Living with ITP can be frightening for patients and their families and these worries have been worsened in the setting of COVID19. One of the factors that makes ITP so challenging is that it is very hard to predict if and when bleeding may occur, and if bleeding might be severe, even life-threatening. This uncertainty makes it difficult to decide which medication to select, and when and how to deploy it to treat patients. The following two articles discuss risk factors that could help in predicting the development of severe bleeds.
Risk Factors for Skin, Mucosal, and Organ Bleeding in Adults with Primary ITP: A Nationwide Study in Japan
This large study describes bleeding symptoms and risk factors for severe bleeding in adult patients with ITP living in Japan. Data from a nationwide database containing the records of 19,415 newly diagnosed adults with between 2005-2014 was analyzed. Among these, 222 records were from patients who experienced an intracranial hemorrhage (ICH) at diagnosis.
The most frequent bleeding manifestations at the time of diagnosis included petechia and purpura (skin bleeding; 64.8%) followed by gingival bleeding (bleeding from the gums; 20.3%), epistaxis (nosebleeds; 12.5%), hematuria (blood in the urine; 6.2%), melena (blood in stool; 6.1%) and ICH (1.1%). The investigators examined the relationship between platelet counts and these clinical symptoms. Predictors of all bleeding events included a platelet count less than 10,000/µL.
Looking at the site of bleeding more closely, the incidence of each bleeding symptom was inversely related to platelet count with the exception of ICH. However, the great majority of ICH occurred at a platelet count less than 20,000/µL, and the incidence of ICH increased sharply when the platelet count was less than 5-10,000/µL. A clear increase in the occurrence of both organ bleeding [including melena (bleeding in the bowel movements) and hematuria(bleeding in the urine)] and mucosal bleeding (including gingival bleeds and epistaxis) was seen when the platelet count fell below 15,000/µL. The risk of skin bleeding was over three times greater at platelet counts at the lower limits of detection than at50,000/µL and the risk of mucosal bleeding was 14.5 greater.
The occurrence of skin and mucosal bleeds did not correlate with age but the overall incidence of organ bleeding did, especially being more frequent in individuals over the age of 60-80 years. Mucosal bleeding was a risk factor for melena and hematuria but surprisingly did not appear to be a significant risk factor for ICH; it has been shown to be associated with intracranial hemorrhage (ICH) in several previous much smaller studies. Hematuria and being over the age of 60 years were risk factors for ICH. Of note, a relatively large (40 patients) study of children with ICH identified the same predisposing factors for ICH: platelet count less than 20,000, especially at counts less than 10,000, and in children with hematuria (Psaila, Blood 2009).
The study does have some important limitations. One is that it only includes adults at diagnosis. Therefore, it is not directly applicable to patients with ongoing ITP. Another is that very little information was available on individual patients, for example what medications they were on and whether they had other conditions that predispose to bleeding. Nevertheless, one take home reinforces current practice guidelines to consider treatment of newly diagnosed ITP who present with a platelet count below 20,000/µL based on the increased risk of bleeding documented in this study and to be especially vigilant in older patients.
There is little doubt about the overall findings of the study. The lower the platelet count and the more bleeding you have, the higher the risk for a severe bleeding event. What is needed now is a laboratory test that would help to distinguish the large number of patients with platelet counts < 20,000/µL who are at low risk for severe bleeding from those at high risk who need urgent treatment. Such efforts are being pursued in children with ITP by several research groups e.g. at Baylor, Houston Texas and in the Netherlands but no specific findings have yet been published.
This study examines the characteristics of adult patients with ITP presenting to emergency departments (ED) at four different Canadian hospitals (between January 2008 – April 2016) with a bleed related to their low platelet count. The outcomes of these ED encounters, treatments used to manage bleeding symptoms, and risk factors for major bleeding events are reviewed.
Participants included adult patients with ITP who had a platelet count less than 20,000/µL when presenting to the ED with a bleed. In total, 57% were newly diagnosed with ITP. Most participants (70%) had primary ITP while the rest had ITP secondary to either drug-induced ITP or other autoimmune conditions, e.g. lupus. A total of 112 patients (totaling 141 ED visits) were included in this study, 29 of whom had one or more major bleeding event during the study period (totaling 32 ED visits). Non-major bleeds documented in the ER included skin bleeds (92%), oral bleeds (60%), nosebleeds (26%), menstrual bleeds (6%), and gross hematuria (6%, considered non-major because anemia did not develop as a result). Median age was 59 years. Major bleeding events included in the 32 ED visits were the 23 for gastrointestinal bleeding, 4 ED visits for an ICH, 3 ED visits for pulmonary hemorrhage, one ED visit for a combined GI+ICH bleed, and one visit for a rectus sheath hematoma (large bleed in one of the abdominal muscles). Median age was 69 years. The average platelet count when presenting to the ED was 4,000/µL. Most patients only had one ED visit during the study, but 21% (about 23 patients in total) had multiple visits. Six participants with a non-severe ED bleeding visit developed a major bleed soon after. All six of these participants had oral bleeding and four had gross hematuria. Three of the four patients who developed gross hematuria went on to develop an ICH and died.
Patients admitted to the hospital with a major bleed received a median of three treatment cycles including 1-4 different therapies: mostly IVIG, corticosteroids, and/or platelet transfusions either alone or in combination. For patients who did not respond to these therapies, platelet transfusions were given a second time in combination with either an alternative second-line ITP therapy (these would include rituximab, TPO agents, immunosuppressive medications like azathioprine, cyclosporin and many others, and splenectomy) with or without tranexamic acid. One emergency splenectomy was performed. The average time it took to receive treatment was approximately 7.5 hours after arriving at the ED.
Outcomes from the 32 major bleeds from 29 participants included three deaths due to ICH, hemorrhagic shock, or bleeding unresponsive to treatment. Nine participants had recurrent major bleeds after an initial platelet count response to treatment. Two of the participants with rebleeding died, and one suffered permanent disabilities. Risk factors identified in this patient population for a major bleed included older age, male gender, and history of using multiple ITP therapies previously indicative of a more difficult to treat form of ITP. All patients with major bleeds had preceding oral bleeding. Those with the worst outcome, including ICH and death, had gross hematuria.
This study amplifies the study from Japan because it includes patients with a prior diagnosis of ITP in addition to those newly presenting. Several features are striking. First, this study focuses on the subset of patients with very low platelet counts; inclusion required a count of 20,000 or less. Second, it points out that most ERs do not have protocols that provide urgent care for infrequent problems like ITP, most of whom are not having major bleeds, as opposed to, for example, heart attacks or strokes. This presumably accounts for much of the 7.5-hour delay between arrival and treatment. This points to the need to develop a universal protocol for rapid management of patients with ITP in the ED from diagnosis to intervention. In 2007, we reported combination treatment with as many as 4 agents may be required but effective in patients who present with severe bleeding (Borucho Blood 2007). In addition, the risk of rebleeding is high and maintenance therapy with TPO agents or other approaches is generally indicated as is monitoring until stable counts are achieved.
Putting these 2 studies together, while serious bleeding is uncommon, rapid and intensive management is required when it does occur. The fact that most patients and ED visits with ITP do NOT need intensive management should not delay its recognition and implementation in those who do. The combination of a very low platelet count, one less than 20,000/µL and especially < 10,000/ µL, and bleeding beyond mild petechiae/purpura, gum oozing or short-term nosebleeds warrants immediate action. Fortunately, the great majority of ITP patients do not develop these complications with proper management and close follow-up.