Time course of hemostatic abnormalities in sepsis and its relation to outcome.

OBJECTIVES: To investigate the time course and the relation to prognosis of coagulation and fibrinolytic abnormalities in patients with septic shock. PATIENTS AND METHODS: Forty-eight consecutive patients admitted to the medical ICU with the diagnosis of septic shock (diagnosed by defined criteria) were studied. Mortality was 25 of 48. Mean age was 57 +/- 7.3 years. Blood samples were obtained on days 1, 4, and 7 after hospital admission to measure tissue-type plasminogen activator antigen (t-PA), urokinase-type plasminogen activator (u-PA), plasminogen activator inhibitor antigen (PAI-1), plasminogen, alpha 2-antiplasmin, fibrinogen, antithrombin III, protein C, protein S, thrombin-antithrombin complexes (TAT), D-dimer, and von Willebrand factor-related antigen (vWF:Ag). RESULTS: All patients showed marked abnormalities in both the coagulation and fibrinolytic systems. There were signs of coagulation activation and elevation of both activators and inhibitors of fibrinolysis. Nonsurvivors showed lower levels of protein C and antithrombin III and higher concentration of TAT than survivors. While both t-PA and PAI-1 concentrations were high in survivors and nonsurvivors, only survivors showed a progressive normalization of both parameters during the study period. Low plasminogen levels and plasminogen/alpha 2-antiplasmin ratio were found in both groups, presenting a trend toward normalization only in survivors. The differences reported were not apparent at the time of hospital admission. CONCLUSIONS: Septic shock is characterized by coagulation activation and fibrinolysis activation and inhibition. Nonsurvivors present a particular hemostatic profile characterized by a more marked activation of coagulation and a more intense inhibition of fibrinolysis. None of the abnormalities studied was significantly different between survivors and nonsurvivors at the time of hospital admission. In the presence of fibrin formation, nonsurvivors present a maintained imbalance in the fibrinolytic response determined by higher PAI-1 plasma concentration, probably contributing to their poor outcome.

Subcutaneous versus intravenous low-dose IL-2 therapy after autologous transplantation: results of a prospective, non-randomized study.

Use of IL-2 therapy after autologous transplantation is currently being explored to reduce relapse rate. Low doses of the cytokine induce significant immunomodulation avoiding the severe side-effects associated with high-dose IL-2 therapy. However, low-dose IL-2 is usually given by continuous infusion through central venous lines with the consequent risks of thrombosis and infections. Twenty-six consecutive patients who received autologous transplants received low-dose IL-2 after stable engraftment had been achieved. The first 13 patients (group A) were scheduled to receive 400,000/IU/m2/day for 3 months by continuous intravenous infusion. Ten of these patients suffered infectious episodes, mainly bacteriemias that often necessitated delaying IL-2 therapy (median delivered dose: 32% of planned). The next 13 patients were then assigned to receive IL-2 (800,000-1,000,000 IU/m2/day for 3 months) subcutaneously (group B). For group B patients, median dose intensity was 84% (P = 0.01 when compared with group A patients). Only one severe infectious episode was observed in these patients. Clinical toxicity in group B patients consisted mainly of s.c. nodules. Immunomodulation, measured as an increase in the absolute number of CD56+ cells and CD56+(bright) cells, was higher in patients who received the cytokine by the subcutaneous route (median peak increase of CD56+ cells: 160 and 220% for group A and B patients respectively; median peak increase of CD56+(bright) cells: 210% and 310% for group A and B respectively, P < 0.05 between groups A and B). No statistically significant increment of T lymphocytes was observed in any group. No hematologic toxicity was observed apart from eosinophilia, which was very marked in group B (P < 0.01). Our results show that low-dose s.c. IL-2 therapy is associated with low clinical and hematologic toxicity after autologous transplantation. The immunomodulation achieved is no less than that achieved with the i.v. approach.

High plasma levels of plasminogen activator inhibitor 1 (PAI-1) in polycythemia vera and essential thrombocythemia are associated with thrombosis.

