Availability of medical and endovascular therapies for venous thromboembolism: a global survey for World Thrombosis Day.

BACKGROUND: Data on availability, affordability, and accessibility is key for the planning of global strategies to reduce the burden of venous thromboembolism (VTE). OBJECTIVES: A survey was conducted for the 10th anniversary of World Thrombosis Day to assess the availability of VTE therapies worldwide and challenges in uniform implementation. METHODS: We gathered information on the approval status, availability, utilization, occurrence of shortages, and spread of medical and interventional therapies for VTE. Furthermore, we collected information by accessing or contacting national or continental medicines agencies, manufacturers or distributors, and online drug repositories. RESULTS: We obtained data from a total of 69 countries: 33 countries in Europe, 19 in Asia, 7 in the Americas, 9 in Africa, and 1 in Oceania. Unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists were available in almost all countries, but shortages were recorded in 13%, 19%, and 15% of them, respectively. Direct oral anticoagulants were available in approximately three-quarters of the surveyed countries. At least one parenteral medication for heparin-induced thrombocytopenia was available in 57% of countries and a shortage was reported in 9% of these. Shortage of thrombolytics was recorded in 50% of countries. Overall, at least one type of catheter-directed therapy system was approved for use in 77% of countries and available in 23% of surveyed institutions. Our findings revealed notable geographic disparities in the worldwide availability of VTE therapies, the access to which appeared to be limited by economic and geopolitical factors. CONCLUSION: We anticipate that this comprehensive information will play a pivotal role in highlighting the shortcomings of VTE therapies and the lack of homogeneous availability globally.

Rivaroxaban for the treatment of noncirrhotic splanchnic vein thrombosis: an interventional prospective cohort study.

Heparins and vitamin K antagonists are the mainstay of treatment of splanchnic vein thrombosis (SVT). Rivaroxaban is a potential alternative, but data to support its use are limited. We aimed to evaluate the safety and efficacy of rivaroxaban for the treatment of acute SVT. In an international, single-arm clinical trial, adult patients with a first episode of noncirrhotic, symptomatic, objectively diagnosed SVT received rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg daily for an intended duration of 3 months. Patients with Budd-Chiari syndrome and those receiving full-dose anticoagulation for >7 days prior to enrollment were excluded. Primary outcome was major bleeding; secondary outcomes included death, recurrent SVT, and complete vein recanalization within 3 months. Patients were followed for a total of 6 months. A total of 103 patients were enrolled; 100 were eligible for the analysis. Mean age was 54.4 years; 64% were men. SVT risk factors included abdominal inflammation/infection (28%), solid cancer (9%), myeloproliferative neoplasms (9%), and hormonal therapy (9%); 43% of cases were unprovoked. JAK2 V617F mutation was detected in 26% of 50 tested patients. At 3 months, 2 patients (2.1%; 95% confidence interval, 0.6-7.2) had major bleeding events (both gastrointestinal). One (1.0%) patient died due to a non-SVT-related cause, 2 had recurrent SVT (2.1%). Complete recanalization was documented in 47.3% of patients. One additional major bleeding event and 1 recurrent SVT occurred at 6 months. Rivaroxaban appears as a potential alternative to standard anticoagulation for the treatment of SVT in non-cirrhotic patients. This trial was registered at www.clinicaltrials.gov as #NCT02627053 and at eudract.ema.europa.eu as #2014-005162-29-36.

Focus on Key Issues in Immune Thrombotic Thrombocytopenic Purpura: Italian Experience of Six Centers.

