Fibrinogen-coated albumin microcapsules reduce bleeding in severely thrombocytopenic rabbits.

Severe thrombocytopenia frequently occurs in patients receiving chemotherapy and in patients with autoimmune disorders. Thrombocytopenia is associated with bleeding, which may be serious and life threatening. Current treatment strategies for thrombocytopenia may require transfusion of allogeneic platelets, which is associated with serious drawbacks. These include the occurrence of anti-platelet antibodies, which may result in refractoriness to further platelet transfusions, and the potential risk of transfer of blood-borne diseases. Therefore, we have recently developed a platelet substitute product (Synthocytes), which is composed of human albumin microcapsules with fibrinogen immobilized on their surface. Here we show that the intravenous administration of these microcapsules not only corrects the prolonged bleeding time in rabbits rendered thrombocytopenic either by anti-platelet antibodies or by chemotherapy, but also reduces bleeding from surgical wounds inflicted in the abdominal skin and musculature. No potential systemic prothrombotic effect of the microcapsules was observed in a model of rabbit venous thrombosis. As for the mechanism of action, experiments with normal and thrombocytopenic human blood in an endothelial cell matrix-coated perfusion chamber demonstrated an interaction between the fibrinogen-coated albumin microcapsules and native platelets. It was shown that the fibrinogen-coated albumin microcapsules could facilitate platelet adhesion to endothelial cell matrix and correct the impaired formation of platelet aggregates in relatively platelet-poor blood. This study indicates that fibrinogen-coated albumin microcapsules can act to improve primary hemostasis under thrombocytopenic conditions and may eventually be a promising agent for prophylaxis and treatment of bleeding in patients with severe thrombocytopenia.

Regulation of interleukin 10 release by tumor necrosis factor in humans and chimpanzees.

Interleukin 10 (IL-10) has been shown to inhibit endotoxin-induced tumor necrosis factor (TNF) production. To assess the role of TNF in the induction of IL-10 in endotoxemia, four healthy men were studied after a bolus intravenous injection of recombinant human TNF (50 micrograms/m2). In addition, 13 healthy chimpanzees were investigated after a bolus intravenous injection of Escherichia coli endotoxin (4 ng/kg), 6 animals received endotoxin only, 4 animals received a simultaneous intravenous injection of a monoclonal anti-TNF antibody, whereas 3 chimpanzees were treated with an anti-TNF F(ab')2 fragment 30 min after the administration of endotoxin. TNF induced a modest rise in IL-10 concentrations peaking after 45 min (47 +/- 32 pg/ml; p < 0.05). IL-10 peaked 2 h after injection of endotoxin (202 +/- 61 pg/ml; p < 0.005). In both anti-TNF-treated groups, the early endotoxin-induced TNF activity was completely neutralized. Simultaneous anti-TNF treatment attenuated endotoxin-induced IL-10 release (73 +/- 13 pg/ml; p < 0.01 versus endotoxin alone), whereas postponed anti-TNF treatment did not significantly affect this response (p = 0.21). These results indicate that TNF, in part, mediates the induction of IL-10 in endotoxemia, resulting in an autoregulatory feedback loop.

Fibrinolytic response to tumor necrosis factor in healthy subjects.

