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

We sent questionnaires to hospitals in Japan in order to study the incidence and conditions of intracranial hemorrhage (ICH) in children with immune thrombocytopenic purpura (ITP). From 1980 to 1995, 11 cases of ICH were reported in eight patients with ITP at 35 institutions. One patient had ICH four times, but only one patient died of the condition. From 1990 through 1995, ICH occurred in four (0.52%) of 772 patients with ITP. None of the patients died. The platelet count when ICH occurred was 5.2 +/- 3.7 x 10(9)/l (mean +/- SD) (n = 11). Four of the eight patients (1980-1995) had received active treatment [e.g. intravenous immunoglobulin G (i.v. IgG)] immediately before ICH occurred. In seven cases (1980-1995), possible causes of ICH, including menstruation (n = 2) and viral infections (n = 3), were identified. Systemic lupus erythematosus (SLE) later developed in three patients. Although the incidence of ICH in children with ITP has not decreased compared with the rates in earlier studies, the mortality rate has decreased markedly. Our results suggest that menstruation, infection, and risk factors for progression to SLE may help to predict ICH in children with ITP. Large-scale prospective trials are needed to identify risk factors for ICH.

Forty-nine children (30 boys and 19 girls) with idiopathic thrombocytopenic purpura (ITP) seen at King Khalid University Hospital (KKUH) Riyadh, during a 7-1/2 year period were retrospectively reviewed with regard to their clinical characteristics, management, and outcome. The age of onset of the disease ranged from 8 months to 11 years with a mean of 4.26 years. Twenty-seven cases presented as acute ITP while 22 cases presented as chronic ITP. The clinicopathological features and response to treatment of the cases were essentially similar to findings in other parts of the world. In a search for a predictor of chronic disease, the platelet counts at four weeks and three months after diagnosis were found to be a significant factor for prediction of chronicity of ITP. If the platelet counts are less than 100x10(9)/L during these periods, the risk of chronic ITP is increased and vice versa. There was, however, no correlation in our patients between duration of symptoms prior to presentation and outcome of the disease as has been reported by investigators in Europe and Australia.

Intracranial Hemorrhage in Egyptian Children with Primary Immune Thrombocytopenia (ITP): Report of 24 Cases in 20 Years

Idiopathic Thrombocytopenic Purpura

Incidence of intracranial hemorrhage (ICH) among children with primary immune thrombocytopenia (ITP) varies among different studies. We published data during the period of 1997-2007 of ICH in children with primary ITP, addressing risk factors and outcome. The aim of this study is to assess changes in incidence, risk factors, and outcome of ICH in children with ITP from last decade and to report the overall 20years' experience. We compared 2008-2018 with the decade before it. Data of children with ITP and ICH during study period and ITP control cases were analyzed. Neurosurgical intervention and outcome were also reported. A total of 4340 children with primary ITP were evaluated. Twenty-five (0.63%) ICH events were reported over 2 decades. Head trauma, hematuria, and platelet counts < 10 × 109/L were the risk factors mostly associated with ICH. Overall mortality was 24%, and a further 28% had neurologic sequelae. Neurosurgical intervention was done in 12% of cases with good outcome.Conclusion: Persistent platelet counts < 10 × 109/L were a significant risk factor for ICH in both time periods, while head trauma and hematuria were more reported in the period of 2008-2018 as significant risk factors for ICH. Outcome was comparable in both periods. What is Known: • ICH is a rare complication of ITP; however, early recognition of risk factors and aggressive treatment might lead to complete recovery without sequalae. Platelet counts less than < 10 × 109/L are the main risk factor for ICH. Few studies reported other significant risk factors. What is New: • Hematuria and head trauma are significant risk factors for ICH in ITP, in addition to having a persistently low platelet count < 10 × 109/L. (more than 90days in chronic ITP, 45days in persistent and 21days in acute ITP) • Combined treatment with IVIG and HDMP followed by platelet transfusion was associated with complete recovery without sequelae in almost 50% of patients.