Immune-mediated thrombotic thrombocytopenic purpura is a rare and challenging hematological disease caused by the antibody anti-ADAMTS13. Though the mortality rate has decreased considerably in recent years, fatalities still remain unacceptable. This study aimed at further adding to the existing knowledge of this medical challenge. We enrolled 89 consecutive patients observed in six Italian centers (from 8 August 2013 to 28 May 2021) with a diagnosis of immune-mediated thrombotic thrombocytopenic purpura. Clinical information and blood parameters were collected for all patients. We describe clinical manifestations and laboratory data, possible risk factors and the therapeutic management of first episodes or relapses. A total of 74 first episodes and 19 relapses (median 3 years (interquartile range (IQR): 2-7)) were recorded. Seventy percent of patients enrolled at the first episode showed neurological signs and/or symptoms. All the patients enrolled at the first episode were treated with plasma exchange (median = 12; IQR: 8-19.5) and methylprednisolone (1 mg/kg/day). Rituximab (375 mg/m2 weekly for four weeks) and caplacizumab were given to 15 (20.2%) and 2 patients (2.6%), respectively. We observed an overall mortality of 5.4% in the follow-up (median 60 months; IQR: 36.0-103.5). All fatalities occurred after a diagnostic delay. Present data point to the importance of the early detection of factors mostly associated with poor outcomes. It is likely that use of caplacizumab could improve the prognosis in those patients.

Use of low-molecular weight heparin, transfusion and mortality in COVID-19 patients not requiring ventilation.

It is still debated whether prophylactic doses of low-molecular- weight heparin (LMWH) are always effective in preventing Venous Thromboembolism (VTE) and mortality in COVID-19. Furthermore, there is paucity of data for those patients not requiring ventilation. We explored mortality and the safety/efficacy profile of LMWH in a cohort of Italian patients with COVID-19 who did not undergo ventilation. From the initial cohort of 422 patients, 264 were enrolled. Most (n = 156, 87.7%) received standard LMWH prophylaxis during hospitalization, with no significant difference between medical wards and Intensive Care Unit (ICU). Major or not major but clinically relevant hemorrhages were recorded in 13 (4.9%) patients: twelve in those taking prophylactic LMWH and one in a patient taking oral anticoagulants (p: n.s.). Thirty-nine patients (14.8%) with median age 75 years. were transfused. Hemoglobin (Hb) at admission was significantly lower in transfused patients and Hb at admission inversely correlated with the number of red blood cells units transfused (p < 0.001). In-hospital mortality occurred in 76 (28.8%) patients, 46 (24.3%) of whom admitted to medical wards. Furthermore, Hb levels at admittance were significantly lower in fatalities (g/dl 12.3; IQR 2.4 vs. 13.3; IQR 2.8; Mann-Whitney U-test; p = 0.001). After the exclusion of patients treated by LMWH intermediate or therapeutic doses (n = 32), the logistic regression showed that prophylaxis significantly and independently reduced mortality (OR 0.31, 95% CI 0.13-0.85). Present data show that COVID-19 patients who do not require ventilation benefit from prophylactic doses of LMWH.

Mortality and Transfusion Requirements in COVID-19 Hospitalized Italian Patients According to Severity of the Disease.

There is paucity of data on the transfusion need and its impact on the overall mortality in patients with COVID-19. We explored mortality in hospitalized patients with COVID-19 who required transfusions. Information on clinical variables and in-hospital mortality were obtained from medical records of 422 patients admitted to medical wards or the Intensive Care Unit (ICU). In-hospital mortality occurred in 147 (34.8%) patients, 94 (63.9%) of whom were admitted to the ICU. The median fatalities age was 77 years (IQR 14). Overall, 100 patients (60 males) received transfusion during hospitalization. The overall mortality was significantly and independently associated with age, ICU admission, Chronic Kidney Disease (CKD), and the number of transfused Red Blood Cell (RBC) units. Specifically, CKD was associated with mortality in patients admitted to medical wards, whereas the number of transfused RBC units predicted mortality in those admitted to the ICU. Transfusion strongly interacted with the admission to ICU (OR: 9.9; 95% CI: 2.5-40.0). In patients with COVID-19, age is one of the strongest risk factors in predicting mortality independently of the disease's severity. CKD confers a higher risk of mortality in patients admitted to medical wards. In those admitted to the ICU, the more RBC units are transfused, the more mortality increases.

Clinical history of cancer-associated splanchnic vein thrombosis.

