Bevacizumab and central nervous system (CNS) hemorrhage

2073 Background: Bevacizumab is widely used and may cause life-threatening bleeding, usually at sites of disease involvement such as the CNS. We attempted to identify clinical characteristics associated with CNS hemorrhage in a broad population. Methods: We did a retrospective review of the FDA Medwatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Results: We searched the database for keywords bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke, and brain. 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1041 reports described non-CNS bleeds. For CNS bleeds, cerebral hemorrhage was the most frequent event reported (n=39), followed by intracranial hemorrhage (n=20) and subarachnoid hemorrhage (n=18). Median age was 62 years; 54% of patients were female. Primary cancer was colorectal (42%), glioma (13%), and breast cancer (10%). Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. 54% of patients received myelosuppressive chemotherapy, and 30% had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. For 70 patients, information on CNS involvement was not reported. Death was reported as a complication of hemorrhage in 48% of patients. Nine patients with brain metastases died and CNS hemorrhage was the cause of death in seven. Six patients with glioma died, and CNS hemorrhage was the cause in three. One patient with brain metastases, and one patient with glioma also experienced a non-CNS bleed. Five patients in each group had received heparin, warfarin or NSAIDs. Low platelet counts were reported in 3 patients with CNS metastases and 2 patients with glioma. The most common factor associated with CNS hemorrhage was medication predisposing to bleeding, followed by thrombocytopenia. Hypertension, a risk factor for CNS hemorrhage, was reported in 4 patients with brain metastases, and 2 patients with glioma. Conclusions: In this database, 154 of 1195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in more than half of the cases.

Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia.

5047 Background: Hemorrhagic complications have been reported in pts treated with various angiogenesis inhibitors, however, reports of intracranial bleeding are rare. Intracranial hemorrhage has been reported during therapy with multitargeted tyrosine kinase inhibitors (TKIs) at higher dose levels during phase I evaluation. Given the occurrence of CNS metastases in RCC and the common use of TKIs, a review of the safety of TKIs in RCC pts with CNS metastases was undertaken. Methods: All pts with mRCC and CNS metastases who were treated with TKIs at the Cleveland Clinic Taussig Cancer Center were investigated. Results: Between 8/2005 and 10/2006, 23 pts with mRCC and CNS metastases were treated utilizing either sunitinib or sorafenib. 7/23 pts received sequential therapy with both TKIs. The median time to development of CNS metastases was 16.0 months (range: 0 - 288 months). Thirteen pts received sunitinib (50 mg daily, 4 out of 6 weeks) and 10 pts received sorafenib (400 mg BID continuously). All 23 pts had known CNS lesions at initiation of TKI treatment and had received prior therapy to the CNS. This consisted of either surgery and whole brain radiation therapy (WBRT; 4pts), WBRT alone (3 pts), conformal radiotherapy in the form or gamma knife or Intensity Modulated Radiation Therapy (13 pts), WBRT and gamma knife (2 pts) or surgical resection alone (1 pt). The median TKI treatment duration (including sequential TKI therapy), was 5.6 months (range: 0.3–20.3 months). No evidence of CNS intratumoral bleeding or other hemorrhagic complications have been observed. Three pts developed new metastatic foci in the brain while on sunitinib. Overall, the median time to progression was 6.5 months (0.9 - 20.3 months). Conclusions: These data suggest sunitinib or sorafenib can be safely administered to RCC pts with previously treated CNS metastases The safety of these agents in patients with untreated CNS lesions is unclear, and therefore pretreatment CNS imaging should be considered. [Table: see text]