Tumor necrosis factor (TNF) may be involved in the disturbance of the procoagulant-fibrinolytic balance in septicemia, leading to microvascular thrombosis. To assess the dynamics of the fibrinolytic response to TNF in humans, we performed a crossover saline-controlled study in six healthy men, investigating the effects of a bolus intravenous injection of recombinant human TNF (50 micrograms/m2) on the stimulation and inhibition of plasminogen activation as well as on plasmin activity and inhibition. TNF induced a brief fourfold increase in the overall plasma plasminogen activator (PA) activity peaking after 1 h (p less than 0.0001), which was associated with rises in the antigenic levels of urokinase-type plasminogen activator (p less than 0.0001) and tissue-type plasminogen activator (p less than 0.0001). Plasminogen activator inhibitor type I antigen remained unchanged in the first hour, but showed a rapid eightfold increase thereafter (p less than 0.0001), which coincided with the decrease in PA activity. Generation of plasmin activity in the first hour was signified by an 11-fold rise in D-dimer levels (p less than 0.0001); inhibition of plasmin was reflected by a 36-fold rise in plasmin-alpha 2 antiplasmin complexes (p less than 0.0001), as well as by a transient 16% decrease in alpha 2-antiplasmin activity (p less than 0.01). In conclusion, TNF induced an early activation of the fibrinolytic system becoming maximal in 1 h, with a rapid inhibition thereafter. Earlier observations in the same subjects showed sustained coagulation activation for 6-12 h. The observed disbalance between the procoagulant and fibrinolytic mechanisms after TNF injection confirms the in vivo relevance of the effects of TNF on vascular endothelium in vitro and may explain the tendency towards microvascular thrombosis in septicemia.

Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia.

High-density lipoprotein (HDL) has been found to neutralize LPS activity in vitro and in animals in vivo. We sought to determine the effects of reconstituted HDL (rHDL) on LPS responsiveness in humans in a double-blind, randomized, placebo-controlled, cross-over study. rHDL, given as a 4-h infusion at 40 mg/kg starting 3.5 h before endotoxin challenge (4 ng/kg), reduced flu-like symptoms during endotoxemia, but did not influence the febrile response. rHDL potently reduced the endotoxin-induced release of TNF, IL-6, and IL-8, while only modestly attenuating the secretion of proinflammatory cytokine inhibitors IL-1ra, soluble TNF receptors and IL-10. In addition, rHDL attenuated LPS-induced changes in leukocyte counts and the enhanced expression of CD11b/CD18 on granulocytes. Importantly, rHDL infusion per se, before LPS administration, was associated with a downregulation of CD14, the main LPS receptor, on monocytes. This effect was biologically relevant, since monocytes isolated from rHDL-treated whole blood showed reduced expression of CD14 and diminished TNF production upon stimulation with LPS. These results suggest that rHDL may inhibit LPS effects in humans in vivo not only by binding and neutralizing LPS but also by reducing CD14 expression on monocytes.

Epinephrine exerts anticoagulant effects during human endotoxemia.

To determine the effect of a physiologically relevant elevation in the plasma concentrations of epinephrine on the activation of the hemostatic mechanism during endotoxemia, 17 healthy men were studied after intravenous injection of lipopolysaccharide (LPS, 2 ng/kg), while receiving a continuous infusion of epinephrine (30 ng/kg/min) started either 3 h (n = 5) or 24 h (n = 6) before LPS injection, or an infusion of normal saline (n = 6). Activation of the coagulation system (plasma concentrations of thrombin-antithrombin III complexes and prothrombin fragment F1+2) was significantly attenuated in the groups treated with epinephrine when compared with subjects injected with LPS only (P <0.05). Epinephrine enhanced LPS-induced activation of fibrinolysis (plasma levels of tissue-type plasminogen activator and plasmin-alpha2-antiplasmin complexes; P <0.05), but did not influence inhibition of fibrinolysis (plasminogen activator inhibitor type I). In subjects infused with epinephrine, the ratio of maximal activation of coagulation and maximal activation of fibrinolysis was reduced by >50%. Hence, epinephrine exerts antithrombotic effects during endotoxemia by concurrent inhibition of coagulation, and stimulation of fibrinolysis. Epinephrine, whether endogenously produced or administered as a component of treatment, may limit the development of disseminated intravascular coagulation during systemic infection.

Reduction of contact activation related fibrinolytic activity in factor XII deficient patients. Further evidence for the role of the contact system in fibrinolysis in vivo.

