bluuebunny/crossref_metadata_2025 huggingface dataset:
MULTICENTRIC SPANISH STUDY OF BIOLOGICAL CAUSES OF DEEP VEIN THROMBOSIS
Authors: Felez J , Rodriguez-Pinto R , Oliver A , Velasco F , de Diego I , Steegmann L J , Martin S
Published: August 2018

305 unselected patients under long-term oral anticoagulation treatment for having presented one o more ep^L sodes of deep vein thrombosis and/or pulmonary embolism, have been studied for the following anomalies: Dysfibrinogenemia, Lupus anticoagulant, Antithrombin-III deficiency, Protein C, Protein S, Heparin Cofactor II, and anomalies in the fibrinolytic components t-PA PAI and Plasminogen. Protein C antigen and activity as well as free Protein S antigen levels have been related to those found in a control group at different intensities of oral anticoagulant

As shown in the table this study, performed on unselected patients from the clinical point of view, has not only confirmed the presence of a previously known congenital defect in 16 patients (5%) but also has per miteed the identification of a previously unkown de- -feet in 45 patients (15%)

Since the identification of a congenital abnormality permits to prevention of new thrombotic episodes and the identification of the afected members, these re- -suits support the convenience of performing such syste matic biological studies in patients suffering from thrombosis
PROFILE DIAGNOSIS OF HEMOSTATIC DISORDERS BY SIMULTANEOUS ASSAY OF HEMOSTATIC MOLECULAR MARKERS
Authors: Teruya J , Shimizu N , Matsuda J , Kazama M , Abe T
Published: August 2018

Simultaneous measurements of molecular markers of platelet, coagulation, fibrinolysis, and vascular system give us precise-and comprehensive information about hemostatic profile of various diseases. We adopted 6-thromboglobulin(B-TG) and platelet factor 4(PF4) for platelet function, fibrinopeptide A(FPA) and soluble fibrin monomer complex(SFMC) for coagulation, fibrinopeptide BB15-42(BB) and fibrin degradation product(FDP), for fibrinolysis, and tissue plasminogen activator(TPA) antigen for vascular system.

(l).The results of normal values were as follow(n=20); 6-TG 40.6ng/ml, PF4 9.9ng/ml, FPA 3-lng/ml, BB 8.2ng/ml, and TPA 4.4ng/ml. (2).The mean values of 6-TG and PF4 were 72.1ng/ml and 30.9ng/ml, respectively in all patients with SLE(n=53)-FPA and BB were 7-lng/ml and 32.2ng/ml, respectively. All the markers mentioned above were significantly increased compared with normal. It means that hemostatic profile of SLE was hyperfunction of platelet, coagulation, and fibriolysis systems. (3)-In patients with ischemic heart diseases(IHD) including angina pectoris and acute myocardial infarction(n=17) B-TG and PF4 increased to 60.1ng/ml and 21.7ng/ml, respectively. But FPA did not change significantly. And BB increased to 4l.8ng/ml. It means that occurrence of IHD is closely related to hyperfunction of platelets rather than coagulation. (4). Patients with occlusive cerebrovascular accident(CVA) were divided into two groups; cases with high FPA and those with normal FPA. The average value of FPA of the former group was 10.2ng/ml and they had higher levels of BB of 23.1ng/ml than normal. TPA was measured before and after venous occlusion (VO) of lOOmmHg for 7 minutes. TPA increased 2 or 3 folds after VO test in normal subjects, but in 5 of 17 cases of CVA it did not change before and after VO test.

It was postulated that the profile diagnosis of hemostatic disorders is possible by simultaneous measurement of molecular markers, because this method informs us what aspect of hemostatic function is hyperactive. It will also provide us the appropriate indication of treatment for various types of thrombotic disease.
IS BETATHROMBOGLOBULIN (BTG) OF PROGNOSTIC VALUE IN PATIENTS WITH TRANSIENT CEREBRAL ISCHEMIA (TIA) ?
Authors: Strano A , Davi G , Catalano I , Francavilla G , Notarbartolo A
Published: August 2018

TIA and stroke have for a long time been recognized as being associated with various abnormalities in platelet function.

Plasma levels of BTG, a marker of platelet release reaction, have been found raised in TIA patients. However plasma measurements can be influenced by venipuncture or handling of the samples Therefore we measured urinary BTG levels and compared plasma and urinary levels of this protein in 18 patients with TIA and 18 controls of equivalent age (41-68 years) and sex.

Plasma BTG levels were not different between TIA subjects (24.1 ± 8.6 ng/ml) and controls (20.2 ± 6.4 ng/ml). Urinary BTG levels were significantly different between TIA patients (0.72 ± 0.24 ng/ml) and controls (0.28 ± 0.09 ng/ml) and platelets from TIA patients were more sensitive to ADP than those from controls.

After 6 months of ticlopidine administration urinary BTG levels in TIA patients fell to within normal ranges, plasma BTG values remained in the normal range and the the AC50 for ADP was significantly increased.

We conclude that only urinary BTG levels may have diagnostic usefulness to evaluate a slight but continous platelet activation of circulating platelets, for istance, by ulcerated plaques in cranial arteries. The interpretation of elevated plasma BTG levels is hampered by the influence of the blood sampling technique which may give rise to false high levels due to platelet release during or after blood sampling. Urinary BTG levels provide a means for following the effects of therapy.