Objective To investigate the clinical characteristics, treatment and prognosis of hepatoblastoma (HB) patients with the central nervous system (CNS) metastasis. Methods The clinical data of 12 patients with CNS metastasis who were admitted to Beijing Tongren Hospital, Capital Medical University from January 2011 to June 2016 were retrospectively analyzed.The clinical features, treatment and prognosis of HB patients with CNS metastasis were summarized. Results (1) Clinical features: all 12 patients were diagnosed as stage-Ⅳ patients according to posto-perative Children ′s Oncology Group (COG ) stage system.The primary positions of extrahepatic metastatic characteristics were as follows: lung metastasis in 12 cases, bone metastasis in 3 cases, and adrenal metastasis in 2 cases, right atrial metastasis in 1 case, and abdominal lymph node metastasis in 1 case.Fetal and epithelial mixed type was the most common type in pathologic Pathologic classification of HB (50%, 6/12 cases). CNS metastasis was detected in all 12 cases during the course of treatment.Brain metastasis were found in 11 cases of CNS imaging features, and 1 case had spinal metastatic tumors.(2)The treatment for CNS metastasis: all cases were given chemotherapy-based comprehensive treatment after being diagnosed as CNS metastasis of HB.Ten cases of CNS metastasis were treated by maintenance chemotherapy and 2 cases received chemotherapy plus intracranial tumor resection.(3)The prognosis of HB with CNS metastasis: the follow-up time was from 7 months to 54 months in 12 HB cases with CNS metastasis, and the median follow-up time was 20 months.The survival time of HB was 1-15 months, and the median survival time was 3.5 months after the diagnosis of CNS metastasis.Two cases of CNS metastasis were given intracranial tumor resection and chemotherapy and were followed up to June 2016, and survival time was 15 months and 5 months respectively.The survival time of other 10 cases without intracranial surgery was 1-6 months, and the median survival time was 3 months.By drawing survival function curve and applying Log-Rank test for CNS transfer children, the survival time of patients given intracranial tumor resection and chemotherapy was longer than those without surgery (P<0.05). Conclusions The occurrence of CNS metastasis occurred in HB patients in phase-Ⅳ patients with pulmonary metastasis.The most common site of CNS metastasis is brain metastasis, which is hematogenous metastatic pathway, and 1 case of spinal cord metastasis was considered as the local invasion and metastasis.For HB cases with CNS metastasis, the survival time is short and the prognosis is poor, but the survival time might be prolonged for the phase-Ⅳ patients with intracranial tumor resection. Key words: Hepatoblastoma; Metastasis; Prognosis

COVID-19-related coagulopathy is a known complication of SARS-CoV-2 infection and can lead to intracranial hemorrhage (ICH), one of the most feared complications of extracorporeal membrane oxygenation (ECMO). We sought to evaluate the incidence and etiology of ICH in patients with COVID-19 requiring ECMO. Patients at two academic medical centers with COVID-19 who required venovenous-ECMO support for acute respiratory distress syndrome (ARDS) were evaluated retrospectively. During the study period, 33 patients required ECMO support; 16 (48.5%) were discharged alive, 13 died (39.4%), and 4 (12.1%) had ongoing care. Eleven patients had ICH (33.3%). All ICH events occurred in patients who received intravenous anticoagulation. The ICH group had higher C-reactive protein (P = 0.04), procalcitonin levels (P = 0.02), and IL-6 levels (P = 0.05), lower blood pH before and after ECMO (P < 0.01), and higher activated partial thromboplastin times throughout the hospital stay (P < 0.0001). ICH-free survival was lower in COVID-19 patients than in patients on ECMO for ARDS caused by other viruses (49% vs. 79%, P = 0.02). In conclusion, patients with COVID-19 can be successfully bridged to recovery using ECMO but may suffer higher rates of ICH compared to those with other viral respiratory infections.

