Pediatric splenic infarction: Assessment of associated clinical conditions and outcome.

Pediatric splenic infarction (SI) is rare yet clinically significant. Publications regarding this complication are mostly limited to case reports. This is a retrospective study examining SI etiology, clinical presentation, management, and outcomes among children. Twenty-two patients (median age: 7.9 years) were included, mostly with pre-existing hematological diseases. Splenomegaly (72%), thrombocytopenia, and anemia were common. Most of the patients did not receive antithrombotic therapy yet only two patients experienced recurrences. During follow up 36% of patients died, however no fatalities were attributed to thrombotic or bleeding complications.

Management of surgery in persons with hemophilia A receiving emicizumab prophylaxis: data from a national hemophilia treatment center.

Background: Persons with hemophilia A may require surgical procedures. Real-world data on invasive procedures in persons with hemophilia A receiving emicizumab prophylaxis are limited. Objectives: To evaluate the safety of invasive procedures in persons with hemophilia A receiving emicizumab prophylaxis and their outcomes in a longitudinally followed cohort. Methods: Data from medical records of persons with hemophilia A with and without factor VIII (FVIII) inhibitors longitudinally followed at our tertiary center, who received emicizumab prophylaxis and underwent all types of invasive procedures, were retrieved. Outcomes of interest were bleeding and thrombotic complications. Results: Overall, 35 patients underwent 56 invasive procedures, 18 (32.1%) were major. The median age was 36.3 years (IQR, 8.8-55.9 years); 12 patients (34.3%) were younger than 18 years at the time of procedure; 17 (48.6%) were patients with FVIII inhibitors. Among major procedures, orthopedic surgeries prevailed. All patients who underwent major procedures received factor replacement with either recombinant activated factor VII (patients with inhibitors) or FVIII (patients without inhibitors). Factor concentrates were administered prior to 32 (84.2%) of the minor procedures. Repeated doses were given according to international expert opinion recommendations and patients' condition.There were 7 bleeding events in 6 patients, 5 were major bleeds, including 1 patient who underwent a minor procedure without factor replacement. None of the patients experienced a thrombotic complication. Conclusion: Invasive procedures can be performed safely in patients receiving emicizumab prophylaxis with close surveillance after surgery. Factor concentrates may be advised in selected patients undergoing minor procedures.

Application of a clinical decision rule and laboratory assays in pediatrics: Adult heparin-induced thrombocytopenia.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is rare among pediatric patients. The diagnosis of HIT depends upon clinical decision tools to assess its pretest probability, supported by laboratory evidence of anti-platelet factor 4 (anti-PF4)/heparin antibodies. AIMS: To compare the use of the 4Ts score clinical decision tool, clinical characteristics, and laboratory findings between pediatric and adult patients with suspected HIT. METHODS: We compiled all pediatric patients in our center for whom HIT testing was performed during the years 2015-2021. These were compared with a cohort of consecutive adult patients. Laboratory diagnosis of HIT was performed with particle gel immunoassay (PaGIA) as screening test and confirmed by an automated latex-enhanced immunoturbidimetric assay (LIA) and/or by functional flow cytometry assay (FCA). RESULTS: The cohort included 34 children (under 18 years) and 105 adults. Adults mostly received heparins for thromboembolism prophylaxis and treatment (72.4%, n = 76), and were more frequently treated with low-molecular-weight heparin (LMWH). Children were mostly exposed during cardiopulmonary bypass and extracorporeal membrane oxygenation (ECMO, 61.8%, n = 21), and were more frequently treated with unfractionated heparin (UFH). Compared with adults, children had significantly higher 4Ts scores. Nevertheless, adults had a slightly higher rate of a positive diagnosis of HIT. Six out of 16 adults with confirmed HIT presented with thrombosis (37.5%), whereas all three pediatric patients with HIT presented with thrombosis (p = .087). CONCLUSIONS: 4Ts scores are higher in children compared with adult patients for whom laboratory tests for HIT were obtained. A potentially higher incidence of thrombosis in children with HIT may be attributable to the severity of underlying illness.

The Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Patients Hospitalized with Acute Pulmonary Embolism.