In 4 patients,in whom ischemic attacks occured during the course of treatment, urinary and plasma BTG were not higher than in subjects in whom no further events occured. Therefore our data suggest that measurements of urinary and plasma BTG values have no prognostic value in TIA patients.
INFLUENCE OF HYPERFIBRINOLYSIS ON THE PROGNOSTIC VALUE OF FACTOR VII IN PATIENTS WITH LIVER INSUFFICIENCY
Authors: Ferro D , Violi F , Quintarelli C , Saliola M , Alessandri C , Cordova C
Published: August 2018

As the most coagulation factors are sintethized by liver cel1,patients with liver failure (LF) have low values of coagulation factors. These latter were investigated to assess their prognostic value in LF patients,but none was proved to be useful in the individual assessment of LF. A previous study showed that in fulminant hepatitis,factor VII,whose half-life is very short,was a marker of imminent death;a further investigation supported this finding in patients with chronic LF. We evaluated the influence of hyperfibrinolysis on the prognostic value of factor VII in 37 consecutive patients affected by liver cirrhosis (LC) in severe decompensated state. 16 died within 30-50 days from the hospitalization,2 1 suvived and was discharged 30-80 days from the hospitalization. Positive FDP ( >10pgr/ml;Thrombo-Wellcotest) was found in both survivors (6) and non survivors (7) patients. Factor VII activity (Mariani's method) clear-cut differentiated survivors and non survivors indipen-dently if they had or not positive FDP. Factor VII activity of non survivors was significant lower and did not overlap that of survivors. The absence of influence of hyperfibrino1ysis on the prognostic value of .factor VII further supports the importance of evaluating this clotting factor on patients with LF.
HEMOSTATIC EVALUATION OF PATIENTS UNDERGOING LIVER TRANSPLANTATION
Authors: Rettke S R , Owen C A , Bowie E J W , Cole T L , Wiesner R H , Krom R A F , Jensen C
Published: August 2018

Significant hemostatic abnormalities can occur during orthotopic liver transplantation (OLT). This study addressed three goals: 1)evaluation of the hemostatic mechanism at each stage of the OLT; 2) the relationship of the coagulation process with the thrombelastograph (TEG); and 3) comparison of results in patients requiring retransplantation or who died, with the overall pattern. To evaluate hemostasis during 50 consecutive OLTs, a detailed coagulation and TEG study was done. The surgical procedure was divided into the following stages: Stage I--induction of anesthesia to occlusion of blood flow to the patient’ s diseased liver; Stage II—occlusion of blood flow to the patient’ s diseased liver to reperfusion of the patient’ s new liver; and Stage III—reperfusion of the new liver until skin closure. 28 ml of arterial blood were sampled at the beginning and end of each stage and up to five days posttransplantation for the following: platelet count, prothrombin time, activated partial thromboplastin time, fibrinogen, prothrombin, factors V, VII, IX, and X, plasminogen, antiplasmin, antithrombin III (functional and immunologic), fibrinolytic split products, and TEG. The patient’ s core temperature and amount of blood products transfused were obtained intraoperatively during each of the six data times. The ischemia time of the donor liver was recorded. Significant hemostatic abnormalities developed during each of the 50 OLTs, especially during reperfusion of the donor liver. In some instances, this was corrected within one hour, but platelet counts continued to fall, and a number of coagulation factors rebounded only partially. The TEG values correlated with laboratory data and blood loss, but the correlations were not strong. The patient’ s requirement for red cells varied with the operative drop in temperature; however, the donor liver ischemia time and length of Stage II made no significant difference. It is concluded that 1) significant deterioration of coagulation factors occurs during OLT, 2) the TEG is an effective screening test that affords prompt information, 3) aggressive measures should be taken to maintain the patient’ s body temperature at 37°C, 4) patient outcome was not predicted by intraoperative hemostatic evaluation.
CEPHALOSPORIN-INDUCED HYPOPROTHROMBINAEMIA: RELATION TO CEPHALOSPORIN SIDE CHAIN, VITAMIN K METABOLISM AND VITAMIN K STATUS
Authors: Shearer M , Andrassy K , Bechtold H , McCarthy P , Koderisch J , Koderisch H
Published: August 2018

An increased incidence of bleeding episodes due to hypopro-thrombinaemia has been associated with several cephalosporins especially those which contain an N-methyl-thio-tetrazole (NMTT) side chain. To study the etiology of cephalosporin-induced hypo-prothrombinaemia in the clinical situation we have investigated the ability of different cephalosporins to alter the metabolism of vitamin K and the relationship between hypoprothrombinaemia and vitamin K status as assessed from plasma levels of vitamin K. Cephalosporins containing an NMTT side chain (latamoxef, cefmenoxime, cefoperazone, cefotetan, cefamandole) or related structure (cefozolin) all caused the transient plasma appearance of vitamink1 2,3-epoxide in response to a 10 mg intravenous dose of vitamin ; those without NMTT (cefotaxime and cefoxitin) did not. The plasma accumulation of vitamin k1 2,3-epoxide was qualitatively similar to, but quantitatively less than, that produced by the oral anticoagulant phenprccoumon. In 36 patients eating normally, the median endogenous plasma vitamin k1 (370 pg/ml) was not significantly different from that in healthy, fasting subjects (372 pg/ml) and clotting tests remained consistently normal for all antibiotics tested. In 22 patients on total parenteral nutrition the median plasma vitamin k1. (223 pg/ml) was significantly lower than normal (p < 0.01) with 61patients having levels below the normal range (< 150 pg/ml) but normal clotting before starting antibiotic therapy. All 7 parenterally-fed patients treated with latamoxef developed hypoprothrombinaemia (as shown by prothrombin time, PIVKA-II and protein C measurements) within 4 days whereas 12 patients treated with cefotaxime or cefoxitin did not. Latamoxef-associated hypoprothrombinaemia was readily reversible by 1 mg of vitamin k1 given intravenously but hypoprothrombinaemia and sub-normal plasma vitamin k1 could recur within 2-3 days. The data suggest that NMTT-cephalosporins are inhibitors of hepatic vitamin K epoxide reductase and that a lowered vitamin K status predisposes to hypoprothrombinaemia.
ALTERATION OF PRIMARY HAEMOSTASIS IN PATIENTS WITH ATHEROSCLEROSIS: ITS POSSIBLE ROLE IN ATHEROGENESIS
Authors: Rak K , Harsfalvi J , Udavardy M , Tornai I , Misz M , Boda Z
Published: August 2018

