Healthcare Risk Management and Monitoring of patient falls in Italian National Service. The experience of a Local Health Authority.

Falls are a widespread concern in hospitals settings. In Italy, falls are the fourth frequent damage claim type after surgical, diagnostic and therapeutic error and 90% of falls are avoidable. The first necessary action for the prevention of falls consists in identifying the possible risk factors, in relation to the characteristics of the patient and those of the environment and the structure that hosts him, in terms of safety, organization and adequacy of the process welfare. In this work we wanted to evaluate the extent, frequency and characteristics of the phenomenon of falls in the population hospitalized at the Local Health Authority called "Roma 2", with the aim of analyzing the critical issues to allow the identification of possible preventive and improvement interventions as well as reducing the risk of falls.

Multi-segment rupture of the 2016 Amatrice-Visso-Norcia seismic sequence (central Italy) constrained by the first high-quality catalog of Early Aftershocks.

We present the first high-quality catalog of early aftershocks of the three mainshocks of the 2016 central Italy Amatrice-Visso-Norcia normal faulting sequence. We located 10,574 manually picked aftershocks with a robust probabilistic, non-linear method achieving a significant improvement in the solution accuracy and magnitude completeness with respect to previous studies. Aftershock distribution and relocated mainshocks give insight into the complex architecture of major causative and subsidiary faults, thus providing crucial constraints on multi-segment rupture models. We document reactivation and kinematic inversion of a WNW-dipping listric structure, referable to the inherited Mts Sibillini Thrust (MST) that controlled segmentation of the causative normal faults. Spatial partitioning of aftershocks evidences that the MST lateral ramp had a dual control on rupture propagation, behaving as a barrier for the Amatrice and Visso mainshocks, and later as an asperity for the Norcia mainshock. We hypothesize that the Visso mainshock re-activated also the deep part of an optimally oriented preexisting thrust. Aftershock patterns reveal that the Amatrice Mw5.4 aftershock and the Norcia mainshock ruptured two distinct antithetic faults 3-4 km apart. Therefore, our results suggest to consider both the MST cross structure and the subsidiary antithetic fault in the finite-fault source modelling of the Norcia earthquake.

Relapsing thrombotic thrombocytopenic purpura with low ADAMTS13 antigen levels: An indication for splenectomy?

With more recent modalities of immunosuppression, splenectomy is now rarely considered in refractory/relapsed thrombotic thrombocytopenic purpura (TTP). However, the surgical approach had shown convincing evidences of high efficacy in the pre-rituximab era and therefore may still represent a lifesaving option in selected challenging cases. To define the characteristics of subjects who may benefit from splenectomy may ease clinical decision making. In this paper we describe the clinical and laboratory data of 2 multiple relapsing TTP cases who successfully underwent splenectomy in the pre-rituximab era. Whereas high anti-ADAMTS13 antibody titre and low ADAMTS13 activity never correlated with remission and relapse, a drop in the ADAMTS13 antigen level was always associated with the acute phase, whereas levels consistently returned to normal following splenectomy, heralding long term remission. Splenectomy may therefore be considered in refractory TTP cases associated with increased ADAMTS13 antigen clearance, irrespective of persistence of inhibitory antibodies.

Link between von Willebrand factor multimers, relapses and coronary microcirculation in patients with thrombotic thrombocytopenic purpura in remission.

