PDSA e-News: December 30, 2020

COVID-19 vaccines and ITP: Should patients be vaccinated?

COVID 19 ITPAs the global impact of COVID-19 grows daily, our priority is always on the health and safety of our ITP community. Here we share important disease and treatment information and helpful resources to keep you current and informed.

Guidelines from PDSA Medical Advisors

The PDSA medical advisors are of the opinion that the risk-benefit ratio favors vaccination against SARS-Cov-2 for patients with ITP who meet FDA and CDC guidelines. No vaccine is “risk free”, but there is no evidence to date to suggest that the apparent very low risk of allergic reactions is any greater in patients with ITP. On the other hand, there is compelling evidence that vaccination markedly, perhaps >90-95%, reduces the risk of serious infection. We are not aware of data to indicate that the currently available vaccines are especially likely to exacerbate ITP. If there is reason for concern that the platelets may have fallen after initial vaccination, a platelet count could be obtained at the time of the booster dose 21-28 days later. More data is needed to determine if the vaccine is as effective (and if the effectiveness is as durable) in patients who received or are receiving therapy for ITP as it is for individuals in the general population. Vaccination is also indicated in patients who have had a splenectomy.

Guidelines from the CDC’s Advisory Committee on Immunization Practices (ACIP)

For patients with bleeding disorders:
COVID-19 vaccine may be given to these patients, if a physician familiar with the patient’s bleeding risk determines that the vaccine can be administered intramuscularly with reasonable safety. ACIP recommends the following technique for intramuscular vaccination in patients with bleeding disorders or taking blood thinners: a fine-gauge needle (23-gauge or smaller caliber) should be used for the vaccination, followed by firm pressure on the site, without rubbing, for at least 2 minutes.

For patients who are immunocompromised:
Immunocompromise is not a contraindication to current COVID-19 vaccine, including those with cancer, leukemia, HIV/AIDS and other immune system problems or taking medication that affects their immune systems. However, patients should be informed that the vaccine might be less effective than in someone who is immunocompetent.

News from the 62nd ASH Annual Meeting and Exposition

This year’s 62nd ASH Annual Meeting and Exposition was virtual due to the global pandemic. Held December 5-8, the meeting attracted thousands of clinicians, scientists, pharmaceutical company personnel and even investment analysts worldwide to share ground-breaking research in the field of hematology. In conjunction with the ASH meeting, PDSA hosted the annual Friday Morning ITP Breakfast , coordinated by PDSA and four of PDSA’s Medical Advisors, James Bussel, MD, Nichola Cooper, MD, Michele Lambert, MD and John Semple, PhD. This year’s virtual event featured fourteen hematology experts who presented their leading-edge ITP research across four hours and multiple time zones. In this issue of the e-news, we report on research PDSA staff and advisors were part of showcasing advanced knowledge on ITP therapies and patients’ overall quality of life living with ITP. Watch for additional ASH reports in the 2020 winter issue of The Platelet News, the PDSA quarterly newsletter.

Anxiety In Adult Patients Living With ITP Stratified Across Different Treatment Types and Groups: A Survey study by PDSA

Woman sitting in a parkThis study looked at the impact of anxiety among adult ITP patients focusing on whether anxiety levels differ depending on treatment. Using surveys from the PDSA Natural History Study Registry, patients were stratified into different groups including: 1) those who have never received treatment 2) those who received treatment in the past but not within the last six months, and 3) those who were currently on therapy or had received treatment for their ITP within the last six months. Patients currently on therapy were further stratified into those receiving a first vs second-line therapy. Among the 357 adults who completed surveys on treatment history, 11% have never received treatment for ITP, 46% have received treatment in the past, and 43% currently receive therapy (within the last six months). Among those currently on treatment, 82% were receiving a monotherapy.

Participants were asked to reflect on the last seven days when completing the QoL survey (n=310), and 66% reported they felt anxious; with 17% reporting this was experienced ‘almost always/often’. Among those who have never been treated, feeling anxious was reported 67% of the time; 18% reported feeling this way ‘almost always/often’. A similar trend was reported in patients not currently on treatment. Among those receiving a first line therapy, anxiousness was reported 74% overall; 19% ‘almost always/often’. Among those receiving a second line therapy, 72% reported feeling anxious; 9% reported feeling this way ‘almost always/often’. Differences in high levels of anxiousness reported among the different treatment groups was not significant as anxiety was constant across all of the different treatment groups.