BACKGROUND: Cancer represents a risk factor for splanchnic vein thrombosis (SVT) and usual site venous thromboembolism (VTE). OBJECTIVES: To compare characteristics and outcomes of patients with cancer-associated SVT and usual site VTE. PATIENTS/METHODS: Patients with solid cancer and SVT were enrolled in an international, prospective registry between May 2008 and January 2012. The comparison cohort included (1:1 ratio) patients with solid cancer and usual site VTE treated at two thrombosis centers who had a minimum of 12 months follow-up at December 2019 or experienced one of the outcomes within 12 months follow-up. Recurrent VTE, major bleeding, and all-cause mortality were evaluated at 12-month follow-up. RESULTS: A total of 264 patients (132 in each cohort) were enrolled. Patients with SVT were less likely to have metastatic disease (36.1% vs 72.5%) or receive cancer therapy at thrombosis diagnosis (29.6% vs 64.9%). The most frequent cancer types were hepatobiliary and pancreatic in the SVT cohort and gastrointestinal in the usual site VTE cohort. Fewer patients with SVT received anticoagulation (68.9% vs 99.2%), and treatment duration was shorter (6.0 vs 11.0 months). The cumulative incidence of major bleeding (2.3% vs 4.7%) was nonsignificantly lower in the SVT cohort, whereas recurrent thrombosis (4.7% vs 5.5%) and all-cause mortality (41.7% vs 39.4%) were comparable between the two cohorts. CONCLUSIONS: The risk of recurrent thrombosis and bleeding appears to be similar in cancer patients with SVT and cancer patients with usual site VTE, despite some differences in baseline characteristics and anticoagulant treatment. Further prospective studies are warranted to confirm these findings.

Platelet-Derived Microparticles Bearing PF4 and Anti-GAGS Immunoglobulins in Patients with Sepsis.

PF4 is a megakaryocyte-derived cationic chemokine that plays a part in innate immunity through its activity on the macrophages. In bacterial sepsis, PF4 binds to glycosaminoglycans (GAGs) on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of anti-PF4 IgG-IgA-IgM. This triggers the immune response in patients receiving heparin therapy who develop heparin-induced thrombocytopenia (HIT). These antibodies have also been identified in patients with chronic Gram-negative infections. Given the complexity of this innate immune response network, our study on 45 patients with sepsis focused on the immune response mediated by platelet PF4. We analyzed the role of IgG-IgA-IgM against PF4-GAGs, and the presence of specific PF4-bearing platelet microparticles (PMPs). Anti-GAGs/PF4 IgG-IgA-IgM levels were significantly higher in septic patients than in control groups (healthy controls or acute patients without sepsis, p < 0.001). PF4-bearing PMP levels were only significantly higher in septic patients (p < 0.001). The occurrence of IgG-IgA-IgM against PF4-GAGs and PF4+ PMPs correlated with an improvement in patients' sepsis. In conclusion, we demonstrated that, in the course of bacterial sepsis, platelet activation leads to the formation of specific PF4-bearing PMPs. These specific microparticles bind to polyanionic sequences on the surface of aerobic bacteria, giving rise to an antigenic complex that induces the early formation of IgG-IgA-IgM against PF4-GAGs as an innate immune response to infection.

PAI-1 and protein C as early markers of veno-occlusive disease in patients treated for Wilms tumor.

BACKGROUND: Hepatic veno-occlusive (VOD) disease has been described in hematopoietic stem cell transplantation (HSCT), solid tumors, and acute lymphoblastic leukemia. The incidence of VOD in Wilms tumor (WT) ranges from 1.2% to 8%. The diagnosis of VOD is clinical, and there are no validated laboratory biomarkers. PROCEDURE: We prospectively evaluated the specificity and sensitivity of plasminogen-activator inhibitor-1 (PAI-1) and protein C as diagnostic markers of VOD in WT patients. Fifty patients treated from 2008 to 2016 for WT were eligible. VOD was diagnosed according to modified Seattle criteria and retrospectively reclassified according to the recently published criteria for VOD in pediatric HSCT patients. RESULTS: VOD occurred in 6 of 50 patients (12%) after 20 to 97 days from starting chemotherapy. The average duration of VOD was 10 days (range, 4-13 days). PAI-1 levels were elevated in all VOD patients, while a decrease in protein C levels was observed in 33% of patients with VOD. PAI-1 antigen (Ag) values ≥ 26.4 ng/mL demonstrated high sensitivity and specificity for the clinical diagnosis of VOD with sensitivity 100%, specificity 93%; whereas protein C levels below 34.5% had sensitivity 67%, specificity 100%. Both PAI-1 and protein C had an high negative predictive value: PAI-1 Ag 100%; protein C 95%. CONCLUSIONS: PAI-1 Ag and protein C have good sensitivity and specificity for the diagnosis of VOD in WT patients. Their high negative predictive value can be used in the differential diagnosis of liver toxicity, especially in VOD episodes with absent or delayed hyperbilirubinemia.