Early risk stratification is essential for determining the appropriate therapeutic management approach of pulmonary embolism (PE). This study aimed to evaluate the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in patients hospitalized with acute pulmonary embolism by investigating its association with mortality in a large-scale population diagnosed and hospitalized with acute PE. We retrieved all consecutive patients hospitalized in an internal medicine department or an intensive care unit in a tertiary medical center from December 2007 to April 2021 with a discharge diagnosis of pulmonary embolism. A total of 2072 patients were included. Patients with above-median NLR (i.e., 5.12) had a higher 30-day mortality risk (adjusted odds ratio (aOR), 2.82; 95% confidence interval (CI) 2.14-3.70) and higher one-year mortality risk (aOR, 2.51; 95% CI 2.04-3.08). Similar trends were demonstrated in a sub-analysis of patients without cancer and hemodynamically stable (i.e., systolic blood pressure over 90 mmHg). Furthermore, the median hospital length of stay in patients with an elevated NLR was higher, and so was the in-hospital mortality rate. Elevated NLR in acute PE is associated with a worse short-term and long-term prognosis and with a longer duration of hospitalization.

Long-term outcome after nonsurgical management of Paget-Schroetter syndrome.

OBJECTIVE: Paget-Schroetter syndrome (PSS) is an uncommon disease with potentially debilitating long-term effects. The optimal therapy for PSS is unclear, and the role of surgical decompression of the thoracic outlet is still being questioned. In this study, we present long-term results of patients treated with catheter-directed thrombolysis (CDT) and anticoagulation without surgical management. METHODS: This is a retrospective case series of all patients who previously underwent treatment of PSS in our institution between the years 2007 and 2019. Patients were evaluated for clinical signs of post-thrombotic syndrome (PTS) using a modified Villalta scoring scale, including measurements of the circumference of the treated and untreated arms. Duplex ultrasound examination of the treated vein was performed, and quality of life was evaluated using the shortened Disabilities of the Arm, Shoulder, and Hand questionnaire. RESULTS: Eighteen consecutive patients previously treated for PSS with CDT and anticoagulation compose the cohort of this study. None underwent surgical thoracic outlet decompression. All were contacted and invited for clinical and ultrasound evaluation. Follow-up was available for all patients. Mean age at diagnosis was 29 years (range, 16-46 years), and 15 (79%) were male. Mean time from the index event to the follow-up clinic visit was 109 months (range, 37-176 months). Patients were treated with anticoagulation for a mean period of 26 months (range, 6-120 months). Seventeen patients (94%) had a Villalta score of 0 to 3, consistent with nonexistence of PTS. Fourteen patients (78%) were completely asymptomatic. Seven patients (39%) had no difference in arm circumference. A difference in arm circumference between the treated arm and the healthy arm of 1 cm and 2 cm was seen in nine (50%) and two (11%) patients, respectively. Based on the shortened Disabilities of the Arm, Shoulder, and Hand score, none of the patients suffered from impaired quality of life. Duplex ultrasound scanning of the affected veins was performed on 16 of the 18 patients (89%). The vein appeared patent in all examined patients. In three patients, the wall of the examined vein was thickened and irregular. CONCLUSIONS: This study suggests that PSS patients can be treated with anticoagulation and CDT alone, without the need for surgical thoracic outlet decompression. This is based on long-term follow-up of these patients objectively evaluated by means of valid scoring systems. These findings suggest that symptoms or signs of PTS rarely develop, the patients do not suffer from impaired quality of life, and patency of the diseased vein is commonly maintained.

Prognostic value of JAK2V617F mutation in pseudotumor cerebri associated with cerebral venous sinus thrombosis.

OBJECTIVES: To examine the clinical characteristics and prognosis of cerebral venous sinus thrombosis (CVST) that presented as pseudotumor cerebri (PTC) patients with JAK2V617F mutation. METHODS: Medical records of all consecutive patients that presented with PTC and a JAK2V617F mutation who were treated were retrospectively reviewed. Data regarding demographics and ocular presenting symptoms and signs, neurological signs, hematological factors treatment, and prognosis were collected. RESULTS: The most common presenting symptoms were headache (5 patients, 83.3%) and visual obscurations (5 patients, 83.3%). CVST of the sagittal sinus and sigmoid sinus were the most common site of thrombus. Platelet count and hemoglobin count were higher than normal during follow-up. There was significant change in the disk edema degree as well as decline in retinal nerve fiber layer (RNFL) thickness (P < 0.001, P < 0.001, Matched pairs). There was no significant change in visual acuity (VA) or mean deviation (MD) during follow-up (P = 0.95, 0.64, respectively, Matched pairs). CONCLUSIONS: Pseudotumor cerebri resulting from CSVT in our patients with JAK2V617F mutation was frequent in young patients and needed medical and surgical treatment, without improvement in visual functions and in third caused poor visual outcome. Therefore, we believe that a screening test for JAK2V617F mutation should be considered for patients with CVST without known risk factor presenting with PTC, especially when sagittal sinus or sigmoid sinus involvement or thrombocytosis or high hemoglobin are found upon presentation. This might lead to more aggressive management which may improve the visual prognosis of those young patients.

