TOPIC:

This is a very interesting, break-through article. Ask if you need help with translation....someone will be able to help.

bloodjournal.hematologylibrary.org/content/117/21/5553.full?ct

It does explain why some patients do not respond to certain treatments and why ITP is different for everyone. It all has to do with the type(s) of antibodies that you have. I believe that those can change over time, some go away and some are acquired, which is why a treatment may stop working for some people.

Research has come a very long way since I was diagnosed in 1998.

That might explain why am having a time that seems to match what gets said on here this year though am still sure if they followed previous instructions fully it would have worked..... but whom am I. just the patient...

Very informative article! I was told in 1995 my body attacked my platelets. Told in 2008 failure in production, and possibly body attacks platelets. All in all, still standing!

ITP can be due to both platelet destruction and problems with production.

Interestingly enough, Eltrombopag did not work at all but Romiplastin did. Although here recently, it appears I am developing some sort of resistance to N-Plate (probably more due to my bitching about going to the doctor once a week), it has been nice to have platelets for this long (~6 months. Diagnosed 1.5 yrs ago). Thank you for the article post

New article about ITP and clots:

Patients with immune thrombocytopenia (ITP) paradoxically have an increased risk of thrombosis. The presence of antiphospholipid antibodies (aPL) has been observed in a substantial proportion of ITP patients, but its clinical significance remains to be established. This study retrospectively investigated the prevalence and clinical significance of aPL in ITP patients and assessed the risk factors for thrombosis. One hundred and sixty-five subjects with ITP were included in the study and followed for a mean period of 63·4 months. Sixty-nine (41·6%) patients were positive for aPL at diagnosis, and their clinical characteristics and course of ITP were not different from those of aPL-negative patients. Twenty-one (12·7%) patients developed a thrombotic event during follow-up and the cumulative incidence rate ratio of aPL-positive to aPL-negative patients for thromboembolism was 3·15 [95% confidence interval (CI) 1·21-8·17] after adjusting for confounding factors. Lupus anticoagulant and hypertension were identified by Cox regression analysis as independent risk factors for thrombosis [hazard ratio (HR) 4·1, 95% CI 1·4-11·9, P = 0·009 and HR 5·6, 95% CI 1·9-15·8, P = 0·001, respectively]. Our results showed that a substantial proportion of ITP patients were aPL-positive, and that lupus anticoagulant and hypertension were independent risk factors for thrombosis. Detection of aPL can provide useful information for identifying patients at high-risk for developing thrombosis.


www.ncbi.nlm.nih.gov/pubmed/23530551

Thanks for this article.

Health and good vibes

Reboot

I can't for the life of me understand why ITP patients are not routinely tested for APL's when diagnosed with ITP, or at least prior to starting TPO's or having a splenectomy. If any of you haven't been tested or are not sure if you've been tested, it might be time to start questioning your doctor about it.

Patients with immune thrombocytopenia (ITP) paradoxically have an increased risk of thrombosis. The presence of antiphospholipid antibodies (aPL) has been observed in a substantial proportion of ITP patients, but its clinical significance remains to be established. This study retrospectively investigated the prevalence and clinical significance of aPL in ITP patients and assessed the risk factors for thrombosis. One hundred and sixty-five subjects with ITP were included in the study and followed for a mean period of 63·4 months. Sixty-nine (41·6%) patients were positive for aPL at diagnosis, and their clinical characteristics and course of ITP were not different from those of aPL-negative patients. Twenty-one (12·7%) patients developed a thrombotic event during follow-up and the cumulative incidence rate ratio of aPL-positive to aPL-negative patients for thromboembolism was 3·15 [95% confidence interval (CI) 1·21-8·17] after adjusting for confounding factors. Lupus anticoagulant and hypertension were identified by Cox regression analysis as independent risk factors for thrombosis [hazard ratio (HR) 4·1, 95% CI 1·4-11·9, P = 0·009 and HR 5·6, 95% CI 1·9-15·8, P = 0·001, respectively]. Our results showed that a substantial proportion of ITP patients were aPL-positive, and that lupus anticoagulant and hypertension were independent risk factors for thrombosis. Detection of aPL can provide useful information for identifying patients at high-risk for developing thrombosis.

www.ncbi.nlm.nih.gov/pubmed/23530551

but its clinical significance remains to be established

Sandi,
Do you have any thoughts how the results of these tests might influence the course of treatment for ITP? Strange predicament: how to balance bleeding risk against clotting risk.

This article reveals how antiphospholipid antibodies are related to a number of CNS conditions:
rheumatology.oxfordjournals.org/content/42/2/200.full
Central nervous system involvement in the antiphospholipid (Hughes) syndrome

Well, a person would need to be more cautious when using TPO's or having a splenectomy because those also raise the clotting risk. Older articles used to state that having APL's would not alter the course of treatment but that should be reviewed (if it hasn't been already).

