COVID-19 Vaccine-Associated Immune Thrombosis and Thrombocytopenia (VITT): Diagnostic Discrepancies and Global Implications.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) has been reported in association with the coronavirus disease 2019 preventative adenovirus vector-based vaccines ChAdOx1 nCoV-19 (Oxford/AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson) in hundreds of recipients across the globe. VITT is characterized by thrombosis, typically at unusual sites, low fibrinogen, and elevated plasma D-dimer, generally manifesting between 4 and 28 days following vaccination. Detection of anti-platelet factor antibodies using an enzyme-linked immunosorbent assay (ELISA) is often confirmatory. Although several similar principles subside in most diagnostic criteria for VITT, the presentation of a positive ELISA assay, use of expert hematology and neurology opinion, and exclusion of possible VITT cases outside the "standard" 4 to 28-day timeframe have contributed a lack of global standardization for defining VITT. Accordingly, the global and regional incidence of VITT differs according to the diagnostic pathway and case definition used. This has influenced the public perception of VITT's severity and the decision to use adenovirus vector-based vaccines for limiting severe acute respiratory syndrome coronavirus 2 infection. We hereby delineate the recognized pathogenic mechanisms, global incidence, discrepancies in diagnostic criteria, recommended treatments, and global implications to vaccine hesitancy from this coagulopathy.

Malignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia.

Vaccine-induced thrombotic thrombocytopenia with cerebral venous thrombosis is a syndrome recently described in young adults within two weeks from the first dose of the ChAdOx1 nCoV-19 vaccine. Here we report two cases of malignant middle cerebral artery (MCA) infarct and thrombocytopenia 9-10 days following ChAdOx1 nCoV-19 vaccination. The two cases arrived in our facility around the same time but from different geographical areas, potentially excluding epidemiological links; meanwhile, no abnormality was found in the respective vaccine batches. Patient 1 was a 57-year-old woman who underwent decompressive craniectomy despite two prior, successful mechanical thrombectomies. Patient 2 was a 55-year-old woman who developed a fatal bilateral malignant MCA infarct. Both patients manifested pulmonary and portal vein thrombosis and high level of antibodies to platelet factor 4-polyanion complexes. None of the patients had ever received heparin in the past before stroke onset. Our observations of rare arterial thrombosis may contribute to assessment of possible adverse effects associated with COVID-19 vaccination.

Identification of occult cerebral microbleeds in adults with immune thrombocytopenia.

Management of symptoms and prevention of life-threatening hemorrhage in immune thrombocytopenia (ITP) must be balanced against adverse effects of therapies. Because current treatment guidelines based on platelet count are confounded by variable bleeding phenotypes, there is a need to identify new objective markers of disease severity for treatment stratification. In this cross-sectional prospective study of 49 patients with ITP and nadir platelet counts <30 × 109/L and 18 aged-matched healthy controls, we used susceptibility-weighted magnetic resonance imaging to detect cerebral microbleeds (CMBs) as a marker of occult hemorrhage. CMBs were detected using a semiautomated method and correlated with clinical metadata using multivariate regression analysis. No CMBs were detected in health controls. In contrast, lobar CMBs were identified in 43% (21 of 49) of patients with ITP; prevalence increased with decreasing nadir platelet count (0/4, ≥15 × 109/L; 2/9, 10-14 × 109/L; 4/11, 5-9 × 109/L; 15/25 <5 × 109/L) and was associated with longer disease duration (P = 7 × 10-6), lower nadir platelet count (P = .005), lower platelet count at time of neuroimaging (P = .029), and higher organ bleeding scores (P = .028). Mucosal and skin bleeding scores, number of previous treatments, age, and sex were not associated with CMBs. Occult cerebral microhemorrhage is common in patients with moderate to severe ITP. Strong associations with ITP duration may reflect CMB accrual over time or more refractory disease. Further longitudinal studies in children and adults will allow greater understanding of the natural history and clinical and prognostic significance of CMBs.

Association of Immune Thrombocytopenia and Interstitial Pneumonia.