In this study the contribution of activation of the contact system to activation of the fibrinolytic system in vivo was investigated in healthy volunteers and in factor XII deficient patients. The plasminogen activating activity in plasma from healthy volunteers after infusion of desamino D-arginine vasopressin (DDAVP) was only partially blocked (for 77%) with specific antibodies to tissue-type plasminogen activator and urokinase type plasminogen activator. The residual activity could be quenched by a monoclonal antibody that inhibits factor XII activity and was not present in patients with a factor XII deficiency. The formation of plasmin upon the DDAVP stimulus as reflected by circulating plasmin-alpha 2-antiplasmin complexes was lower in factor XII deficient patients than in healthy volunteers. Activation of the contact system occurred after DDAVP infusion in healthy volunteers and was absent in factor XII deficient patients. These results indicate that DDAVP induces a plasminogen activating activity that is partially dependent on activation of the contact system and that contributes to the overall fibrinolytic activity as indicated by the formation of plasmin-alpha 2-antiplasmin complexes. This fibrinolytic activity is impaired in factor XII deficient patients which may explain the occurrence of thromboembolic complications in these patients.

Platelet-activating factor: mediator of the third pathway of platelet aggregation? A study in three patients with deficient platelet-activating factor synthesis.

Thrombin, collagen, and Ca2+-ionophore A23187 aggregate platelets in the presence of inhibitors of the first (ADP-mediated) and second (cyclooxygenase-dependent) pathway of platelet activation. This aggregation, via a third pathway, was hypothesized to be mediated by the alkoxyether lipid platelet-activating factor (PAF). We recently demonstrated virtual absence of plasmalogen-type alkoxyether lipids and deficiency in key enzymes of their biosynthesis in Zellweger patients. We hypothesized that PAF synthesis might also be impaired. We report two Zellweger patients with an undetectable A23187-induced PAF synthesis of leukocytes (patients, less than 3 pmol PAF/10(8) granulocytes (PMN); four age-matched controls, 249-2,757 pmol PAF/10(8) PMN; five adult controls, 291-5,433 pmol PAF/10(8) PMN). In a third patient, residual PAF synthesis was detected. However in all patients the thrombin-induced third mechanism of platelet aggregation was present. We therefore conclude that PAF may not be the mediator of the third pathway.

Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees.

Knowledge of the pathogenetic mechanisms responsible for the activation of the coagulation system associated with endotoxemia is important for the development of improved modalities for prevention and treatment. We analyzed the appearance in plasma of TNF, IL-6, and indices of coagulation and fibrinolytic system activation in normal chimpanzees after intravenous infusion of endotoxin. Endotoxin infusion elicited reproducible and dose-dependent elevations in serum TNF and IL-6, as well as marked increases in thrombin generation in vivo as measured by immunoassays for prothrombin activation fragment F1 + 2, thrombin-antithrombin III complexes, and fibrinopeptide A. Activation of the fibrinolytic mechanism was monitored with assays for plasminogen activator activity and plasmin-alpha 2-antiplasmin complexes. To potentially intervene in the molecular pathways elicited by endotoxin, pentoxifylline, an agent that interrupts "immediate early" gene activation by monocytes, or a potent monoclonal antibody that neutralizes tissue factor-mediated initiation of coagulation, were infused shortly before endotoxin. Pentoxifylline markedly inhibited increases in the levels of TNF and IL-6, as well as the effects on coagulation and fibrinolysis. In contrast, the monoclonal antibody to tissue factor completely abrogated the augmentation in thrombin generation, but had no effect on cytokine levels or fibrinolysis. We conclude that the endotoxin-induced activation of coagulation appears to be mediated by the tissue factor-dependent pathway, the fibrinolytic response triggered by endotoxin is not dependent on the generation of thrombin, and that the release of cytokines may be important in mediating the activation of both the coagulation and the fibrinolytic mechanisms in vivo.

Identification of a contaminant protein in the purification of human factor V. Comparison of two purification methods.

