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.

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.

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.

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.

Defective ADAMTS13 synthesis as a possible consequence of NASH in an obese patient with recurrent thrombotic thrombocytopenic purpura.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a rare and devastating hematologic disorder frequently associated with multiple organ failure and sometimes death. This syndrome is mainly associated with severe deficiency of ADAMTS13, a disintegrin and metalloprotease with thrombospondin (TSP)-1 repeats, cleaving high molecular weight von Willebrand Factor (ULVWF) multimers. Decreased plasma ADAMTS13 activity results in the accumulation of ULVWF multimers with consequent platelet activation. Recently, obesity has been considered as a potential independent risk factor for TTP, but the reason of this association is still unknown. METHODS AND RESULTS: We describe an unusual case of fatal recurrent TTP in a morbid obese female with non-alcoholic steatohepatitis (NASH) and severe ADAMTS13 activity deficiency due neither to an inhibitory autoantibody nor to a gene mutation. CONCLUSIONS: Visceral obesity is associated with non-alcoholic fatty liver disease (NAFLD) and NASH: we hypothesized that these conditions can influence ADAMTS13 antigen and activity. In fact, hepatic stellate cells (HSC) are the main producers of ADAMTS13, and a decrease in ADAMTS13 activity has been reported in liver disease.

Discrepant ratios of arterial vs. venous thrombosis in hemophilias A and B as compared to FVII deficiency.

BACKGROUND: The occurrence of a thrombotic event in congenital bleeding disorders has drawn considerable attention in recent years. Both patients with hemophilia and patients with von Willebrand disease and even those with rare coagulation disorders have been shown to present occasional thrombotic events. Little is known on the comparative prevalence of arterial vs. venous thrombosis in these patients. OBJECTIVES: The purpose of the present investigation was to evaluate the prevalence of arterial vs. venous occlusions in hemophilia A and B vs. FVII deficiency. METHODS: A time unlimited search of the literature was carried out using pertinent key words. Arterial or venous occlusions had to be proven by objective methods. RESULTS: Eighty-five patients with hemophilia A or B have been reported to have had an arterial occlusion vs. six cases of FVII deficiency. On the contrary, 34 patients with hemophilia A or B and 32 cases with FVII deficiency have been reported to have presented with a venous thrombosis. The ratios of arterial vs. venous thrombosis are 3.72, 1.13, and 2.50 for hemophilia A, hemophilia B, and hemophilia A + B combined, respectively, and 0.19 for FVII deficiency. CONCLUSIONS: Hemophilia A and hemophilia B do not protect from arterial occlusions (mainly acute coronary syndromes), whereas they assure some protection from venous thrombosis. The opposite seems true for FVII deficiency. The potential significance of this discrepancy is discussed.

A cluster of factor XI-deficient patients due to a new mutation (Ile 436 Lys) in northeastern Italy.

A new mutation (Ile 436 Lys) was found in a cluster of patients in northeastern Italy. The mutation was present in five patients at the homozygote level and in one patient as a compound heterozygote with an already known mutation namely Glu 117 stop. All these patients showed a mild bleeding tendency mainly associated with deliveries or surgery. The first two patients were two sisters, and their parents were consanguineous. The third patient was the only homozygote in the family, and parents apparently were not consanguineous. The fourth and fifth patients were a brother and a sister, and in this case too, parents were not consanguineous. The sixth patient, a compound heterozygote, negated also the existence of consanguinity between his parents. There were also seven heterozygotes among the family members of the patients homozygous for this new mutation (Ile 436 Lys). Finally, there were two heterozygotes for the Glu 117 stop mutation in the family of the sixth patient. The heterozygotes, regardless of the mutation, were asymptomatic. The Ile436Lys mutation is characterized by low factor XI activity and antigen, namely is a cross-reaction material negative form. Molecular modeling indicates that the Ile436Lys mutation causes a large conformational change within the 432-442 loop. No relation could be traced among the different families; however, all their ancestors were autochthonous of the same two small towns. Furthermore, no Jewish ancestry could be found. The close geographical area in which all these patients were found and the absence of the same mutation in the general population of the area strongly suggests a founder effect and that the mutation is responsible for the defect. The compound heterozygosis with the Glu 117 stop mutation, common among Jews, was not surprising because of the past strict ties of the Republic of Venice with the Middle East.

The clinical significance of the lack of arterial or venous thrombosis in patients with congenital prothrombin or FX deficiency.