From thrombasthenia to next generation thrombocytopenia: Neonatal alloimmune thrombocytopenia induced by maternal Glanzmann thrombasthenia.

BACKGROUND: Glanzmann thrombasthenia (GT) is a rare autosomal recessive disorder of platelet function caused by mutations in the genes coding for integrin αIIbß3. The aim of this study was to examine the outcome of newborns of GT mothers, with emphasis on thrombocytopenia and bleeding manifestations and their relation to maternal antiplatelet antibodies. PROCEDURE: Medical files of all female patients with GT treated in a single tertiary center from 1999 to 2017 were searched for details on pregnancy and birth. The medical files of their newborns were retrieved, and data on the postnatal course were collected. RESULTS: Nine babies were born to five patients with GT at our center during the study period. Three of the nine newborns had severe thrombocytopenia, and all three were offspring of GT mothers who were positive for antiplatelet antibodies. CONCLUSION: Pregnant GT patients should be examined for platelet antibodies. Assessment and management protocols (including treatment with intravenous immunoglobulins) for fetal and neonatal alloimmune thrombocytopenia should be considered.

Combination of hemostatic therapies for treatment of patients with hemophilia A and inhibitors.

BACKGROUND: Therapy application and monitoring of patients with hemophilia A (HA) and inhibitors are challenging. In the current study, combined FVIII - bypass therapy was implemented for a cohort of severe HA patients with inhibitors. METHODS: Plasma of 15 HA patients with inhibitors was spiked ex vivo with FVIII, rFVIIa, FEIBA and their combinations and thrombin generation (TG) was studied. Some patients who experienced hemarthroses or required minor surgeries were treated by a combined concomitant administration of FVIII+FEIBA as IV bolus doses. RESULTS: TG spiking studies showed individual responses not correlated to inhibitor titer. Combinations of agents augmented TG as compared to any single agent, while combined FVIII+FEIBA yielded the highest TG, supporting it as a potential treatment. Following emergent successful surgery of child treated by concomitant FVIII+FEIBA, a total of 396 episodes in 7/15 patients were treated with concomitant FVIII+FEIBA. Five patients were treated for bleeding episodes only, whereas 2 were children undergoing immune tolerance induction (ITI) with FEIBA prophylaxis. Four minor surgeries were performed on FVIII+FEIBA repeated infusions. Neither thrombosis nor any other adverse events were documented. CONCLUSION: A combination of FVIII+FEIBA may be effective and safe as an alternative treatment option for some high-responding inhibitor patients.

Assessment of Functional Fibrinolysis in Cord Blood Using Modified Thromboelastography.

BACKGROUND: The fibrinolytic system in newborns is immature and probably impaired. The aim of this study was to prospectively evaluate functional fibrinolytic capacity of newborn's cord blood using a new thromboelastometry (rotational thromboelastogram, ROTEM®) test. METHODS: Infants born at Sheba Medical Center were studied prospectively. Cord blood was obtained immediately after clumping, and ROTEM parameters were assessed applying non-activated TEM (NATEM) assay with increasing concentration of tissue plasminogen activator (tPA, 0-200 U/ml). Baseline clotting time (CT), clot formation time (CFT), alpha angle, and maximum clot firmness (MCF) were compared among infants versus adults. Each infant's demographic information was prospectively followed up until discharge. RESULTS: One hundred one newborns were tested. CT and CFT values were lower and alpha angles were higher among neonate's cord blood compared to adults (n = 23; P = 0.001, 0.03, and 0.02, respectively). The addition of tPA significantly shortened CT and CFT, and reduced alpha angles and MCF in both groups. The lysis index at 30 min (LI30) and lysis onset time (LOT) decreased significantly, and fibrinolysis was more rapid in the newborns. Hematocrit and platelet counts in neonates correlated with LI30 (P = 0.035 and 0.037, respectively) and LOT (P = 0.02) when higher tPA concentrations were used. ROTEM values were unrelated to the occurrence of postnatal complications. CONCLUSIONS: This first report of functional fibrinolysis in cord blood demonstrated that neonatal fibrinolysis may be augmented as compared to adult values. Further studies are required to validate this test and assess its predictive value and clinical relevance.