INTRODUCTION: ADAMTS13 deficiency results in unusually large von Willebrand factor (ULVWF) multimers in the circulation and a higher risk of microthrombi due to high shear stress. In patients treated for acquired thrombotic thrombocytopenic purpura (TTP), a persistently severe ADAMTS13 deficiency (<10%) in remission is associated with more relapses. A reduced plasma ADAMTS13 activity and increased VWF levels are associated with a higher risk of myocardial infarction. Assessing coronary flow reserve (CFR) enables a better cardiovascular risk stratification: a lower CFR correlates inversely with cardiovascular risk. The aim of the study was to establish whether patients with TTP in remission have an impaired coronary microcirculation, in terms of a lower CFR, and whether there is any correlation between ADAMTS13 activity, the presence of ULVWF multimers, and the occurrence of relapses. METHODS: The clinical information and hemostatic parameters of 24 patients with TTP in remission managed at our center were analyzed. The CFR was assessed in a subgroup of the TTP patients and compared with a control group consisting of 50 healthy volunteers. RESULTS: The CFR was statistically lower in patients in remission of TTP than in controls, but there were no differences between TTP patients with normal and lower CFR. The occurrence of relapses correlated with the presence of ULVWF multimers and with a residual ADAMTS13 activity. CONCLUSIONS: When compared with healthy controls, TTP patients in remission have an impaired coronary microcirculation and the occurrence of relapses in the former reveal the presence of ULVWF multimers.

Factor X Friuli Coagulation Disorder: Almost 50 Years Later.

The story of factor X (FX) Friuli. Factor X Friuli was discovered in 1969 to 1970. However, the story of that disease was an international event since patients with this defect were studied in France and in Italy, and different diagnoses were reached-FVII; FX; combined prothrombin complex; and combined FII, FVII, and FX deficiencies. The diagnostic difficulties were due to the peculiar clotting pattern presented by these patients, namely, prolonged partial thromboplastin time, prolonged prothrombin time but normal Russell viper venom clotting time. Only suitable anti-FX antisera clarified the pattern. Altogether 12 homozygotes and 102 heterozygotes have been followed during 4 decades. Six homozygotes died, 2 of them due to HIV infection and 1 due to hepatitis B liver cirrhosis. The other 3 died of nontransfusion-related morbidity. Bleeding tendency has been moderate in agreement with the extrinsic or intrinsic system assay results-FX level of 4% to 5% is considered normal. Heterozygotes may present occasional bleeding manifestations usually during surgery or delivery. Molecular analysis have shown that the mutation responsible for the defect is a Pro343Ser substitution in exon 8. Chimeric FX Friuli mice have been useful in studying the effect of FX levels on embryonic or natal mortality of these animals. No new homozygote but several heterozygotes have been recently seen. The study of FX Friuli has revolutionized the diagnostic approach to FX deficiencies. The FX should be assayed by all assay systems. The FX Friuli has never been described in any other country, and all patients studied come from the Friuli Meduna River Valley.

Congenital prothrombin defects: they are not only associated with bleeding but also with thrombosis: a new classification is needed.

OBJECTIVE: Congenital prothrombin deficiency is one of the rarest clotting disorders. It is commonly subdivided in Type I defects or cases of 'true' prothrombin deficiency characterized by a concomitant decrease in FII activity and antigen and in Type II or dysprothrombinemias, in which FII activity is low but FII antigen is normal or near normal. A bleeding tendency, often a severe one, is the hallmark of the two-defects even though the bleeding is usually less severe in the Type 2 defects or dysprothrombinemias. PATIENTS AND METHODS: An extensive search of published cases of prothrombin deficiency was carried out in Pubmed and Scopus. The search started in 2012, after the publication of the first family with dysprothrombinemia and venous thrombosis. A few additional families were found. RESULTS: Recent studies have demonstrated that the Type 2 defects are heterogeneous. Several heterozygous mutations involving the Arg596 residue of exon 14 have been demonstrated not be associated with a bleeding tendency but, surprisingly, with venous thromboses. Mutations in close areas of prothrombin have failed to show the same pattern. CONCLUSIONS: These observations have required a reclassification of prothrombin defects. To the Type I and Type II defects, a Type III has to be added characterized by the absence of bleeding and the presence of venous thrombosis. It is not clear yet if this special variant of Type II defect is limited to the Arg596 mutations or if other residues may be involved.

A structure-function analysis in patients with prekallikrein deficiency.