There's a warning in the SPC for both Nplate and Revolade where APS gets a mention ..

www.medicines.org.uk/emc/medicine/23117/SPC/Nplate+with+Reconstitution+Pack/

"Thrombotic/thromboembolic complications

Platelet counts above the normal range present a risk for thrombotic/thromboembolic complications. The incidence of thrombotic/thromboembolic events observed in clinical trials was 6.0% with romiplostim and 3.6% with placebo. Caution should be used when administering romiplostim to patients with known risk factors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking."

That's a good find, Ann. I'm glad to see that. What I don't particularly like is the mention of clotting with counts 'above normal range'. That is misleading since we've seen patients clotting with counts below normal range. I hope that statement is meant to mean while using TPO's without having the known risk factors.

Ann, Sandi, Thank you. You've given me a lot to think about.
The article I cited lists a number of CNS conditions which tend to correlate with APS, and Ellen may have some of them, perhaps including migraine headache, though I need to reread the article more closely. In any case, I think it would be a good idea for her to be tested. I would hate it, though, if a positive antiphospholipid antibody test were to take away TPOs as an option, but it's better to know.

Yes, it is better to know. I asked my Hemo about being tested quite a few times, and he always told me it wasn't necessary. He said that my counts went too low to have APL's because generally ITP is mild when someone has APS. My counts were under 5k at times. My Rheumatologist finally tested me (upon request) and it turned out that I did have Anticardiolipin Antibodies (one the three APL's). You never know.

B-cell depletion therapy may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). Capitalizing on a multicenter randomized placebo-controlled trial, we investigated the effects of rituximab on the antibody and cellular responses to Streptococcus pneumoniae polysaccharide vaccine and Haemophilus influenzae type b (Hib) conjugate vaccine in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n=17) or placebo (n=7). Among 20 evaluable patients, 3/14 (21%) in the rituximab group and 4/6 (67%) in the placebo group achieved a 4-fold increase in anti-pneumococcal antibodies (p=0.12). For anti-Hib antibodies, 4/14 (29%) and 5/6 (83%), respectively, achieved a 4-fold increase (p<0.05). Fewer patients in the rituximab group demonstrated functional Hib killing (2/14 [14%] versus 5/6 [83%], p<0.05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, pre-plasma cell blasts and interferon-γ secreting T-cells were reduced in rituximab-treated patients. We found that antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with the depleted B-cell pool. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in patients with ITP.


bloodjournal.hematologylibrary.org/content/early/2013/07/12/blood-2013-04-494096.abstract?ct&ct=5211f05c98b763faaf593dbb389ead734d3f37a931a1d9976215782a1af0b6d6089b2ed1d0cceec1380b576cb3f25c4fb95a417db08bf46d8771e349098204bc

May-Hegglin anomaly (MHA) is a rare autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and inclusion bodies in leukocytes. Recent evidence links MHA to mutations in the MYH9 gene. MHA has not been reported in Taiwan before. We report a 25-year-old Taiwanese man who presented with prolonged bleeding after dental extraction. Examination of peripheral blood smear revealed thrombocytopenia (platelet = 35,000/μL), giant platelets, and Döhle-like cytoplasmic inclusions in neutrophils. A strong family history of thrombocytopenia favored hereditary macrothrombocytopenia over idiopathic thrombocytopenic purpura (ITP). Electron microscopy revealed a spindle shape and parallel order of filaments in the inclusions, consistent with the diagnosis of MHA. We performed mutational analysis using polymerase chain reaction followed by direct sequence of the MYH9 gene for the patient, his maternal uncle and cousin, and all showed the same heterozygous R1933X mutation in exon 40. MHA should be considered when a young patient has thrombocytopenia, frequently misdiagnosed as ITP. Morphological examination of peripheral blood smear, family history tracing and genetic studies are required to make an accurate diagnosis and avoid unnecessary and even harmful therapies such as corticosteroids and splenectomy.

www.ncbi.nlm.nih.gov/pubmed/23759689

www.itpsupport.org.uk/american/%209.%20Can%20I%20Die%20from%20ITP.pdf

Thrombopoietin Levels Help Predict TPO Treatment Response

Thrombopoietin stimulates the bone marrow to produce more platelets. However, people with ITP often fail to produce higher thrombopoietin levels to compensate, as seen in those with other low platelet diseases. In a new study, researchers looked at the TPO levels of people with various reasons for low platelets, including 21 with ITP who were treated with the TPO receptor agonists, romiplostim or eltrombopag. The study participants with ITP who had TPO levels greater than 95pg/mL did not respond well to the TPO agents. The authors conclude: “Elevated TPO levels in ITP patients may predict a poor clinical response to treatment with TPO receptor agonists.”

Note: A test to measure TPO levels is available through Quest Diagnostics (test no. 16336).

Makar RS et al. “Thrombopoietin (TPO) levels in patients with disorders of platelet production: Diagnostic potential and utility in predicting response to TPO Receptor agonists.” Am J Hematol. 2013 Aug 1.
www.ncbi.nlm.nih.gov/pubmed/23913253

ituxan and Vaccines Don’t Mix

If you received vaccinations within six months of receiving rituximab (Rituxan®), they were probably ineffective. In a new study, people who received pneumonia and flu vaccines six months after their rituximab treatments had a significantly lower response to these vaccines than the placebo group. Nearly 20% did not respond to the vaccines at all. Rituximab depletes B-cells (cells that make antibodies) and also reduces cellular immunity (the part of the immune system that doesn’t include antibodies), both needed for a healthy immune system. This cellular depletion lasts at least six months and has implications for the lack of response to vaccinations and the increased risk of infection seen in rituximab patients.