Difficulties focusing were reported (51%; 9% reporting this occurred ‘almost always/often’). Among those who have never been treated, difficulties were reported (48%; 12%, ‘almost always/often’). Those not currently receiving treatment had difficulties focusing due to anxiety (50%; 4% reporting this ‘almost always/often’). Those on first line treatment indicated focus was impacted by anxiety overall (60%; 36% ‘almost always/often’) and those receiving second-line therapy reported (58%; 8% ‘almost always/often’). Differences in high levels of anxiety affecting concentration reported among the treatment groups was significant revealing a higher anxiety profile among those using corticosteroids. When difficulty with focus due to anxiety was compared between those receiving corticosteroids and those receiving a TPO-RA specifically, anxiety was significantly higher in the steroid group this trend was not found to be statistically significant among other second line therapies.

Higher anxiety levels affecting focusing appeared related to treatment type in those currently receiving therapy. Corticosteroid users were more impacted by their anxiety than those receiving TPO-RAs which may be a side-effect of the therapy itself as steroids are known to interfere with mood and concentration, or could be attributed to coping with the uncertainty of ITP, especially if newly diagnosed, a group potentially mainly using corticosteroids. We did not stratify by phases of ITP in this study but that may be something to look at in future.


Comments by PDSA Medical Advisors:
As in many situations, patients report they are well and in good health a high percentage of the time: “I’m fine”. However, when specifically asked about their anxiety, their ability to focus, their energy levels and many other aspects of day to day living, most patients with ITP are affected to various intensities. This may contribute to a desire to not visit the doctor frequently. On the flip side, if a doctor is only assigned 15 minutes for a follow up visit per patient, that does not leave much time to explore what a patient’s life is like. The physician must spend most of this limited time on the medical aspects of ITP. These and other findings have been identified in a few recent I-WISh publications and emphasize that this neglected area is important.

Importance Of Glycoside Residues On Haemostatsis of Patients With Immune Thrombocytopenia

Blood in test tubeProteins containing diverse sugar-like molecules, called glycoproteins, are found on the surface of platelets, as they are on all cells. Among these are proteins that contain a chemical called sialic acids. There is some evidence to suggest that when sialic acids are removed chemically or naturally, they may accelerate platelet removal from the circulation. Differences in the extent of the loss of sialic acids might contribute to the severity of ITP and resistance to therapy. In this study, the relationship between the loss of sialic acids from platelets of adult patients with ITP and platelet count, platelet activation, apoptosis (a form of cell death), and lymphocyte distribution was assessed compared against platelets from healthy controls.

The results revealed that platelet count and activation appeared to be related to the presence of glycoside residues on platelet surface proteins. For instance, alpha1,6-frucose and alpha-mannose (types of sugars) were elevated in the participants with ITP as was a specific type of glucosamine residue. ITP participants also had higher platelet levels of an enzyme called neuraminidase, which removes the sialic acids from glycoproteins. There was also an increase in platelet caspases, enzymes involved in apoptosis, and a class of phospholipids on the surface of platelets called phosphatidylserine, which may accelerate clotting reactions. Adults with ITP who had a platelet count <30 x 109/L had the most amount of phosphatidylserine and showed a reduced ability for platelet (re)activation. The exposure to phosphatidylserine allowed for binding with prothrombinase complexes which may account for why some ITP patients do not experience significant bleeding even in the presence of a low platelet count.

Overall, the researchers believe that glycoside residues on platelets modulate their function, lifespan and hemostasis.

*This work was partially supported by a grant from PDSA.

Comments from PDSA Medical Advisors:
Although it is clear that autoantibody-mediated removal of platelets from the circulation is the primary driver of thrombocytopenia and the severity of thrombocytopenia correlates with bleeding, patients differ in clinical presentation and the apparent paradoxical increase in thrombosis as well as bleeding remains unexplained. These analyses of sugar residues on platelet proteins may provide insights into different causes of platelet clearance and function that might contribute to clinical heterogeneity. In particular, while still controversial, this form of platelet removal secondary to loss of sialic acid is thought to require a totally different approach to treatment. Platelets contain a molecule called neuraminidase that removes the sialic acid and “moving this molecule” to the platelet surface is likely responsible for the loss of sialic acid. These studies are both difficult to perform/standardize and larger and longer studies will be needed to establish correlation with disease severity, bleeding or clotting symptoms or history and response to treatment before they become established clinical laboratory tools. Nevertheless, identification of “disease modifiers” might promote insights into phenotyping, e.g. risk of bleeding, and reveal potential new targets for intervention. Focusing on the ‘glyco’ (sugar part) of the platelet glycoproteins instead of focusing on the protein part may reveal new insights into platelet biology and clinical variability.