Coagulation factor V has been isolated from human plasma by the methods of Bolhuis and of Kane to investigate reported differences in purity and specific activity. The specific activities of the preparations are 10 and 40 units/mg, respectively. The Kane preparation shows a single band (Mr 330 000) in polyacrylamide gel electrophoresis in the presence and absence of dithiothreitol, but the Bolhuis preparation shows an additional band at Mr 190 000 upon reduction with dithiothreitol. This suggests the presence of a contaminant which could account for the lower specific activity. Modification of the Bolhuis technique to include ion-exchange chromatography on DEAE-Sepharose resulted in separation of the two isolated proteins. The proteins were identified as factor V, with characteristics indistinguishable from Kane factor V, and a dimeric subunit of alpha 2-macroglobulin (Mr 350 000). Contamination by alpha 2-macroglobulin may explain the I2-component described in some preparations of bovine factor V, which is the basis of speculation that bovine factor V has a second polypeptide chain modulating stability and activity.

Isolation and partial characterization of human factor V.

Factor V was isolated from human citrate plasma by very mild purification steps. Cryoprecipitation, fractionation with polyethylene glycol 6000, gel filtration of AcA 44 and adsorption of haptoglobin to immobilized hemoglobin were applied successively, resulting in factor V preparations with a specific activity of 14.5 unit/mg. The yield was 28 percent. A molecular weight of 296 000 was determined by gel filtration and the apparent sedimentation constant found by ultracentrifugation in a sucrose gradient was 7.8 S. Parallel experiments with citrate plasma resulted in the same molecular weight and sedimentation constant. Polyacrylamide gel electrophoresis of factor V in the presence or absence of sodium dodecyl sulfate showed a single protein band. Incubation with human thrombin resulted in an 8-fold activation of the purified factor V.

Synthesis of platelet-activating factor by human blood platelets and leucocytes. Evidence against selective utilization of cellular ether-linked phospholipids.

Synthesis of platelet activating factor (PAF) in blood platelet suspensions may be due to leucocyte contamination. We therefore investigated PAF synthesis in human blood platelet suspensions and granulocyte- (PMN)-enriched leucocyte suspensions upon stimulation by thrombin and Ca2+-ionophore A23187, both in the presence and absence of the presumed PAF catabolism inhibitor phenylmethylsulfonyl fluoride (PMSF). PAF synthesis was measured by aggregation of washed rabbit platelets and by [3H]acetate incorporation. In contrast to A23187, thrombin was unable to stimulate PAF synthesis by leucocytes. As thrombin did induce PAF synthesis by platelet suspensions, this was evidently not due to leucocyte contamination. A23187 also induced PAF synthesis by platelets, but this was dependent upon the platelet isolation method and possibly associated activation. The ratio of [3H]acetate incorporation into 1-alkyl- versus 1-acyl-2-acetylglycerophosphocholine upon stimulation of non-PMSF-treated leucocytes and platelets amounted to 12.8 and 1.2, respectively. These values are at least 10-fold higher than the ratio of 1-alkyl versus 1-acyl species in the cellular phosphatidylcholine precursor for PAF. By PMSF pretreatment, the distribution of incorporated [3H]acetate between 1-ether- and 1-ester-linked species became similar to that in the precursor phosphatidylcholines of the respective cell type, due to increased recovery of [3H]acetate in the acyl compounds. Both leucocyte and platelet homogenates rapidly degraded acylacetylglycerophosphocholine to (acetyl)glycerophosphocholine, and this deacylation was inhibited by PMSF pretreatment of the cells. We conclude that upon cell stimulation a phospholipase A2 converts both alkylacylglycerophosphocholine and diacylglycerophosphocholine to the 2-lysoanalogs in a ratio similar to the occurrence of the parent compounds. The acetyltransferase subsequently acetylates both compounds to acylacetylglycerophosphocholine and alkylacetylglycerophosphocholine (PAF), respectively. Deacylation of the 1-ester-linked species, either before or after acetylation, gives the impression of selective utilization of 1-ether-linked species for PAF production. It is only after inhibition of the deacylation by pretreatment of the cells with PMSF that a mainly nondiscriminative use of 1-ether- and 1-ester-linked species by both phospholipase A2 and acetyltransferase becomes evident.

Utility of impedance plethysmography in the diagnosis of recurrent deep-vein thrombosis.