Central nervous system (CNS) bleeding is one of the most severe and debilitating manifestations occurring in patients with rare bleeding disorders (RBDs). The aim of this study was to retrospectively collect data on patients affected with RBDs who had CNS bleeding, to establish incidence of recurrence, death rate, neurological sequences, most frequent location, type of bleeding and efficacy of treatments. Results pertained to 36 CNS bleeding episodes in 24 patients with severe deficiency except one with moderate factor VII (FVII) deficiency. Six patients (25%) experienced a recurrence and two had more than one recurrence. Seven patients (29%) had an early onset of CNS bleeding before the first 2 years of life, others (71%) later in life. In 76% of cases, CNS bleeding was spontaneous. CNS bleeding was intracerebral in 19 cases (53%), extracerebral in 10 (28%) and both intracerebral and extracerebral in two cases (6%). Neurosurgery was performed in 11 cases, in association with replacement therapy in seven cases. Seizures were noted in four patients. Residual psychomotor abnormalities were seen in two patients. No death was recorded. To prevent recurrence, 17/24 patients (71%) were put on secondary prophylaxis. In conclusion, recurrence of CNS bleeding was confirmed to be relatively frequent in patients with severe FV, FX, FVII and FXIII deficiencies. Most patients were managed with replacement therapy alone, surgery being reserved for those with worsening neurological conditions. Our results indicate that some RBDs require early prophylactic treatment to prevent CNS bleeding. Optimal dosage and frequency of treatment need further evaluation.

To describe differences in characteristics among neonates treated with extracorporeal life support (ECLS) in the first week of life for respiratory failure compared with later in the neonatal period and to assess risk factors for central nervous system (CNS) hemorrhage and mortality among the two groups. Review of the Extracorporeal Life Support Organization registry from 2001 to 2010 of neonates ⩽30 days comparing two age groups: those ⩽7 days (Group 1) to those >7 days (Group 2) at ECLS initiation. Among 4888 neonates, Group 1 (n=4453) had significantly lower mortality (17 vs 39%, P<0.001) but greater CNS hemorrhage (11 vs 7%, P=0.02) than Group 2 (n=453). Mortality and CNS hemorrhage improved significantly with increasing gestational age only for Group 1 patients. CNS hemorrhage occurred more frequently in Group 1 patients receiving venoarterial (VA) than with venovenous ECLS (15 vs 7%, P<0.001). In Group 1, lower birth weight and pre-ECLS pH and VA mode were independently associated with mortality. In Group 2, higher mean airway pressure was independently associated with mortality. Complications of ECLS therapy, including CNS hemorrhage and renal replacement therapy were independently associated with mortality for both groups. Neonates cannulated for ECLS after the first week of life had greater mortality despite lower CNS hemorrhage than neonates receiving ECLS earlier. Premature infants cannulated after 1 week had fewer CNS hemorrhages than premature infants treated with extracorporeal membrane oxygenation starting within the first week of life.

A retrospective study on clinical manifestations of neonates with FXIII-A deficiency

Life-threatening bleeding (LTB) is one of the major complications of hemophilia with a high risk of mortality. Objective The aim of this study was to assess incidence, risk factors, treatment and outcome of LTB in Senegalese people with hemophilia (PWH). Methods We analyzed the characteristics of LTB in a cohort of 274 PWH after 10 years of follow-up. Results We included 274 patients (241 HA and 33 HB). The mean age was 16.45 years and the median age was 13 years. The mean annual bleeding rate (ABR) was 1.65 (2.83 for severe form, 1.54 for moderate form, and 1.22 for mild form). A replacement therapy with clotting factor concentrates (CFC) was administered to 217 patients (79.2%); 56 patients (20.4%) received low-dose prophylaxis (LDP). Prevalence of inhibitors was 4.7% (13/274). All patients were HIV and HCV antibody negative. We observed 31 cases of LTB in 22 patients with an incidence of 8.03%. Central nervous system (CNS) bleeds were most frequent (6.2%) and accounted for 54.8% of severe bleeding. The delay between the first signs and the emergency visit was 78.9 hours. Inhibitors were positive in one patient among those who presented LTB. These bleeding were treated with CFC in 16 patients, surgical drainage (1 patient) and electrocoagulation during gastroscopy (1 patient). Eleven patients had complete remission and two had sequelae. We reported 0.32 death per 100 person-years. CNS bleeds were the main cause (77.7%). Four patients were secondarily on LDP. We observed a significant correlation between treatment (after 2 hours) and mortality. Conclusion LTB is a serious and lethal complication in PWH in absence of early management. A good awareness of patients and their family would further reduce this incidence, especially in resources-limited countries.