We attempted to determine if a hypercoagulability state exists in patients with polycythemia vera (PV) and essential thrombocythemia (ET). We studied the hematocrit level, platelet count, use of any antiaggregant drugs, thrombotic or bleeding accidents and plasma levels of antithrombin III, protein C, total protein S, free protein S, vWF:Ag (Von Willebrand's factor related antigen), thrombin-antithrombin complexes, D-dimer, fibrinolytic activity, tissue plasminogen activator, plasminogen and PAI-1 in 33 patients (19 with ET and 14 with PV). PAI-1 plasma concentration was significantly higher in, both ET and PV patients than in the control group, and were higher in those patients with previous thrombotic episodes than in asymptomatic patients or with previous bleeding episodes. Increasing age was associated to more thrombotic episodes while younger patients presented with more hemorrhagic complications. A linear correlation between platelet count and PAI-1 levels in PV patients (r = 0.44, p < 0.05) and ET patients (r = 0.30, p < 0.05) was found. Fibrinolytic activity in patients with ET was significantly decreased when compared to the control group. A hypofibrinolytic state could be an additional factor which could be used as a predictive index of the thrombotic or bleeding tendency in each patient.

Coagulative system activation and fibrinolytic system inhibition activities arise from tumoral draining vein in colon carcinoma.

UNLABELLED: Hypercoagulability and activation/inhibition of the fibrinolytic system have been observed in abdominal cancer surgery. Because surgery itself and also neoplastic diseases are associated with these situations, a method for separating the origin of these two processes was designed. Eighteen patients with colon cancer who underwent a surgical procedure were studied: Immediately before surgery blood was taken from a peripheral vein. During the surgical procedure, before the exclusion of tumoral tissue from general circulation and at the same time of a second peripheral vein blood sample, a blood sample was taken from the main tumoral draining vein. Platelet-poor plasma samples were aliquoted and stored at -72 degrees C, ready for analytical procedures. RESULTS: A moderate activation of the fibrinolytic system during surgery was observed, expressed by elevation of tissue plasminogen activator (t-PA) (P<.05) and D-dimer (DD) (P<.05) levels, without changes in fibrinogen (FG), plasminogen (PG) or antiplasmin (AP) levels. There were no modifications in antithrombin III (AT-III) and protein C (PC) levels. In the tumoral draining vein samples, there was a high elevation of levels of thrombin-antithrombin III complexes (TAT) (P<.001) and PAI-1 (P<.01), compared with the second sample peripheral vein. There was no difference between peripheral and tumoral vein sample levels of AT-III, PC, FG, DD, PG and AP. CONCLUSIONS: The tumour itself is the origin of hypercoagulability (TAT) and fibrinolytic system inhibition (PAI-1); the surgical procedure elicits an evident though moderate activation of the fibrinolytic system (t-PA and DD elevation).

High F1.2 fragment of prothrombin, thrombin-antithrombin III complex (TAT) and soluble fibrin plasma levels demonstrate hypercoagulability induced during loco-regional thrombolytic therapy with rt-PA.

In order to investigate the coagulation and fibrinolysis state in arterial peripheral thrombosis and thrombolysis, we studied 33 consecutive patients (mean age = 65, range: 28-88), 25 males and 8 females diagnosed of acute or subacute lower limb arterial thrombosis, treated with an intrathrombus infusion of rt-PA (0.1 mg/Kg/h) for three hours. Plasma levels of antithrombin III (AT-III), protein C (PC), plasminogen (Pg) and alpha 2-antiplasmin (AP), total and free protein S (PS), thrombin-antithrombin III complex (TAT), F1.2 fragment of prothrombin (F1.2), fibrinogen (Fg), soluble fibrin monomers (FM), tissue-plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), total fibrinogen/fibrin degradation products (TDP) and D dimer (DD) were determined prior to the therapeutic regime, at the end of the treatment, and 24 hours later. Levels of AT-III and protein C were somewhat low during the complete study. There was an increase in t-PA, TDP and D Dimer and a decrease of fibrinogen, alpha 2-antiplasmin and plasminogen at 3 hours. An elevation of TAT, fibrin monomers and F1.2 levels was found at three hours. A positive correlation between TAT and F1.2 was observed (r = 0.57, p < 0.05). There was also a positive correlation between soluble fibrin and TAT (r = 0.59, p < 0.05) and with F1.2 (r = 0.56. p < 0.05). These latter facts reflect an hypercoagulable situation induced during loco-regional thrombolytic therapy.