OBJECTIVE: To investigate the structure-function relation in prekallikrein (PK) deficiency. PK is one of the proteins of the contact phase of blood coagulation which at the present time is the object of a revival of interest. METHODS: All patients with PK deficiency who had been investigated by molecular biology techniques are the object of the present investigation. Details of patients were obtained from personal files and a time-unlimited PubMed search. Only cases with a molecular-biology-based diagnosis were included. RESULTS: Twelve families were included. The total number of missense mutation was 10, together with 3 stop codons and 2 insertions. These mutations involved mainly exons 11 and 14. There were eight proved homozygotes and three compound heterozygotes. In one instance, homozygosity was probable but not proved. In nine cases, the defect was Type I, whereas it was Type II in the remaining three. No bleeding manifestations were present in 11 of the 12 probands. One proband had epistaxis, but she had hypertension. Altogether, four patients had hypertension and one of them had also two myocardial infarctions. CONCLUSIONS: Despite the paucity of cases, it was established that the majority of mutations involved the catalytic domain. It is auspicable that future reports of patients with this disorder should include molecular studies. This would certainly contribute to the understanding of the contact phase of blood coagulation.

Congenital FX Deficiency Rio Tercero: A New Heterozygous Missense Mutation (Cys241Gly) with a Potentiating Effect by a Polymorphism (c. 503-57C>T).

OBJECTIVE: The aim was to report a new family with congenital FX deficiency. PATIENTS AND METHODS: The proposita is a 41 year old female with a moderate bleeding tendency (easy bruising, menorrhagia). Parents were not consanguineous. Family history was positive for a mild bleeding tendency. RESULTS: Coagulation and genetics studies revealed that the proposita and two of her siblings were heterozygotes for a new mutation Cys241Gly in exon 6 but had different FX level (2-3% of normal in the proposita and about 50% in the two siblings. The same was true for one of her three children. The mother and the other two children of the proposita had also slightly decreased FX levels but no mutation. On the suspicion that the proposita was carrying another defect which had escaped the Sanger method, we carried out a whole exome analysis and discovered that the proposita and one of her siblings were also homozygous for a mutation of a known polymorphism (c.503-57C>T). The daughter of the proposita was instead, besides being a carrier of the missense new mutation Cys241Gly, heterozygous for the same polymorphism. The mother and two other daughters were also heterozygous for the polymorphism. There were no deletions or duplications. CONCLUSION: The polymorphism present in the family seems to be capable of potentiating the defect induced by the new mutation. This, safe for epigenetics phenomena, is the only possible explanation for the discrepancy found in the FX level between mother and daughter despite the fact that both carried the same new mutation.

Bleeding manifestations in heterozygotes with prothrombin deficiency or abnormalities vs. unaffected family members as observed during a long follow-up study.

: To investigate the prevalence of bleeding in heterozygotes for prothrombin deficiencies. Homozygotes or compound heterozygotes with Factor II (FII) levels of less than 10% of normal are always severely symptomatic.On the contrary little is known about the heterozygous population who have FII levels around 40-50% of normal.Forty-four patients heterozygous for this defect, in comparison with age and sex matched 44 unaffected family members, have been followed during a mean observational period of 22.5 years (range 4-35 years). The study was carried out in Padua between the years 1971 and 2010.The mean prothrombin activity was 0.49 IU/dl (range 0.38-0.62) and 0.91 IU/dl (range 0.81-1.10) in the heterozygotes and in the normal counterparts, respectively.In total, 14 patients showed bleeding manifestations vs. only three among the controls. Bleeding was sometimes spontaneous but more frequently occurred after tooth extractions, surgery, or delivery.Some heterozygous patients had also to be given replacement therapy to control the bleeding. No substitution therapy was ever needed for the normal counterparts.The prothrombin activity levels in the patients who were symptomatic tended to be lower than in those who remained asymptomatic.The difference in the frequency of bleeding and in the bleeding score between patients and unaffected family members was statistically significant (P = 0.007 and 0.0007).Prothrombin levels of about 40-50% of normal may not represent well tolerated hemostatic levels in case of surgical procedures, tooth extraction, or delivery. These data may have general clinical significance even for patients who have acquired defects.

Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden.

The most common causes of morbidity and mortality in myeloproliferative neoplasms (MPN) are thrombotic and hemorrhagic complications. The JAK2V617F mutation, commonly found in MPN, correlates with several clinical and laboratory characteristics even if the relevance of JAK2V617F allele burden in the natural history of these diseases is unclear. In this study we searched, a relation between thrombotic and hemorrhagic complications and JAK2V617F allele burden level in MPN patients. We evaluated 253 consecutive MPN [121 essential thrombocythemia (ET), 124 polycythemia vera (PV), and 8 primary myelofibrosis (PMF)] patients in whom the JAK2V617F allele burden was available, all studied and followed (median 8.8 years) in our department. Patients were stratified accordingly to their JAK2V617F allele burden, into four quartiles (1st <25%, 2nd 26-50%, 3rd 51-75%, and 4th >75%). Significantly higher incidence of thromboses (p = 0.001) and hemorrhages (p < 0.001) during follow-up has been observed in higher quartiles when compared to lower ones. Thrombosis- and hemorrhage-free survivals were poorer in patients belonging to the highest quartile. Our data suggest that MPN patients with JAK2V617F allele burden higher than 75% have to be considered as high risk patients, being prone to develop thrombo-hemorrhagic complications during the disease course.

Bleeding manifestations in heterozygotes with congenital FVII deficiency: a comparison with unaffected family members during a long observation period.

OBJECTIVES: To determine whether heterozygotes with FVII deficiency have a bleeding tendency or not. PATIENTS AND METHODS: Eighty-four patients (OK) heterozygous for FVII deficiency, at the onset of the study, were paired with unaffected family members and followed for a long period of time (mean 22.6 years) for the occurrence of bleeding. Diagnosis of heterozygosis had to be based on family studies, clotting, immunological assays and genetic analysis. RESULTS: The mean FVII activity level was 0.51 IU/dl (range 35-65) and 94 IU/dl (range 88-118) in the heterozygotes and in the normal counterparts, respectively. Documented bleeding manifestations occurred in eight heterozygotes and in seven normal subjects. Statistical analysis of the difference was not significant. Bleeding manifestations were easy bruising, bleeding after tooth extractions, menorrhagia, epistaxis with no difference among the two groups. There was no strict correlation between bleeding and FVII activity levels. CONCLUSIONS: The study indicates that heterozygotes for FVII deficiency show rare bleeding manifestations which are also present in the unaffected family members with normal FVII levels. This indicates that Factor VII activity levels played no role in the occurrence of the bleeding symptoms. Furthermore, FVII levels of around 0.40 IU/dl are capable of assuring a normal hemostasis.

Weight loss reduces anti-ADAMTS13 autoantibodies and improves inflammatory and coagulative parameters in obese patients.

Obese patients have been described at increased risk of thrombotic thrombocytopenic purpura, a disease caused by anti-ADAMTS13 autoantibodies. ADAMTS13 has a structure homology with the adipokine thrombospondin-1. We previously demonstrated an increased presence of anti-ADAMTS13 antibodies in obese patients. We aimed to study the changes induced by weight loss after bariatric surgery on some inflammatory and coagulative parameters and their link with anti-ADAMTS13 autoantibodies. We studied 100 obese patients before and after weight loss induced by bariatric surgery and 79 lean volunteers as controls. We measured anthropometric, metabolic and inflammatory parameters, thrombospondin-1, ADAMTS13 activity, anti-ADAMTS13 autoantibodies, Von Willebrand factor. At baseline, 13 % of patients was positive for anti-ADAMTS13 autoantibodies, while all controls were negative. Thrombospondin-1 levels were higher in obese subjects with than without antibodies, with a positive correlation between the two parameters. In multiple logistic regression analysis only thrombospondin-1 levels predicted positivity for anti-ADAMTS13 antibodies. After weight loss both anti-ADAMTS13 antibodies and thrombospondin-1 reduced significantly. Weight loss in obesity improves the inflammatory and coagulative profile, and in particular anti-ADAMTS13 autoantibodies, ADAMTS13 activity and thrombospondin-1.

