Evaluation of an automated platelet aggregation method for detection of congenital or acquired platelet function defects.

BACKGROUND: Light transmission aggregometry (LTA) is the most widely used laboratory method for an initial screening of patients with a suspected platelet function defect (PFD), and its use has also been proposed for assessing the efficacy of antiplatelet treatment (APT). An automated LTA method has been developed by Sysmex (Kobe, Japan) on a routine coagulation analyzer (CS-2400), together with a new research parameter called PAL (platelet aggregation level) to evaluate patients on APT. MATERIALS AND METHODS: We evaluated the performance of CS-2400 compared to a stand-alone lumi-dual-aggregometer device in the diagnosis of PFD and in assessing the efficacy of APT. For these purposes, the study population was represented by a cohort of 23 patients with a previous diagnosis of PFD and a cohort of 28 patients on APT. RESULTS: Compared to healthy volunteers, patients with PFD showed a statistically significant reduction (p<0.05) in the maximal %light transmission, irrespective of the agonist used, both with the CS-2400 and the lumi-dual-aggregometer. As regards PFD patients, CS-2400 was effective in identifying the more severe defects, with a good sensibility and specificity, but less effective in identifying milder forms of PFD, such as platelet secretion defects. Patients on APT showed a statistically significant (p=0.001) reduced median %light transmission and PAL scores compared to healthy controls. DISCUSSION: Thanks to this LTA technology, CS-2400, a routine coagulation analyzer widely available in routine laboratories, could prove useful for initial assessment of patients with a suspected PFD. Moreover, the PAL scores were a fairly accurate reflection of the platelet response to APT.

Post-lumbar puncture cerebral vein thrombosis.

Lumbar puncture (LP) is rarely complicated by cerebral vein thrombosis (CVT), especially if other risk factors coexist. We describe the case of a 28-year-old woman who developed CVT after corticosteroid treatment and LP performed for suspected multiple sclerosis. The day after LP, she developed intense headache and on Day 8 generalized tonic-clonic seizures. A brain computed tomography scan showed thrombosis of the superior sagittal sinus and cortical veins. Thrombophilia screening showed heterozygous G20210A prothrombin mutation. Anticoagulant therapy with low molecular weight heparin and then warfarin was administered until Day 16 after LP, when a brain magnetic resonance imaging showed a subdural hematoma. Warfarin was interrupted and dabigatran was started. The patient recovered completely, both from the initial thrombotic event and the hemorrhagic complication. This case highlights the importance to keep in mind CVT in the differential diagnosis of post-LP headache not responsive to standard therapy, and suggests that dabigatran can be considered an effective and safe treatment of CVT.

Drug Design and Development for Rare Hematologic Diseases.

The last decade has seen an exponential increase in therapeutic options for rare hematologic diseases [...].

Caplacizumab use for immune thrombotic thrombocytopenic purpura: the Milan thrombotic thrombocytopenic purpura registry.

•Data on caplacizumab use for thrombotic thrombocytopenic purpura (TTP) in Italy are missing.•Twenty-six Italian patients were treated with caplacizumab for an acute immune TTP episode.•Caplacizumab was effective in treating acute TTP in the Italian real-world clinical setting.•Two major bleeds leading to drug discontinuation were observed.

A retrospective study on the use of low-molecular-weight heparin for prevention of pregnancy-related recurrent venous thromboembolism and obstetrical complications.