Degree of hypercoagulability and hyperfibrinolysis is related to organ failure and prognosis after burn trauma.

Severely burned patients often present a hypercoagulability situation. However, its magnitude, time course, and relationship with organ failure and outcome remains to be established. Forty-three patients were studied on the first and seventh day after burn for hypercoagulability and fibrinolysis parameters. A hypercoagulability and hyperfibrinolysis state was found the first day after burn demonstrated by high levels of activated factor VII (VIIa, p<0.01), thrombin-antithrombin III complex (TAT, p<0.01), tissue plasminogen activator (t-PA, p<0.001) and D dimer (DD, p<0.01) and low levels of antithrombin III (ATIII, p<0.01), protein C (PC, p<0.01), plasminogen (PG, p<0.001) and alpha2 antiplasmin (AP, p<0.001). A paradoxical coexisting hypofibrinolysis was found as suggested by a low global fibrinolytic activity in the euglobulin plasma fraction fibrin plate assay (FA, p<0.01) and high levels of tissue plasminogen activator inhibitor type 1 (PAI-1, p<0.01). On day 7, a less marked hypercoagulability situation was found, with low ATIII (p<0.01) and PC (p<0.01), persisting the hypofibrinolytic situation observed on the first day. Non-survivors (NS) showed higher levels of VIIa (p<0.01), TAT (p<0.05) and t-PA (p<0.05), and lower levels of ATIII (p<0.05), PC (p<0.05) and AP (p<0.001) than survivors (S) on the first day. Also, there was a positive correlation of Marshall organ failure score with ATIII, (r2=0.49, p<0.001), PC, (r2=0.14, p<0.045) and PG levels, (r2=0.41, p<0.0003). Severely burned patients show a state of transient disseminated intravascular coagulation, related to the development of organ failure and outcome.

Fibrinolytic parameters and lipoprotein (a) levels in plasma of patients with coronary artery disease.

Fibrinolysis and lipid disturbances have been considered as independent risk factors for coronary artery disease. Besides this, lipoprotein(a), which is characterized by its homology with plasminogen may interfere with the fibrinolytic function. To evaluate the eventual correlation between fibrinolytic parameters, lipoprotein (a) and other risk factors, 46 patients with coronary artery disease (34 with chronic angina pectoris and 12 with myocardial infarction) were studied. Increased basal values of t-PA antigen (8.2 and 6.6 vs. 4.2 ng/ml) but decreased response after stimulus (2.2 and 1.8 vs. 3.8 ng/ml) and increased levels of lipoprotein(a) (24.7 and 35.9 vs. 10.5 mg/dl) were the most relevant differences between coronary artery disease patients and controls. No correlation between lipoprotein(a) and fibrinolytic parameters was found. Therefore plasma concentration of the main plasma fibrinolytic parameters and lipoprotein(a) seem to be unrelated though the relevance of this interaction at a local level needs to be studied.

Hypofibrinolysis associated with vasculopathy in non insulin dependent diabetes mellitus.

