Immune Thrombocytopenic Purpura and Intracerebral Hemorrhage, Incidence, and Mortality

Introduction: Intracerebral hemorrhage (ICH) is a devastating complication of immune thrombocytopenic purpura (ITP). Using a large database, we sought to determine its incidence and mortality. Methods: We used a de-identified database (TriNetX) to gather information on patients with ITP with subsequent ICH (cohort 1), propensity score-matched with patients with ITP and no ICH (cohort 2). Primary endpoint was mortality, with secondary endpoints of percutaneous endoscopic gastrostomy (PEG) placement, craniotomy, palliative care encounters, intensive care unit (ICU) management, seizure, falls, pulmonary embolism (PE), myocardial infarction (MI), deep venous thrombosis (DVT), ischemic stroke (IS), and other venous embolism and thrombosis (VTE). Results: Incidence of ICH in patients with ITP was 1.540% in all ages, and 0.774% in those under age 18. After matching, 942 patients from each cohort were identified. Mean age was 58.3 years versus 61.2 years in cohort 1 and 2, respectively. Mortality rate was 34.076% vs. 20.17% (p <0.0001, OR 2.046 with 95% CI 1.661,2.520) at five years. Thirty-day survival was 83.46% vs. 95.17% (p<0.0001), and 365-day survival 68.59% vs. 85.33% (p<0.0001). PEG placement was seen in 21 (2.229%) patients in cohort 1, and less than 10 patients (<1.062%) in cohort 2 (p<0.0464). 2.442% vs. 0% underwent craniotomy (p<0.0001), palliative care was involved in 15.711% vs. 7.962% (p<0.0001), ICU care was seen in 27.389% vs. 11.783% (p<0.0001), with a mean ICU stay of 8.075 vs. 5.812 days (p=0.0537). 6.582% vs. 3.715% had PE (p=0.0049), 7.643% vs. 7.113% experienced MI (p=0.6595), 9.236% vs. 4.883% had DVTs (p=0.0002), 23.673% vs. 5.732% had seizures (p<0.0001), 9.023% vs. 6.582% suffered falls (p=0.0482), 7.537% vs. 3.503% suffered IS (p<0.0001), and 15.074% vs. 8.174% experienced other VTE (p<0.0001). Conclusion: ICH occurs in approximately 1.54% of ITP patients, and is associated with a 34% mortality rate, increased PEG tube placement rates, palliative care involvement, ICU care, craniotomy, PE, IS, DVT, seizures, and falls.


Introduction
Intracerebral hemorrhage (ICH) is a devastating complication of immune thrombocytopenic purpura (ITP). In 2009, Psaila et al. reported data from a national survey estimating ICH incidence was 0.19%-0.78% in children (age 17 or younger), with a mortality rate of approximately 25% [1]. We sought to investigate this claim in children, as well as the incidence in adults, using a global research network to retrospectively examine the incidence of ICH in patients with ITP while also looking at the mortality rate as a primary endpoint. Secondary endpoints include PEG tube placement, craniotomy, palliative care encounters, intensive care unit (ICU) management, seizure, falls, pulmonary embolism, myocardial infarction, deep venous thrombosis, ischemic stroke, splenectomy, and other venous embolism and thrombosis.

Materials And Methods
This was a retrospective case-control study. We used a de-identified database network (TriNetX) to retrospectively query via International Classification of Disease (ICD-10) codes and procedural codes via Common Procedural Terminology (CPT) codes to evaluate all patients with a diagnosis of ITP and ICH (cohort 1) versus ITP alone (cohort 2). Data came from 63 health care organizations (HCOs) spanning 11 countries. Data includes demographics, diagnoses, medications, laboratory values, genomics, and procedures. The identity of the HCOs and patients are not disclosed to comply with ethical guidelines against data re-identification. Because of the database's federated nature, an IRB waiver has been granted. Our use of this database and its validity was informed by previous literature, and exact details of the network have been previously described [2][3][4][5]. Data is uploaded from each HCO data center. Some HCOs send data directly from the electronic health record, whereas others use data warehouses using known data models