Serial impedance plethysmography has been shown to be a safe and effective alternative to venography in the management of patients with clinically suspected acute venous thrombosis. The rate of normalization of an initial abnormal impedance plethysmogram and, consequently, the usefulness of impedance plethysmography in the management of patients with recurrent symptoms is, however, unknown. In a prospective cohort follow-up study, 161 consecutive patients with proved venous thrombosis and abnormal impedance plethysmograms were studied for one year. After 3, 6, 9, and 12 months, the impedance plethysmograms had normalized in 67%, 85%, 92%, and 95% of the patients, respectively. Thirty-five patients (22%) returned with clinically suspected recurrent thrombosis, of whom 31 had normal impedance plethysmograms prior to their return. In 18 of these patients, repeated tests were normal; these patients did not undergo anticoagulant therapy, and follow-up disclosed no subsequent adverse consequences. In the other 13 patients, the test again became abnormal; 11 patients were shown by venograms to have recurrent deep-vein thrombosis. Consequently, 29 (83%) of the 35 patients in whom the suspicion of recurrent thrombosis arose could have been managed with impedance plethysmography alone without the necessity for venography or anticoagulant therapy. It is concluded that normalization of impedance plethysmography tests occurs in almost all patients within nine months, and that serial impedance plethysmography is useful for patient management in nearly 90% of patients presenting with recurrent symptoms.

Disseminated intravascular coagulation and hypotension after intravasation of barium.

Prolonged hypotension and disseminated intravascular coagulation were seen in a patient after intravasation of barium sulfate contrast medium during a barium enema examination. High endotoxin levels were measured in the contrast material. In vitro, this material induced generation of bradykinin. The clinical features observed may be explained by contact activation of the Hageman factor-dependent pathways caused by the contrast material and/or by circulating endotoxins. Treatment of this rare but severe complication occurring during a barium enema procedure should be directed against the endotoxic shock.

Detection of deep vein thrombosis with impedance plethysmography and real-time compression ultrasonography in hospitalized patients.

BACKGROUND: Serial testing with impedance plethysmography or compression ultrasonography has been demonstrated to be feasible and accurate for the detection of deep vein thrombosis (DVT) in symptomatic outpatients, and these techniques are replacing contrast venography in this patient category. Limited data, however, are available on the clinical utility of these noninvasive tests in symptomatic hospitalized patients. The objectives of our study were to determine the feasibility of ascending contrast venography and to evaluate the accuracy of these two noninvasive methods for the detection of DVT in symptomatic hospitalized patients. METHODS: A prospective, "blind" comparison of impedance plethysmography and compression ultrasonography with ascending contrast venography was performed in consecutive hospitalized patients with clinically suspected DVT of the leg. RESULTS: Of the 127 potentially eligible patients, 44 had to be excluded; 25 of these could not undergo venography (feasibility of venography, 80.3%). The sensitivity, specificity, and positive and negative predictive values of impedance plethysmography for proximal DVT were 96%, 83%, 82%, and 97%, respectively. For compression ultrasonography, these measures for proximal DVT were 97%, 86%, 87%, and 97%, respectively. The overall prevalence of DVT was 53%, of which 85% was located proximally. CONCLUSIONS: Contrast venography cannot be performed in about 20% of consecutive symptomatic patients. Both impedance plethysmography and compression ultrasonography are feasible and valid alternatives to contrast venography in the diagnostic treatment of these patients.

Treatment of intermittent claudication with physical training, smoking cessation, pentoxifylline, or nafronyl: a meta-analysis.