Introduction: Four-Factor PCC (4F-PCC) is labeled for the reversal of vitamin K antagonists and may be considered off label for the reversal of factor Xa inhibitors. A fixed-dose strategy of 4F-PCC for the reversal of factor Xa inhibitors has the potential to minimize delay to reversal, avoid confusion during the ordering process, and lead to cost savings. The purpose of this study is to evaluate the safety and efficacy of fixed-dose 4F-PCC for the management of life-threatening bleeds associated with factor Xa inhibitors. Methods: This was a single center retrospective chart review conducted from May 2019 to January 2022. Patients were included if they were 18 years or older, experienced a life-threatening bleed while on a factor Xa inhibitor, and received 4F-PCC at a fixed dose of 2000 units. Exclusion criteria included: reversal for non-emergent surgery, receipt of 4F-PCC at an outside hospital, and/or receipt of an additional reversal agent. The primary outcome was achievement of hemostasis using a hemostatic effectiveness scale described by Sarode et al. Secondary outcomes included incidence of thrombosis within seven days of 4F-PCC administration and mortality. Results: A total of 39 patients received 4F-PCC for the reversal of a factor Xa inhibitor; 26 patients had central nervous system (CNS) bleeding and 13 had a non-CNS bleed. Overall 49% achieved excellent hemostatic effectiveness, 3% achieved good hemostatic effectiveness, 28% achieved poor, and in 20% we were unable to assess hemostatic effectiveness. In the subset of patients with CNS bleeding, 61% had either excellent or good effectiveness, 8% had poor, and 31% were unable to assess. There was one patient who experienced thromboembolism within seven days of reversal. In-hospital mortality was 18%. Conclusions: The results of this study demonstrate that a fixed-dose 4F-PCC dosing strategy for the reversal of factor Xa inhibitors produces reasonable hemostatic effectiveness and is safe. The rates of effectiveness seen in the subset of patients with CNS bleeding are similar to what has previously been reported for a weight-based dosing strategy. Randomized prospective studies are needed comparing 4F-PCC to andexanet alfa, the FDA labeled reversal agent for factor Xa inhibitors.

Central nervous system (CNS) hemorrhage is a serious complication related to direct oral anticoagulant (DOAC) therapy. Current recommendations about re-initiation of anticoagulation treatment are limited to expert opinions. For this purpose, we analyzed the data of all consecutive DOAC patients with CNS hemorrhage, in whom DOACs were reinitiated. Over a 6-year period (2012-2018), all consecutive patients with CNS hemorrhage (subdural, subarachnoid, intracerebral, spinal), while receiving DOACs, were included in this observational single-center cohort study. DOAC therapy was reinitiated only in patients with well-controlled arterial hypertension and diabetes, as well as exclusion of vascular malformations and cerebral amyloid angiopathy. The composite primary endpoint comprised of recurrent CNS hemorrhage, ischemic stroke, and mortality; secondary endpoints were separate aforementioned outcomes. Of the 54 patients included, 18 died within a month of CNS hemorrhage. The average observational time was 590days. DOACs were reinitiated in 13/36 patients (36%); of these patients, three died: none due to ischemic stroke or recurrent CNS bleeding. In 23 patients, anticoagulation was not reinitiated; of these patients, 10 died: three from recurrent CNS hemorrhage, one due to ischemic stroke, and six from causes unrelated to stroke. In carefully selected patients, re-initiation of DOAC therapy did not increase the rate of both endpoints. Recommendations for DOAC re-initiation, which include hypertension and diabetes control, as well as treated vascular malformations, and excluded cerebral amyloid angiopathy, appear to be valid in clinical practice.