A prediction model for successful anticoagulation in cirrhotic portal vein thrombosis.

BACKGROUND AND OBJECTIVE: Portal vein thrombosis (PVT) is a common complication in cirrhosis, and when complete, it increases morbidity and mortality in liver transplant candidates. The aim of the study was to assess the hemostatic status, as well as clinical characteristics of thrombus and patients, as predictors of therapeutic efficacy of anticoagulation for the treatment of PVT in cirrhotics. PATIENTS AND METHODS: Patients with cirrhosis consecutively treated for PVT with enoxaparin were enrolled. All patients underwent evaluation of coagulation status and thrombophilia screening. Thrombus characteristics and extension were evaluated at baseline and during follow-up. Anticoagulation was continued until recanalization or up to 12 months. Variables correlated with the response to anticoagulation were used to create a predictive score that was validated in an external multicenter cohort. RESULTS: A total of 65 patients were included and had partial PVT in most cases (72%). Treatment with enoxaparin resulted in an overall response rate of 66% (43/65) after a median time of 4.4 months and 76% (33/43) within the first 6 months. At multivariate analysis, efficacy of anticoagulation correlated with the severity of liver disease, complete verus partial PVT, age of the thrombus, and time interval from treatment start (<6 months). The areas under the curve of the statistical model for predicting the response to anticoagulation were 0.84 and 0.76 for the training (n=65) and validation (n=60) cohorts, respectively. CONCLUSION: Early diagnosis and early treatment are key factors for the successful management of PVT in cirrhosis, so that screening of PVT and prompt start of anticoagulant treatment should be mandatory.

Long-Term Outcome of Splanchnic Vein Thrombosis in Cirrhosis.

INTRODUCTION: Little is known about the long-term outcome of cirrhotic patients with splanchnic vein thrombosis (SVT). This prospective cohort study aimed to describe the clinical presentation, bleeding incidence, thrombotic events, and mortality in patients with SVT associated with cirrhosis. METHODS: Among 604 consecutive patients with SVT enrolled over 2 years, 149 had cirrhosis. Major bleeding, thrombotic events, and all-cause mortality were recorded during a 2-year follow-up. In a subgroup, the degree of recanalization with or without anticoagulation therapy, and the correlation between clinical events and liver disease severity were also investigated. RESULTS: The most common thrombosis sites were the portal (88%) and mesenteric veins (34%). At presentation, 50% of patients were asymptomatic. Anticoagulation was administered to 92/149 patients for a median of 6.5 months. Vessel recanalization was documented in 47/98 patients with a radiological follow-up. Anticoagulation was associated with a 3.33-fold higher of recanalization rate, and a lower recurrent thrombosis rate, while patients with and without anticoagulation experienced a similar rate of major bleeding episodes. Mortality rates were 6.8 per 100 patient-years for patients with thrombosis completely or partially resolving during the follow-up, and 15.4 per 100 patient-years for those with stable or progressing thrombosis. An impact of SVT on survival was only apparent in patients with more advanced liver disease (Child-Pugh B-C). CONCLUSIONS: Patients with SVT and cirrhosis have a substantial long-term risk of recurrent thrombotic events, which is reduced by anticoagulation therapy without any increase in bleeding risk. Anticoagulation can improve the likelihood of vessel recanalization, and is associated with a lower risk of death for decompensated patients.

Venoocclusive disease due to chemotherapy for pediatric acute lymphoblastic leukemia is associated with increased levels of plasminogen-activator inhibitor-1.

