Impact of the post-COVID-19 condition on health care after the first disease wave in Lombardy.

BACKGROUND: Lombardy was affected in the early months of 2020 by the SARS-CoV-2 pandemic with very high morbidity and mortality. The post-COVID-19 condition and related public health burden are scarcely known. SETTING AND DESIGN: Using the regional population administrative database including all the 48,932 individuals who survived COVID-19 and became polymerase-chain-reaction negative for SARS-CoV-2 by 31 May 2020, incident mortality, rehospitalizations, attendances to hospital emergency room, and outpatient medical visits were evaluated over a mid-term period of 6 months in 20,521 individuals managed at home, 26,016 hospitalized in medical wards, and 1611 in intensive care units (ICUs). These data were also evaluated in the corresponding period of 2019, when the region was not yet affected by the pandemic. Other indicators and proxies of the health-care burden related to the post-COVID condition were also evaluated. MAIN RESULTS: In individuals previously admitted to the ICU and medical wards, rehospitalizations, attendances to hospital emergency rooms, and out-patient medical visits were much more frequent in the 6-month period after SARS-CoV-2 negativization than in the same prepandemic period. Performances of spirometry increased more than 50-fold, chest CT scans 32-fold in ICU-admitted cases and 5.5-fold in non-ICU cases, and electrocardiography 5.6-fold in ICU cases and twofold in non-ICU cases. Use of drugs and biochemical tests increased in all cases. CONCLUSIONS: These results provide a real-life picture of the post-COVID condition and of its effects on the increased consumption of health-care resources, considered proxies of comorbidities.

A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A.

BACKGROUND: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy. METHODS: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites. RESULTS: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00). CONCLUSIONS: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).

Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis.

A recent randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET), showed a higher risk of inhibitor development with recombinant factor VIII (rFVIII) than plasma-derived concentrates (pdFVIII). We investigated whether risk stratification by F8 mutation identifies patients who do not suffer this deleterious effect of rFVIII. Among 235 randomized patients with severe hemophilia A previously untreated with FVIII concentrate, 197 with null mutations were classified as high risk and 38 with non-null mutations were classified as low risk. With pdFVIII, no inhibitors occurred in those with low genetic risk, whereas high-risk patients had a cumulative incidence of 31%. The risk among low- and high-risk patients did not differ much when they were treated with rFVIII (43% and 47%, respectively). This implies that patients with low genetic risk suffer disproportionate harm when treated with rFVIII (risk increment 43%), as also shown by the number needed to harm with rFVIII, which was 6.3 for genetically high-risk patients and only 2.3 for low-risk patients. Risk stratification by F8 mutation does not identify patients who can be safely treated with rFVIII, as relates to immunogenicity. This trial was registered at the European Clinical Trials Database (EudraCT) as #2009-011186-88 and at www.clinicaltrials.gov as #NCT01064284.

Changing Concepts of Cirrhotic Coagulopathy.

The state of clinical art of the coagulopathy of cirrhosis changed considerably over the last decade. Until 2005, cirrhosis was considered as the epitome of the hemorrhagic coagulopathies and the abnormal hemostasis tests associated with the disease were corrected with infusion of fresh frozen plasma or platelets to minimize the risk of bleeding. Since that time, a great deal of work has been done and there is now a change of paradigm. The prothrombin time once considered as an isolated measure of bleeding risk was rejected, and cirrhosis shifted from a purely hemorrhagic construct to a mixed and thrombosis-prone paradigm. In this article we examine the interesting history of how these conceptual changes came about.

Alloantibodies in von Willebrand disease.

The development of alloantibodies against von Willebrand factor (VWF) represents a rare but serious complication of treatment of von Willebrand disease (VWD), occurring in ~5% to 10% of type 3 VWD patients. Affected patients can present with a range of symptoms, including lack or loss of hemostatic response to infused VWF concentrates up to anaphylactic reactions in rare cases. It is classically reported in multitransfused patients and occurs most frequently in patients with partial or complete VWF gene deletions. A positive family history of anti-VWF antibodies also appears to be a risk factor. There is a lack of standardization of laboratory methods for antibody identification and characterization. Issues of variability in laboratory approaches as well as the rarity of the complication act as a barrier to future studies. Recombinant factor VIII as well as bypassing agents and immune tolerance have been reported as effective treatments; however, aside from case reports, little exists in the literature to guide management. The imminent clinical availability of recombinant VWF has prompted a resurgence of interest in this area. Additional study is warranted to address the deficiencies in our understanding of this treatment complication.

Global hemostasis tests in patients with cirrhosis before and after prophylactic platelet transfusion.

