Carlos Fondevila

Low-intensity oral anticoagulation plus low-dose aspirin versus high-intensity oral anticoagulation alone : A randomized trial in patients with mechanical prosthetic heart valves

BACKGROUND Mechanical heart valve replacement requires lifelong anticoagulant treatment. Aspirin has proved useful in further reducing thromboembolic events when added to oral anticoagulants. However, increased (gastrointestinal) bleeding was observed at the doses previously tested for this combination in heart valve prostheses. METHODS We performed a prospective randomized trial to compare the combination of low-intensity oral anticoagulants (international normalized ratio 2.5 to 3.5) plus aspirin (100 mg/day) (arm A) versus high-intensity oral anticoagulants alone (arm B) (international normalized ratio 3.5 to 4.5). Arm A included 258 patients and arm B 245 patients. The two groups were comparable for all baseline characteristics. RESULTS The outcomes of the study were embolism, valve thrombosis, and major hemorrhage. The median follow-up was 23 months. The two treatments offered similar antithrombotic protection. The incidence of embolic episodes was 1.32 per 100 patient-years (95% confidence interval 0.53 to 2.7) for arm A and 1.48 per 100 patient-years (95% confidence interval 0.59 to 3.03) for arm B. Major hemorrhage occurred in 1.13 per 100 patient-years (95% confidence interval 0.41 to 2.45) for arm A and 2.33 per 100 patient-years (95% confidence interval 1.17 to 4.14) for arm B. Gastrointestinal bleeding was not increased by this combined reduced dose of aspirin and coumarin.

Bleeding risk factors in chronic oral anticoagulation with acenocoumarol

We studied major bleeding complications, death related to hemorrhage, and tried to identify predisposing factors for bleeding in outpatients treated with acenocoumarol. We evaluated 811 outpatients attending a specialized anticoagulant therapy unit. The intended INR range was 3.5–4.5 for mechanical heart valve replacement (N= 384) and 2.0–3.0 for other indications (N= 427). The variability of INR for the total follow‐up and the 2 months before the hemorrhage was calculated. The total follow‐up was 1,963.26 years with 27,321 control tests. We observed 47 major bleeding episodes, including 2 fatal (central nervous system hemorrhages), in 37 patients. 49.5% of the patients had underlying diseases. The rate of major and fatal hemorrhage was 2.39 and 0.10 episodes per 100 patients year, respectively. Hemorrhagic complications were more frequently observed in patients with a more intense intended range (8.2% in the INR 3.5–4.5 group vs. 1.5% in the 2.0–3.0 INR group). The risk of major bleeding increased in patients with an achieved INR higher than 6 and in those with higher INR variability during follow‐up. The estimated probability of bleeding also increased with time: it was 0.102% at 78 months, and at the beginning of therapy it was 0.006% and 0.007% at 1 and 4 months, respectively. The intensity of anticoagulation and the deviation of the INR from the target are the most important risk factors for bleeding in patients taking acenocoumarol. Monitoring the variability of INR can help identifying patients predisposed to bleeding. However, the screening for underlying disease should always be performed. Am. J. Hematol. 63:192–196, 2000.

Effect of acenocoumarine on the breast-fed infant

Apart from teratogenic phenomena and the potential risk of maternal or neonatal peripartum haemorrhage, the use of oral anticoagulants during pregnancy poses an additional hazard: the risk of transferring some anticoagulant activity to the nursing infant through breast milk. We analysed the coagulation status of seven full term breast-fed neonates whose mothers were under chronic anticoagulant therapy with acenocoumarine as thromboembolic prophylaxis following cardiac valve replacement. Prothrombin Times (PT) observed in neonates were significantly higher than the corresponding maternal values. Data were subsequently compared with those obtained from a control group comprising forty-two full term neonates nursed by non-anticoagulated mothers: coagulation profiles again showed no signs of any noticeable antivitamin K effect. Our results indicate that mothers given acenocoumarine at therapeutic doses may safely breast-feed their infants: anticoagulant activity in breast milk seems to be negligible as assessed by neonates PT.

Poly (I:C) downregulates platelet production and function through type I interferon.