Complex study was performed in order to evaluate the primary haemostasis of patients with generalized atherosclerosis. Signs referring to hypercoagulability and platelet activation are known from previous studies. The purpose of this work was to investigate the primary haemostasis in every detail. Assays were performed in 20 atherosclerotic patients and 10 control persons. Methods: platelet count, Ivy bleeding time (Simplate II), platelet retention (Adeplat T), in vivo platelet consumption (Borchgrevink), study of vWFAg by Laurell’s rocket and crossed immunoelectrophoresis (using Clottimmun-AHG Assoc. Protein, Behring), plasma B-TG (Amersham), the stable metabolites of TXA2 (TXB2) and PGI2 (6-KPGF) by RIA-kits. Results: platelet counts and bleeding times were not different, in vivo platelet consumption was also similar, but platelet retention proved to be increased in patients (40 vs 27 %). Increase of vWFAg level characterized atherosclerotic patients (277±83 vs 102±28 %); the relative mobility (RM) ratio which indicates the migration distance of vWFAG in CIE was significanty altered (0.33 compared to 0.26) meaning that the molecular forms of protein with faster mobility were increased to a greater degree than forms with slow mobility. B-TG plasmatic level was increased in patients (115 vs 28 ng/ml), the quotient of TXB2 and 6-KPGF was much bigger (4.7 vs 0.4). In conclusion: the most striking change was the elevation of plasmatic vWFAg level together with its structural alteration, i.e. predominance of the smaller oligomers. Primary haemostasis seems to be more active than normal, atherosclerosis represents a hyperadhesive and/or prethrombotic state. Although all the findings may be the result of vessel wall lesions, the observed changes may also have a causal role in the progression and complications of atherosclerosis.
SOLCO-TRANS AUTOTRANSFUSION AND PLATELET FUNCTION DURING AORTIC SURGERY
Authors: Blbby S R , Crow M J , Puri S R , Penny A F , Rajah S M , Kester R C
Published: August 2018

The potential for HIV transmission from bank blood has renewed interest in methods of operative autotransfusion. Widespread acceptance of such techniques will depend on the safety and function of the salvaged blood. In 11 patients undergoing elective aortic reconstruction, we have studied changes in platelet function during the use of Solco-trans* - a simple, disposable, non-mechanical autotransfusion device. All patients received 1 mg/kg heparin prior to aortic cross-clamping, after which 440 mis blood was salvaged into the Solco-trans device, which contained 60 mis ACD-A. Platelet count, aggregation to collagen and ADP, thrombin-stimulated total ATP, APTT and plasma heparin levels were measured:- 1) pre-operatively, 2) post-heparinisation, 3) in the operative pool, and 4) in the Solco-trans reservoir, whilst citrate, ionised calcium, plasma Hb and pH were recorded only in the Solco-trans device.

CONCLUSION: There is a significant decrease in platelet numbers, aggregation and ATP content (p<0.05, Wilcoxon signed rank test)in the acidotic, hypocalcaemicand highly hoemolysed environment of the Solco-trans reservoir. In large volume autotransfusion, additional fresh platelet concentrates will be required.

*Cabot Ltd
RELATIONSHIPS BETWEEN HAEMOSTATIC ENDOTHELIAL FUNCTIONS AND GLOMERULAR FILTRATION RATE IN SHORT-TERM TYPE I DIABETES MELLITUS
Authors: Montani N , Solerte S B , Gamba G , Fioravanti M , Ferrari E
Published: August 2018

It is known that the increase of glomerular filtration rate (GFR) represents an early sign of diabetic nephropathy. The changes of endothelial functions observed in diabetes might play a role in this respect. As F VIII vWF and fibronectin are synthetized by endothelial cells, we evaluated these components in 33 diabetic patients with short-term Type I (insulin dependent) diabetes mellitus, without retinopathy and macro-vascular complications. 15 pts. (mean age 29 ± 7 yrs; mean diabetes duration 2.9 ± 0.9 yrs) presented high GFR (154 ± 19 ml/min per 1.73 m2 ; albuminuria 7.2 ± 3.2 μg/min) and 18 pts. (mean age 30 ± 6 yrs; mean diabetes duration 3.0 ± 1 yrs) normal GFR (105 ± 11 ml/min per 1.73 m2 ; albuminuria 5 ± 2.8 μg/min).

The following results were obtained:

In conclusion the significant increase of FVIIIR:Ag and fibronectin levels in short-time type I diabetic patients with high GFR suggests an early endothelial cell function damage also related to the Door metabolic control.
ACCELERATED IN VITRO HAEMOSTASIS AND DECREASED SPONATEOUS THROMBOLYSIS IN DIABETICS
Authors: Rademaker M , Thomas D J , Kirby J D , Kovaos I B
Published: August 2018

Diabetics have an increased risk of developing coronary, cerebral, and peripheral vascular occlusions. The mechanism of the accelerated haemostatic/thrombotic system is not known and studies on 'hyperactive platelets' and the fibrinolytic system in diabetes are inconclusive. We have used the Haemostatometer to assess haemostasis and thrombolysis in diabetic patients. The Haemostatometer, a new instrument, allows quantitative measurement of haemostasis by monitoring the pattern of haemostatic plug formation (HPF) in holes punched through polyethylene tubing through which non-anticoagulated blood flows under standard conditions (1,2). The pattern and speed of blood coagulation subsequent to HPF was also measured as was the spontaneous thrombolysis time (STT) (taken as the time until expulsion of the haemostatic plug from heparinised blood). Blood was sampled from 20 diabetic patients (10 insulin (IDD) and 10 non-insulin dependant (NIDD)) as well as 20 age mathched controls. All values are for mean ± SEM. Both IDD and NIDD had shorter bleeding times (HPF) than did controls: 2.16 ± 0.44 min vs 3.08 ± 1.14 min (p=0.03) (the initial phase of HPF was even more significantly shorter: 0.53 ± 0.06 min vs 1.03 ± 0.14 min (p<0.0l). The STT in NIDD was significantly longer than in controls: 56.8 ± 3.1 min vs 36.9 ± 4.0 min (p=0.002) while in IDD, the STT was shorter at 22.0 ± 0.5 min (p=0.018 when compared vs controls 36.9 ± 4.0 min).