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

2021 Chinese consensus on the diagnosis and management of primary immune thrombocytopenia in pregnancy.

Intracranial Hemorrhage

Dear Editor, Severe hemorrhage in children with immune thrombocytopenic purpura (ITP) is rare and occurs in 3% of patients [1]. Intracranial hemorrhage (ICH), the most feared bleeding complication, has an estimated incidence of 0.1–0.5% [1–3]. Mortality rate of ICH is high and varies from 24–57% [2–4]. We report a patient with acute ITP who developed fatal ICH shortly after starting high-dose methylprednisolone. A 5-year-old girl with an unremarkable medical and family history presented to her pediatrician with acute onset of bruising and petechiae. Physical examination revealed no other abnormalities. Blood pressure was 112/60 mmHg. Laboratory studies showed an isolated trombocytopenia of 1 × 109/L (Table 1). She was diagnosed with acute ITP and managed conservatively. Four days after presentation, she developed large ecchymoses and epistaxis causing anemia. Intravenous immunoglobulins (IVIg; 0.8 g/kg once) and packed red cells were administered (Fig. 1). Platelet count remained low (1 × 109/L) and mucosal bleeding continued. The girl was referred to our department for further management. We saw a pale, tachycardic girl with multiple ecchymoses and active mucosal bleeding from nose and mouth. Hemoglobin was 7.4 g/dL and platelet count 2 × 109/L. After a second gift of IVIg, prednisone 2 mg/kg/day, an erythrocyte transfusion and a large dose of platelets (ten donor units), platelet count rose to 21 × 109/L, hemoglobin stabilized and the clinical condition of our patient improved dramatically. However, 36 h later, profuse mucosal bleeding from nose and mouth recurred at a platelet count of 1 × 109/L. We started high-dose methylprednisolone (15 mg/kg) together with another platelet transfusion. Shortly after starting the methylprednisolone infusion, she complained of severe headache and instantly developed generalized seizures. Blood pressure at that moment was elevated: 170/90 mmHg. Computed tomography (CT) showed extensive bifrontal ICH. Unfortunately, our patient died of progressive herniation caused by massive cerebral edema, despite continuous platelet transfusions and intensive care management. Autopsy was not performed. Table 1 Results of laboratory studies in our patient Fig. 1 Overview of platelet counts and interventions in our patient. i = IVIg; white bar = prednisone 2 mg/kg/day; white arrow = high-dose methylprednisolone infusion; black circle = platelet transfusion; black diamond = erythrocyte transfusion. ... The main reason for clinicians to treat children with acute ITP and minor bleeding symptoms is to raise platelet counts in order to prevent severe bleeding complications and in particular ICH. The question is whether treatment really prevents these bleeding complications. The majority of children with severe bleeding or ICH described in literature developed these complications despite prior therapy [1–5]. Why do some patients develop ICH despite therapy? Apart from known risk factors like head trauma, use of non-steroidal anti-inflammatory drugs, intracranial arteriovenous malformation, and bleeding beyond petechiae and ecchymoses [2, 3], there are some other possible explanations. Patients may suffer from refractory ITP and remain severely thrombocytopenic despite therapy, leaving them at risk for bleeding complications [6]. However, there is also a possibility of either causing or worsening ICH due to adverse effects of drug therapy. In our patient, the temporal relationship between starting methylprednisolone and development of headache and ICH remains remarkable. A sudden rise in blood pressure, a known adverse effect of high-dose methylprednisolone, could have initiated or worsened ICH. In conclusion, this report shows that treatment of ITP cannot always prevent ICH and may even be involved in initiating or worsening ICH.

A Multicenter Study Evaluating the Safety of Romiplostim at Maximal Dosage for Emergency Bleeding Situations in Immune Thrombocytopenia

