Platelet-mediated angiogenesis is independent of VEGF and fully inhibited by aspirin.

BACKGROUND AND PURPOSE: Platelets are major players in every step of vessel development through the local delivery of angiogenesis-modulating factors, including the pro-angiogenic protein VEGF and the anti-angiogenic endostatin. Although thrombin is a potent agonist and is highly elevated in angiogenesis-related diseases, studies regarding its action on the release of platelet angiogenic factors are scarce and controversial. Herein, we have investigated the role of thrombin not only in VEGF and endostatin release but also in net platelet angiogenic activity. EXPERIMENTAL APPROACH: Human platelets were stimulated with thrombin in the presence of the various inhibitors of the signalling pathways involved in platelet activation. Supernatants/releasates were used to determine the levels of angiogenic molecules and to induce angiogenic responses. KEY RESULTS: We found that thrombin induced the secretion of both VEGF and endostatin; however, the overall effect of the releasates was pro-angiogenic as they promoted tubule-like formation and increased the proliferation of endothelial cells. Both responses were only slightly suppressed in the presence of a VEGF receptor-neutralizing antibody. Pharmacological studies revealed that while inhibitors of PKC, p38, ERK1/2, Src kinases or PI3K/Akt exerted only partial inhibitory effects, aspirin fully blocked the pro-angiogenic activity of the releasate. CONCLUSIONS AND IMPLICATIONS: In contrast to current belief, platelet pro-angiogenic responses are independent of VEGF and appear to be the result of the combined action of several molecules. Moreover, our data reinforce the notion that aspirin is a good candidate for a therapeutic agent to treat angiogenesis-related diseases.

Clinical and prognostic usefulness of serum proteomic profile in hepatic colorectal metastases: a pilot prospective study.

PURPOSE: To analyze the use of proteomic profiles to discriminate healthy from patients with colorectal liver metastases (CLM) and to predict neoplastic recurrence after CLM resection. METHODS: From April 2005 to October 2008, 70 patients operated for first curative resection of CLM and 60 healthy controls underwent determination of preoperative serum proteomic profile. We performed a preliminary training with patients and controls and obtained a classification system based on these patients' proteomic profiles training. The system was then tested about the ability to predict the colon versus rectum origin, metachronous or synchronous appearance, risk of recurrence after CLM resection and whether a sample was from a control or a CLM patient. RESULTS: Sensitivity, specificity, positive and negative predictive values for detecting CLM patients were 75, 100, 100 and 54.6 %, respectively. Best CLM appearance time identification was 50 % and primary tumor origin identification was 62.5 %. Best classifications of neoplastic recurrence within the first year after CLM resection and during the follow-up period were 47.5 and 45 %, respectively. Larger training sets and prevalence-based training sets led to better classification of patients and characteristics. CONCLUSION: Proteomic profiles are a promising tool for discriminating CLM patients from healthy patients and for predicting neoplastic recurrence.

Sindrome hemofagocitico asociado a EMTC y crisis renal esclerodermica / Hemophagocytic syndrome associated to mixed connective

Una paciente de 63 años con diagnostico de enfermedad mixta del tejido conectivo (polimiositis, esclerosis sistemica progresiva, RNP+) consulta por episodio de lesiones equimoticas en abdomen, manos y pies con plaquetopenia y laboratorio compatible con coagulopatia por consumo. En la puncion de medula osea se encuentra, celularidad disminuida con serie megacariocitica ausente y abundantes macrofagos con fenomemo de hemofagocitosis

Sindrome hemofagocitico asociado a EMTC y crisis renal esclerodermica / Hemophagocytic syndrome associated to mixed connective

Una paciente de 63 años con diagnostico de enfermedad mixta del tejido conectivo (polimiositis, esclerosis sistemica progresiva, RNP+) consulta por episodio de lesiones equimoticas en abdomen, manos y pies con plaquetopenia y laboratorio compatible con coagulopatia por consumo. En la puncion de medula osea se encuentra, celularidad disminuida con serie megacariocitica ausente y abundantes macrofagos con fenomemo de hemofagocitosis (AU)

Reversal of excessive oral anticoagulation with a low oral dose of vitamin K1 compared with acenocoumarine discontinuation. A prospective, randomized, open study.

We performed a prospective, randomized, open study in 109 outpatients under chronic anticoagulation with acenocoumarine, presenting with International Normalized Ratios (INRs) > or = 6.0 and no or minor bleeding. All the patients withheld one dose of acenocoumarine; in addition, a treated group also received 1 mg oral vitamin K1. We aimed at a post-intervention INR < 6.0, with a target zone of 2.0-4.0. The INRs were lowered from a mean of 8.1 +/- 1.7 to 4.9 +/- 2.5 in the controls (P = 0.0000) and from 8.4 +/- 2.4 to 3.3 +/- 3 in the treated patients (P = 0.0000). There were no differences in the percentage of patients with post-intervention INRs < 6.0 or within the therapeutic zone. One-third of the treated patients and only 2% of the controls reached INRs < 2.0 (P = 0.0003). Oral vitamin K1 offered no advantage to the simple discontinuation of one dose of acenocoumarine. A substantial number of treated patients were consequently exposed to under-anticoagulation.

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.

Anticoagulation in pregnant women with mechanical heart valve prostheses.

OBJECTIVE: To evaluate the outcome of pregnancy in women with mechanical heart valve prostheses in relation to the anticoagulant treatment used in the first trimester and the incidence of thrombotic and bleeding complications. METHODS: 92 pregnancies in 59 women were followed between 1986 and 1997. In 31 pregnancies, oral anticoagulants were discontinued when pregnancy was diagnosed and subcutaneous heparin was started (12 500 U every 12 hours) adjusted to prolong the adjusted partial thromboplastin time to twice the control level. In the second trimester oral anticoagulants were resumed but changed to heparin again 15 days before the expected delivery date. In 61 pregnancies oral anticoagulants were continued during the first trimester. The same regimen of heparin was used for delivery. RESULTS: Abortion or fetal losses were similar (p = 0. 5717) in women exposed to oral anticoagulants in the first trimester (13/61; 25%) compared with those who received adjusted subcutaneous heparin (6/31; 19%). Embolic episodes were more common (p = 0.0029) in women who received heparin (4.92%) compared with those on oral anticoagulants (0.33%). Embolic episodes were cerebral and transient. No valve thromboses were observed. No malformations appeared in the 71 newborns, except for one case of hydrocephalus. There were no maternal deaths secondary to thrombotic complications. The only death was the result of major bleeding after the delivery of a premature stillborn. CONCLUSIONS: Oral anticoagulants seem to be safer for the mother than adjusted subcutaneous heparin. Heparin does not offer a clear advantage over oral anticoagulation in the pregnancy outcome.

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.

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.

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.