The pathogenesis of diabetic vasculopathy has been related to modifications in hemostasis and fibrinolysis. 50 non insulin dependent diabetes mellitus patients have been studied. Euglobulin clot lysis time, fibrin plate, tissue plasminogen activator (t-PA) antigen, plasminogen activator inhibitor (PAI) activity, Protein C and S, cholesterol, triglycerides and Hb A1c were determined in blood samples. Diabetic patients showed decreased fibrinolytic activity, as measured by ECLT, with clearly increased PAI levels. Fibrinolytic response to venous occlusion was lower than normal. Vascular complications were associated both with an even higher PAI activity and with a decreased fibrinolytic response to venous occlusion. Elevated PAI activity and decreased fibrinolytic response to stimulus may contribute to vascular disease in diabetes.

Improvement in lipid and haemostasis patterns after Helicobacter pylori infection eradication in type 1 diabetic patients.

Helicobacter pylori has been implicated in the cardiovascular risk of diabetic patients. The aim of our study was to investigate whether the Helicobacter pylori infection plays a role in the lipid and haemostasis patterns of type 1 diabetic patients. Twenty nine patients with type 1 diabetes mellitus and H. pylori infection were enrolled (Chlamydia pneumoniae negative). The H. pylori infection status was assessed by serology and urease breath test. In all patients levels of total cholesterol, triglyceride, HDL cholesterol, LDL cholesterol, lipoprotein (a) (Lpa) C reactive protein (CRP), fibrinogen, thrombin/antithrombin III complex (TAT), plasminogen activator inhibitor type 1(PAI-1), tissue plasminogen activator (t-PA) and von Willebrand antigen were measured. All patients were evaluated before and after H. pylori eradicating treatment with amoxicillin, clarithromycin and omeprazole. Twenty two patients were eradicated and seven remained infected. In H. pylori eradicated patients, HDL cholesterol increased (59.7+/-18.9 mg/dl vs 65.2+/-15. 9 mg/dl, P << 0.05), after treatment. After H. pylori eradication, the levels of CRP and TAT decreased (48+/-0.7 ng/l vs 3.3+/-0.4 ng/l;P << 0.05), (27.7+/-44.7 microg/ml vs 2.1+/-1.4 microg/ml, P << 0.05), respectively. The decrease in TAT was higher in the group of H. pylori (+) patients with higher levels of TAT (TAT >> 20 ng/ml, 92.8+/-41.6 ng/ml vs 1.9+/-2.0 ng/ml, P << 0.005; TAT 4Eth 20 ng/ml; 10.1+/-5.2 ng/ml vs 2.2+/-0.6 ng/ml, P << 0.05). These changes did not occur in patients without H. pylori eradication. Eradication of H. pylori infection in type 1 diabetic patients modifies some parameters of lipid and haemostasis patterns, (increase of HDL-cholesterol, reduction of Lpa and decrease of CRP and TAT) and so contributes to improvement of cardiovascular risk factors in these patients.

[Pentoxifylline is not useful in the prevention of toxicity associated with bone marrow transplantation]. / La pentoxifilina no es útil en la prevención de la toxicidad asociada al trasplante de médula ósea.

BACKGROUND: To evaluate the possible beneficial effect of pentoxifylline (PTX) on both the decrease of toxicity related to bone marrow transplantation (BMT) and the acceleration of the hematopoietic graft. METHODS: Twenty consecutive patients treated with BMT received pentoxifylline (400 mg/6 hours, orally) up to day +50 to prevent toxicity derived from BMT. A previous group of 29 consecutive patients transplanted in the same center were used as controls. The different clinical toxicities (mucositis, kidney failure, hepatic venocclusive disease, graft versus host disease, number of days with fever, day of hospital discharge and survival at day +50), the time elapsed until the hematopoietic graft and the levels of tumoral necrosis factor alpha were evaluated. RESULTS: No significant differences were observed in any of the parameters studied in the two groups of patients. CONCLUSIONS: Treatment with pentoxifylline does not prevent the toxicity derived from BMT or accelerate the hematopoietic grafting.

Effectiveness of a diagnostic algorithm combining clinical probability, D-dimer testing, and computed tomography in patients with suspected pulmonary embolism in an emergency department.