Central nervous system (CNS) hemorrhage is a potentially life-threatening condition, especially in patients with acquired coagulopathy. In this setting, treatment of CNS bleeding includes hemostatic therapy to replenish coagulation factors. There is currently a debate over the hemostatic efficacy of plasma in many clinical settings, alongside increasing concern about transfusion-associated adverse events. Despite these concerns, plasma is widely used. Moreover, plasma transfusion practice is variable and there is currently no uniform approach to treatment of traumatic, surgical or spontaneous CNS hemorrhage. This study addresses the need for guidance on the indications and potential risks of plasma transfusion in these settings. An Expert Consensus Panel was convened to develop recommendations guiding the use of plasma to treat bleeding and/or coagulopathy associated with CNS hemorrhage. The panel did not advise on the best treatment available but rather proposed recommendations to be used in the formulation of local procedures to support emergency physicians in their decision-making process. Evidence was systematically gathered from the literature and rated using methods established by the Scottish Intercollegiate Guidelines Network. The evidence was used to develop graded consensus recommendations, which are presented along with the evidence-based rationale for each in this report. Sixty-five articles were identified covering both vitamin K antagonist-anticoagulation reversal and treatment of bleeding/coagulopathy in non-anticoagulated patients. Recommendations were then developed in four clinical scenarios within each area, and agreed on unanimously by all members of the panel. The Panel considered plasma to be reasonable therapy for CNS hemorrhage requiring urgent correction of coagulopathy, although physicians should be prepared for potential cardiopulmonary complications, and evidence suggests that alternative therapies have superior risk-benefit profiles. Plasma could not be recommended in the absence of hemorrhage or coagulopathy. Consideration of the absolute risks and benefits of plasma therapy before transfusion is imperative.

Objective To analyze the changes of laboratory indices in serum and cerebrospinal fluid(CSF)for children retinoblastoma(RB)before and after chemotherapy between central nervous system (CNS) metastasis group and extraocular stage group, and to conclude the clinical significance. Methods From September 2005 to December 2013, 11 cases were collected in Beijing Tongren Hospital who were diagnosed as CNS metastasis and were assorted into CNS metastasis group.According to age, gender and eye difference, 11 cases were chosen for the extraocular stage group.Twenty-two cases were given 6 cycles of chemotherapy.The chemotherapy protocol was Carboplatin + Teniposide + Vincristine(CTV) or Carboplatin + Etoposide + Vincristine(CEV). In each chemotherapy cycle all patients underwent lumbar puncture and intrathecal injection therapy.Serum levels of neuron specific enolase (NSE), serum lactate dehydrogenase (LDH) and CSF levels of NSE, quantitative protein and white blood cell count of the two groups were monitored before initiating chemotherapy and after the third and sixth cycles of chemotherapy.Multi factor variance analysis of the data was compared between the two groups in the dynamic changes of laboratory indices before and after chemotherapy using repeated measurements. Results The serum NSE levels of CNS metastasis group before initiating chemotherapy and after the 6th cycle of chemotherapy were (120.19±105.19) μg/L and (39.07±24.10) μg/L, respectively.The serum NSE levels of extraocular stage group before initiating chemotherapy and after the 6th cycle of chemotherapy were (29.03±11.94) μg/L and (21.03±5.01) μg/L, respectively.Serum NSE levels of the two groups showed significant changes before and after chemotherapy (F=7.115, P=0.000). Serum NSE level of CNS metastasis group was significantly higher than that of the extraocular stage group(F=41.500, P=0.007). Serum LDH levels of the two groups showed no statistically significant changes before and after chemotherapy (F=0.892, P=0.525). The CSF-NSE level of CNS metastasis group was significantly higher than that of extraocular stage group(F=15.706, P=0.001). CSF quantitative protein level of the CNS metastasis group was significantly higher than that of extraocular stage group(F=15.228, P=0.001). CSF white blood cell count of the CNS metastasis group were significantly higher than that of extraocular stage group(F=5.514, P=0.003). Conclusions Serum NSE level can be used as a laboratory indicator for monitoring CNS metastasis stage and extraocular stage of RB.The CSF-NSE values can be used as a diagnostic tool for CNS metastasis and monitoring of disease progression.CSF quantitative protein and white blood cell count can be used as auxiliary laboratory index for CNS metastasis diagnosis.Serum LDH cannot be used as a valuable laboratory index for diagnosis of CNS metastasis cases and extraocular cases. Key words: Retinoblastoma; Neuron specific enolase; Lactate dehydrogenase; Cerebrospinal fluid

