CONTENTS:

The Role of Genomics in ITP

AI generated DNA strandITP is an acquired autoimmune bleeding disorder. However, there have been occasional reports of multiple family members having ITP, suggesting a hereditary (or genetic) component in some families. Individuals who have a hereditary platelet disorder do not have ITP, meaning their low platelet count is due to an underlying condition versus ‘primary’ ITP or ‘secondary’ ITP where the low platelet count is due to an immune attack on the platelets (either because of an underlying condition in secondary ITP or without any known reason in primary ITP). There is one group of medical conditions that can cause secondary ITP that is from a problem in how the immune system functions or is regulated. These are called inborn errors of immunity (IEI) or primary immune dysregulation (PIRD).

A growing number of studies have demonstrated changes in the genome (a person’s genetic makeup) can impact the immune system and have been found in IEIs.1,2 These IEIs can cause secondary ITP when affected individuals present with an isolated low platelet count rather than infection. In fact, some family members with an IEI may never have an issue with infection. This raises the question: how often are IEIs seen in ITP and how often do they go undiagnosed?

At the American Society of Hematology (ASH) annual conference in December of 2022, a case was reviewed that illustrated the complexity of genetic testing. One of the previously reported papers published in 2019 has shown that 65% of children with Evans syndrome, which is a condition that causes a low platelet count and autoimmune hemolytic anemia, who were enrolled in the Obs’Cerevance registry (a large pediatric ITP registry in France) had a genetic abnormality identified. Specifically, a pathogenic (meaning disease causing) variant in a gene known to play a role in the immune system was detected through genetic testing.

Researchers have also found that these sometimes small variations in the genes (called single nucleotide polymorphisms or SNPs) may be more common in patients with chronic or refractory ITP, but it is not clear if this is true because chronic/refractory patients are also much more likely to get more extensive testing (including genetic sequencing) than those patients with newly diagnosed ITP.

There are multiple ongoing studies looking at the association between immune function (and especially genetic changes in how the immune system works) and ITP in both pediatric and more recently in adult patients. While the pediatricians have long suspected changes in the immune landscape of patients that develop chronic ITP, the possibility of underlying genetic changes as the cause of ITP in adults is a new concept and work is just starting in this area.

Take home message: All pediatric patients with chronic ITP should be screened for an IEI or other autoinflammatory disease. Investigations into the cause of chronic ITP should be considered even after resolution of ITP or with new symptoms with a history of ITP. It is felt that such individuals with ITP likely have an abnormal immune response, and this should prompt an immune evaluation.


References:

  1. https://ash.confex.com/ash/2022/webprogram/Paper168077.html
  2. https://ash.confex.com/ash/2022/webprogram/Paper159319.html


Comments from PDSA Medical Advisors:
These results suggest that testing for IEI or other autoinflammatory disorders should be considered in the pediatric population with chronic ITP, especially if associated with autoimmune hemolytic anemia (Evans syndrome), as this might affect surveillance and management. It is likely that as time goes on, improved genetic assessment of all children with ITP on a research basis will identify new markers that predict risk and response in the future.

 

HMB in ITP

Two women sitting down, facing each other and talkingBy Kristina Haley, MD

Heavy menstrual bleeding (HMB) is common, occurring in about 1 out of 5 people with the potential to menstruate1. Someone has HMB if their periods last longer than 7 days, if bleeding soaks through one or more pad or tampon every 1 hour for several hours in a row, if they are having to double up with pads and tampons to manage menstrual flow, if they are needing to change products overnight, or if they are passing large clots (bigger than a quarter)2. HMB can result in iron deficiency, decreased school or work attendance, decreased participation in activities, and decreased health-related quality of life. There are many causes of HMB, including irregular ovulation, fibroids, medication effects, infections, and bleeding disorders. Individuals with ITP can have HMB, especially since we think of the platelets as important helpers in controlling bleeding in mucocutaneous sites like the uterus.

While we know that HMB can be a symptom of ITP, data is limited regarding the incidence of this symptom in the different phases of ITP, likely related at least in part to menstrual stigma. The i-WISh (ITP World Impact Survey) study was a cross-sectional survey study including 1507 patients (65% female) and 472 physicians across 13 countries. About 40% of all patients surveyed reported HMB at ITP diagnosis and over 80% reported the symptom as severe3. In a study of chronic ITP, including 37 individuals, 39% had HMB as defined by the Pictorial Bleeding Assessment Chart at the time of the study (PBAC – patient completed chart indicating number of pads/tampons used and degree of saturation over the course of a month)4. Seventy-eight percent had problems with their period at the time of the survey or at any time during their ITP diagnosis4. In this study, they did not find a correlation between platelet count and HMB4. As a part of this study, the authors also did a review of currently available ITP literature and reports of HMB. The challenge in many of the studies they identified was that HMB was not well-defined. However, across 8 studies that they evaluated, HMB was reported in 6-79% of individuals. In one of the studies, HMB was defined as severe bleeding at the first period requiring blood transfusions and occurred in 25% of their small study population (n=20)4.

In addition to ITP directed therapies, HMB may require additional treatments specific to the symptom. Treatments may include anti-fibrinolytic medications like Tranexamic Acid (TXA) or hormonal medications like a combined estrogen/progestin pill or a progestin intrauterine device. Choosing a medication to help control periods is an important discussion for a patient to have with their provider, weighing benefits and risks of each option and tailoring therapy to an individual’s needs and expected ITP course. It is important for the clinical team to ask individuals about their periods and offer therapies to help decrease bleeding. Patients can feel empowered to tell their teams about their periods and request further information on treatment options.


References: 


Dr. Kristina Haley is the Director of The Hemostasis & Thrombosis Center at Oregon Health & Science University.  She co-directs the OHSU Spots, Dots, & Clots Clinic, a combined hematology/gynecology for adolescents. Dr. Haley spends time educating medical students, residents and fellows as well as community health care providers on all things non-malignant hematology.   Dr. Haley’s research includes projects aimed at characterizing the symptoms and treatment of bleeding in women with bleeding disorders through a national dataset as well as improving the understanding of platelet disorders.