BACKGROUND: There is no consensus on the efficacy of physical training, smoking cessation, and pharmacological therapy (pentoxifylline or nafronyl oxalate) in the treatment of patients with intermittent claudication at Fontaine stage II of disease. METHODS: A MEDLINE and manual search was used to identify relevant publications. Uncontrolled or retrospective studies, double reports, and trials without clinically meaningful outcomes were excluded. Included studies were graded level 1 (randomized and double- or assessor-blind), level 2 (open randomized), or level 3 (nonrandomized). Pain-free and total walking distance were the main outcomes considered; when feasible, end-of-treatment results were combined with appropriate meta-analytical procedures. RESULTS: In 5 level 2 studies, physical training increased pain-free and total walking distance significantly (139.0 m [95% confidence interval {CI}, 31.0 to 246.9 m] and 179.1 m [95% CI, 60.2 to 298.1 m], respectively). In a level 3 study, smoking cessation resulted in a nonsignificant increase in total walking distance of 46.7 m (95% CI, -19.3 to 112.7 m). In 6 level 1 studies, pentoxifylline increased both pain-free and total walking distance by 21.0 m (95% CI, 0.7 to 41.3 m) and 43.8 m (95% CI, 14.1 to 73.6 m), respectively. In 4 level 1 trials, nafronyl significantly increased pain-free walking distance (58.6 m [95% CI, 30.4 to 86.8 m]) and total walking distance (71.2 m [95% CI, 13.3 to 129.0 m]). CONCLUSIONS: Physical training increased pain-free and total walking distance in level 2 studies. Only level 3 studies support the usefulness of smoking cessation. In level 1 studies, pentoxifylline and nafronyl increased pain-free and total walking distance, but the average effects were relatively small.

The clinical course of patients with suspected pulmonary embolism.

BACKGROUND: The outcome of patients with suspected pulmonary embolism is known to a limited extent only. OBJECTIVE: To address this limited knowledge in a cohort in whom pulmonary embolism was proved or ruled out. METHODS: Consecutive patients with clinically suspected pulmonary embolism underwent lung scintigraphy and angiography if required. Pulmonary embolism was excluded by normal results of a lung scan or angiogram, and, if so, anticoagulant therapy was withheld. Pulmonary embolism was proved with a high-probability perfusion-ventilation lung scan or a confirmatory angiogram if a nondiagnostic lung scan was obtained. These patients were treated with heparin intravenously and anticoagulants orally on a long-term basis. All patients were followed up for 6 months, with a special focus on recurrent thromboembolism, bleeding complications, and mortality. RESULTS: A total of 487 consecutive inpatients and outpatients were included. Pulmonary embolism was excluded or proved in 243 and 193 patients, respectively. In 51 patients a definite diagnosis could not be established. The overall prevalence of pulmonary embolism was 39%. In patients in whom pulmonary embolism was proved, excluded, or uncertain, recurrent venous thromboembolism was observed in 2.6%, 0.9%, and 2%, respectively. Serious bleeding complications occurred in 7 patients (3.3%; 95% confidence interval [CI], 1.8%-6.3%), 2 cases of which were fatal. The total mortality after 6 months in patients with proved or excluded pulmonary embolism was 17% (95% CI, 12%-23%) and 11% (95% CI, 7%-15%), respectively. Death was related to (recurrent) pulmonary embolism in 5% and 0% of these cases, respectively. CONCLUSIONS: During a 6-month period, recurrent pulmonary embolism occurred in approximately 5 patients (2.5%) who were treated for a previous episode. Fatal bleeding complications attributable to the use of anticoagulants were encountered in 1%. The mortality among patients with suspected pulmonary embolism was considerable. However, most deaths were unrelated to pulmonary embolism, but were the result of serious underlying illnesses.

Management of clinically suspected acute venous thrombosis in outpatients with serial impedance plethysmography in a community hospital setting.

The reported high sensitivity and specificity of impedance plethysmography (IPG) in the diagnosis of proximal vein thrombosis were evaluated in a prospective cohort follow-up study, in which IPG was performed three times over a period of seven days in 243 consecutive outpatients with clinically suspected deep venous thrombosis (DVT). The test was abnormal in 112 patients (46%). The positive predictive value of an abnormal IPG for venography-proved DVT was 90%. One hundred thirty-one patients (54%) with repeatedly normal tests were considered not to have DVT, and anticoagulants were withheld. During six months of follow-up, completed in all patients with repeatedly normal IPG, no patient died of venous thromboembolism and no patient returned with clinically suspected pulmonary embolism. One patient (0.8%) returned after two months with recurrent leg symptoms, and venous thrombosis was documented (95% confidence limits, 0.02% to 4.21%). Another patient, who was nonsymptomatic, had an abnormal IPG at the three-month follow-up visit, and venography revealed venous thrombosis. Patients sent by general practitioners to a community hospital, with clinically suspected acute DVT, can be effectively managed by serial IPG alone.