Objective Chest physicians often encounter patients with interstitial pneumonia with autoimmune features. However, there have so far been few reports of patients presenting with concurrent immune thrombocytopenia (ITP) and interstitial pneumonia. The prevalence of interstitial pneumonia in patients with ITP is less well known. Methods We surveyed patients diagnosed with ITP and interstitial pneumonia at the departments of Hematology and Respiratory Medicine to evaluate the association between these diseases. Results Among 73 patients with ITP, 7 patients (9.6%) presented with interstitial pneumonia, including 4 patients (2%) who developed ITP in the course of 204 patients with interstitial pneumonia. All 7 patients were men. Four patients were positive for some autoantibodies. Two patients had autoimmune diseases other than ITP. There were significant differences in age and gender between the ITP patients with and without interstitial pneumonia. Conclusion The present study suggests the possibility that the development of ITP, other autoimmune diseases, and interstitial pneumonia may be mutually associated. Advanced age and male sex in ITP may be significant predisposing factors for interstitial pneumonia. Clinicians should be aware of the potential for the coexistence of these diseases.

TAFRO Syndrome with an Anterior Mediastinal Mass and Lethal Autoantibody-Mediated Thrombocytopenia: An Autopsy Case Report.

TAFRO syndrome, a rare systemic inflammatory disease, can lead to multiorgan failure without appropriate treatment. Although thrombocytopenia is frequently seen in patients with TAFRO syndrome, little is known about its pathogenesis. Moreover, while recent studies have reported the presence of an anterior mediastinal mass in some patients, the pathological status of this remains unclear. Here, we report a case of fatal bleeding in a patient with TAFRO syndrome accompanied by an anterior mediastinal mass. A 55-year-old female was transferred to our hospital with a 2-week history of fever, epistaxis, and dyspnea. Laboratory tests revealed severe thrombocytopenia, computed tomography (CT) showed pleural effusions, and bone marrow biopsy revealed reticulin myelofibrosis. We suspected TAFRO syndrome, but the CT scan showed an anterior mediastinal mass that required a biopsy to exclude malignancy. She soon developed severe hemorrhagic diathesis and died of intracranial hemorrhage despite intensive treatment. She had multiple autoantibodies against platelets, which caused platelet destruction. An autopsy of the mediastinal mass revealed fibrous thymus tissues with infiltration by plasma cells. Our case suggests that thrombocytopenia could be attributed to antibody-mediated destruction and could be lethal. Hence, immediate treatment is imperative in cases of severe thrombocytopenia, even when accompanied by an anterior mediastinal mass.

Long-term efficacy of partial splenic embolization for the treatment of steroid-resistant chronic immune thrombocytopenia.

Thrombopoietin-receptor agonists have been recently introduced for a second-line treatment of immune thrombocytopenia (ITP). Splenectomy has tended to be avoided because of its complications, but the response rate of splenectomy is 60-80% and it has still been considered for steroid-refractory ITP. We performed partial splenic embolization (PSE) as an alternative to splenectomy. Between 1988 and 2013, 91 patients with steroid-resistant ITP underwent PSE at our hospital, and we retrospectively analyzed the efficacy and long-term outcomes of PSE. The complete response rate (CR, platelets > 100 × 109/L) was 51% (n = 46), and the overall response rate (CR plus response (R), > 30 × 109/L) was 84% (n = 76). One year after PSE, 70% of patients remained CR and R. The group with peak platelet count after PSE ≥ 300 × 109/L (n = 29) exhibited a significantly higher platelet count than the group with platelet count < 300 × 109/L (n = 40) at any time point after PSE. The failure-free survival (FFS) rates at 1, 5, and 10 years were 78, 56, and 52%, respectively. Second PSE was performed in 20 patients who relapsed (n = 14) or had no response to the initial PSE (n = 6), and the overall response was achieved in 63% patients. There were no PSE-related deaths. These results indicate that PSE is a safe and effective alternative therapy to splenectomy for patients with steroid-resistant ITP as it generates long-term, durable responses.

Management of myocardial infarction in immune thrombocytopenic purpura with anti-phospholipid antibodies.