Thrombocytopenia is a frequent complication of viral infections; the underlying mechanisms appear to depend on the identity of the virus involved. Previous research, including reports from our group, indicates that as well as having antiviral activity type I interferons (IFN I) selectively downregulate platelet production. In this study we extended understanding of the role of endogenous IFN I in megakaryo/thrombopoiesis by evaluating platelet and megakaryocyte physiology in mice treated with polyinosinic:polycytidylic acid [poly (I:C)], a synthetic analogue of double-stranded RNA, Toll-like receptor-3 ligand and strong IFNβ inducer. Mice-treated with poly (I:C) showed thrombocytopaenia, an increase in mean platelet volume and abnormal haemostatic and inflammatory platelet-mediated functionality, indicated by decreased fibrinogen binding and platelet adhesion, prolonged tail bleeding times and impaired P-Selectin externalisation, RANTES release and thrombin-induced platelet-neutrophil aggregate formation. These changes were associated with an increase in size and an abnormal distribution of bone marrow megakaryocytes within the vascular niche and were directly correlated with the plasmatic and bone marrow IFNβ levels. All these effects were absent in genetically modified mice lacking the IFN I receptor. Our results suggest that IFN I is the central mediator of poly (I:C)-induced thrombocytopenia and platelet dysfunction and indicate that these abnormalities are due to changes in the last stages of megakaryocyte development. These data provide new evidence for the role of IFN I in megakaryocyte distribution in the bone marrow niches and its influence on thrombopoiesis and haemostasis.

Nucleosomes and neutrophil extracellular traps in septic and burn patients

NETosis is a host defense mechanism associated with inflammation and tissue damage. Experimental models show that platelets and von Willebrand factor (VWF) are key elements for intravascular NETosis. We determined NETosis in septic and burn patients at 1 and 4days post-admission (dpa). Nucleosomes were elevated in patients. In septics, they correlated with Human Neutrophil Elastase (HNE)-DNA complexes and SOFA score at 1dpa, and were associated with mortality. Patients neutrophils had spontaneous NETosis and were unresponsive to stimulation. Although platelet P-selectin and TNF-α were increased in both groups, higher platelet TLR-4 expression, VWF levels and IL-6 were found in septics at 1dpa. Neither platelet activation markers nor cytokines correlated with nucleosomes or HNE-DNA. Nucleosomes could be indicators of organ damage and predictors of mortality in septic but not in burn patients. Platelet activation, VWF and cytokines do not appear to be key mediators of NETosis in these patient groups.

Persistence of low platelet adhesiveness in von Willebrand disease during pregnancy.

Platelet adhesiveness (PA) is a valuable measure of ex vivo platelet function. A low PA is a usual feature of von Willebrand disease (vWd). However, PA has rarely been measured during vWd pregnancies. The aim of this work was to observe the behaviour of PA in vWd pregnancies. PA was measured during pregnancy in 33 vWd patients. Intrapregnancy PA remained low without any significant variation compared with non-pregnancy values. Advanced gestation was not accompanied by any increase in PA in spite of the concomitant normalization showed by the other markers of vWd. A low intrapregnancy value was not predictive of an increased risk of bleeding at labour. A low PA could be the only clue for vWd during gestation warranting both a vigilant postpartum attitude and a thorough haemostatic evaluation after pregnancy.

Prevalence of Anemia and Occult Blood Losses in the Long-Term Follow-Up of Cardiac Mechanic Valve Patients Treated with a Combination of Low-Dose Aspirin Plus Low-Intensity Acenocoumarin

Mechanic replacement of cardiac prostheses requires lifelong and high-intensity oral anticoagulant treatment. The addition of aspirin to coumarin treatment has resulted in more effective thromboembolic prevention, though it also led to increased (digestive) bleeding. Aspiriri enhanced the risk of apparent or occult gastrointestinal bleeding in a dose-dependent fashion. The combined use of low-dose aspirin/low-intensity coumarins might offer a safer approach. We prospectively evaluated the prevalence of anemia markers in 127 prosthesic valve patients, receiving two treatment modalities: Group A comprised 62 patients who received 100 mg acetylsalicylic acid (ASA) added to acenocoumarin [international normatized ratio (INR) 2.5-3.5]. Group B comprised 65 patients receiving acenocoumarin alone (INR, 3.5-4.5). We found no significant differences in the mean values for the blood markers of anemia or for the presence of blood losses in urine and feces. The addition of low-dose ASA to less intense chronic anticoagulation does not increase the risk of developing anemia. Key Words: Anticoagulants—Aspirin—Coumarins—Gastrointestinal hemorrhage—Heart valve prosthesis.