Over-anticoagulation by vitamin K antagonists and gender differences.

BACKGROUND: Several studies have shown that in patients treated with vitamin K antagonists (VKAs) time spent in therapeutic range (TTR) is lower in females than in males. This retrospective study has evaluated a possible association among over-anticoagulation and gender, type and indications to VKAs, TTR and bleeding. Moreover, the decrease of the INR level, after VKAs withdrawal, was considered. METHODS: From December 2020 to January 2004, 1230 patients with venous thromboembolism or atrial fibrillation were enrolled. Age, gender, type of VKAs, clinical indications, INR values and bleeding events were recorded. TTR was calculated considering the entire period of treatment. RESULTS: A total of 1616 and 1759 over-anticoagulation episodes were found in males and females, respectively. The median INR value was 4.5 (4.0-19.04). Thirty-two percent of the patients did not have an overdose throughout the observation period. The median number of over-anticoagulation per year was significantly higher in females (0.39-year) than in males (0.28-year). After 24 h of VKAs withdrawal, INRs were similar in both genders. Logistic regression analysis showed that the episodes of over-anticoagulation per year were associated with females, atrial fibrillation, warfarin therapy, follow-up length longer than 4 years, and TTR <73%, but were not associated to bleeding episodes. CONCLUSION: The higher number of over-anticoagulation can explain the lower TTR in females. An excess of anticoagulation is not associated with bleeding events. The recovery of INR performs better when acenocoumarol is used, therefore, in patients who present several episodes of over-anticoagulation, acenocumarolo could replace warfarin.

Clinical history and gastrointestinal bleeding in patients taking oral anticoagulants.

BACKGROUND: Common risk factors for gastrointestinal bleeding (GIB) are advanced age and the use of antiplatelet or anticoagulants drugs for the prevention of cardiovascular diseases. METHODS: In this prospective real-world observational study, oral anticoagulated patients were recruited and followed between June 2013 and December 2019. The primary end-point was to evaluate a possible relationship between bleeding events and patients' clinical history of gastrointestinal disease prior to the start of the therapy. The secondary end-points were time of GIB appearance and the percentage of idiopathic or provoked events, i.e., bleeding due to a gastrointestinal disease. In case of GIB event all the patients were studied by means of endoscopic procedures. Cox regression was used to calculate the relative hazard ratios (HRs) of GIB for each considered clinical variable. RESULTS: 734 patients on both VKAs or DOACs were studied. Overall, 46 hemorrhagic events were recorded: 6 were major bleeding (0.42/100 patient-years) while 43 were clinically relevant non major bleeding (2.8/100 patient-years). The Cox regression analysis did not show any relationships among GIB and the variables considered. CONCLUSION: The patients' clinical history is neither a predictor for GIB bleeding nor a guide to the choice of the oral anticoagulant to be administered. Routinely applying bleeding risk screening, such as occult blood in the stool, should be added to the periodic laboratory checks for early recognition of patients at higher risk of GIB.

Bleeding diathesis and gastro-duodenal ulcers in inherited cytosolic phospholipase-A2 alpha deficiency.

Arachidonic acid (AA), when cleaved from phospholipids by cytosolic phospholipase A2 alpha (cPLA2a), generates eicosanoids, with pro-hemostatic, pro-inflammatory, vasoactive and gastro-protective functions. We describe a patient (27-year-old man) and his twin-sister with early-onset bleeding diathesis and recurrent gastro-intestinal (GI) ulcers. Platelet aggregation/δ-granules secretion by collagen was impaired, but normal by AA; serum levels of thromboxane (Tx) B2 and 12-hydroxyeicosatetraenoic acid, and urinary levels of 11-dehydro-TxB2 were extremely low. Patients were homozygous for 1723G>C transition in PLA2G4A gene, which changed the codon for Asp575 to His. GI ulcers affected 5/14 heterozygous (< 40 years) and 1/16 wild-type homozygous (> 60 years) family members; none had bleeding diathesis. The proband, his sister and mother also had mildly reduced factor XI levels. Platelet messenger RNA expression did not differ among subjects with different PLA2G4A genotypes. Conversely, platelet cPLA2a was undetectable by Western Blotting in the proband and his sister, and decreased in 1723G>C heterozygous subjects, suggesting that the variant is transcribed, but not translated or translated into an unstable protein. We described a syndromic form of deficiency of cPLA2a , characterised by recurrent GI ulcers and bleeding diathesis, associated with mild inherited deficiency of factor XI. Unlike other reported patients with cPLA2a deficiency, these patients had extremely low levels of platelet TxA2 biosynthesis.

Incidence of neutropenia and infections during combination treatment of chronic hepatitis C with pegylated interferon alfa-2a or alfa-2b plus ribavirin.

BACKGROUND: Combination therapy with pegylated interferon (peginterferon) plus ribavirin is associated with several side effects, including neutropenia and infection. AIMS: To evaluate the incidence of neutropenia and infection between all consecutive patients with hepatitis C who were treated in two centers with peginterferon-alfa-2a and peginterferon-alfa-2b, in combination with ribavirin and actively monitored for occurrence of any infection. METHODS: A total of 319 consecutive patients with chronic hepatitis C received once-weekly peginterferon alfa-2b at a weight-adjusted dose (n=162) or peginterferon alfa-2a at a flat dose (n=157), plus ribavirin. RESULTS: Neutropenia was observed in 53 patients overall (17%). There were 73 infections in 73 subjects (23% of the treated population); 4/73 required hospitalization. Infections included respiratory infections (n=23), cellulitis (n=17), dental abscesses (n=13), gastroenteric infections (n=2), and other types of infections (n=18). The incidence of all infections was significantly associated with age, especially over 60 years (p<0.01) but not with neutropenia or type of pegylated interferon. CONCLUSIONS: During the treatment with pegylated interferons and ribavirin, we did not find a correlation between neutropenia and infections. This result provides a support for the notion that current guidelines for pegylated interferons dose reduction in the treatment of chronic hepatitis C for hematologic toxicity could be overly strict.

