Relationship Between Platelet Autoantibodies and Response to Corticosteroid Treatment in Adult Patients with Primary ITP

Doctor and patient shaking handsMany patients with immune thrombocytopenia (ITP), though not all, have autoantibodies against their own platelets detected in the laboratory. Autoantibodies are proteins that mistakenly target a normal part of the body, in this case platelets, for destruction and removal. Platelets have several different proteins on their surface (called antigens) to which autoantibodies bind. This study measured autoantibodies against three different platelet antigens to determine if there was a relationship between a patient’s response to a combination steroid treatment (dexamethasone + prednisone) and the specific autoantibody they detected.

This study compared outcomes in 72 of the 112 ITP participants who had autoantibodies against at least one of the three platelet antigens mentioned above detected (referred to as the antibody-positive group) compared with 40 participants who did not have autoantibodies against their platelets detected (the antibody-negative group).

Researchers considered a patient to have had a ‘complete response’ (CR) to the steroid treatment if their platelet count reached at least 100,000 without bleeding events. A treatment ‘response’ (R) was defined as a platelet count of at least 30,000, or more than twice the platelet count, before receiving the steroid treatment, without bleeding events. ‘No response’ (NR) was when the platelet count remained less than 30,000, or less than twice the platelet count from before the steroid treatment, or if a bleeding event occurred.

More participants in the antibody-positive (69.44%) cohort achieved a ‘CR’ than those in the antibody-negative (40.00%) group. Interestingly, although autoantibodies against three different platelet antigens were studied, only participants with autoantibodies detected against the glycoprotein IIb/IIIa antigen had a greater ‘CR’ rate than the antibody-negative participants. On the other hand, participants with autoantibodies against the other antigens (glycoprotein Ib/IX or P-selectin) did not have a notable difference in ‘CR’ rate compared to the antibody-negative group.

Overall, this study showed that ITP patients who have platelet autoantibodies, particularly against a platelet antigen called glycoprotein IIb/IIIa, may respond better to corticosteroid treatment.


Comments from PDSA Medical Advisors

Testing for autoantibodies to platelets in individuals with clinically diagnosed ITP is complicated and confusing. Confusing because it seems that there is so-called “epitope spreading,” meaning that once one antibody to the platelets is formed, such as to GPIIB/IIIA, and causes some of them to be destroyed, other anti-platelet antibodies may form such as to GPIB/IX. It is thought that this explains why some patients have multiple targets of their antiplatelet antibodies. Testing is complicated because it is not very sensitive (meaning it’s not diagnostic and missing things) and because some of the antibodies may be induced if platelets are destroyed for any other reason such as infection. Therefore, testing for these antibodies is not part of the evaluation process recommended by the American Society of Hematology or the updated International Consensus Report on the investigation and management of primary ITP.

The data in the article is interesting primarily because only 4 of the 72 antibody-positive patients did not respond at all to steroid treatment, whereas 8 of 20 antibody-negative patients did not respond. This is only 5.6% in the antibody-positive group compared to 40% in the antibody-negative group. There could be at least 2 interpretations: 1) the testing is very good and there were less responses and less CR in the antibody-negative group because this group did not have ITP at all. This can definitely happen: a person with low platelets looks like they have ITP, but they actually have another reason for the low platelets, and 2)the antibody testing is not good and the results are random and happen to look good. If this is true, it would be incorrect to assume that a failure to detect antibodies means that antibodies are not present, and the low platelet count is caused by another antibody-independent mechanism.

The low steroid response (40%) in the “antibody-undetected,” or antibody-negative, group is quite unusual and more information is needed about the actual treatment regimen and other tests that were used to exclude secondary forms of ITP and non-immune causes of thrombocytopenia. It would have been helpful to know in this study whether the same difference was seen among individuals treated with IVIG, which also works by inhibiting antibody-mediated damage. We currently do not recommend that testing for platelet antibodies be used either to make a diagnosis of ITP or to decide whether corticosteroids are indicated as treatment.