Correlation between ADAMTS13 activity and neurological impairment in acute thrombotic microangiopathy patients.

Differential diagnosis between thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies (TMA) is usually difficult because of frequently overlapping clinical presentations. Severely depressed ADAMTS13 activity (<10 %) seems distinctive for TTP because of its pathogenetic role. However a long debate exists in the literature about its sensibility and specificity. Our aim was to search for clinical differences between TMA patients referred to our laboratory, comparing them for protease activity <10 versus ≥10 %. ADAMTS13 activity ≥10 % patients (n = 73) showed a higher prevalence of drug- (p = 0.005) and cancer-associated (p < 0.001) TMA. Mean platelet count and renal dysfunction prevalence was lower (p < 0.001), while neurological impairment was more frequent (p = 0.001) in the <10 % ADAMTS13 activity group (n = 109), confirming previous literature findings. When taken neurological manifestations singularly, epilepsy (p = 0.04), focal motor deficit (p < 0.001) and cranial nerve palsy (p = 0.007) were more frequent in the <10 % activity group. In our case series, a <10 % ADAMTS13 activity depicts a group of patients with clinical features similar to TTP patients. Focal motor impairment or epileptic manifestations could further address toward a TTP diagnosis. Studies about treatment efficacy and follow-up are advised to determine whether laboratory findings can guide therapeutic decisions.

Meat intake and non-Hodgkin lymphoma: a meta-analysis of observational studies.

PURPOSE: High intake of meat has been inconsistently associated with increased risk of non-Hodgkin lymphoma (NHL). We carried out a meta-analysis to summarize the evidence of published observational studies reporting association between red meat and processed meat intake and NHL risk. METHODS: Analytical studies reporting relative risks with 95 % confidence intervals (95 % CI) for the association between intake of red and/or processed meat and NHL or major histological subtypes were eligible. We conducted random-effects meta-analysis comparing lowest and highest intake categories and dose-response meta-analysis when risk estimates and intake levels were available for more than three exposure classes. RESULTS: Fourteen studies (four cohort and ten case-control) were included in the meta-analysis, involving a total of 10,121 NHL cases. The overall relative risks of NHL for the highest versus the lowest category of consumption were 1.14 (95 % CI 1.03, 1.26) for red meat and 1.06 (95 % CI 0.98, 1.15) for processed meat. Significant associations were present when the analysis was restricted to case-control studies but not when restricted to cohort studies. No significant associations were found for major NHL etiological subtypes. Dose-response meta-analysis could be based only on eight studies that provided sufficient data, and compared to no meat consumption, the overall NHL relative risk increased nonlinearly with increased daily intake of red meat. CONCLUSION: The observed positive association between red meat consumption and NHL is mainly supported by the effect estimates coming from case-control studies and is affected by multiple sources of heterogeneity. This meta-analysis provided mixed and inconclusive evidences on the supposed relationship between red and processed meat consumption and NHL.

Prevalence of bleeding manifestations in 128 heterozygotes for Factor X deficiency, mainly for FX Friuli, matched versus 128 unaffected family members, during a long sequential observation period (23.5 years).