The shortened bleeding time (HPF) in diabetics is most probably a manifestation of hyperactive platelets and could contribute to the increased risk of thrombosis seen. In NIDD the prolonged thrombolysis (STT) may be a contributing factor to the development of diabetic angiopathy, which is thought to be prevented by good diabetic control (ie insulin). This suggests that the diabetic vascular endothelium retains some capacity to generate plasminogen activator in response to insulin.

(1). Gorog P and Kovacs IB. Haemostasis 16: 337-345, 1986.

(2). Gorog P. Angiology 37: 99-105, 1986.
HAEMOSTATIC PARAMETERS, ENDONEURIAL OXYGEN TENSION AND SURAL NERVE HISTOLOGY IN DIABETES MELLITUS
Authors: Ford I , Newrick P G , Malik R , Preston F E , Ward J D , Greaves M
Published: August 2018

We have examined coagulation parameters in 15 neuropathic (Group A) and 10 complication-free diabetic patients (Group B). Venesection and sample testing were performed under standard conditions. Group A underwent sural nerve biopsy and 14 also had measurements of endoneurial oxygen tension. Factor VIII related antigen was higher in Group A (l-617u/ml ± 0.67) compared to Group B (0.944u/ml ± 0.26); (mean ± SD; p<.0.05) perhaps suggesting endothelial cell damage, although this did not correlate with capillary basement membrane thickness or endothelial cell number nor with endoneurial oxygen levels. Platelets from Group A were more sensitive to arachidonate than those of Group B, showing aggregation thresholds in platelet rich plasma of 0.36 ± 0.17mM and 0.57 ± 0.9mM respectively compared with 0.65 ± 0.37mM in non-diabetic controls.

Platelets from Group A subjects also produced more thromboxane B2 in response to arachidonate than Group B or normal controls (37.95 ± 27.5; 25.5 ± 13.0; 16.55 ± 15-5pmol/107 platelets). Blood fibrinolytic capacity measured by euglobulin clot lysis time, was diminished in NIDDs (post-occlusion ECLT 165.7 mins ± 116.0), compared to IDDs (55.5 ± 34.5) (p<0.05) due at least in part to excess of tissue plasminogen-activator inhibitor, although we found no significant difference in ECLT between Group A and Group B. Interaction between haemostatic and microvascular abnormalities in diabetes may contribute to the pathogenesis of diabetic neuropathy.
DIABETES MELLITUS: HYPERCOAGULABILITY AID HYPOFIBRIHOLYSIS
Authors: Alava I , Garcia Frade L J , de la Calle H , Havarro J L , Creighton L J , Gaffney P J
Published: August 2018

A hypercoagulable state has been related to the presence of microvascular and macrovascular disease in Diabetes Mellitus. The aim of this study was to establish when this hypercoagulable state appears and the response of the fibrinolytic system.

43 patients (29 males, 14 females, aged 19-73), 28 insulin-dependent (10 of them with micro and/or macrovascular disease), 15 non insulin- dependent (all of them with vascular disease) were studied.

Platelet aggregation and adenine nucleotides, plasma and serum thromboxane B2 (TxB2), Factor VIII Coagulant (VIII-C), Factor VIII Related antigen (VIII-RAg), Factor VIII Ristocetin Cofactor (VIII-RCoF), Fibronectin, Tissue Plasminogen Activator (t-PA) and X-Oligomers fibrin fragments were measured.

In the diabetic patients maximal aggregation was induced by a threshold concentration of adenosin diphosphate and arachidonic acid lower than in controls (p<0.01 and p<0.05). Diabetic patients also presented elevated platelet ADP and decreased platelet c-AMP. They had higher plasma TxB* levels than the control group.

FVIII-C, FVIII-RAg and Fibronectin were increased (p<0.001) both in patients type I and II, with and without vasculopathy. FVIII-RCoF was highly increased in vasculopathy (p<0.001) while was non significant without it.

The patients with vasculopathy presented decreased t-PA plasma levels (p<0.05). lo difference in X-Oligomers was found related to controls.

These findings suggest: 1) A hypercoagulable state previously to the development of clinical vasculopathy. 2) A decreased fibrinolytic response associated to vasculopathy.
IDENTIFICATION OF A FIBRINOLYTIC DEFECT IN TWO FAMILIES WITH A TENDENCY TO THROMBOSIS
Authors: Ostermann H , Koenig S , Pollmann H , Schmitz-Huebner U
Published: August 2018

We identified two families in whom one member each suffered from deep venous thrombosis and subsequent pulmonary emboli at the age of 15 and 17. We were able to investigate several members of both families with regard to their fibrinolytic system. Blood sampling was done before and after ten minutes of venous occlusion. Parameters measured were euglobulin clot lysis time (ECLT), tissue-type plasminogen activator (t-PA) activity, t-PA concentration and plasminogen activator inhibitor (PAI) activity, besides several other constituents of the coagulation and fibrinolytic system commonly associated with thrombophilia.

In the first family six persons could be evaluated. A prolonged ECLT was found in four probands. Three of them had no measurable t-PA activity after stasis, t-PA concentration after stasis was below the normal range in two and borderline in one of them.