Between 1960 and 1991, 156 episodes of central nervous system (CNS) bleeding were documented in 106 patients from a total population of 1,410 hemophiliacs (7.5%). Ninety-one hemophilia A patients presented 131 bleeding episodes; 15 hemophilia B patients had 25 episodes. 32% of these episodes took place in patients less than 5 years of age. 46% were age 10 or less, and 72% were age 20 or less. The mean age was 14.8 years in hemophilia A and 9 years in hemophilia B patients. A significant increase in the mean age of hemophilia A patients has been observed over the last 10 years; this may be related to HIV infection. A history of recent trauma was documented in 39.7% of the episodes. Spontaneous CNS bleeding was predominant in severe hemophilia (85.2%). One hundred and fifty-four CNS bleeding episodes were intracranial and 2 intraspinal. Of the intracranial episodes, 37.7% were subarachnoid, 29.8 subdural, and 22.7% intracerebral. Factor VIII or IX inhibitors were present in 11.3% of the patients; this figure is slightly lower than that observed in our total hemophilic population. Over 50% of the patients had psychoneurological sequelae; the most frequent were seizure disorders and motor impairment. The overall mortality rate was 29.2%. The mortality was more closely related to the CNS bleeding site than to the severity of hemophilia. Treatment should be based on prompt and prolonged replacement therapy to ensure hemostatic levels of antihemophilia factors.