Acquired antithrombin III deficiency: laboratory diagnosis, incidence, clinical implications, and treatment with antithrombin III concentrate.

Antithrombin III (ATIII) is the predominant naturally occurring inhibitor of serine proteases generated during blood coagulation [Rosenberg RD: Annu Rev Med 1978; 29: 367-378]. Since 1965, several assays have been developed that allow rapid and precise determination of ATIII in plasma. As a consequence, the existence of acquired ATIII deficiency in many pathologic conditions has been described. Acquired ATIII deficiency is based on decreased synthesis, increased loss or increased consumption, or induced by drugs. An inherited ATIII deficiency is associated with a lifelong tendency to venous thromboembolism. In contrast, the clinical significance of acquired ATIII deficiency has been less well defined. A precise estimate of the risk of thromboembolism in the acquired ATIII deficiency state cannot easily be provided, owing to the lack of studies in consecutive patients. In 1978, a purified human ATIII concentrate became available for clinical investigation. Despite numerous small studies, the value of ATIII replacement therapy in patients with acquired deficiency remains to be demonstrated.

Coagulopathy in Ruptured or Dissecting Aortic Aneurysms.

A consumption coagulopathy was demonstrated in each of four patients with either ruptured aneurysm of the aorta or a dissecting aortic aneurysm. The most prominent features of this disorder were (1) a prolonged prothrombine time due to a decrease of one or more clotting factors, and (2) formation of fibrin and fibrinogen degradation products. Recognition of this coagulation disorder could be a valuable diagnostic tool to differentiate a ruptured or dissecting aortic aneurysm from other conditions with a similar acute onset. The coagulation disorder could be due to liberation of coagulant material from the aortic wall into the circulation or to an accumulation of clotting factors at the site of the lesion, secondary to the local exposition of tissue factors from the torn arterial wall. The probability of the latter mechanism is suggested by the local increase of radioactivity after the injection of 125I-fibrinogen.

Impaired fibrinolysis in cyclosporine-treated renal transplant patients. Analysis of the defect and beneficial effect of fish-oil.

Cyclosporine treatment has been associated with thrombotic vascular complications. We investigated the activity of the fibrinolytic system and its capacity to respond upon DDAVP stimulation in a group of 20 cyclosporine-treated patients as compared with a group of 9 azathioprine-treated patients. Furthermore, the effect of the administration of fish-oil to these patients on the endogenous fibrinolytic activity was studied in a double-blind randomized, placebo-controlled cross-over study. The cyclosporine-treated patients showed a significantly reduced plasminogen activator activity and plasmin generation response upon the infusion of DDAVP as compared with the azathioprine group. In the cyclosporine group 60% of the patients had an impaired fibrinolytic response, whereas this was found in only 11% of the azathioprine-treated patients (P < 0.05). The impairment of the endogenous fibrinolysis activity could be attributed either to a defective release of plasminogen activator from the vessel wall (67% of patients) or to high plasma levels of plasminogen activator inhibitor 1 (33% of patients). Administration of fish-oil resulted in a significant improvement of the impaired fibrinolysis in the cyclosporine group. Particularly, in patients with a defective release of plasminogen activator from the vessel wall, fish-oil treatment resulted in a normalization of the fibrinolytic activity. These results indicate that cyclosporine treatment induces an impaired fibrinolysis that may contribute to the frequent occurrence of thromboembolic complications and eventually the impairment of renal function in cyclosporine-treated patients. The beneficial effect of the administration of fish-oil on the endogenous fibrinolysis may result in a reduction of the adverse events associated with cyclosporine treatment.