Given past experience with widespread viral infections, for example influenza, we expected that SARS-CoV-2 would create a large number of de novo cases of immune thrombocytopenia (ITP). Perhaps a silver lining on the cloud of SARS-CoV-2 is that for patients with ITP, the virus is not having a major effect, as evidenced by few reports of ITP in conjunction with SARS-CoV-2 infection. We performed a retrospective review of patients ≥18 years diagnosed with COVID-19 and ITP seen at New York Presbyterian–Weill Cornell Medicine (NYP-WCM) or Shandong Provincial Chest Hospital–Shandong University (SPCH-SDU) from February to August 2020. Ten patients from NYP-WCM and two from SPCH-SDU were identified (Table I). The study was approved by the Institutional Review Board of NYP-WCM and the Medical Ethical Committee of SPCH-SDU. There were 10 patients with pre-existing ITP and two with presumed new SARS-CoV-2-associated ITP (Table I). Patient 8 was diagnosed with ITP during hospitalization for COVID-19 and Patient 10 developed isolated ITP six weeks following SARS-CoV-2 infection; neither had a prior history of thrombocytopenia. For those with pre-existing ITP, SARS-CoV-2 infections were managed as outpatients (n = 3), ER visits (n = 2), and hospitalizations (n = 5). During active COVID-19, five patients required ITP treatment for platelet nadirs of 8–33 × 109/l. Patient 7 received platelet transfusion, steroids and intravenous immunoglobulin (IVIg). Patients 1 and 9 received IVIg alone. Patient 1 had been on weekly romiplostim, twice daily mycophenolate mofetil (MMF) and IVIg as needed since 2017. She had fevers, fatigue, body aches and was ITP-Bleeding Assessment Tool: Skin 1 (petechiae), Mucosae 1 (epistaxis).1 Due to morbid obesity, limited mobility, and advanced age, she received weekly home infusions of IVIg 80 g for counts <10–20 × 109/l. Patient 9, on prednisone 15 mg daily for platelets 20–30 × 109/l, was hospitalized at SPCH-SDU. He received IVIg 10 g daily for two days with platelet improvement from 18 to 28 × 109/l. Patient 8 received inpatient IVIg 15 g daily for three days, methylprednisolone 80 mg BID, and convalescent plasma for SARS-CoV-2-associated ITP with platelets increasing from 33 to 83 × 109/l. Several weeks following SARS-Cov-2 diagnosis, Patient 10 received IVIg with steroids for de novo ITP with platelet improvement from 6 to 82 × 109/l. Patient 7 had chronic ITP with platelets of 8 × 109/l requiring platelet transfusions. In the setting of multiorgan failure, he declined additional treatment and passed away. Two patients received steroids alone for exacerbations of known ITP during infection with SARS-CoV-2. Patient 11's platelets dropped from 60–70 to 23 × 109/l two weeks after diagnosis. His platelets improved to 180 × 109/l on prednisone 20 mg daily. Patient 4's platelets dropped from a baseline of 60–70 to 26 × 109/l. She received dexamethasone 40 mg for four days with platelets rising to 105 × 109/l. Five patients (Patients 2, 3, 5, 6, 12) did not modify their ITP treatment despite COVID-19. Three (Patients 2, 3, 6) were on treatment (eltrombopag, steroids, rituximab, respectively). Patient 5 was discharged from the ER with haematology follow-up for platelets 26 × 109/l and Patient 12 was diagnosed with SARS-Cov-2 on routine screening for caesarean section with platelets 94 × 109/l. Patients 3, 4, 6, 8 were hospitalized and received prophylactic anticoagulation with enoxaparin 40 mg SC daily (NYP-WCM) or nadroparin 3 800 U SC daily (SPCH-SDU) without bleeding events. Patient 6 developed deep vein thrombosis (DVT) and pulmonary embolus (PE) despite prophylactic enoxaparin. He received therapeutic heparin and was discharged on apixaban. Patient 2 presented with a new headache due to cerebral venous sinus thrombosis and was discharged on apixaban. Treatments of ITP, ongoing or newly initiated, can impact the course and outcome of SARS-CoV-2. Thrombosis is a major concern in patients with SARS-CoV-2 infection2, 3 and immunosuppression could worsen infection. The American Society of Hematology offers recommendations limited by data to expert opinion4 for ITP management in SARS-CoV-2 infection. IVIg is not immunosuppressive, rapidly increases platelets, and has anti-inflammatory effects. To avoid prolonged visits and SARS-CoV-2 exposures, home administration (like Patient 1) is useful. Steroids may risk increasing viral susceptibility early in infection; however, published reports and our own experience suggest steroid use does not often lead to worse outcomes in COVID-19.5-7 No consensus exists regarding increased severity of COVID-19 infection in patients who have received rituximab or are on other chronic immunosuppressants.8-10 Anti-CD20 agents impair humoral responses to de novo infections and vaccines for at least 4–6 months. We agree with avoiding immunosuppressives or rituximab during the COVID-19 pandemic pending reasonable alternatives.11 We also caution use of splenectomy due to increased thrombotic risk and risk of overwhelming sepsis. The risk of thrombotic events with SARS-CoV-2 is well documented2, 3 and prophylactic anticoagulation is recommended in hospitalized patients including those with ITP.4, 12, 13 Cases of thrombosis in COVID19-infected ITP patients have been reported, including two patients included in this report.5, 7, 14 Patient 6 developed DVT/PE despite prophylactic anticoagulation. Although an advantage of thrombopoietin receptor agonists (TPO-Ras) would be absence of immunosuppression, caution is recommended during the COVID19 pandemic in patients with additional thrombotic risk factors such as post-splenectomy and platelet counts >100 × 109/l (Patient 2). Follow-up information through February 2021 is available for seven patients (Patients 1, 2, 3, 6, 8, 9, 10). None required hospitalization for recurrent ITP flares. Both patients with presumed new SARS-CoV-2-associated ITP (Patients 8, 10) maintain normal platelet counts without platelet-specific treatment. Patient 8 did not require treatment beyond IVIg and steroids received during hospitalization. Patient 10 was successfully tapered off steroids in October 2020. The starting platelet counts in our 12 patients were somewhat higher than in the 14-patient French series6 which had a high percentage of de novo cases whereas 10 of our 12 involved pre-existing ITP. As with ITP in the absence of SARS-CoV-2 infection, treatment needs to be individualized. Steroids, IVIg, rituximab, immunosuppressives, splenectomy and TPO-RAs are discussed above and considerations based on experience applicable to SARS-CoV-2 infection emphasized. Ongoing experience continues to be gathered to better inform care to SARS-CoV-2 infected ITP patients. EL, XL, MH, JB performed the research and analyzed the data, EL and JB wrote the paper, XL and MH revised the paper. All authors approved the final manuscript. EL, XL and MH have no disclosures. JBB has served on advisory boards and/or consulted for Amgen, Novartis, Dova, Rigel, UCB, Argenx, Momenta, Regeneron, RallyBio, and CSL-Behring.

Immune Thrombocytopenia in Very Elderly Patients: Particularities in Presentation and Management. Results from the Multicenter Prospective Carmen-France Registry

Urgent Management of Bleeding in Immune Thrombocytopenia: Towards a Standardized Protocol in the Emergency Department

Treatment with Intravenous Immunoglobulin Does Not Prevent Chronic Immune Thrombocytopenia in Children: Results of a Randomized Controlled Trial

Prevalence and Characteristics of Intracranial Hemorrhage and Acute Ischemic Stroke in Pediatric Patients with Immune Thrombocytopenia and Thrombotic Thrombocytopenic Purpura: A Systematic Review and Meta-Analysis