BACKGROUND/AIMS: Cirrhosis presents with variable degrees of thrombocytopenia that might cause bleeding during invasive procedures. Transfusion of one standard adult platelet dose is often employed to prevent bleeding in thrombocytopenia, but the threshold platelet count that is clinically effective is not well established because clinical studies and laboratory tools to judge on efficacy are insufficient. However, in vitro studies showed that patients with cirrhosis generate as much thrombin as healthy individuals provided that their platelet count is at least 100 × 10(9) /L. METHODS: To assess the in vivo relevance of these in vitro studies, we investigated 26 thrombocytopenic patients with cirrhosis, undergoing 36 variceal ligations, to see whether transfusion of one standard adult platelet dose was able to attain the above platelet count. We also evaluated the effect of platelet transfusion on such global hemostasis tests as thrombin generation and thromboelastometry. RESULTS: Transfusion did slightly increase platelet count [pre- vs. post-infusion: 39 × 10(9) /L(16-64) vs. 52 × 10(9) /L(19-91), P < 0.001], without significant effect on thrombin generation, probably because post-transfusion platelet count was less than the target of 100 × 10(9) /L in all patients. In addition, the percentage of patients with abnormal thrombin generation (i.e. below the lower limit of normal range) was scarcely affected by transfusion (pre- vs. post-infusion: 36% vs. 42%). The small post-transfusion increase in platelet count was paralleled by some degree of improvement of thromboelastometry, but none of the patients reached normal values after transfusion. CONCLUSIONS: Infusing one standard adult platelet dose secures only a small increase in platelet count without normalizing thrombin generation and thromboelastometry tests. To obtain greater increases in platelet count and normalization of laboratory tests more intensive platelet transfusions or treatment with non-transfusional drugs are probably needed.

ADAMTS13 content in plasma-derived factor VIII/von Willebrand factor concentrates.

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy syndrome caused by a congenital or acquired deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor (VWF) and thus prevents the formation of platelet-rich thrombi in the microcirculation. TTP can be fatal if not appropriately and timely treated with the infusion of fresh frozen plasma (FFP) or exchange plasmapheresis, that reverse the process of microangiopathy by removing anti-ADAMTS13 autoantibodies and replacing functional ADAMTS13. The treatment of TTP with FFP is not free from risks and must be administered in hospitals or clinics, owing to the substantial amount of plasma volume infused or exchanged and the frequent need of catheter application. Moreover, most FFPs are not subjected to treatments to remove or inactivate blood-borne infectious agents. A number of recent reports indicate that certain plasma-derived VWF-factor VIII (FVIII) concentrates are clinically effective in the treatment of congenital TTP. In this study, we measured ADAMTS13 levels in various plasma-derived VWF-FVIII concentrates, showing that Koate(®) -DVI (Grifols), contained relatively high amounts of ADAMTS13 and that Alphanate(®) (Grifols) was the closest other product in terms of protease content. Koate(®) -DVI contains, on average (five lots tested), 0.091 ± 0.007 Units of ADAMTS13 activity per IU of FVIII. On the basis of this analysis and other reports of VWF-FVIII concentrate utilization in congenital TTP, potential dosing, and future clinical developments are discussed.

Management of inherited von Willebrand disease in Italy: results from the retrospective study on 1234 patients.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is due to quantitative and/or qualitative defects of von Willebrand factor (VWF). Despite the improved knowledge of the disease, detailed data on VWD types requiring specific treatments have not been reported thus far. To determine the number and types of VWD requiring therapy with desmopressin (DDAVP) and/or VWF/FVIII concentrates in Italy, a national registry on VWD (RENAWI) was organized. Only 16 of 48 centers included VWD in the RENAWI with diagnoses performed locally. Patients with uncertain results were retested by two expert laboratories using multimeric analysis and mutations of the VWF gene. A total of 1234 of 1529 (81%) cases satisfied the inclusion criteria and could be classified as VWD1 (63%), VWD2A (7%), VWD2B (6%), VWD2M (18%), VWD2N (1%), and VWD3 (5%). VWD types were also confirmed by DNA analyses and occur in young adults (83%), mainly in women (58%). Mucosal bleedings (32 to 57%) are more frequent than hematomas (13%) or hemarthrosis (6%). Most patients were exposed to an infusion trial with desmopressin (DDAVP) and found responsive with the following rates: VWD1 (69%), VWD2A (26%), VWD2M (29%), and VWD2N (71%). However, DDAVP was not always used to manage bleeding in all responsive patients and VWF/FVIII concentrates were given instead of or together with DDAVP in VWD1 (30%), VWD2A (84%), VWD2B (62%), VWD2M (63%), VWD2N (30%), and VWD3 (91%). Data of the RENAWI showed that correct VWD identification and classification might be difficult in many Italian centers. Therefore, evidence-based studies should be organized only in well-characterized patients tested by laboratories that are expert in the clinical, laboratory, and molecular markers of VWD.