In the second family 13 members could be invest-gated. Three adults were found to have a prolonged ECLT. Two of these had very low t-PA activity after stasis, with normal increase in t-PA antigen. Their PAI was increased above the normal range. Six children showed no measurable PAI and increased levels of t-PA activity before stasis. After stasis four children had a prolonged ECLT. Two of them had low t-PA antigen levels, while all of them showed normal t-PA activity increases.

These findings suggest, that there may be hereditary defects related to activators and inhibitors of the fibrinolytic system in the investigated families. These could possibly be responsible for the occurence of venous thrombosis early in life. However, results in the second family show that not all of the prolonged ECLT values can be explained by changes of t-PA and PAI.
CLINICAL RELEVANCE OF D.DIMER AND COAGULATION INHIBITORS IN LIVER CIRRHOSIS
Authors: Aurousseau M H , Eclache V , Amiral J
Published: August 2018

D.Dimer was measured by a latex agglutination assay and an enzyme immunoassay (E.I.A.) in 25 patients suffering from liver cirrhosis. High levels of D.Dimer (> 500 ng/ml) were found in 13/25 patients’ plasma, by the latex test as well as EIA. Fibrinogen Degradation Products (FDP), measured by the Merskey method, were present in 7/25 samples, whereas soluble fibrin monomer complexes were only detected in 2/25 patients. In both cases, D.Dimer was elevated and FDP were in the normal range. Only one patient developped a Disseminated Intravascular Coagulation (DIC). None of the others had any thromboembolic event.

Anticoagulant plasma proteins, Protein C (pC), total and free Protein S (pS) and Antithrombin III (AT III), were measured, in these patients, using the Laurell method.

Mean values measured were :

AT III : 50 % ± 16 total pS : 69 % ± 20

pC : 38 % ± 28 free pS : 63 % ± 30

Using immunoassays, pS showed the lowest decrease, in comparison to the other coagulation inhibitors.

These values were compared to some procoagulant activities : prothrombin, factors VII ± X and factor V.

4 good correlation was observed between AT III and prothrombin (r = 0.752 p < 0.01), whereas a poorer one was obtained between pC and factors VII and X (r = 0.455 p < 0.02). There was no correlation between pC and pS, nor between pC and factor V. Despite marked decrease of coagulation inhibitors in liver cirrhosis, low incidence of thrombotic accidents was observed (1/25) probably due to a parallel decreased synthesis of procoagulant factors. However, an in vivo blood activation associated to a reactive fibrinolysis was evidenced by measurement of pathological levels of D.Dimer in 13/25 patients. In this way, D.Dimer is a more sensitive and specific marker, than total FDP, to evaluate blood activation in liver cirrhosis. D.Di Test allows a rapid estimation and gives similar results to the EIA method.
DEFIBROTIDE VS. HEPARIN IN ACUTE THROMBOFLEBITIS THERAPY
Authors: Palmieri G , Palmieri R , Ambrosi G , Ferraro R , Bucci L , Agarthi A M
Published: August 2018

Defobrotide(D) a natural polydeoxyribonucleotide of mammalian lung origin is a new substance with no anticoagulant or hemodinamic effects?it has shown considerable profibrinolytic and antithrombotic activities. The ability of (D) to increase generation of prostaci-clmCPGI2) from vascular tissue has been demonstrated; this substance also promotes substantial release from vascular tissues of a plasminogen activator factor which plays an important role in preventing thrombotic oclusion of vascular segments.Widely accepted therapies in deep venous thrombosis and Acute Thromboflebitis (A.f.; are based on anticoagulant treatments (heparin and/or oral anticoagulant agentsWe have evaluated the efficacy of (D> in (A.T.) vs. heparin in 40 pts.(28 females 12 males;mean age=50) with an open randomized study.Group A:20 pts.have been administered CD; 200mg.four times a day l.m. for 10 days.Group B:20 pts.have been administered Sodic Heparin 30000 U.I. intravenously with successive dosage based upon APTT values.Both groups have been treated with an oral anti coagulant agentCacenocoumaro1) after the tenth day.

No clinical differences between the treatments have been observed and in no pts. treated with CD; we noted significant changes m laboratory parameters evaluated: complete blood count,glycemia BUN creatinine ALT AST LDH.Clinical eficacy was excellent in both groups also supported by augmented fibrinolysis and instrumental improvement(strain-gauge plethismography;.

The absolute safety of (D> therapy shows its possible alternative role when compared to heparin treatment in (A.T.> of any origin.
THE VARIATION OF ARACHIDONIC ACID METABOLISM OF PMN LEUKOCYTES IN CEREBRAL THROMBOSIS
Authors: Wang Z , Lehuu B , He Y , Raun C
Published: August 2018

It was suggested that there is a transfer of metabolites between leukocytes,paltelets and endothelial cells,and that the leukocytes might take part in thrombosis and haemostasis. In order to ascertain whether the arachidonic acid metabolism of PMN leukocytes changes when cerebral thrombosis occurs, we studied this metabolism using isolated human PMN leukocytes, stimulated by ionophor A23187. PGE2 and TXB2 were measured with the method of radioimmunoassay, while leukotrienes(LT) were separated and measured by HPLC. The amount of PGE2, TXB2 and LTs produced by PMN leukocytes of 8 normal volunteers was compared with that of 8 patients suffering from cerebral thrombosis. All these patients were confirmed by CT examination. We found that the production of TXB2, LTB4 and its derivative 20-0H-LTB4 of PMN leukocytes of patients was significantly enhanced. The PGE2 production of PMN leukocytes of patients was also higher than that 0? the volunteers, but without statistically significant difference.