Nazi I et al. “The effect of rituximab on vaccine responses in patients with immune thrombocytopenia.” Blood. 2013 Jul 12.
www.ncbi.nlm.nih.gov/pubmed/23851398

Now we're talking! This could be huge, but I wonder how long it will be until it's disproven.



Antiplatelet Antibody Tests Gain Clout

In the past, many doctors did not order antiplatelet antibody tests for people with suspected ITP since these tests could not accurately diagnose the disease. Now researchers have found another potential use for the tests: helping to predict treatment response and the general course of ITP.

In one study, researchers measured antiplatelet antibodies attached to three different regions on the platelets of people with ITP: GPIIb/IIIa, GPIb/IX, and GPIa/II. Those with antibodies to GPIIb/IIIa had a much higher response to IVIg and prednisone than people with the other antibody types or those diagnosed with ITP who had no measurable antibodies.

In another study, scientists tested the antiplatelet antibody levels of those newly diagnosed with ITP using the MAIPA diagnostic test, then followed these patients to see if there was a correlation between antibody levels and their disease prognosis. The scientists concluded: “…indirect MAIPA positivity at disease onset is associated with more severe hemorrhage and predicts a chronic course in adult ITP patients.”

Liu XF et al. “Relationship between the expression of autoantibodies against platelet membrane glycoprotein and therapeutic effect in primary immune thrombocytopenia.” Zhonghua Xue Ye Xue Za Zhi.(Chinese Journal of Hematology) 2013 Jul;34(7):610-3.
www.ncbi.nlm.nih.gov/pubmed/23906456

Grimaldi D et al. “Antiplatelet antibodies detected by the MAIPA assay in newly diagnosed immune thrombocytopenia are associated with chronic outcome and higher risk of bleeding.” Ann Hematol. 2013 Aug 4.
www.ncbi.nlm.nih.gov/pubmed/23912633

Article re: contraceptives:

www.bmj.com/content/347/bmj.f5298

New consensus on ITP management:

bloodjournal.hematologylibrary.org/content/115/2/168.full

CD8+ T-cell deficiency is a feature of many chronic autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, dermatomyositis, primary biliary cirrhosis, primary sclerosing cholangitis, ulcerative colitis, Crohn's disease, psoriasis, vitiligo, bullous pemphigoid, alopecia areata, idiopathic dilated cardiomyopathy, type 1 diabetes mellitus, Graves' disease, Hashimoto's thyroiditis, myasthenia gravis, IgA nephropathy, membranous nephropathy, and pernicious anaemia. It also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined. Here it is proposed that this CD8+ T-cell deficiency underlies the development of chronic autoimmune diseases by impairing CD8+ T-cell control of Epstein-Barr virus (EBV) infection, with the result that EBV-infected autoreactive B cells accumulate in the target organ where they produce pathogenic autoantibodies and provide costimulatory survival signals to autoreactive T cells which would otherwise die in the target organ by activation-induced apoptosis. Autoimmunity is postulated to evolve in the following steps: (1) CD8+ T-cell deficiency, (2) primary EBV infection, (3) decreased CD8+ T-cell control of EBV, (4) increased EBV load and increased anti-EBV antibodies, (5) EBV infection in the target organ, (6) clonal expansion of EBV-infected autoreactive B cells in the target organ, (7) infiltration of autoreactive T cells into the target organ, and (8) development of ectopic lymphoid follicles in the target organ. It is also proposed that deprivation of sunlight and vitamin D at higher latitudes facilitates the development of autoimmune diseases by aggravating the CD8+ T-cell deficiency and thereby further impairing control of EBV. The hypothesis makes predictions which can be tested, including the prevention and successful treatment of chronic autoimmune diseases by controlling EBV infection.

www.ncbi.nlm.nih.gov/pubmed/22312480

Sandi,

Fascinating article. I read it on Facebook today and was wondering if anyone had any thoughts.

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 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.ncbi.nlm.nih.gov/pubmed/23637127

Thanks Sandi. That was just in time for Ellen's hematology appointment today, to help explain why Ellen does not want a splenectomy! I wonder how long it will be before the protocol is changed.

The protocol has been changed. This article makes it seem as if splenectomy is a first line treatment right after failed steroids. I did e-mail Carolyn from the PDSA about it and was hesitant to post it for that reason. But - I felt that the information was too important to pass up.

This is the current consensus which lists splenectomy as a second line treatment along with a few others:

bloodjournal.hematologylibrary.org/content/115/2/168.full

Sandi,
First line is steroids, IVIG, anti-D. That is all.
For many doctors splenectomy is the second line treatment after first line steroids do not produce a complete remission. I think it should be MUCH farther down this list, if on the list at all. Splenectomy is still the second line treatment preferred by many.

Ha ha, isn't that what I said?