Understanding diffusion in confined systems: methane in a ZK4 molecular sieve. A molecular dynamics simulation study.

The equilibrium probability distribution of N methane molecules adsorbed in the interior of n alpha cages of the ZK4 zeolite, the all-silica analogue of zeolite A, is modeled by a modified hypergeometric distribution where the effects of mutual exclusion between particles are extracted from long molecular dynamics simulations. The trajectories are then analyzed in terms of time-correlation functions for the fluctuations in the occupation number of the alpha cages. The analysis digs out the correlations induced by the spatial distribution of the adsorbed molecules coupled with a migration mechanism where a molecule can pass from one alpha cage to another, one-by-one. These correlations lead to cooperative motion, which manifests itself as a nonexponential decay of the correlators. Our results suggest ways of developing improved lattice approaches that may be useful for studying diffusion in much larger systems and for a much longer observation time.

Blood coagulation, fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis.

OBJECTIVE: To evaluate the coagulative/fibrinolytic cascade and the circulating markers of the endothelial injury in systemic sclerosis (SSc). METHOD: Plasma was obtained from 29 patients with SSc and tested for thrombin-antithrombin (TAT), fragments 1+2 (F1+2), dermatansulphate (DS), thrombomodulin (TM), lipoprotein (a) [Lp(a)], von Willebrand factor (vWF), tissue type plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimers, intercellular adhesion molecole-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and E-selectin. The data were correlated with lung (forced vital capacity, diffusing lung capacity for carbon monoxide, vital capacity) and skin (skin score) involvement. RESULTS: Coagulation was significantly activated (increase in F1+2, P <.001; TAT, P <.01; and Lp(a), P <.05). TM was not significantly different from controls. vWF was significantly increased (P <.01), and its supranormal multimers increased in more than 50% of patients. DS was significantly increased in diffuse cutaneous SSc (P <.01). Fibrinolysis was impaired as shown by reduced D-dimers (P <.01) and decreased levels of PAI (P < 0.01). The markers of endothelial injury were also significantly elevated. DS correlated significantly with forced vital capacity (P <.01) and forced vital capacity ratio (P <.01). CONCLUSION: Injury to the endothelium reduces endothelial function, as suggested by impairment of fibrinolysis and activation of the coagulative pathway. The loss of the balance between fibrinolysis and coagulation contributes to vessel engulfment with fibrin and breakdown of vessel patency. The increase of circulating DS suggests that this factor may be a new marker of endothelial injury.

Warfarin or acenocoumarol: which is better in the management of oral anticoagulants?

Warfarin is employed more frequently than acenocoumarol because of its longer half-life (36 h), theoretically providing more stable anticoagulation, and avoiding factor VII fluctuations that potentially occur during acenocoumarol treatment (half-life 10 h). The aim of our study was to compare acenocoumarol with warfarin in the same group of 103 patients who started oral anticoagulation with acenocoumarol and then changed to warfarin. In these patients we compared the previous period of six months on acenocoumarol treatment (July-December 1996) with a new six-month period on warfarin (July-December 1997). We wished to know whether warfarin could improve the quality and the stability of oral anticoagulation of our patients and whether there was a difference between the two drugs in the weekly mean dose per patient. Moreover in order to detect the possible daily fluctuation of factor VII, we evaluated a further group of 54 patients. A subgroup of these patients was treated with warfarin while another received acenocoumarol. In the first group of patients, 1,158 and 1,064 PTs were carried out with acenocoumarol and warfarin, respectively. The percentage of PTs in the therapeutic range was 59% with acenocoumarol and 62% with warfarin (p=0.4). The mean number of visits per patient was 12 and 11, and the mean number of visits in the therapeutic range was 7 and 7, respectively. The last check in file method did not show any difference between the two drugs. Overdose states were 51 (4.4%) with acenocoumarol and 30 (2.8%) with warfarin (p=0.4). A good correlation (r=0.92) was found between the acenocoumarol and the warfarin weekly mean dose. The mean warfarin/acenocoumarol weekly dose ratio was 2.08 (range: 1.25-3.30; CI 95%: 1.99-2.16). In the second group of patients, factor VII levels with both drugs were higher 24 h after administration than 16 h after, showing that their daily fluctuation was independent of the drug's half-life, since factor VII levels in patients with a low vitamin K intake were not increased. Our results showed that warfarin did not appear to be better than acenocoumarol in the performance of an Anticoagulation Clinic in terms of PTs within the therapeutic range per patient. It seems that the behaviour of factor VII was affected by the intake of vitamin K rather than by the short half-life of acenocoumarol.

Frequency of the delta F508 mutation in a sample of 175 Italian cystic fibrosis patients.

A sample of 175 Italian cystic fibrosis patients has been analysed for the presence of the delta F508 mutation. The frequency of this mutation among 137 patients with pancreatic insufficiency is equal to 57%; in 23 patients with pancreatic sufficiency it is 26%. A high proportion of the unknown mutations is associated with the same rare haplotype found in association with delta F508, suggesting that at least another mutation occurred on a chromosome characterized by the same haplotype.