BACKGROUND: The risk of venous thromboembolism (VTE) is increased during pregnancy and it is further increased together with pregnancy complications in women with personal history of VTE and thrombophilia abnormalities. It is unclear how the use of low-molecular-weight heparin (LMWH) may prevent such complications. OBJECTIVE: To evaluate the potential benefits and risks of the use of LMWH for prevention of pregnancy-related VTE and obstetrical complications in the first pregnancy after a previous VTE. METHODS: This retrospective cohort study includes fertile women referred to the Thrombosis Center from January 2000 to September 2018 for a thrombophilia work-up, after having had at least one previous VTE and one pregnancy thereafter. Data on pregnancy-related recurrent VTE, pregnancy outcomes and the use of LMWH were collected. RESULTS: Among 208 women, no thrombosis or major bleeding was recorded in 138 pregnancies conducted with LMWH, whereas 10 VTE (14%) were recorded in 70 pregnancies conducted without. Nine women (90%) with recurrent VTE had had a previous hormone-related event. The incidence of miscarriage was lower in pregnancies with LMWH than in those without (11% vs. 26%, relative risk 0.4, 95% confidence interval: 0.2-0.8), whereas late obstetrical complications and terminations were similar in the two groups. The prevalence of terminations was doubled in women with thrombophilia (12%) than in those without (6%). CONCLUSIONS: LMWH prophylaxis during pregnancy appears to be effective and safe for the prevention of recurrent VTE and may reduce the incidence of miscarriage.

Anticoagulant Therapy in Patients with Antiphospholipid Syndrome.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the persistent positivity of antiphospholipid antibodies (aPLA) together with thrombosis or obstetrical complications. Despite their recognized predominant role, aPLA are not sufficient to induce the development of thrombosis and a second hit has been proposed to be necessary. The mainstay of treatment of APS is anticoagulant therapy. However, its optimal intensity in different presentations of the disease remains undefined. Moreover, decision on which patients with aPLA would benefit from an antithrombotic prophylaxis and its optimal intensity are challenging because of the lack of stratification tools for the risk of thrombosis. Finally, decision on the optimal type of anticoagulant drug is also complex because the central pathway responsible for the development of thrombosis is so far unknown and should be carried out on an individual basis after a careful evaluation of the clinical and laboratory features of the patient. This review addresses the epidemiology, physiopathology, diagnosis and management of thrombosis and obstetrical complications in APS, with a special focus on the role of direct oral anticoagulants.

Assessment of post-partum haemorrhage risk among women with moderate thrombocytopenia.

It is unknown whether moderate thrombocytopenia represents a risk factor for post-partum haemorrhage (PPH). We assessed PPH risk among women with a platelet count of between 100 and 50 × 109 /l and stratified the risk for O/non-O blood group. We included consecutive women undergoing vaginal delivery or caesarean section with moderate thrombocytopenia. Women with >150 × 109 /l platelets at delivery were selected as controls and matched for age, type of birth and ethnicity. Odds ratios (ORs) with their 95% confidence intervals (95% CIs) were calculated as risk estimates. A total of 94 thrombocytopenic women and 94 controls were included in the study. The rate of PPH was significantly higher in thrombocytopenic women than in controls (37% vs. 10%, p < 0.001); there was a higher risk of PPH in the thrombocytopenic group when compared to the control group (adjusted OR 4.7, 95% CI 2.1-10.8, p < 0.01) and this association was stronger in blood group O carriers (adjusted OR 11.0, 95% CI 2.4-49.6, p < 0.01). In conclusion, our study shows that a moderate thrombocytopenia is a risk factor for PPH, especially in blood group O carriers.

Off-Label Use of Thrombopoietin Receptor Agonists: Case Series and Review of the Literature.

Since their license in 2008, studies on thrombopoietin receptor agonists (TPO-RAs) are proceeding at a fast pace. Their favorable efficacy and safety profile makes them good candidates for the management of thrombocytopenia in different settings, even beyond their current indications. In the last 10 years, we faced patients with refractory thrombocytopenia that required treatment with off-label TPO-RA, despite the paucity of data in the literature and the possible risks, particularly that of thrombosis. We hereby report our 10-year real-life single-center experience of TPO-RA used off-label. Fourteen patients were divided into three groups according to the etiology of thrombocytopenia: myelodysplastic syndromes, post-transplantation, and lymphoproliferative diseases. Clinical features and results are reported within each group. Overall, TPO-RA proved effective in all these conditions achieving responses also in heavily pretreated patients. The overall response rate (ORR) was 100% in patients with thrombocytopenia after transplantation and in those with lymphoproliferative diseases and 75% in patients with myelodysplastic syndromes. The median duration of therapy was 285 days (range 93-1,513 days). Four patients (29%) discontinued treatment because of lack of response (n=2) or a sustained response (n=2). No grade 3-4 adverse events occurred, particularly no thrombosis. In our real-life experience, TPO-RAs were effective and safe and proved of value in the challenging management of patients with refractory thrombocytopenia associated with different conditions.