OBJECTIVE: The aim of our study was to assess the clinical effectiveness of a simplified algorithm using the Wells clinical decision rule, D-dimer testing, and computed tomography (CT) in patients with suspected pulmonary embolism (PE) in an Emergency Department (ED). METHODS: Patients with clinically suspected PE from the Emergency Department were included from May 2007 through December 2008. Clinical probability was assessed using the Wells clinical decision rule and a VIDAS D-dimer assay was used to measure D-dimer concentration. Patients were categorized as "pulmonary embolism unlikely" or "pulmonary embolism likely" using the dichotomized version of the Wells clinical decision rule. Pulmonary embolism was considered excluded in patients with unlikely probability and normal D-dimer test (< 500 ng/ml). All other patients underwent CT, and pulmonary embolism was considered present or excluded based on the results. Anticoagulants were withheld from patients classified as excluded, and all patients were followed up for 3 months. RESULTS: 241 patients were included in the study. The prevalence of PE in the entire population was 23.6%. The combination of unlikely probability using the dichotomized Wells clinical decision rule and a normal D-dimer level occurred in 23.6%, thus making CT unnecessary. During the followup period, no thromboembolic events were recorded and there were no deaths related to venous thromboembolic disease (3-month thromboembolic risk 0% [95% CI, 0%-8%]). CONCLUSIONS: In this study we have confirmed the effectiveness of a diagnostic management strategy using a simple clinical decision rule, D-dimer testing, and CT in the evaluation and management of patients with clinically suspected pulmonary embolism.

[Cerebral venous thrombosis: when etiology makes the difference]. / Trombosis venosa cerebral: cuando la etiología marca la diferencia.

OBJECTIVES: To make a retrospective study of the clinical, etiological, diagnostic and prognostic features of cerebral vein and sinus thrombosis (CVST) diagnosed at our University Hospital. METHODS: We performed a systematic research of the clinical records of our University Hospital's electronic database (1977-2009) using the key words <>. RESULTS: Ninety-five possible cases were found, and 16 were excluded due to alternative or uncertain diagnosis. Seventy-nine patients (43 females), median age of 46 years (2-82), were studied. Hereditary or acquired thrombophilia was detected in 22 patients (27.8%): prothrombin G20210A mutation (10), factor V Leyden (3), protein C deficiency (2), homozygous MTHFR C677T mutation (1), antiphospholipid syndrome (7) and hematological conditions (3). CVST was associated with infection in 17 cases, intracranial neoplasm in 9, malignancy in 13, treatment with prothrombotic drugs in 20 (including substitutive/antineoplastic hormones and oral contraceptives) and other causes in 8. Thirteen cases were idiopathic. Clinical presentation was intracranial hypertension in 83.5%, focal deficits in 45.6% and seizures in 12.6 %. Transverse (57%) and superior sagittal sinus (49.4%) were the most commonly involved. Seizures occurred in 25.3%, venous infarction in 41% and severe intracranial hypertension in 22.8 %. Up to 31.6 % required surgical drainage, decompressive craniectomy or ventricular drainage. Nine cases associated peripheral venous thromboembolism and 4 CVST recurred. Evolution was favorable (modified Rankin scale 0-2 at 3 months) in 74.7%. Mortality rate was 13.9% (11 patients). Neoplastic and infectious origin was significantly associated with mortality and disability. CONCLUSION: We describe a large retrospective series of CVST where infectious and neoplastic etiologies were linked to an unfavorable outcome.

High prevalence of lupus anticoagulant in hemodialysis patients.

Coagulation studies were performed in 47 hemodialysis patients in order to assess abnormalities predisposing to thrombosis. A very high incidence of Lupus Anticoagulant was detected, a finding not previously described. This work is a preliminary report of this association and of its possible clinical implications.

Increased levels of plasma von Willebrand factor in migraine crisis.