OBJECTIVES: The main objective of the study was to evaluate the incidence of bleeding manifestations in heterozygotes for FX deficiency vs. unaffected family members. Secondary objective was to compare the prevalence of arterial or venous diseases found in the two groups. PATIENTS AND METHODS: A total of 128 heterozygote patients for FX deficiency were investigated. A total of 102 patients had FX Friuli; 26 patients had other forms of FX deficiency. At time of diagnosis, each patient was paired with an unaffected family member, matched by gender and age (±5). Patients and their normal counterparts were checked every 1-2 yr for a mean period of 23.5 yr. The occurrence of bleeding manifestations was recorded and scored. The occurrence of arterial diseases and venous thrombosis was also recorded as a secondary finding. RESULTS: A total of 38 heterozygote patients (29.7%) had one or more than one bleeding manifestation. The most frequent one was bleeding after tooth extraction or surgery. On the contrary, only three control subjects (2.3%) had documented hemorrhagic symptoms. There was a good correlation between bleeding and FX levels. Arterial disease (acute coronary syndromes, ischemic stroke, stable angina, peripheral arteries disease) was found in eight patients (6.3%) with FX deficiency and in seven unaffected subjects (5.5%). On the contrary, no venous thrombosis was seen in the affected group, whereas three cases (2.3%) of documented venous thrombosis were observed in the control group (two deep veins and one superficial vein). CONCLUSIONS: Heterozygotes FX deficiency may be accompanied by a mild bleeding tendency. This has important implications to assure a safe FX level in case of surgery or invasive procedures. Furthermore, mild FX deficiency seems to have no protective effect on arterial disease but does seem to protect from venous thrombosis.

Pulmonary embolism in congenital bleeding disorders: intriguing discrepancies among different clotting factors deficiencies.

Pulmonary embolism is a complication of deep vein thrombosis. It occurs in the population with a normal clotting mechanism, but it may also occur in patients with congenital bleeding conditions. Here, we report on all cases of pulmonary embolism in congenital hemorrhagic disorders. All reported cases of pulmonary embolism in congenital coagulation disorders have been gathered by a time-unlimited PubMed search. Cross-checking of the references listed at the end of the single papers was carried out to avoid omissions. Seventy-two patients had an objectively demonstrated pulmonary embolism. The event occurred in patients with fibrinogen, factor V, factor VIII (FVII), FVIII, FIX, and FXI deficiency, and in those with von Willebrand's disease. No embolism was reported in FII, factor X, and FXIII deficiency. Thirty were women and 28 were men, whereas in the remaining 14 cases, sex was not reported. Age varied from 6 to 81 years (mean age 34.3 years). The management varied from only supportive to the administration of unfractionated heparin, low-molecular-weight heparin, and anti-vitamin K medications, accompanied by adequate replacement therapy. Evolution was fair or good in the majority of cases, but there were 10 fatalities. Risk factors were present in 61 patients. The most frequent of these were replacement therapy (35 cases), surgery (34), and old age (13). Some patients had more than one risk factor. Eleven patients had no risk factors. There are discrepancies in the prevalence of pulmonary embolism among different clotting disorders. The conditions most frequently affected are FVII deficiency and fibrinogen defects. The significance of the findings is discussed.

Acquired Isolated FVII Deficiency: An Underestimated and Potentially Important Laboratory Finding.

OBJECTIVE: To investigate all cases of isolated factor VII (FVII) deficiency as gathered from personal files or by a PubMed search. PATIENTS AND METHODS: Personal files dealing with patients studied in Padua during the years 1970 to 2010 were reevaluated. The PubMed search was time unlimited and was carried on 2 occasions during 2014. Cross-checking of the references, listed in every article, was also carried out to avoid omissions. Inclusion criteria were isolated FVII defect of less than 40% of normal, negative coagulation pattern in the family, normal level of other vitamin K-dependent clotting factors, and normalization of the clotting factor after the therapeutic procedures, unless the patient died. RESULTS: Twenty-nine patients met the inclusion criteria (18 male and 9 female, in 2 cases gender was unreported). This number included 1 personal case. Mean age was 37.9 (range 3-80). Underlying diseases were the following: neoplasia, infections, polytrauma, penicillin administration, nephrotic syndrome Wiskott Aldrich syndrome, and left heart failure (1 case, each); 2 patients had no underlying disease. Bleeding was variable but usually mild. There were 11 fatalities. CONCLUSIONS: Isolated FVII deficiency is a rare defect, which appears to be a finding associated with several morbid conditions, especially sepsis and tumors. This indicates the need for a careful investigation of even a mild prolongation of prothrombin time, especially when fibrinogen and partial thromboplastin time are normal.