These results demonstrate that leukocytes and their arachi donic acid metabolites might play some role in the pathogenetic sequence of cerebral thrombosis. And it is possible that LTB4 is not only a potent inducer of neutrophil chemotaxis and leukocyte aggregation, but also an associated factor in the ischemic vascular disease. It seems that the increasing production of TXB2 and LTB4 by PMN leukocytes is not the main reason of cerebral thrombosis. Hoever, it might accelerate the degree of brain tissue ischemia. We observed that corticosteroids, as an inhibitor of phosphoIipase A2,strikingly reduced the production of arachidonic acid metabolites by leukocytes. Therefore, it is probable that the efficacy of corticosteroids on cerebral thrombosis is, in part, due to inhibit the production of these arachidonic acid metabolites of leukocytes.
ERYTHROCYTES(RBC) AS SUICIDAL ENDOGENOUS SCAVENGERS IN IMMUNE TRIGGERED GRANULOCYTE(PMN)MEDIATED VASCULAR DAMAGE
Authors: Boogaerts M A , Zachée P , Emonds M P , Goossens W , Verwilghen R L , Lins R L
Published: August 2018

PMN produced toxic oxygen radicals(TOR)have been implicated in the generation of endothelial injury in a number of clinical conditions e.g. in apheresis,hemodialysis, ARDS and atherosclerosis. RBC have shown to inhibit TOR induced damage in a number of hyper-oxic lung injury models.We surmised RBC may serve as endogenous TOR scavengers in those in vivo situations where PMN are immunologically triggered(e.g. complement-activation in hemodialysis)to produce endothelial damage.However, RBC in their role as scavengers may became more vulnerable to further oxydant stress and display a reduced life span.Confluent monolayers of 51cr-labeled human umbilical vein endothelial cells will release 7.5 ± 1.3% of their label upon incubation with complement triggered PMN.When these PMN (l)are premixed with RBC(10),the endothelial damage can be inhibited by 78.4 ± 3.2%.This inhibition can be reproduced by replacing intact RBC by their hemolysates,but not by red cell ghosts.In a 51cr-RBC cytotoxicity system,phorbolester stimulated PMN will lyse 52.6 ± 4.2% RBC.Addition of unlabeled RBC(1/5),inhibits cytotoxicity by 31.1%,their hemolysate by 100%.Pretreatment of added unlabeled RBC with the anion channel blocker DIDS,did not significantly block the scavenger effect.

RBC-targets fron hemodialysis-patients(n=8),are more vulnerable to PMN mediated cytotoxicity than normal controls(+24.1%,p<0.001). This vulnerability is further increased(+16.3%,p<0.05)during the early stages of the hemodialysis-procedure,at the time when granulocyte counts are lowest and TOR-generation highest.The GSH of he-modialysis-RBC can be more rapidly depleted upon challenge byAPH, while they also display a significant higher methemoglobin production upon sodium ascorbate challenge,both indicative of their, increased oxidative sensitivity. High dose Vitamin C(10™3M)or desfe-rioxamine(10™3M)inhibit all RBC cytotoxicity.

We conclude that RBC serve as endogenous scavengers of TOR,generated by PMN,triggered by corplement activation during hemodialysis. However,by doing so,they became themselves more vulnerable to further oxidative stress,which may contribute to the chronic anemia of hemodialysis-patients.
INHIBITION BY AD6 (8-MONOCHLORO -3-BETA-DIETHYLAMINOETHYL -4- METHYL -7- ETHOXY CARBONYL METHOXY COUMARIN) OF POLYMORPHONUCLEAR LEUKOCYTES ADHESION TO ENDOTHELIAL CELLS
Authors: Breviario F , Bertocchi F , Prosdocimi M , Deiena E
Published: August 2018

Increased leukocyte adhesion to the endothelial lining of blood vessels is an essential event in inf laaaation and the pathogenesis of certain vascular deseases. The aonocyte product interleukin-1 (IL-1) has been shown to enhance the adherence of huaan periferal blood polyaorphonuclear leukocytes (PMN) to huaan uabilical vein endothelial cells (EC). In this study AD6, a couaarin derivative which inhibits platelet aggregation and coronary throabus foraation in experimental aniaals, was found .to inhibit PMN adhesion to control and IL-i-treated EC. Suspensions of washed 51Cr labeled PMN were added to cultured huaan uabilical vein EC which have been treated either with buffer or IL-i (10 units/ml for 4 hours). The aaount of PMN adherent to 105 EC art ter 5 min incubation was about 2.1×105 to control and 4×105 to IL-i-treated EC. When AD6 was added to the aediua during the adhesion experiaent PMN adhesion was inhibited in a concentration dependent way. The ainiaal active concentration of the drug was 0.5μM( 20-30% inhibition to both control and IL-1 treated EC) but inhibition was aaxiaal at SOOjiM ( 80-90 % inhibition to control and 65-80 % to IL-i-treated EC ). AD6 also blocked (90-95 % inhibition at 500μM) PMN adhesion to plastic wells. The drug effect on PMN required at least 5 min incubation to be apparent and declined after 30 min. AD6 pretreataent of either PMNs or ECs followed by washing reduced PMN adhesion to unstimulated or IL-i-treated EC.The effect was however aaxiaal when both cell types were treated with AD6, thus indicating that the inhibitory activity of AD6 was directed at both ECs and PMNs and night be cumulative.
TISSUE THROMBOPLASTIN-INDUCED REVERSIBLE DIC AS AN IN VIVO MODEL OF THROMBIN GENERATION AND INHIBITION
Authors: Marbet G A , Zbinden B , Satiropas P , Duckert F
Published: August 2018