To the Editor Patients with immune thrombocytopenia (ITP) are at risk for life-threatening bleeding complications, particularly intracranial hemorrhage (ICH). ICH occurs in <1% of patients with ITP 1. No study has assessed the risk factors of ICH in adults with ITP. This case-control study aimed to determine ICH risk factors in adults with primary ITP. A French multicenter case-control retrospective study was conducted over 22 years (1998–2012) using the national hospital discharge database (PMSI), and included patients aged 18 years and older with primary ITP and ICH, with platelet count ≤100 × 109/L at the time of ICH. Each center provided two controls per case. The controls were defined as the next two patients with primary ITP who were hospitalized after the ICH case, whatever was the reason of hospitalization provided that the platelet count was <50 × 109/L at inclusion. Patients with secondary ITP were excluded. Data collected included patients and ITP characteristics before ICH, the events preceding ICH (e.g., head trauma in the 7 days preceding ICH, infections in the month preceding ICH, medications interfering with hemostasis at the time of ICH, cerebral vascular malformations) and the description of ICH. The Committee of Protection of Persons of Ile-de-France X approved this study. Bleeding severity of ITP was classified as mild (only skin bleeding or no bleeding), intermediate (for visible mucosal and skin bleeding), or visceral (including gastrointestinal, hematuria, gynecological and retinal) and was based on the worst bleeding that occurred during ITP history before the ICH for cases and before the last visit for controls. At the time of ICH, bleeding severity was assessed by the Khellaf bleeding score 2. All categorical data were analyzed by chi-square or Fisher's exact test. All continuous data were analyzed by nonparametric Mann–Whitney test. A logistic regression model was used to determine ICH risk factors. A two-sided P < 0.05 was considered statistically significant. Ten cases (37%) presented ICH during newly diagnosed ITP; for five of them, the ICH was diagnosed concomitantly with ITP. Bleeding symptoms before ICH onset are described in Table 1: the frequency of cutaneous bleeding and hematuria differed between cases and controls; the frequency of overall visceral hemorrhage and life-threatening bleeding was greater for cases than controls. Overall, 20/27 cases (74%) received treatment for ITP before ICH as compared with all controls (P = 0.0002). For five cases, ICH was diagnosed concomitantly with ITP, so no previous treatment was administered. For two cases, the platelet count was >30 × 109/L, so no treatment was required before the ICH. Only 16% (3/19) of cases responded to steroids versus 85% (45/53) for controls. Events preceding ICH are described in Table 1: head trauma preceded ICH in five cases and in two of the controls (P = 0.038). The two groups did not differ in consumption of medications that interfered with hemostasis. A total of 10/27 cases (37%) experienced infection within 5 days (range: 0–22 days) before ICH. Infection data for controls were missing; three cases showed intracranial vascular malformations. For 19/27 cases (70%), at least one of the following factors preceded the ICH: cranial trauma, cranial vascular malformation, drugs interfering with hemostasis or infection; 12(44.4%), 5 (18.5%), and 2 (7.4%) patients had 1, 2 or at least 3 factors, respectively; 12/27 (44.4%) cases had precipitating factors excluding infection. According to multivariate analysis, risk of ICH was increased with life-threatening bleeding (OR: 21 [1.9–243], P = 0.0143) and nonresponse to steroids during ITP (OR: 59 [6.7–523.7], P = 0.0002) and reduced with cutaneous bleeding (OR: 0.01 [0–0.34], P = 0.01). At the time of ICH, the median platelet count for cases was 6 × 109/L (range: 1–86 × 109/L); 4 (15%) had a platelet count >30 × 109/L and at least one precipitating condition. The median bleeding score 2 (excluding the ICH score) at the time of ICH was 8 (range: 0–29). Only 12/23 cases (52%) with platelet count <30 × 109/L at the time of ICH were treated with steroids, IVIg and fractionated platelet transfusion combined as recommended in the guidelines published in 2011. The mortality rate was 44% (n = 12). This is the first case–control study of risk factors for ICH in adult patients with ITP. A case-control study of 40 children with ITP and ICH found increased risk of ICH with cranial trauma and hematuria 3. Our controls were from hospitalized patients for easier identification, their platelet count at inclusion <50 × 109/L instead of 100 × 109/L in order to select patients with more active disease but this may represent a bias by selecting controls with more severe disease. Life-threatening bleedings were significantly related to ICH occurrence. Cortelazzo