PDSA E-News: January 25, 2024


In this issue of the e-news, we want to share with you the preliminary results of a research study that was presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition held in San Diego, California, December 9-12, 2023, and involved PDSA staff and many of our medical advisors, in addition to several of PDSA’s patient members representing the voice of the ITP patient. This work was led by Donald Arnold, MD, one of PDSA’s medical advisors and his research associate Emily Sirotich.

Treatment of Critical Bleeding Events in Patients with Immune Thrombocytopenia: A Systemic Review

Red blood cells illustration

A critical bleeding event is not common among individuals with immune thrombocytopenia (ITP) but has been reported to occur in a small number when the platelet count is below 20,000. A critical bleed is defined as one involving one or more of the following body parts: intracranial (brain), intraspinal (spine), intraocular (eyes), retroperitoneal (behind the abdominal cavity), or intramuscular if it results in hemodynamic instability (bleeding that causes a decrease in blood pressure) or respiratory compromise (bleeding that causes a lower blood oxygen level and impairs breathing). Critical bleeds can be fatal if not treated promptly. As a result, there is a need to understand how best to treat critical bleeds in an emergency situation. Evidence based treatment guidelines are needed.

As an initial step to increase understanding about best practices for treatment of critical bleeding in ITP patients, a systemic review was conducted. This systemic review involved combing through publications using four well established medical databases (OVID Medline, Embase, CENTRAL, and PubMed) to compile data. Eligible publications for data collection included randomized controlled trials, observational studies, case series, and case reports that enrolled ITP patients who received one or more treatments to manage their critical bleed. Data collected was then evaluated using a GRADE approach which provides a commonly used way to structure evidence and determine its certainty and significance.

Following a review of the literature, 42 publications met the inclusion criteria. The 42 studies reported on 79 ITP patients (41 children; 19 adults; and 19 of unknown age). The majority of the critical bleeds reported were intracranial. Other sites included gastrointestinal bleeding, ocular bleeding, and intraperitoneal (abdominal) bleeding. Patients were treated with IVIG, corticosteroids, platelet transfusions, TPO-RA, or splenectomy alone or in combination with other treatments. There were over 30 combinations of treatments reported. The most common interventions included either IVIG alone (18 patients), IVIG + corticosteroids (11 patients), corticosteroids + platelet transfusions (4 patients), corticosteroids alone (4 patients), and corticosteroids + IVIG + platelet transfusions (3 patients).

Although mortality, platelet count responses to treatment, resolution of bleeding, and disability (defined as neurological sequalae or altered mental state) were investigated, not all these variables were reported in every publication, which made it difficult to relate outcomes to treatment.

Overall, those who were given a corticosteroid alone or in combination had less disability than those who did not. The use of IVIG, either alone or in combination, resulted in poorer outcomes. Platelet transfusions lead to a more rapid platelet count increase, and those who had a splenectomy as part of their emergent treatment achieved a better platelet count response than those who did not. Mortality was higher among those who received a TPO-RA.


Comments from PDSA Medical Advisors

This review of the treatment of critical bleeding in ITP raises several issues. First, the fact that only 79 individuals were identified in a comprehensive review of the literature speaks to how infrequent this occurs, but also that many patients are treated successfully without the need to report outcomes. Second, the small number of individuals precludes formal comparisons among regimes. Third, patients in the different treatment cohorts were not documented to have similar sites or severity of bleeding prior to treatment. This may be the reason why patients treated with IVIG, which is given to the most severely affected patients, may have appeared to be less successful than corticosteroids. In the absence of new data to the contrary, patients with the most severe bleeding, lowest platelet counts, and clinical instability should be treated with a combination of IVIG, high dose of corticosteroids and platelet transfusions. TPO-RAs can be considered as adjunctive therapy to lessen the duration and intensity of other treatments. Tranexamic acid, which slows clot breakdown, may also be given. Attention to drugs that impair platelet function, control of hypertension, history of GI bleeding, avoidance of falls and other general measures to reduce the risk of bleeding should also be implemented.


ITP Pathogenesis: Understanding the Immune System Attack on our Platelets

PowerPoint slide from Dr. Semple's presentation showing the military members

PDSA medical advisor Dr. John Semple compares our immune system function to the military, and answers the question: “How do we make an immune response against our own platelets?”

Here is how he explains the roles of some of the important military members (immune system):

The General: CD4+ T Helper Cells. Initiate an attack (immune response) and continue it. Originate in the bone marrow, attend military school, and study weapons (antigen affinity) in the Thymus. They were awarded in military school for “precise recognition of danger and foreign weapons” (antigen activation) and “multi-tasking” for helping or retreating the troops (immune response).

The General’s Wife: CD4+ T Regulatory Cells. Regulate the General and halt the attack. The General and his wife met in the Thymus and continue to work together in the Spleen; the General’s wife easily settles his aggressiveness and desire to attack (induces tolerance).

The Colonel: CD8+ T Cells. Responsible for binding to and killing the enemy (viruses) and won an award for hand-to-hand enemy destruction (cytotoxicity) in the Thymus military school, where they learned not to attack their own military (immune system).

The Captain: B Cells. Responsible for the production of supplies (antibodies) and won the award in Bone Marrow military school for best student sniper (specific immune response). Privates: Macrophages. The privates are trained everywhere (in all tissues). They attack anything and warn the General of danger (antigen processing and presentation).

In a well-functioning military, platelets have a lifespan of 10 days. As they age, the privates recognize old, wrinkled platelets and eat them. The private then presents old platelet weapons (antigens) to the General, but the General’s wife tells him not to react as the platelet doesn’t pose any danger. When the enemy (a virus) is present with foreign weapons (antigens), it activates the private. The private captures the enemy, presents his weapons to the General, the General’s wife hides (lack of suppression), and the Captain is recruited to prepare enough supplies (antibodies) to attack the enemy. If the enemy returns, the General calls upon the Colonel who remembers and kills the enemy.

In a dysfunctional military (autoimmunity in ITP), the General’s wife is very sick. As a result, the General can’t think straight and loses his tolerance. When the enemy arrives, it is attacked by the private; he informs the General of danger and the General recruits the Captain to prepare a surplus of supplies against the enemy. Because of the Captain’s overactivity and lack of regulation from the General, some of the supplies are used to wrongly attack all platelets. Although the Colonel was originally recruited to destroy the enemy, he notes some of the supplies have been assigned to attack and destroy the platelets in the spleen (this is what causes high rates of platelet destruction!). The same Colonels can infiltrate the bone marrow and wreak havoc on megakaryocytes (this is a potential cause of decreased production).

Dr. Semple’s excellent use of a military analogy helps expand our understanding of what goes wrong in our immune system that results in attacks on our platelets in ITP.



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