We have tried a kinetical approach to characterize the dynamics of thrombin generation, thrombin action and heparin-enhanced inhibitors in vivo. Integrals (φ) of free thrombin concentration over time were calculated from fibrinogen decrease to characterize tissue thromboplastin-induced DIC in the dog. DIC with φ < 8nMmin was reversible. Dynamic thrombin inhibition (DTI), measured as pseudo-first order rate constant of thrombin inactivation by plasma (baseline DTI = 6.31± 0.79/min, n=30) increased to 68.69±59.98/min (n=7) with heparin (H) and to 22.48±14.91/min (n=5 with pentosan polysulfate (PPS). DTI correlated significantly with heparin doses (p< 0.002), and with the prolongation of APTT (p<0.0 2) and of prothrombin time (p < 0.05). The efficiency β of tissue thromboplastin (Tp) to trigger DIC ( φ per ml TP) was reduced from β =3.81±3.16nMmin/ml to 0.74±0.52nMmin/ml by H (p < 0.01) and to 1.16±1.10nMmin/ml (n.s.) by PPS. As expected from the product DTI.φ = 23.4 ± 13.8nM there was no detectable decrease of prothrombin, of the combined activity of antithrombin III + heparin cofactor II (ATHC) or of heparin cofactor II (HC, specific assay by dermatan sulfate activation) in reversible DIC without glycosaminoglycan protection. However, increasing doses of TP at constant PPS protection induced a statistically significant and persistent decrease of prothrombin by 17.6±9.91 and of HC by 20.4±8.81 indicating HC enhancement by PPS in vivo. The model is suitable for the study of glycosa-minoglycans and thrombin inhibitors.
THE MECHANISM OF THE HYPERCOAGULABLE RESPONSE TO HAEMORRHAGE
Authors: Blare S , McCollum C N , Greenhalgh R M
Published: August 2018

Gastrointestinal haemorrhage causes a hypercoagulable state and early blood transfusion increases both rebleeding and transfusion requirements [1]. The role of x- and B-adreno-receptors in the mechanism of this hypercoagulable state and the effects of infusions have been studied in NZW rabbits.

Haemorrhage was simulated by aspirating 20% of the blood volume from the median ear artery. Coagulation was measured before haemorrhage and at 30-minute intervals using the Biobridge Impedance Clotting Time (ICT). Three different groups of rabbits were used: (a) normal controls, (b) B-blocked with propranolol 1mg/kg, and (c) x- and B-blocked with phentolamine 3mg/kg and propranolol 1mg/kg. Equal volumes of (i) Haemaccel, (ii) fresh blood or (iii) stored blood were then given 30 minutes after haemorrhage.

Mean ± sem ICT was 6.0±0.15 minutes before haemorrhage, with no difference between the groups, suggesting that x- and B-blocking drugs have no effect on baseline coagulation. Haemorrhage produced a hypercoagulable state with the mean ICT shortened from 6.1±0.2 to 2,2±0.2 minutes (p<0.01). This response was significantly reduced to 5.2±0.4 and 5.1±0.2 minutes by both B-blockade and combined x- and B-blockade respectively.

Haemaccel had no significant effect on the hypercoagulable state, with the ICT going from 2.6±0.2 to 2.8±0.3 minutes. However, fresh and stored blood both reversed hypercoagulability with ICT increasing from 2.6±0.3 to 4.6+0.2 and 5.1±0.1 minutes respectively.

In this model the hypercoagulable response to haemorrhage appears to be mainly B- mediated and is partially reversed by both fresh and stored blood, but not by Haemaccel.

1. Blair SD, Janvrin SB, McCollum CN, Greenhalgh RM (1986). Br J Surg 73: 783-785.
THE INFLUENCE OF CHEMOTHERAPY ON THE PLASMATIC COAGULATION AND FIBRINOLYTIC SYSTEM IN LUNG CANCER PATIENTS
Authors: Ruiz M A , Marugán I , Estellés A , Espafia F , Aznar J , García-Conde J
Published: August 2018

Following the administration of cytostatic drugs, an increase in thromboembolic phenomena has been described in cancer patients. Such hemostatic alterations may be related to degree of hipercoa-gulability observed following chemotherapy, in comparison to previous levels. In terms of the fibrinolytic system, however, no - clearly defined alterations have been detected. We studied the - changes in plasmatic coagulation and fibrinolysis in 40 patients with non-operable stage III and IV lung cancer (30 epidermoid - ad 10 microcytic neoplasms) following cytostatic chemotherapy. Two studies were done on each patient, i.e., one at the time of diagnosis, -and the other 48 hours after completing the first chemotherapeutic cycle. The results show significant (p 0,05) post-chemotherapy increases in fibrinopeptide A (FPA) levels (pre: 2.95 ± 3.98, post: 8.15 ± 9.40 ng/ml), as well as a decrease in fibrinolytic activity reflected by a drop (p 0.01) in functional tissue plasminogen activator (t-PA) (pre: 1.53 ± 1.66, post: 0.91 ± 0.95 ng/ml). Morever, a tendency towards reduced euglobulinic precipitate lysis on fibrin agar was observed (pre: 122.8 ± 85.7, post: 105 ± 71.5%). The other parameters evaluated, i.e., antithrombin III, plasminogen immunologic t-PA and functional PA inhibitor - (PAI) showed no significant changes.

We have also studied the potential accumulative effect of three chemotherapy courses and the results were compared to the situation at the time of diagnosis. A significant increase p 0.01 in functional PAI has been observed (pre: 1.85 ± 2.38, post: 5.41 ± 3.74 U/ml). The possible participation of tumor mass in the elevation of these parameter was considered: but no relation betwen tumor mass and increase PAI have been detected.

Chemotherapy is apparently capable of conditioning a decrease in fibrinolytic activity in these cancer patients, this could be related to the enhanced tendency of these patients to developing - thromboembolic phenomena following cytostatic chemotherapy.
ALTERATIONS IN COAGULATION AND FIBRINOLYSIS IN LUNG CANCER PATIENTS
Authors: Ruiz M A , Estellés A , Marugán I , Navarro I , Aznar J , García-Conde J
Published: August 2018

Lung cancer has commonly been associated with to both clinical problems of thromboembolism and to biological alterations in -coagulation and fibrinolysis.