Sometimes it is difficult to distinguish anti-phospholipid syndrome (APS) from immune thrombocytopenic purpura (ITP). Here we present successful management of ITP with anti-phospholipid antibodies, complicated by acute coronary syndrome (ACS), using CT coronary angiography (CTCA). The therapy for ITP may be changed for APS if ACS was thromboembolic event. As coronary angiography is thought to be very dangerous for patients with severe thrombocytopenia, noninvasive CTCA was desirable for our patient. Since no occlusion or narrowing was observed in CTCA, she has been safely treated as ITP with immunosuppressive agents throughout the course without antiplatelet or antithrombin therapy.

[Primary coronary intervention for acute ST-elevation myocardial infarction in a patient with immune thrombocytopenic purpura]. / Immün trombositopenik purpurali bir hastada akut ST yükselmeli miyokart enfarktüsü için primer koroner girisim uygulamasi

The ideal treatment for acute myocardial infarction in patients with idiopathic thrombocytopenic purpura (ITP) is not well-known. A 42-year-old male patient with a previous diagnosis of chronic and refractory ITP was admitted with chest pain of four-hour onset. Findings of electrocardiography was consistent with acute anteroseptal myocardial infarction. He had no risk factors for coronary heart disease and was not receiving treatment for ITP, and his platelet count varied between 11,000 and 40,000/µl before presentation, without any event of bleeding. Transthoracic echocardiography showed hypokinesia of the anterior, middle, and apical segments. Cardiac enzyme levels were elevated and platelet count was 41,000/µl. Coronary angiography revealed total occlusion of the left anterior descending artery. Primary percutaneous coronary intervention (PCI) was performed, which included predilation and stenting of the lesion. There were no bleeding or ischemic complications during or after PCI and the patient was discharged on the fifth day without any symptoms. He was instructed to take 75 mg clopidogrel daily for two weeks. He was symptom-free at a control visit after this period, with normal left ventricular wall motion on echocardiography.

Autologous 111 In-labelled platelet sequestration studies in patients with primary immune thrombocytopenia (ITP) prior to splenectomy: a report from the United Kingdom ITP Registry.

While splenectomy is an effective therapy for primary immune thrombocytopenia (ITP), possible complications and observed non-complete response (CR) in one-third of patients demonstrate the need for further research into potential pre-surgical predictors of outcomes. Past investigations into platelet sequestration studies, a hypothesized predictive test, have adopted heterogeneous methods and varied widely with regard to power. By studying patients with primary ITP who underwent autologous (111) In-labelled platelet sequestration studies at Barts and The London NHS Trust between 1994 and 2008, we evaluated the effectiveness of sequestration site in predicting short, medium, and long-term CR (platelet count >100 × 10(9) /l) to splenectomy through multivariate (gender, age at splenectomy, and mean platelet lifespan) logistic regression modelling. In total, 256 patients with primary ITP underwent scans; 91 (35·5%) proceeded to splenectomy. Logistic regression revealed significant adjusted odds ratios for CR of 7·47 (95% confidence interval [CI], 1·89-29·43) at 1-3 months post-splenectomy, 4·85 (95% CI, 1·04-22·54) at 6-12 months post-splenectomy, and 5·39 (95% CI, 1·34-21·65) at last follow-up (median: 3·8 years [range: 0·5-13·1 years]) in patients with purely or predominantly splenic versus mixed or hepatic sequestration. These findings demonstrate the utility of autologous (111) In-labelled platelet sequestration studies as an adjunct predictive instrument prior to splenectomy.

Successful combination of antifungal agents and surgical resection for pulmonary aspergillosis in a child with Hodgkin disease: review of the literature.

The authors report on a 14-year-old adolescent boy suffering of Hodgkin disease in remission, who developed autoimmune anemia and thrombopenia. He was treated with high-dose steroids and he developed serious invasive lung aspergillosis, which was treated with antifungal agents and surgical intervention. Children suffering from cancer are prone to develop systemic fungal infections secondary to the severe immunosuppression caused by the disease itself and the antineoplastic therapy. Intravenous antifungal medications and, when feasible, surgery are used for treatment of pulmonary aspergillosis. Factors related to better outcome are early diagnosis, remission of underlying disease, aggressive antifungal therapy, and recovery from neutropenia.

Side effects of corticosteroid therapy in children with chronic idiopathic thrombocytopenic purpura.

