Intracranial Hemorrhage

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

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.

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

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.

Bevacizumab is widely used and may cause life-threatening bleeding. We attempted to identify clinical characteristics associated with central nervous system (CNS) hemorrhage in a broad population. We performed a retrospective review of the FDA MedWatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Our search used keywords: bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke and brain. A total of 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1,041 reports described non-CNS bleeds. Median age was 62 years, and the primary cancers were consistent with indications for bevacizumab. Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. Thirty percent had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. Death was reported as a complication of hemorrhage in 48 %. The most common predisposing factor for CNS bleeds was use of medications associated with bleeding, followed by thrombocytopenia. In this database, 154 of 1,195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in two-thirds of cases.

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.

The American Heart Association recommends extended cardiac monitoring for the diagnosis of subclinical atrial fibrillation (AF) among patients with acute ischemic stroke and no clear source of embolism. In this meta-analysis by Dr. Tsivgoulis and colleagues, investigators pooled high-quality observational cohort and randomized clinical trial data involving nearly 3,000 patients to evaluate the probability of identifying AF, initiation of anticoagulation, and stroke recurrence risk. Although all cardiac monitors increased the risk of AF detection and anticoagulation initiation, implantable loop recorders were associated with the highest probability of AF detection and anticoagulation initiation. Compared with patients who underwent conventional monitoring, those with prolonged monitoring were associated with a lower risk of recurrent stroke, although this risk was driven by patients monitored in observational (nontrial) cohort studies (relative risk [RR] 0.29, 95% CI 0.15–0.59 vs RR of stroke in randomized clinical trials 0.72, 95% CI 0.49–1.07). Dr. Meinel emphasizes that intracranial and systemic hemorrhages ought to be considered along with recurrent ischemic stroke in the decision to anticoagulate a patient with AF. The investigators acknowledge that intracranial hemorrhages are a highly fatal complication after anticoagulation, and although the risk of death due to major extracranial hemorrhage is also considerable, the mortality rate is far lower than what is seen among intracranial hemorrhages. Fortunately, most bleeding events and deaths due to such events are generally low (<5%). Owing to lack of available data on bleeding rates and mortality in many studies reported in this meta-analysis, the investigators cannot be certain of the low risks across all populations. That said, there were no significant differences in all-cause mortality with prolonged vs conventional cardiac monitoring in 2 of the included studies. Dr. Scharf also comments that the burden of subclinical AF and etiologies of recurrent stroke (e.g., small vessel or large vessel atherosclerosis) are also integral to evaluating the efficacy of anticoagulation in these patients. All authors eagerly await the results of randomized trials evaluating the potential benefit of anticoagulation after AF detection through prolonged cardiac monitoring. The American Heart Association recommends extended cardiac monitoring for the diagnosis of subclinical atrial fibrillation (AF) among patients with acute ischemic stroke and no clear source of embolism. In this meta-analysis by Dr. Tsivgoulis and colleagues, investigators pooled high-quality observational cohort and randomized clinical trial data involving nearly 3,000 patients to evaluate the probability of identifying AF, initiation of anticoagulation, and stroke recurrence risk. Although all cardiac monitors increased the risk of AF detection and anticoagulation initiation, implantable loop recorders were associated with the highest probability of AF detection and anticoagulation initiation. Compared with patients who underwent conventional monitoring, those with prolonged monitoring were associated with a lower risk of recurrent stroke, although this risk was driven by patients monitored in observational (nontrial) cohort studies (relative risk [RR] 0.29, 95% CI 0.15–0.59 vs RR of stroke in randomized clinical trials 0.72, 95% CI 0.49–1.07). Dr. Meinel emphasizes that intracranial and systemic hemorrhages ought to be considered along with recurrent ischemic stroke in the decision to anticoagulate a patient with AF. The investigators acknowledge that intracranial hemorrhages are a highly fatal complication after anticoagulation, and although the risk of death due to major extracranial hemorrhage is also considerable, the mortality rate is far lower than what is seen among intracranial hemorrhages. Fortunately, most bleeding events and deaths due to such events are generally low (<5%). Owing to lack of available data on bleeding rates and mortality in many studies reported in this meta-analysis, the investigators cannot be certain of the low risks across all populations. That said, there were no significant differences in all-cause mortality with prolonged vs conventional cardiac monitoring in 2 of the included studies. Dr. Scharf also comments that the burden of subclinical AF and etiologies of recurrent stroke (e.g., small vessel or large vessel atherosclerosis) are also integral to evaluating the efficacy of anticoagulation in these patients. All authors eagerly await the results of randomized trials evaluating the potential benefit of anticoagulation after AF detection through prolonged cardiac monitoring.

Twenty years' experience of immune thrombocytopenia and intracranial haemorrhage in the Nordic countries-A NOPHO study.

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

Recurrent Intracranial Hemorrhage and Venous Thromboembolism Following Initial Intracranial Hemorrhage in Patients with Brain Tumors on Anticoagulation

Intracranial hemorrhage (ICH) is the most feared and devastating complication of anticoagulant treatment, leading to death or disability in two thirds of cases. Once ICH occurs, the decision of whether to resume anticoagulation is a true therapeutic dilemma that requires balancing the competing risks of hematoma growth or recurrent ICH and disabling thromboembolic events. Although the risk of thromboembolism in patients off anticoagulation is higher than the overall risk of ICH recurrence, there is a marked paucity of prospective large population-based data on the real risk of ICH recurrence on warfarin. The lack of randomized controlled trials probably reflects the ethical challenge of prescribing patients a medication to which they have an apparent contraindication. Therefore, in clinical practice, the risk is usually, and inappropriately, extrapolated from the overall risk of major bleeding on warfarin (approximately 3%), in which older age and elevated international normalized ratio are factors associated with an increased risk. The little evidence available on resuming oral anticoagulation after ICH comes from either expert opinions or few nonrandomized mainly retrospective studies.1,2 These studies included highly selected high-risk patients and showed nonconclusive and even discrepant results. This limited and weak evidence along with our own …

Death and Disability from Warfarin-Associated Intracranial and Extracranial Hemorrhages

Intracranial Hemorrhage

An intracranial hematoma is a rare, yet significant, complication following spinal surgery. The authors describe two cases with acute intracranial hematoma formation after excision of a cervical subdural schwannoma. One was a 14-year-old girl who developed bilateral intracranial extradural hematomas immediately following excision of the C4 subdural schwannoma. The other was a 59-year-old woman who had an acute cerebellar hematoma after removal of the C2–C5 subdural schwannoma. During the surgeries of both cases, spinal dura was partially removed together with the tumor and the dural sac could not be repaired, resulting in large amounts of intraoperative CSF loss and persistent postoperative CSF leakage. Both patients failed to regain consciousness from anesthesia after surgery, and a cranial CT scan identified large intracranial hematomas. Urgent hematoma evacuation was ultimately performed to save the patients. Based on the authors’ experience and literature review, a conclusion was drawn that considerable CSF leakage and a sharp decrease of CSF pressure are common features during the excision of a spinal subdural tumor, which may lead to acute intracranial hematomas. Continual postoperative monitoring in patients with this condition should be of a very high priority. A CT or MRI should be immediately investigated to exclude intracranial hematomas for any patient with delayed emergence from anesthesia following spinal surgery. Hematoma evacuation is indispensable once an intracranial hematoma is identified in the patient who fails to regain consciousness from anesthesia post surgery. Furthermore, the possible pathophysiological mechanisms responsible for the formation of an intracranial hematoma after spinal procedures, particularly after manipulations of a cervical subdural tumor, are discussed.