Clinical and radiographic presentation of superior mesenteric vein thrombosis in Crohn's disease: a single center experience.

BACKGROUND: Mesenteric vein thrombosis (MVT) is a rare and frequently underdiagnosed complication of Crohn's disease (CD). This study describes the clinical and radiological characteristics of CD /patients with superior mesenteric vein thrombosis (MVT) diagnosed by CT/MRI. PATIENTS AND METHODS: The database of Crohn's disease patients treated in Sheba Medical Center between 2005-2010 was searched for MVT diagnosis. Imaging studies of identified patients were retrieved and reviewed by an experienced abdominal radiologist. MVT was defined by superior mesenteric vein obliteration and/or thrombus in the vessel lumen on abdominal imaging. The clinical and radiologic data of these patients were collected from the medical records. RESULTS: MVT was demonstrated in 6/460 CD patients. Five patients had stricturing disease, and one patient had a combined fistulizing and stricturing disease phenotype. All patients had small bowel disease, but 3/6 also had colonic involvement. No patient had a prior thromboembolic history or demonstrable hypercoagulability. One patient had an acute SMV thrombus demonstrable on CT scanning, the remaining patients showed an obliteration of superior mesenteric vein. Two patients received anticoagulation upon diagnosis of thrombosis. No subsequent thromboembolic events were recorded. CONCLUSIONS: The incidence of mesenteric vein thrombosis is likely to be underestimated in patients with Crohn's disease. Both CT and MRI imaging demonstrate the extent of enteric disease and coincident SMV thrombosis. In our cohort, thrombosis was associated with stricturing disease of the small bowel. The clinical impact of SMV thrombosis and whether anticoagulation is mandatory for all of these patients remains to be determined.

Thrombophilic factors in idiopathic intracranial hypertension: a report of 51 patients and a meta-analysis.

Several studies have suggested that thrombophilic risk factors are more prevalent in individuals with idiopathic intracranial hypertension (IIH), and that a prothrombic state may be involved in the etiopathogenesis of this disease. We examine thrombophilic factors in a group of patients with IIH in relation to obesity. In addition, we reviewed the relevant literature and performed a meta-analysis. Thrombophilia work-up was performed on 51 patients with IIH at least 1 month following their first episode. Samples for the analysis of factor V Leiden (FVL), prothrombin gene variant (PGV) G20210A and methylenetetrahydrofolate reductase (MTHFR) were available in an additional 30 patients, that is 81 patients in all. Meta-analysis was performed. Of the 51 patients 40 were obese. Increased concentrations of fibrinogen, D-Dimer, factor VIII, factor IX and factor XI were found in 15, 7, 7, 6 and 2 patients, respectively, all obese. The circulating anticoagulant, measured by dilute Russell's viper venom time (dRVVT assay), found mainly in obese. All 51 patients were negative for the anticardiolipin antibody (IgG immunoglobulin G) and IgG anti-beta2 glycoprotein I. In the meta-analysis antiphospholipid antibodies were significantly associated with IIH [odds ratio (OR) of 4.25 (1.68-12.60)], similar to the association with high factor VIII [OR = 16.17 (2.87-91.01)], higher plasminogen activator inhibitor-1 (PAI-1) levels [OR = 6.91 (2.28-20.91)], and high lipoprotein (a) [LP(a)] [OR = 3.54 (1.54-8.70)]. Obesity often observed in IIH patients is frequently linked with thrombophilic factors. Thus, we believe that dysmetabolism could be the thrombophilic target for treatment in patients with IIH.

Variable responsiveness to clopidogrel and aspirin among patients with acute coronary syndrome as assessed by platelet function tests.

Unresponsiveness to clopidogrel or aspirin has been reported in patients with acute coronary syndrome (ACS). Platelet aggregometry (PA) and the Impact-R [Cone and Plate(let) Analyzer (CPA) technology, measuring whole blood platelet adhesion under flow conditions] were compared in detecting laboratory unresponsiveness to clopidogrel and aspirin among ACS patients. Platelet-rich plasma (PRP) samples were evaluated in 404 patients by PA using adenosine diphosphate (ADP) and arachidonic acid (AA) and whole blood samples by the Impact-R ADP- and AA-response tests. The first cohort (n=114) was assayed by PA on days 1 and 4 of the onset of ACS. A patient with relative decrease of /=70%. A patient with an absolute value of AA-induced maximal aggregation >/=60% was defined as laboratory NR patient to aspirin. The second cohort (n=290) was tested on day 4 by both systems and results analyzed by receiver operating characteristic curve. The following cut-off values of the Impact-R surface coverage were obtained:

Using cone and plate(let) analyzer to predict bleeding in cardiac surgery.