Discussion
In this retrospective case-control study, we assessed the incidence, morbidity, and mortality of ICH following the diagnosis of ITP in all ages utilizing data, including ICD-10 codes from a de-identified database spanning over 11 countries and 63 healthcare organizations. After propensity-score matching, we were able to gather data on two large cohorts with more than 900 patients. We controlled for variables, including age, sex, race, anticoagulation use, and common comorbidities to reduce potential confounding.
Our study reports an incidence of ICH in all ITP patients of 1.540% (0.770% in patients under 18  [6]. Further stratification of ICH incidence in ITP patients within both pediatric and adult populations continues to be reported in wide ranges. This is likely due to the varying parameters in retrospective and prospective studies, respective cohort sizes, and methodologies that have been utilized in the literature [7]. Compared to other database studies, our study reports a higher incidence of ICH in ITP patients. Bhatt et al. observed trends in the National Inpatient Sample (NIS) database using ICD codes from 2007-2016 and reported an overall incidence of 1.1% in all patients and 0.7% in pediatric patients [8]. Danese et al. noted the incidence of 1.5% in adults from 2003-2006 [9]. An and Wang published outcomes of adult hospitalizations with ITP in the US from 2006 to 2012 and found the incidence of ICH at 1.28% [10]. Despite the wide variation of incidence among the literature with varying methodology, our analysis supports the overall summation and tone of the literature: ICH continues to remain rare but a grave complication of ITP in both pediatric and adult populations associated with a higher level of care, significant adverse events, and mortality.
Mortality for patients with ITP alone was found to be 20%, comparable to other mortality rates reported in patients with ITP [8]. Those who experienced the complication of ICH had an overall mortality rate of 34% and significantly higher mortality at 30-, 90-, and 365-day time points (p<0.0001) compared to ITP patients without ICH. Thus, ITP patients with ICH are twice as likely to experience mortality than patients with ITP alone. ICD-10 codes for ICU level of care and palliative care consultation were pursued more for ICH ITP patients as well (p<0.0001). Bhatt et al. in 2020 reported an overall mortality of 26.7% in ITP patients with ICH within their database study. They additionally report a longer length of stay (LOS) for ITP patients with ICH, which correlates to our findings and increased hospitalization cost [8].
Interventions such as craniotomy and PEG placement were pursued in 2.4% and 2.2%, respectively, in ITP patients with ICH compared to no invasive cranial intervention and 1.1% PEG placement in patients with ITP alone. Regarding neurological sequelae, the rate of seizures and falls were significantly higher in ITP patients who experienced ICH, reflecting the critical nature of this diagnosis and potential sequelae from it.
ICH in ITP patients was associated with a significantly elevated risk of thromboembolic events: ischemic stroke (p=0.0001), pulmonary embolism (p=0.0049), DVT (p=0.0002), and other thromboembolic events (p= <0.0001). The literature documents that despite low platelet count in ITP patients, thrombocytopenia does not prevent thromboembolic disease. The pathophysiology of arterial and venous thromboembolic events in ITP patients remains elusive [11,12]. ITP is a condition involving low platelet counts, but hypofunctioning and hyperfunctioning platelets; platelet microparticles (PMPs) continue to remain the longstanding hypothesis encompassing a potential mechanism within this paradoxical presentation; these PMP levels were found to be significantly elevated in ITP patients who experienced neurologic complications and had confirmed CT imaging revealing small cerebral infarcts [13]. There are currently no clinical guidelines regarding the management of thrombotic events in ITP patients [14], and current literature is limited to case reports, case series, and small cohort studies involving the complex judgment of administering anticoagulation in a patient with impaired coagulation and increased risk of bleeding [15][16][17][18][19]. Thrombopoietic therapies have been pursued and utilized for management of ITP [20]; our findings specifically for ITP patients with ICH may raise caution for the administration of these agents given the significant risk for prothrombotic events in this population. Further research on the pathophysiology and management of this clinical challenge is needed.
Our analysis was not without limitations. The major limitation of this study was that it was retrospective in nature. Furthermore, due to the nature of the database, we were unable to collect patient-level data on specific outcomes. We were unable to report on radiology information. We do not have information on the type of diagnostic test used for confirmation of disease. The data collected was for billing purposes, not for clinical use, and thus much clinical information is missing. In addition, some misidentification is inevitable in database studies.

Conclusions
ICH occurs in approximately 1.54% of ITP patients. ITP with ICH is associated with an approximately 34% mortality rate, increased PEG tube placement rates, palliative care involvement, ICU care, craniotomy, pulmonary embolism, ischemic stroke, DVT, seizures, and falls.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.