We describe three cases of sinusoidal obstruction syndrome/venoocclusive disease (SOS) in pediatric patients with acute lymphoblastic leukemia (ALL). All three episodes occurred during or just after the induction or reinduction phase of treatment based on prednisone/dexamethasone, vincristine, daunorubicin, and pegylated-l-asparaginase. SOS episodes were categorized as mild/moderate and resolved in 7, 10, and 16 days using supportive measures or defibrotide therapy. In all three episodes, the clinical diagnosis of SOS was associated with a significant increase in plasminogen-activator inhibitor-1 (PAI-1) that reduced with patient clinical improvement. PAI-1 warrants study as a diagnostic marker for SOS in ALL.

A venous thromboembolism risk assessment model for patients with Cushing's syndrome.

Cushing's syndrome (CS) is associated with an incidence of venous thromboembolism (VTE) about ten times higher than in the normal population. The aim of our study was to develop a model for identifying CS patients at higher risk of VTE. We considered clinical, hormonal, and coagulation data from 176 active CS patients and used a forward stepwise logistic multivariate regression analysis to select the major independent risk factors for thrombosis. The risk of VTE was calculated as a 'CS-VTE score' from the sum of points of present risk factors. VTE developed in 20 patients (4 pulmonary embolism). The group of CS patients with VTE were older (p < 0.001) and had more cardiovascular events (p < 0.05), infections and reduced mobility (both p < 0.001), higher midnight plasma cortisol levels (p < 0.05), and shorter APTT (p < 0.01) than those without. We identified six major independent risk factors for VTE: age ≥69 years and reduced mobility were given two points each, whereas acute severe infections, previous cardiovascular events, midnight plasma cortisol level >3.15 times the normality and shortened APTT were given one point each. A CS-VTE score <2 anticipated no risk of VTE; a CS-VTE score of two mild risk (10 %); a CS-VTE score of three moderate risk (46 %); a CS-VTE score ≥4 high risk (85 %). Considering a score ≥3 as predictive of VTE, 94 % of the patients were correctly classified. A simple score helps stratify the VTE risk in CS patients and identify those who could benefit from thromboprophylaxis.

How to effectively manage the event of bleeding complications when using anticoagulants.

Since affecting hemostasis, all the anticoagulant drugs carry a risk of bleeding. Minor bleeds may be managed without the need to reverse the anticoagulant effect, which is instead a key step to ensure efficacious hemostasis in major and life-threatening bleeding. Drug withdrawal applies to all anticoagulants. Unfractionated heparin can be neutralized by protamine, which may partly neutralize low-molecular-weight heparins. There is no antidote for fondaparinux, and recombinant factor VIIa (rFVIIa) may be considered for critical bleeding. For vitamin K antagonists-induced major bleeding, rapid reversal with prothrombin complex concentrates (PCC) or plasma and intravenous vitamin K to confer lasting correction are recommended. PCC, activated PCC and rFVIIa are suggested for major bleeding related to new direct oral anticoagulants (DOAC), despite proper studies are lacking. Premarketing studies are ongoing on new antidotes (idarucizumab, andexanet, aripazine), which appear to be suitable for the treatment of DOAC-induced life-threatening hemorrhage.

Perioperative thromboprophylaxis in Cushing's disease: What we did and what we are doing?