In 29 symptomatic children of both sexes with chronic idiopathic thrombocytopenic purpura (CITP) with platelet counts < or = 30,000/mm3, of mean age 7.2 +/- 1.3 years, the side effects of long-term glucocorticoid therapy were evaluated. Patients were divided into three groups based on the different glucocorticoid protocols they were receiving. Baseline measurements (t0) of height (H) as standard deviation score (SDS), body mass index (BMI) as kg/m2 and bone mineral density (BMD) at the femoral neck (FBMD) and lumbar spine L2-L4 (LBMD) by a dual energy X-ray absorption technique, expressed as Z score, with follow-up measurements at 1 (t1) and 2 (t2) years were assessed. Group I patients (10 pts) treated with oral prednisone (2 mg/kg/die-for one month for 2 cycles) showed significantly different HSDS, BMI, FBMD and LBMD at t1 and t2 (P < 0.005) than other groups treated respectively with pulsed high doses of dexamethasone (24 mg/m2 over 4 days/months for 6 cycles) and methylprednisolone (9 mg/kg/die for 5 days for 3-4 months). These findings suggest that pulsed high doses of glucocorticoid lead to fewer side effects than oral prednisone therapy.

Recombinant FVIIa in the management of intracerebral haemorrhage in severe thrombocytopenia unresponsive to platelet-enhancing treatment.

Intracranial haemorrhage (ICH) is a dramatic and potentially life-threatening presentation of children with thrombocytopenia. Management is limited to supportive care. Recent evidence suggests that ongoing bleeding following the initial ICH may result in greater neurological morbidity and mortality. Haemostatic agents, including recombinant factor VIIa (rFVIIa), a product licensed for use in patients with haemophilia and inhibitors, may be helpful in reducing bleeding in children with refractory thrombocytopenia. We present the case of a 16-year-old girl with severe refractory immune thrombocytopenia, who presented with a major ICH and responded to treatment that included rFVIIa and platelet transfusions. The dose of rFVIIa was empirically chosen and based on reported cases in the literature. The case highlights a number of issues regarding off-label use of rFVIIa and demonstrates the need to prospectively collect accurate information on the off-label use of this new potentially useful medication.

Laparoscopic splenectomy: multi-detector row CT for preoperative evaluation.

PURPOSE: To prospectively evaluate multi-detector row spiral computed tomography (CT) for determination of splenic volume, splenic vascular anatomy, and presence of accessory spleens and parenchymal lesions in patients who were undergoing laparoscopic splenectomy. MATERIALS AND METHODS: Twenty-two patients who were candidates for laparoscopic splenectomy underwent multiphasic multi-detector row CT. Two observers evaluated splenic volume with two hand-tracing editing modalities. Variability between the two observers was calculated with a reliability coefficient (Cronbach alpha). A linear regression equation for each modality was generated to identify the correlation between the two observers. Multi-detector row CT angiography was evaluated for assessment of splenic vascular anatomy. Presence and number of both accessory spleens and parenchymal lesions were recorded. RESULTS: Mean splenic volume was 1,050 and 1,046 mL, respectively, for observers A and B by using each-section editing (technique 1) and 1,067 and 1,068 mL for observers A and B by using distanced editing (technique 2). For each editing modality, alpha reliability coefficient was higher than 0.99. Both techniques 1 and 2 were very highly predictive of specimen weight and had R2 values of greater than 0.99 (P <.001). CT angiograms correctly showed polar arteries in all cases and the presence of the arteria pancreatica magna in one case. Multi-detector row CT demonstrated the presence, number, and size of all accessory spleens and of focal parenchymal lesions. CONCLUSION: Multi-detector row CT volumetric and anatomic evaluation provided accurate and reproducible information.

Comparative evaluation of Tc-99m-heat-denatured RBC and Tc-99m-anti-D IgG opsonized RBC spleen planar and SPECT scintigraphy in the detection of accessory spleen in postsplenectomy patients with chronic idiopathic thrombocytopenic purpura.