The cone and plate(let) analyzer is an established method for assessing platelet function. It evaluates adherence of platelets on an extracellular matrix, expressed as a percentage of surface coverage and the average size of the aggregates. The purpose of this study was to determine the applicability of the cone and plate(let) analyzer in monitoring platelet function and predicting postoperative bleeding. The relationship between postoperative bleeding, perioperative platelet function, and other parameters was studied. A significant decrease in surface coverage was detected upon establishment of cardiopulmonary bypass (from 6.9% +/- 3.9% to 4.7% +/- 1.7%) with a return to preoperative values at the end of surgery. Preoperative average size and surface coverage were the only parameters that significantly and linearly correlated with postoperative bleeding. Patients with an aggregate average size < 20 microm(2) had a significantly higher incidence of severe bleeding (> 965 mL) than those with a size > 20 microm(2) (44% vs. 0%), and a higher mean blood loss (908 +/- 322 mL vs. 337 +/- 78 mL). Similar results were obtained for surface coverage < 5%, indicating the predictive value of these parameters. Preoperative platelet function as evaluated by the cone and plate(let) analyzer is an independent risk factor determining postoperative bleeding.

Platelets but not monocytes contribute to the plasma levels of factor XIII subunit A in patients undergoing autologous peripheral blood stem cell transplantation.

Factor XIII subunit A (FXIII A) is synthesized by megakaryocytes, and monocytes/macrophages. In addition, the liver has been reported as an extrahaematopoietic source of FXIII A. At present, the extent of contribution of either haematopoietic or extrahaematopoietic sources to the plasma FXIII A level is unknown. We studied the effect of bone marrow aplasia due to high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ASCT) on plasma FXIII A activity and concentration in 20 patients with haematological or solid tumour malignancies. A multiple linear regression model was used to assess the effect of gender, age, malignancy and treatment types, platelet and monocyte counts, abnormal liver function tests, prothrombin time, and number of platelet transfusions on FXIII activity measured in plasma before and following ASCT. Significant correlation between platelet counts and FXIII A activity in plasma was observed (r = 0.51, P = 0.0001), which remained after the adjustment for the aforementioned parameters (multiple R = 0.52, P = 0.0001). In contrast, no significant correlation between FXIII A levels and monocyte counts was observed (r = 0.19), and this lack of correlation persisted after the adjustment. These results suggest that in the ASCT model, following myeloablation, platelets but not monocytes are the haematopoietic cells that contribute significantly to plasma FXIII A levels. In addition, extra-haematopoietic sources of FXIII synthesis may also contribute to FXIII levels in plasma.

Elevated insulin-like growth factor-1 and insulin-like growth factor binding protein-2 in malignant pleural effusion.

Insulin-like growth factor-1 (IGF-1) and its binding proteins (IGFBPs) are produced by many tissues and are present in serum and other biological fluids. Alterations in sera of IGF-1 and 2 and IGFBPs were demonstrated in patients with malignancy, infection and other diseases causing pleural effusion. In this study the IGF-1 and IGFBP-2 content and the specific electrophoretic patterns of IGFBPs in samples of sera and pleural effusions of 25 patients with malignancy, infection and congestive heart failure were investigated. IGF-1 levels in exudative effusions of malignant solid tumors were significantly higher [(mean +/- SD), 20.9+/-7.5 nmol/L, n = 9] than in lymphoma (11.0+/-5.2 nmol/L, n = 5; p < 0.05), infection (11.4+/-6.5 nmol/L, n = 6; p < 0.05) and transudative effusion of congestive heart failure (4.3+/-3.3 nmol/L, n = 5; p < 0.02). IGFBP-2 was markedly increased in effusions of malignant solid tumors (2.14+/-0.82 mg/L, n = 9) compared with exudates of lymphoma, infection and transudates (1.10+/-0.70, 1.22+/-0.32 and 0.93+/-0.52 nmol/L, respectively, p < 0.05). Moreover, in effusion of solid tumors, IGFBP-2 levels were higher than those in corresponding sera, which suggests local production of this binding protein. The demonstration of IGFBP-2 in solid tumor cells by immunohistochemistry further supports this possibility. This work demonstrates the existence of the IGF-1/IGFBP system in pleural fluids from different etiologies and implies possible use of IGF-1 and IGFBP-2 as a potential marker of malignant effusions.