Of note, at least two past studies have identified important components of steroid response in ITP. One was that taking atorvastatin (the leading statin in clinical use, also called Lipitor) improved steroid response. The second was the identification of a polymorphism (a genetic marker) of steroid response. Like the platelet antibody testing reported in the article, none of these findings are very strong and none say “do treat” or “don’t treat” anyone with steroids. They suggest that they will improve responsiveness by a “small amount.” Notwithstanding these caveats, other studies looking at the relationship between platelet antibody detection and response to treatment might provide insights into other mechanisms of platelet abnormalities in ITP.

IFNG-AS1 and GAS5 as Potential Molecular Indicators for Childhood ITP

DNS RNAThere are two types of genetic material: DNA and RNA. Most people have heard of DNA because it contains our ‘genetic code’ for how our body should grow and develop. RNA, on the other hand, applies the code from DNA to make proteins to carry out specific functions for the body to grow and develop. So, they work together.

Non-coding RNA genes (specifically, IFNG-AS1 and GAS5) are essential for our immune systems to function properly. This study looked at whether children with ITP had abnormal expression within their IFNG-AS1 and GAS5 RNA genes, and if such gene expression within these two genes could also be used to help predict whether someone was more likely to develop chronic ITP.

Eighty-eight children with ITP (ranging from 1-13 years old) were enrolled in this study along with 88 children without ITP (ranging from 2-13 years old) as a healthy control group. Researchers found that children with ITP had approximately three times more IFNG-AS1 expression and four times more GAS5 expression levels than the group without ITP. When participants were separated into groups according to how long they had ITP, the children who had ITP for more than three months had higher IFNG-AS1 and GAS5 levels than those who were newly diagnosed.

This study also looked at how IFNG-AS1 and GAS5 gene expression levels impacted a patient’s response to ITP therapy. The term ‘complete response’ was used if a patient received therapy and achieved a platelet count greater than 100,000/µl without bleeding. A ‘partial response’ meant that the patient received therapy and achieved a platelet count between 30,000-100,000 or a two-fold increase in platelet counts before therapy. ‘No response’ referred to a platelet count less than 30,000 or less than a two-fold increase from their platelet counts before therapy. It was found that patients who had a ‘partial response’ or ‘no response’ to treatment had higher levels of IFNG-AS1 and GAS5 expression compared to those who had a ‘complete response.’

Approximately 6% of childhood ITP participants in this study had reported a family history of ITP. Among participants who had a positive family history, higher levels of IFNG-AS1 and GAS5 expression were seen compared with participants without a family history of the condition.

Lastly, this study showed that as a patient’s platelet count increased after ITP treatment, the expression levels of IFNG-AS1 and GAS5 decreased. Overall, the authors of this study indicated IFNG-AS1 and GAS5 gene expression could be used to predict treatment response and chronicity at the time of an ITP diagnosis which may be helpful for treatment planning.


Comments from PDSA Medical Advisors

We know that some patients respond better to steroids than others. This article using genetic markers (changes in genes and gene expression) provides another reason for poor steroid response. As background, all cells have what are colloquially called “pumps.” These pumps can be ‘on’ or ‘off.’ When they are ‘on,’ they can take medications that enter the cell and promptly send them out of the cell. The pump that was initially studied is called the multidrug resistance pump (MDR). While it does not kick out all drugs, it kicks out many and thus could provide a means of resistance even when multiple drugs are given together.

This article identifies two genetic markers in patients with ITP that may identify people whose pumps might be turned ‘on,’ not just in stem cells but in other cells as well. This would increase resistance to several treatments. Thus, if someone with this predisposition to having their pumps ‘on’ developed ITP (or another disorder requiring steroid treatment), they might do worse (as shown in this study) than another person with a similar degree of ITP severity, because a number of treatments would not work either as well or at all. In fact, two previous studies of patients with ITP demonstrated this functional phenomenon of pumps in a number of difficult-to-treat patients in 2002 and 2003.

In the future, if and when we test all newly diagnosed ITP patients with a multigene panel, patients with the gene markers reported in this article might be known early to be at risk for this phenomenon and ideally begin with other treatments.