OBJECTIVE: Radionuclide imaging specific for functioning splenic tissue is considered the method of choice to detect an accessory spleen in patients of chronic idiopathic thrombocytopenia purpura (ITP), who present with relapse after splenectomy. Radioimmunospleen scintigraphy with Tc-99m-labeled autologous RBC opsonized with anti-D IgG (RIS) is claimed to be more sensitive and specific than Tc-99m heat-denatured RBC spleen scintigraphy (HDRS) in the detection of an accessory spleen. We compared the efficacy of RIS with HDRBC for the detection of accessory spleens METHODS: A total of 45 patients (male:female = 17:28, age range: 6-58 years) who presented with relapse of ITP after splenectomy underwent scintigraphy with both methods. An average of 3 years had passed since surgery. All patients were imaged by a dual-head gamma camera with high-resolution collimators; planar static images and SPECT of abdomen were acquired. RESULTS: Accessory spleens were detected in 31% (14 of 45) of patients, 6 had 1 each and 8 had more than 1 (including 1 patient who had 13 accessory spleens). Both methods were concordant in all the patients. There was no difference in the scintigraphic picture (planar and SPECT) or in the size and number of accessory spleens detected. CONCLUSION: Tc-99m-labeled anti-D IgG opsonized autologous RBC spleen scintigraphy provides no additional diagnostic information over heat-denatured RBC spleen scintigraphy. Heat-denatured RBC scintigraphy thus remains the procedure of choice in the detection of accessory spleens.

Reduced bone mineral density in childhood chronic idiopathic thrombocytopenic purpura treated with high-dose methylprednisolone.

PURPOSE: To evaluate whether repeated courses of high-dose methylprednisolone (HDMP) affect the lumbar spine bone mineral density (BMD) in children with chronic idiopathic thrombocytopenic purpura (ITP). MATERIALS AND METHODS: This study included 24 patients with chronic ITP and 149 healthy controls. The patients were allocated into three groups according to the number of HDMP courses (30 mg/kg per day as a single dose for 7 days); group 1 (10 patients), group 2 (9 patients), and group 3 (5 patients) had received less than 5, 6-10, and more than 10 courses, respectively. Lumbar spine BMD and body composition were measured using dual energy X-ray absorptiometry of lumbar spine (L2-L4), and volumetric bone mineral density (vBMD) values were calculated and compared with the controls. The z score of the vBMD was also calculated and compared in the patients of each other groups. Serum markers of the bone turnover were measured to exclude other factors that could effect BMD. RESULTS: The vBMD values of the patients, corrected BMDs for age, were significantly lower than the values of controls (P = 0.018). It was significantly lower in group 3 than groups 1 and 2 (P = 0.005 and P = 0.006, respectively), but there was no statistically significant difference between groups 1 and 2 (P = 0.87). The vBMD z scores were significantly lower in group 3 than in groups 1 and 2 (P = 0.003 and P = 0.004, respectively), and also in group 2 than in group 1 (P = 0.034). There were a weak negative correlation between the cumulative dose of HDMP and vBMD (r = -0.39, P = 0.054), and strong negative correlation between the cumulative dose of HDMP and vBMD z score (r = -0.63, P = 0.001). CONCLUSION: Children with chronic ITP are at risk for decreased BMD because of the repeated courses of HDMP; especially more than 2100 mg of cumulative dose. We therefore recommend that BMD should be monitored in patients with chronic ITP who received repeated courses of HDMP.

Laparoscopic accessory splenectomy with intraoperative gamma probe localization for recurrent idiopathic thrombocytopenic purpura.

Laparoscopic excision of retained splenic tissue has been described as a treatment of recurrent hematologic disease after formal splenectomy. It is associated with a shorter hospital stay, more rapid recovery, and lower or equivalent morbidity compared with open surgery. However, intraoperative identification of residual splenic tissue remains difficult, particularly when preoperative computed tomography or magnetic resonance imaging results are unremarkable. It has been suggested that the laparoscopic approach has a lower success rate due to the loss of tactile feedback. We report a case of successful laparoscopic excision of retained splenic tissue using technetium sulfur colloid injection and intraoperative gamma probe localization in a patient with recurrent idiopathic thrombocytopenic purpura, 12 years after open splenectomy. This represents the first report of this intraoperative adjunctive measure for the laparoscopic identification and excision of functional accessory splenic tissue.