clots. That's a known risk.

I just figured out why you were confused by my post. The article I posted above was not the one you posted: it was CITED by the one you posted. I have edited my post for clarity.

TPOs were mentioned in your article, but were referred to as TRAs (thrombopoietin receptor agonists) which is a more accurate terminology. Elsewhere, I have seen TPO-RA and TPOr-A used as acronyms.

Here is a longer quote from the article you posted:
www.sciencedirect.com/science/article/pii/S0037196313000437 Seminars in Hematology
Volume 50, Supplement 1, January 2013
Immune Thrombocytopenia Patients Requiring Anticoagulation—Maneuvering Between Scylla and Charybdis

"For the new thrombopoietin receptor agonists (TRAs) initially an increased risk had been discussed. Recent studies find that this is only true when TRAs are given in non-ITP indications.29 and 30 In ITP patients with TRAs the risk seems not to be higher than in ITP patients without TRAs.31, 32 and 33 Nevertheless and interestingly, platelet counts>150,000 (German Fachinformation) or >200,000 (US food and Drug Administration prescribing information) should be avoided with TRAs."

On the other hand, hot off the press:

www.ncbi.nlm.nih.gov/pubmed/26051432 Med Clin (Barc). 2015 Jun 4
Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: An updated systematic review and meta-analysis of randomized controlled trials.
Catalá-López F, Corrales I, de la Fuente-Honrubia C, González-Bermejo D, Martín-Serrano G, Montero D, Saint-Gerons DM.

Results: Fifteen studies with 3026 adult thrombocytopenic patients were included. Estimated frequency of thromboembolism was 3.69% (95% CI: 2.95-4.61%) for TPOr agonists and 1.46% (95% CI: 0.89-2.40%) for controls. TPOr agonists were associated with a RR of thromboembolism of 1.81 (95% CI: 1.04-3.14) and an ARR of 2.10% (95% CI: 0.03-3.90%) meaning a NNH of 48. Overall, we did not find evidence of statistical heterogeneity (p=0.43; I2=1.60%).

Conclusion: Our updated meta-analysis suggested that TPOr agonists are associated with a higher risk of thromboemboembolic [sic] events compared with controls, and supports the current recommendations included in the European product information on this respect.

However, this study does not appear to distinguish between ITP patients and other non-ITP thrombocytopenic patients, which for the previous study, was a distinction that made a difference.

Now some wild conjecture:
While it seems intuitive that TPOs would increase rates of thromboembolic events, I can imagine a scenario by which this might not be the case. One might distinguish between good thrombosis (which occurs when there is a break in the wall of a vein or artery) and thromboembolism (which occurs where there is no such break). If one assumes that the platelet microparticles are solely responsible for increasing the risk of thromboembolism in ITP patients, it could be the case that TPOs do not increase the quantity of microparticles, and therefore do not change the rate of thromboembolic events even though the increased quantity of healthy platelets decreases the frequency of bleeding episodes.

too tired to read now..you're on a roll Rob

I know, Ann. I guess I am part pit bull - I get my teeth into something and can't let go!

This topic seems really important to me, for my wife's sake and for many others:
Do TPOs really increase the risk of thromboembolism for ITP patients?
And is there a difference between Promacta and Nplate regarding risk?
Ellen does not want any treatment which increases her risk of stroke one iota.

The experts really do seem to disagree, and there are some really good names on both sides.

I so wish I could read! I start and after about 2 minutes I fall asleep! Maybe before I go into work tonight I can try and read those articles!

I'm not ignoring you, Rob. I need to find a time to read all of this when I have the time and my head is clear.

I'm finally getting to this. This part is a bit startling:

Results: Out of 2 733 224 ADR reports colligated in VigiBase®during the study period, 4714 were included in the study. TPO-RA indication was ITP in 96.6% of the reports. We found 598 cases of thrombosis: 203 arterial thromboses (94 IS and 110 MI) and 324 venous thrombosis. Among the 324 venous thromboses, 131 (40.4%) were pulmonary embolisms, 45 (13.9%) portal thromboses, and 17 (5.2%) cerebral venous thromboses were found. In multivariate analyses, there was an increased risk of thrombosis (ROR=1.46; 95% CI [1.18-1.82]) and venous thrombosis (ROR=1.46; 95% CI [1.10-1.94]) with eltrombopag. There was no statistically significant difference between the two TPO-RAs regarding arterial thrombosis (ROR=1.29; 95% CI [0.89-1.87]), IS (ROR=1.28; 95% CI [0.79-2.05]) and MI (ROR=1.53; 95% CI [0.96-2.43]). Age was independently associated with the risk of thrombosis. Female gender was a risk factor for venous thrombosis (ROR=1.55; 95% CI [1.16-2.06]); in contrast, it was a protective factor for arterial thrombosis (ROR=0.65; 95% CI [0.44-0.94]) and MI (ROR=0.55; 95% CI [0.34-0.90]). Exposure to oral contraceptive was also an independent risk factor for venous thrombosis (ROR=3.45; 95% CI [1.20-9.90]). Exposure to IVIg was associated with MI (ROR=2.13; 95% CI [1.23-3.68]).