Evans syndrome in adults: an observational multicenter study.

Evans syndrome (ES) is a rare condition, defined as the presence of 2 autoimmune cytopenias, most frequently autoimmune hemolytic anemia and immune thrombocytopenia (ITP) and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations, and outcomes. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirements, occurrence of complications, and death. ES was secondary to or associated with underlying conditions in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of patients, mainly low grade and at ITP onset. Almost all patients received first-line treatment (steroids with or without intravenous immunoglobulin), and 23% needed early additional therapy for primary refractoriness. Additional therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates >80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of patients, respectively, mainly grade ≥3, and correlated with the number of therapy lines. In addition to age, other factors negatively affecting survival were severe anemia at onset and occurrence of relapse, infection, and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.

Plasma levels of extracellular vesicles and the risk of post-operative pulmonary embolism in patients with primary brain tumors: a prospective study.

Primary brain tumors are associated with an increased risk of pulmonary embolism (PE), particularly in the early post-operative period. The pathophysiological mechanisms of PE are poorly understood. This study aims to describe prospectively extracellular vesicles (EVs) levels and investigate whether or not their variations allow to identify patients at increased risk of post-operative PE. Consecutive meningioma or glioma patients candidate to tumor resection were included in the study if a pulmonary perfusion scan (Q-scan) performed before surgery ruled out PE. EVs derived from platelets (CD41+) or endothelial cells (CD144+), tissue factor-bearing EVs (CD142+) and their procoagulant subtype (annexin V+) were analyzed by flow cytometry before surgery (T0), within 24 h (T1), two (T2) and seven days (T7) after surgery. Q-scan was repeated at T2. Ninety-three patients with meningioma, 59 with glioma and 76 healthy controls were included in the study. CD142+ and annexin V+/CD142+ EVs were increased at T0 in meningioma and glioma patients compared to healthy controls. Twenty-nine meningioma (32%) and 16 glioma patients (27%) developed PE at T2. EVs levels were similar in meningioma patients with or without PE, whereas annexin V+ and annexin V+/CD142+ EVs were significantly higher at T1 and T2 in glioma patients with PE than in those without. Procoagulant EVs, particularly annexin V+/CD142+, increase after surgery and are more prevalent in glioma patients who developed PE after surgery than in those who did not.

Thrombotic Complications in Patients with Immune-Mediated Hemolysis.

Autoimmune hemolytic anemias are rare and heterogeneous disorders characterized by hemolysis, which is a well-recognized risk factor for thrombosis. The most common immune-mediated anemias are represented by autoimmune hemolytic anemia and paroxysmal nocturnal hemoglobinuria, both associated with a high rate of thrombosis. Multiple pathophysiological mechanisms for thrombosis have been proposed, involving hemolysis itself and additional effects of the immune system. Despite the increasing awareness of the thrombotic risk in these conditions, evidence-based guidance on prevention and management of thrombotic events is lacking. We herein report available evidence on epidemiological data on thrombosis and thrombophilia in immune-mediated hemolysis, together with possible underlying pathophysiological mechanisms. In addition, we summarize current recommendations for treatment of thrombosis in immune-mediated hemolysis. In particular, we address the issue of thrombotic complications treatment and prophylaxis by proposing a therapeutic algorithm, focusing on specific situations such as splenectomy and pregnancy.