Tapering Thrombopoietin Receptor Agonists In Primary Immune Thrombocytopenia: Recommendations Based On The RAND/UCLA Modified Delphi Panel Method

Doctow with patientWhile TPO-RA’s have been used successfully to treat ITP for a while now, there is little known about how long such a therapy is required, and when and how to safely stop the medication in those who have responded well to the drug. It was originally believed that that patients would need to remain on TPO-RAs indefinitely. However, case reports and cohort studies have shown that some patients are able to maintain a hemostatic platelet count off all treatment after discontinuing their TPO-RA. In light of this, a panel 6 adult hematologists and 3 pediatric hematologists with an average of over 25 years of experience and one patient representative developed a consensus statement on when it is appropriate to consider tapering TPO-RAs in children and adults with persistent or chronic primary ITP, how to taper patients off therapy, how to monitor patients after discontinuation of treatment, and how to restart therapy in the event of relapse. This was accomplished by rating how appropriate it would be to begin the tapering process among patients receiving TPO-RA monotherapy in 432 different patient scenarios, how to monitor such patients after discontinuing the TPO-RA, and how to restart therapy when applicable.

The results revealed five patient characteristics found to significantly impact ratings and decisions to agree to a tapering of TPO-RA in specific cases. These included platelet count, history of bleeding, intensification of treatment, risk of trauma, and use of anticoagulants or platelet inhibitors. There was a consensus that it would be inappropriate to discontinue treatment in patients using a TPO-RA monotherapy who are responding but still have low platelet counts, in patients with less than normal but adequate platelet counts who have a history of major bleeding, in patients at risk for trauma, and those who are using anticoagulants or platelet inhibitors irrespective of platelet count. Conversely, consensus was achieved that it is appropriate to try to discontinue TPO-RA monotherapy when ITP patients have normal/above normal platelet counts, no history of major bleeding, and those who have not required aggressive treatment in the last six months.

The panel of experts created a consensus statement that could serve as a guide for clinical care and reflect areas of greatest agreement among a panel of experts based on currently available, albeit limited, evidence. There consensus statements for tapering included the following: it is inappropriate to discontinue TPO-RA monotherapy without tapering, eltrombopag and romiplostim can be tapered by decreasing the dose periodically to the minimum available dose while maintaining the time interval between doses, it is appropriate to measure the platelet count soon after the patient has discontinued treatment (e.g., within 1-2 weeks) and with decreasing frequency over time assuming a successful clinical taper, and in many cases it is appropriate to consider restarting therapy when the patient’s platelet count is <30 x 109/L and there are signs of bleeding beyond skin manifestations. Thresholds for restarting therapy may differ among patients based on history and other clinical parameters.


Comments from PDSA’s Medical Advisors:
It is increasingly clear that a subset of ITP patients, perhaps close to one-third, no longer require treatment with TPO-RAs when followed from months to years. Whether this is due to an “immunomodulatory” effect of TPO-RAs or is consistent with reports of similar outcomes in patients treated with corticosteroids or other treatments merits closer scrutiny. Whatever the cause, it is important that clinicians who see only occasional patients with ITP appreciate that an attempt to taper and possibly discontinue TPO-RAs is appropriate in patients with good responses who are at low risk of bleeding should they relapse as indicated by this study. It is at least as important to appreciate that platelet counts above 30x10-9/L are sufficient for hemostasis in most patients for most situations. One might assume that the likelihood of having sustained remission would correlate with the duration of treatment, but criteria for treatment duration prior to a trial of taping has not been established. Unfortunately sophisticated analysis of complex situations like when one can successfully discontinue a TPO-RA, even if based on sophisticated tools like a Delphi analysis, is nonetheless limited by the quality of the data. In this case, the data is inadequate such that definitive findings are not yet available and have to be made on a patient-by-patient assessment of risk and patient preference.


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