Several reports have dealt with the occurrence of both arterial and venous thrombosis in patients with haemophilia A, haemophilia B, and von Willebrand disease. Similar thrombotic events have been occasionally reported also in rare congenital coagulation disorders, particularly in fibrinogen or FVII deficiencies. On the contrary no sure venous or arterial thrombotic event has ever been reported in congenital prothrombin or Factor X deficiency. The significance of this observation is discussed. This discrepancy cannot be explained on the basis of the rarity of the two conditions, since in similarly rare congenital bleeding disorders such as FV or FXIII deficiency a few patients with thrombosis have been described. It appears that only these two defects are able to allow a sure protection from thrombosis. These observations may indirectly support the rationale for the use of direct thrombin or Factor X inhibitors in the prophylaxis and/or therapy of thrombotic manifestations.

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.

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.

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.

Novel point mutation in a leucine-rich repeat of the GPIbalpha chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard-Soulier syndrome affecting two unrelated families: the N41H variant.

In Italy, a significant proportion of patients with autosomal dominant inheritance of macrothrombocytopenia have been recognized as having heterozygous Bernard-Soulier syndrome carrying the Bolzano-type defect. This condition prompted a systematic review of our out-patients with chronic isolated macrothrombocytopenia. We recognized that the affected members of two unrelated families represented a new variant of heterozygous Bernard-Soulier Syndrome with autosomal dominant inheritance. Sequencing analysis of the GPIbalpha gene revealed a novel heterozygous mutation, A169C, resulting in an N41H substitution in the protein. This aminoacid belongs to the first leucine-rich repeat of the chain. The molecular modeling suggests that the replacement of the N41 with a histidine (N41H) drastically disturbs the structure of the first portion of GPIbalpha N-terminal, directly involved in von Willebrand factor binding. As a consequence, platelet aggregation to 1.2 mg/mL of ristocetin is slightly impaired and flow cytometry reveals a reduced binding of monoclonals directed against N-terminal epitopes of the GPIbalpha.

Genetic study in patients with factor XII deficiency: a report of three new mutations exon 13 (Q501STOP), exon 14 (P547L) and -13C>T promoter region in three compound heterozygotes.

A group of 29 patients with congenital factor XII (FXII) deficiency belonging to nine distinct families have been investigated. All were cases of true deficiency in the sense that there was no discrepancy between FXII activity and FXII antigen. From a clotting point of view, 11 patients appeared homozygous, as both FXII activity and antigen were very low (< or =1% and traces of antigen). In other words, they were cases with no cross-reactivity material. In the heterozygotes, FXII activity and antigen were about 50% of normal in all cases. The molecular studies revealed that seven patients were real homozygotes for the mutation -8G>C in the promoter region confirming the conclusions reported by coagulation tests. On the contrary, the remaining patients with a homozygote-like phenotype were instead found to be compound heterozygous for two distinct mutations. Three of these mutations were new mutations, namely the combination of -8G to C with 501Q to T (exon 13), 547P to L (exon 14) and -13C to T in the promoter, respectively. The remaining mutations seen were not new. It is interesting that all compound heterozygotes showed a clotting and immunological pattern similar to that shown by homozygotes, namely very low FXII activity and antigen. The new mutations were not present in the group of 98 normal persons of both sexes with the same geographical background. The wide diffusion of the -8G>C mutation in this group of patients coming from a limited geographical area suggests a founder effect. The significance and importance of genetic analysis in addition to clotting and immunological studies in FXII deficiency is emphasized.

A case of Bernard-Soulier Syndrome due to a homozygous four bases deletion (TGAG) of GPIbalpha gene: lack of GPIbalpha but absence of bleeding.

More than 20 DNA mutations with different inheritance pattern have been described in patients with Bernard-Soulier Syndrome (BSS), leading to abnormal or absent synthesis and/or expression of GPIbalpha. Clinical phenotype shows considerable variation between individuals, such as bleeding, platelet count and the percentage of large platelets. We describe in a BSS patient the first case of homozygous four bases deletion (TGAG) in the gpIbalpha gene coding sequence, leading to a premature stop codon. In the propositus, blood smears revealed giant platelets (30 x 10(9) platelets/L), and platelet agglutination to ristocetin was absent. Propositus' parents are consanguineous. His father and paternal grandmother showed a mild thrombocytopenia (108 x 10(9)/L and 120 x 10(9)/L platelets respectively) while mothers and sister's referred normal platelet counts. The surface expression of GPIbalpha was practically undetectable by flow-cytometry and western blot in the patient and was reduced in the father. Proband's DNA analysis revealed a homozygous four-base-pair deletion (TGAG), starting from the last base of the codon for Ser39, leading to a coding frame shift with a new termination codon after 11 novel amino acids. The same mutation was seen in heterozygosis in both parents. This is the first report of GPIbalpha TGAG deletion in homozygous state even if the defect has already been described in a case of compound heterozygosis. Surprisingly, the propositus does not report any spontaneous bleeding tendency.

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.

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.