598 out of 4,714 cases experienced thrombosis? That seems to be 1/7 people. Am I reading this right? The risk is higher with Promacta?

Rob16 wrote:
Now some wild conjecture:
While it seems intuitive that TPOs would increase rates of thromboembolic events, I can imagine a scenario by which this might not be the case. One might distinguish between good thrombosis (which occurs when there is a break in the wall of a vein or artery) and thromboembolism (which occurs where there is no such break). If one assumes that the platelet microparticles are solely responsible for increasing the risk of thromboembolism in ITP patients, it could be the case that TPOs do not increase the quantity of microparticles, and therefore do not change the rate of thromboembolic events even though the increased quantity of healthy platelets decreases the frequency of bleeding episodes.

I don't believe that microparticles are the sole reason for clotting events though. It could be a major factor, but there are other things to consider. APS that goes undetected, the use of birth control pills, age, heredity, splenectomized vs. non-splenectomized, response to the drug itself.....heck, there are even articles about IVIG causing clots when counts are driven too high, too fast.

One of your articles ended with: Platelet kinetics, reactivity in ITP, and risk of bleeding and thrombosis are influenced by a variety of factors, therapeutic intervention being only one among them. Emerging therapies targeting platelet production present new opportunities for treatment, but careful consideration of the interplay between all factors affecting platelet count and risks of bleeding and thrombosis is required to maintain a safe equilibrium.

Another one ended with this: CONCLUSIONS: Our updated meta-analysis suggested that TPOr agonists are associated with a higher risk of thromboemboembolic events compared with controls, and supports the current recommendations included in the European product information on this respect.

Those two paragraphs say plenty. A risk of thromboemboembolic events exists when ITP is present for a variety of reasons. That has been established. These articles contradict each other which bothers me. I've seen reports of thromboemboembolic events, it's occurred to people here, and it's the recommendation of the manufacturer to keep the platelet counts down. I think I'm sticking to that until something huge comes along that proves it untrue.

Anyway, great job on the articles! The last one was particularly interesting.

Sandi wrote: I'm finally getting to this. This part is a bit startling:
...
598 out of 4,714 cases experienced thrombosis? That seems to be 1/7 people. Am I reading this right? The risk is higher with Promacta?

That is how I read it, too: 4,714 patients taking eltrombopag or romiplostim (nearly all for ITP) resulted in 598 thrombotic events, which is 1/7.9.

Not knowing the relevant numbers of patients taking each medication, we cannot deduce the risk for each treatment, but assuming it is 50/50, then the resulting rates for eltrombopag or romiplostim are 1/6.6 and 1/9.7 respectively.

What we do not know from this study are the comparable rates for other treatment scenarios, and how this would compare to a non-ITP population matched demographically. We also do not know how well the various clinicians respected the 50k/ml target platelet count recommendations.

Most importantly, we do not know how many of the patients were post-splenectomy (probably most!). It could be that the patients were at a high risk for thrombosis before they started TPO-RAs, already having the risk factors from ITP and from splenectomy.

Still, 1/7.9 is a scary number!

But, what we do get from this study is that Nplate appears to be significantly less risky than Promacta.

Sandi wrote: Those two paragraphs say plenty. A risk of thromboemboembolic events exists when ITP is present for a variety of reasons. That has been established. These articles contradict each other which bothers me. I've seen reports of thromboemboembolic events, it's occurred to people here, and it's the recommendation of the manufacturer to keep the platelet counts down. I think I'm sticking to that until something huge comes along that proves it untrue.

The contradiction bothers me, too, and I would certainly stick to the 50k/ml guidelines for sure. It is scary how many doctors are NOT adhering to those guidelines. Still, bigger and better studies are needed to sort this out.

Do you have any idea what the rate of thromboembolic events might be after a "successful" splenectomy? I do not think I have ever seen hard numbers on that.

No, I don't know the numbers. That would be another topic to research.

This is an updated study that appears to show that Nplate is not a risk factor for developing thrombosis and is quite safe on all measures. Drew Provan is one of the authors. It was accepted for publication July 2015.
This study updates a similar study cited previously on this thread.

link.springer.com/article/10.1007/s12185-015-1837-6#page-1
Integrated analysis of long-term safety in patients with chronic immune thrombocytopaenia (ITP) treated with the thrombopoietin (TPO) receptor agonist romiplostim

This study analyses pooled data from 14 trials including 1059 patients with ITP and 1520 patient-years. On all measures, romiplostim was as safe or safer than the group placebo/SOC "standard of care". The measures were: haemorrhage, thrombosis, haematological malignancy/Myelodysplastic syndrome, and non-haematological tumors.