et al. found a previous significant bleeding episode during ITP to be a major risk factor for severe hemorrhage (relative risk 27.5, P < 0.0005) 4. Risk of ICH was reduced with cutaneous bleeding and this might not be simply due to reporting bias, as suggested for children 3, but cutaneous bleeding could be associated with early ITP diagnosis and treatment. We found that nonresponse to steroids during ITP was strongly associated with ICH occurrence. No previous study assessed the response to ITP therapy before ICH. Portielje reported that a lack of response to ITP therapy during the 2 years after ITP diagnosis increased four-fold the risk of death due to hemorrhage or infection 5. In our study, 19 cases (70%) had at least one of the precipitating factors. Some patients with severe thrombocytopenia developed ICH, while others did not, assuming the role of precipitating factors and the role of residual platelets' function 6. Patients with mild bleeding scores seemed at low risk of ICH in the absence of a potential triggering factor. This finding reinforces the decision to treat patients with ITP based on bleeding severity rather than platelet count. The patients over 60 years of age did not exhibit an increased ICH risk. However, three of the four patients who had ICH at platelet count >30 G/L were aged ≥70-years old. In conclusion, this study showed that patients presenting with life threatening bleeding, nonresponse to steroid treatment, and precipitating factors are at high risk of ICH. Contribution: S.M.B. collected and analyzed the data and wrote the manuscript. O.F. designed and supervised all steps in the study and contributed to writing the article. B.G. coordinated, designed the study and helped write the article. A.S.M. contributed to the study design. A.A. reviewed the brain CT or MRI images. M.B. and V.L. analyzed data. F.A. contributed to data analyses. F.B. and M.K. helped write the article. The remaining authors contributed to data collection by identifying cases and selecting controls. The authors thank Mrs. Joan, Meriem, and Hayat Tazir, the American Journal expert and Laura Smales for manuscript corrections. Sara Melboucy-Belkhir,1* Mehdi Khellaf,2 Alexandre Augier,3 Marouane Boubaya,4 Vincent Levy,4 Guillaume Le Guenno,5 Louis Terriou,6 Bertrand Lioger,7Mikaël Ebbo,8 Anne-Sophie Morin,9 Marie-Paule Chauveheid,10 Marc Michel,11Farid Belkhir,12 Frédégonde About,13 Christian Rose,14 Guillaume Moulis,15Arsene Mekinian,16 Jérôme Stirnemann,17 Thomas Papo,10 Stéphane Cheze,18Eric Rosenthal,19 Jean-François Viallard,20 Nicolas Schleinitz,8 Lionel Galicier,21 Daniel Adoue,15 Olivier Lambotte,22 Mohamed Hamidou,23Bertrand Godeau,11 and Olivier Fain16 1Department of Internal Medicine, Saint-Quentin Hospital, Saint-Quentin, France; 2Department of Emergency, Henri Mondor Hospital, AP-HP, Université Paris-Est Créteil, Créteil, France; 3Department of Radiology, Avicenne Hospital, AP-HP, Université Paris XIII, Bobigny, France; 4Department of Clinical Research, Avicenne Hospital, AP-HP, Université Paris XIII, Bobigny, France; 5Department of Internal Medicine, Estaing University Hospital, Clermont Ferrand, France; 6Department of Hematology, Claude Huriez University Hospital, Lille, France; 7Department of Internal Medicine, Bretonneau University Hospital, Tours, France; 8Department of Internal Medicine, La Conception Hospital, Assistance Publique Hôpitaux de Marseille, Université Aix-Marseille, Marseille, France; 9Department of Internal Medicine, Jean Verdier Hospital, AP-HP, Bondy, Université Paris XIII, Bondy, France; 10Department of Internal Medicine, Bichat Hospital, AP-HP, Université Paris VII, Paris, France; 11Department of Internal Medicine, Henri Mondor Hospital, AP-HP, Université Paris-Est Créteil, Créteil, France; 12Department of Onco-radiotherapy, Saint-Quentin Hospital, Saint-Quentin, France; 13Department of Statistics and Public Health, Henri Mondor Hospital, AP-HP, Université Paris-Est Créteil, Créteil, France; 14Department of Hematology, Saint-Vincent de Paul Hospital, Lille, France; 15Department of Internal Medicine, Purpan University Hospital, Toulouse, France; 16Department of Internal Medicine, Saint Antoine Hospital, DHUi2B, Université Paris VI, Paris, France; 17Department of Internal Medicine, Geneva University Hospital, Geneva, Switzerland; 18Department of Hematology, Clémenceau University Hospital, Caen, France; 19Department of Internal Medicine, L'Archet 1 University Hospital, Nice, France; 20Department of Internal Medicine, Haut-Lévêque University Hospital, Pessac, France; 21Department of Clinical Immunology, Saint Louis University Hospital, Paris, France; 22Department of Internal Medicine, Bicêtre Hospital, AP-HP, Université Paris Sud, Le Kremlin-Bicêtre, France; 23Department of Internal Medicine, Hôtel Dieu University Hospital, Nantes, France