How I treat age-related morbidities in elderly persons with hemophilia.

In persons with hemophilia, life expectancy is now approaching that of the general male population, at least in countries that can afford regular replacement therapy with coagulation factor concentrates. The new challenges for comprehensive treatment centers are thus to provide optimal health care for this aging population of patients, who often present not only with the comorbidities typically associated with hemophilia (arthropathy, chronic pain, blood-borne infections), but also with common age-related illnesses such as cardiovascular disease and cancer. There are no evidence-based guidelines for the management of these conditions, which often require drugs that interfere with hemostasis, enhance the bleeding tendency, and warrant more intensive replacement therapy. At the moment, elderly patients with hemophilia affected by other diseases should be managed like their age-group peers without hemophilia, provided replacement therapy is tailored to the heightened risk of bleeding associated with the need for invasive procedures and drugs that further compromise the deranged hemostasis. More detailed advice is provided on the schedules of replacement therapy needed to tackle cardiovascular diseases, such as acute coronary syndromes and nonvalvular atrial fibrillation, because these conditions will become more and more frequent challenges for the comprehensive treatment centers.

Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients.

Type 2B von Willebrand disease (VWD2B) is caused by an abnormal von Willebrand factor (VWF) with increased affinity for the platelet receptor glycoprotein Ib-alpha (GPIb-alpha) that may result in moderate to severe thrombocytopenia. We evaluated the prevalence and clinical and molecular predictors of thrombocytopenia in a cohort of 67 VWD2B patients from 38 unrelated families characterized by VWF mutations. Platelet count, mean platelet volume, and morphologic evaluations of blood smear were obtained at baseline and during physiologic (pregnancy) or pathologic (infections, surgeries) stress conditions. Thrombocytopenia was found in 20 patients (30%) at baseline and in 38 (57%) after stress conditions, whereas platelet counts were always normal in 16 patients (24%) from 5 families carrying the P1266L/Q or R1308L mutations. VWF in its GPIb-alpha-binding conformation (VWF-GPIb-alpha/BC) was higher than normal in all except the 16 cases without thrombocytopenia (values up to 6-fold higher than controls). The risk of bleeding was higher in patients with thrombocytopenia (adjusted hazard ratio = 4.57; 95% confidence interval, 1.17-17.90) and in those with the highest tertile of bleeding severity score (5.66; 95% confidence interval, 1.03-31.07). Prediction of possible thrombocytopenia in VWD2B by measuring VWF-GPIb-alpha/BC is important because a low platelet count is an independent risk factor for bleeding.

Different clinical severity of first episodes and recurrences of thrombotic thrombocytopenic purpura.

The clinical course of thrombotic thrombocytopenic purpura (TTP) is characterized by recurrent disease episodes in up to 50% of cases. The clinical presentation and severity of different TTP episodes have not been systematically compared. Laboratory and clinical information from 51 patients with recurrent disease, derived from 136 patients with TTP included in the Milan TTP registry (URL: http://www.ttpdatabase.org), were used to compare mortality, symptoms and disease-related laboratory measurements in different disease episodes. The prevalence of severe neurological symptoms (coma, seizures, and focal neurological defects) was significantly lower in recurrences than in the first episode. Platelet counts and haemoglobin levels at presentation were higher in recurrences than in the first disease episode, and lactate dehydrogenase levels were lower. Also, mortality tended to be lower in the second and third disease episodes than in the first. Recurrences of TTP are generally milder than first episodes. These differences in severity should be taken into account in clinical research on TTP and in patient management.

Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis.

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.

Acquired coagulation disorders: revisited using global coagulation/anticoagulation testing.

Acquired coagulation defects are characterized by a decrease of both pro- and anti-coagulants. Because of this, we hypothesise that global tests, such as the prothrombin and partial thromboplastin times (PT and APTT), might be unsuitable for their investigation. Indeed, these tests are not good predictors of bleeding in acquired coagulopathies as they are in the congenital ones. This article discusses the possible reasons for this, using cirrhosis and the neonatal period as epitomes of acquired coagulation defects. Both display normal thrombin generation in the presence of thrombomodulin, in spite of prolonged PT and APTT. We surmise that, because of their design, the PT and APTT are responsive to thrombin generated as a function of pro-coagulants, but much less to thrombin inhibited by the anti-coagulants, especially protein C, which is activated to a limited extent in the absence of thrombomodulin. In conclusion, the PT and APTT can tell us whether or not a patient is deficient in one or more pro-coagulants, but not whether this deficiency is counterbalanced by a parallel deficiency of anti-coagulants. Thrombin generation assays are more suitable than PT and APTT for use in acquired coagulation defects.