We evaluated some coagulation and fibrinolytic parameters of the plasmatic coagulation and fibrinolytic system (Fibrinopeptide A (-FPA-) for enzimoimmunoassay, immunological tissue plasminogen activator (t-PA) for enzimoimmunoassay, functional (t-PA) for -chromogenic substrate and functional t-PAinhibitor (PAI) in 40 non-operable lung cancer patients (Table I) comprising 39 males and one female, aged 45 to 67 (average 59). The results are compared with those from a control group of 20 healthy male volun-ters aged 32 to 58 (average 48).

Table II shows the results obtained (mean ± SD) for the parameters found to be significantly different to those of the control group. An increase is seen in the levels of FPA, functional t-PA and PAI in the lung cancer group. In the case of the extensive -lung tumor patients, FPAfpa and t-PA levels are significantly higher than for the group of locally advanced neoplasmas.

The plasma of lung cancer patients therefore shows fibrinolytic alterations and an increase in thromboplastin activity.
Effect of dexamethasone and endothelial cell supernatant on u-PA produced by human promyelocyte cells treated with phorbol myristate acetate (PMA)
Authors: DUBOR F , DOSNE A M , CHEDID L
Published: August 2018

After treatment with PMA the human promyelocytic HL60 cells were induced to differentiate into a monocyte-macrophage population and to produce a high amount of plasminogen activator in the supernatant. This response was detected from 0,5 ng/ml of PMA and culminated at 5 ng. The plasminogen activator appeared of urokinase-type as showed by fibrinenzymographic analysis : the enzymatic profile of cell supernatant showed 2 lysis band (Mr 33.000 and 55.000) corresponding to those of urokinase of low and high mol. weight. Dexamethasone (100 pM) suppressed the production of this macrophage u-PA without evidence of plasminogen activator inhibitor (PAI) generation in the supernatant : free PAI was not detected in urokinase inhibition assays ; complexes of u-PA-PAI were not observed in fibrinoenzymographic studies. Supernatant of human endothelial cells added to HL60 cell supernatant neutralized the two molecular species of macrophage u-PA and gave rise to complexes (Mr 110.000 and 84.000) detected by fibrinoenzymography. These results suggested different possible levels for controlling u-PA of inflammatory macrophages including interaction with endothelial cells secretion since endothelial PAI is increased by some inflammatory monokine and also by dexamethasone, it appears that endothelium could have a regulatory role on inflammatory fibrinolysis.
TUMOR CELLS INTERACTIONS WITH SUBENDOTHELIAL EXTRACELLULAR MATRIX IN A PERFUSION SYSTEM: ROLE OF PLATELETS
Authors: Ricetti M M , Samaden A , Fregoni V , Vigotti M , Piovella F , Ascari E
Published: August 2018

It has been suggested that platelets may facilitate tumor metastasis by increasing tumour cell (TC) adhesion to vascular endothelium mainly through the formation of platelet/TC aggregates. In order to further investigate this we have utilized an in vitro model combining extracellular matrices (EM) from cultured vascular endothelial cells and two neoplastic clones from a mFS6 murine fibrosarcoma: one expressing high metastatic potency (M4) and one with low metastatic potential (M9). These two sublines express an in vitro platelet aggregating activity which has previously been characterized and which correlates with in vivo metastasizing capacity. To reproduce the in vivo flow conditions a flat perfusion chamber was used (*). Glass coverslips, carrying the EM were perfused for 10’ at a wall shear rate of 450 sec™1 with reconstituted heparinized human blood containing 3×10s/ml TC, with or without platelets. Coverage of the EM with adherent TC was evaluated by a morphometric method and expressed as percent TC coverage. M4 cells adhered to EM more than did M9 cells: 4.3% TC coverage for M4, versus 2.5% TC coverage for M9. In the presence of platelets, TC adherence was greatly increased, being 9.7% for M4 and 7.8% for M9. In the experiments performed in the presence of thrombocytes no platelet/TC thrombi were found onto the EM and no TC-induced platelet aggregation was detected in blood after perfusion. Our results confirm that platelets favour the occurrence of metastasis and suggest that other mechanisms than platelet/TC aggregates formation might be involved in this process.

(*) K.S. Sakarlassen et al. J.Lab.Cl in.Med. 102:522, 1983
INTERACTION BETWEEN HEMOSTATIC COMPONENTS AND TUMOR CELLS
Authors: Esumi N , Todo S , Imashuku S
Published: August 2018

Involvement of platelets and coagulation systems in the hematogenous metastasis of tumor cells has been suggested from in vivo and in vitro studies, however, there is still controversy about the exact role of hemostasis in metastasis. To date, at least three types of platelet aggregating mechanisms and three types of tumor cell procoagulants have been reported in different tumor cells.

We investigated platelet aggregating activity (PAA), procoagulant activity (PCA) and the relationship between these two activities, using eight human neuroblastoma cell lines, three human leukemia cell lines and human mature lymphocytes. PCA in tumor cells was measured by the single stage recalcification time and the assay with chromogenic substrate S2222. PAA was determined turbidometrically with an aggregometer by adding cell suspensions of tumor cells to platelet rich plasma (PRP). The effects of protease inhibitors, enzymes and thrombin inhibitors on PAA and PCA were also studied.

Neuroblastoma cell suspensions showed high PCAs which were reduced in Factor VII deficient human plasma, indicating a tissue factor-like activity. NCG line possessing the highest PCA also showed a high PAA, which was inhibited by pretreatment of cell suspensions with phospholipase A2 and abolished in the presence of heparin, hirudin or MD805 in the assay system. Human leukemia cell lines and mature lymphocytes had weak to moderate PCAs without showing PAA, but became active to express PAA after being removed of cell surface sialic acid by neuraminidase. These results suggest that in neuroblastoma, PCA closely linked with PAA may play a role in the hematogenous metastasis. In hemopoietic cells, PAA expressed when cell surface sialic acid is removed does not correlate with PCA, and sialic acid in these cells possibly prevents direct interaction with platelets in the hemostatic homeostasis.