PURPOSE: Cushing's disease (CD) is associated with an increased risk of thrombotic events, particularly after surgery. No guidelines are available on the management of patients with CD undergoing pituitary transsphenoidal surgery (TSS). We aimed to compare the effectiveness of different prophylactic procedures on the prevention of thrombotic events after surgery in CD. METHODS: We retrospectively collected data on 78 consecutive patients who underwent TSS for CD between 2001 and 2012 at Padova's Neurosurgical Unit, recording their hemostatic, hormonal and anthropometric parameters. Patients were divided into two groups according to their perioperative management. Group A (34 patients) received fractionated heparin for a maximum of 14 days after surgery. Patients in group B (44 patients) were given no early glucocorticoid replacement therapy, and treated with subcutaneous enoxaparin 4,000-8,000 U/daily (depending on their weight) for 30 days plus graduated elastic stockings until mobilization, and early ambulation. RESULTS: The whole cohort of patients had clotting and anticoagulant factors significantly higher than the normal range. The two groups were comparable for age, BMI, ACTH, urinary free cortisol levels, outcome of surgery, and main clotting parameters. The surgical procedure did not change during the study period. Three venous thrombotic events [venous thromboembolic events (VTE), 2 associated with pulmonary embolism] were recorded in group A, none in group B (p = 0.079). No hemorrhagic events were reported. CONCLUSIONS: Provoked thrombotic events pose a major problem in the management of CD patients after surgery, regardless of the procedure's outcome. The prophylactic regimen proposed in this paper afforded an efficacy prophylaxis against postoperative VTE in patients with CD. Due to the rarity of CD, a multicenter study on a larger sample of cases would be warranted in order to collect more thrombotic events.

Antithrombotic treatment of splanchnic vein thrombosis: results of an international registry.

Treatment of splanchnic vein thrombosis (SVT) is a clinical challenge due to heterogeneity of clinical presentations, increased bleeding risk, and lack of evidences from clinical trials. We performed an international registry to describe current treatment strategies and factors associated with therapeutic decisions in a large prospective cohort of unselected SVT patients. A total of 613 patients were enrolled (mean age 53.1 years, standard deviation ± 14.8); 62.6% males; the majority (468 patients) had portal vein thrombosis. Most common risk factors included cirrhosis (27.8%), solid cancer (22.3%), and intra-abdominal inflammation/infection (11.7%); in 27.4% of patients, SVT was idiopathic. During the acute phase, 470 (76.7%) patients received anticoagulant drugs, 136 patients (22.2%) remained untreated. Incidental diagnosis, single vein thrombosis, gastrointestinal bleeding, thrombocytopenia, cancer, and cirrhosis were significantly associated with no anticoagulant treatment. Decision to start patients on vitamin K antagonists after an initial course of parenteral anticoagulation was significantly associated with younger age, symptomatic onset, multiple veins involvement, and unprovoked thrombosis. Although a nonnegligible proportion of SVT patients did not receive anticoagulant treatment, the majority received the same therapies recommended for patients with usual sites thrombosis, with some differences driven by the site of thrombosis and the pathogenesis of the disease.

Coagulation activation in children with sickle cell disease is associated with cerebral small vessel vasculopathy.

BACKGROUND: Thrombotic complications in Sickle Cell Disease (SCD) arise since infancy, but the role of the coagulation system in children has been poorly explored. To determine its role in the development of clinical complications in childhood we measured coagulation and endothelial parameters in children with SCD at steady state. METHODS: Markers of thrombin generation, fibrin dissolution and endothelial activation were evaluated in 38 children with SS-Sß°, 6 with SC disease and 50 age and blood group matched controls. Coagulation variables were correlated with markers of hemolysis and inflammation, with the presence of cerebral and lung vasculopathy and with the frequency of clinical complications. RESULTS: SS-Sß° patients presented higher levels of factor VIII, von Willebrand factor antigen (VWF:Ag) and collagen binding activity, tissue plasminogen activator antigen (t-PA:Ag), D-dimer, p-selectin, prothrombin fragment1+2 (F1+2) and lower ADAMTS-13:activity/VWF:Ag (p<0.05) compared to controls and SC patients. In SS-Sß° patients coagulation variables correlated positively with markers of inflammation, hemolysis, and negatively with HbF (p<0.05). Patients with cerebral silent infarcts showed significant decrease in t-PA:Ag and ADAMTS-13 Antigen and a tendency toward higher D-dimer, F1+2, TAT compared to patients without them. D-dimer was associated with a six fold increased risk of cerebral silent infarcts. No correlation was found between coagulation activation and large vessel vasculopathy or other clinical events except for decreased t-PA:Ag in patients with tricuspid Rigurgitant Velocity >2.5m/sec. CONCLUSIONS: SS-Sß° disease is associated with extensive activation of the coagulation system at steady state since young age. ADAMTS-13 and t-PA:Ag are involved in the development of cerebral silent infarcts.