INTRODUCTION: To evaluate the participation of the vessel wall in the pathogenesis of migraine attack, we measured the plasma levels of von Willebrand factor (vWF), a protein secreted from the endothelial cells. MATERIAL & METHODS: 17 patients suffering from migraine without aura and 25 healthy volunteers were studied. von Willebrand factor and platelet aggregation tests were studied by conventional methods. RESULTS: The levels of vWF:antigen increased from 72.4 +/- 29 U/dl in the intercrisis to 130.2 +/- 75 U/dl during the attack (p < 0.01). We did not detect difference in the platelet aggregability in both phases. Plasma vWF activity measured as ristocetin cofactor (vWF:RCo) was similar in intercrisis and crisis (100.6 +/- 31 U/dl vs 94.5 +/- 44 U/dl). CONCLUSIONS: There is a plasma release of vWF molecules during the migraine crisis. This feature is not platelet dependent and is probably a consequence of endothelial stress.

Von Willebrand factor availability in platelet concentrates stored for 5 days.

Von Willebrand factor (vWF) availability was assessed in platelet concentrates (PCs). After 5 days of storage, 82 +/- 9% of basal levels of ristocetin cofactor activity (vWF:RCo) remained in PCs. vWF antigen (vWF:Ag) increased up to 166 +/- 38% (P < 0.05) in the same period. Autoradiograph pattern of vW:Ag showed an increase in low molecular weight multimers, and fast migrating multimeric forms were visualized by crossed immunoelectrophoresis on day 5. Studies carried out in platelet free plasma stored as PCs showed similar changes in vWF:RCo but increments in vWF:Ag were not detected. These data indicate that PCs maintain vWF:RCo levels of clinical value even after 5 days of storage and suggest that vWF comes out from platelets to plasma during storage.

[Current status of thrombolysis. The need for coadjuvant antithrombotic therapy]. / Estado actual de la trombolisis. Necesidad de la terapéutica antitrombótica coadyuvante.

Thrombolytic therapy yields a 80% repermeabilitation in the acute myocardium infarct if applied soon. In other thrombotic sites such as deep venous thrombosis, pulmonary thromboembolism and peripheral arterial thrombosis, with no large cooperative randomized clinical trials, its usefulness is clear, tough selectively. The high rethrombosis frequency is the major drawback of this therapy. The concomitant use of an anti-thrombotic and/or anti-aggregant agent, even tough the possible higher risks of hemorrhages, seems a key element to improve the results obtained with thrombolysis.

High plasma urokinase-type plasminogen activator levels are present in patients with acute nonlymphoblastic leukemia.

An exaggerated hemorrhagic syndrome is a characteristic in acute non-lymphoblastic leukemia (ANLL) and it determines the patient's outcome. Disseminated intravascular coagulation as a result of a procoagulant factor release and primary hyperfibrinolysis due to plasminogen activators also released by leukemic cells have been implicated in the development of this syndrome. The aim of this work was to evaluate urokinase-type plasminogen activator (u-PA) and related parameters of the fibrinolytic system in 14 ANLL patients. Our results showed an increased u-PA concentration in ANLL patients compared to controls [2.63 (1.61-4.62) vs. 0.95 (0.77-1.48) ng/ml, p < 0.01]. u-PA levels correlated positively with tissue-type plasminogen activator. The relevance of the enhancement of u-PA in this clinical setting was supported by the fact that it was the only analytical parameter positively correlated with patient mortality (p < 0.05). Though u-PA levels do not seem to be the determining factor in the development of the hemorrhagic syndrome of ANLL patients, a contributory role of this plasminogen activator is suggested from our results.

Hereditary hemorrhagic telangiectasia: analysis of platelet aggregation and fibrinolytic system in seven patients.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder characterized by the presence of generalized mucocutaneous and visceral telangiectasias associated with recurrent bleeding. In order to analyze the mechanism of bleeding in HHT we studied the hemostatic system and platelet in vitro aggregation in 7 unrelated patients suffering from HHT. Unlike the authors of previous reports, we could not find any significant alteration of the parameters measured suggesting a possible local role of the affected endothelial cells.