Proteasome inhibitor prevents experimental arterial thrombosis in renovascular hypertensive rats

2004 ◽  
Vol 92 (07) ◽  
pp. 171-177 ◽  
Author(s):  
Justyna Ostrowska ◽  
Marek Z.Wojtukiewicz ◽  
Ewa Chabielska ◽  
Wlodzimierz Buczko ◽  
Halina Ostrowska
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Proteasome Inhibitor ◽  
Cardiovascular Events ◽  
Proteasome Activity ◽  
Vehicle Group ◽  
Control Group ◽  
20S Proteasome ◽  
Hypertensive Rats ◽  
Indirect Mechanism

SummaryRecent studies indicate that highly selective proteasome inhibitors can be useful in prevention of some cardiovascular events. Here we demonstrate that proteasome inhibitor, Z-IleGlu (Ot-Bu) Ala-Leucinal (PSI), is active in the prevention of platelet-dependent arterial thrombosis induced in renovascular hypertensive rats (two-kidney, one clip Goldblatt model, and 2K1C, n=5).The administration of PSI intravenously at a single dose of 0.3 mg/kg before induction of arterial thrombosis markedly increased carotid final flow rate, as compared to control (vehicle) group (10.36 ± 1.8 ml/min and 1.2 ± 1.2 ml/min, respectively), significantly decreased the wet (1.23 ± 0.23 mg and 4.1 ± 0.94 mg, respectively), and dry (0.46 ± 0.145 mg and 1.46 ± 0.39, respectively) thrombus weight, and completely prevented arterial occlusion. Moreover, platelets from PSI treated thrombotic 2K1C rats, showed in response to collagen a significant inhibition of aggregation in the whole blood (10.26 ± 0.6 ohms vs. 15.51 ± 0.91ohms in the control group). In contrast, collagen-induced platelet aggregation was not inhibited in vitro, after pre-treatment of the blood with PSI at the concentration of 10μM that effectively inhibited the 20S proteasome activity in platelets, indicating that ex vivo anti-aggregatory effect of PSI proceeds through an indirect mechanism not associated with suppression of 20S proteasome activity in platelets. In conclusion, our in vivo findings demonstrate that proteasome inhibitor, Z-Ile-Glu(Ot-Bu)Ala-Leucinal, prevents the development of arterial thrombosis in renovascular hypertensive rats and effectively suppresses platelet aggregation by an indirect mechanism. Thus the data provide a new insight into the potential role for the proteasome-dependent pathway in cardiovascular events.

AR-H067637, the Active Metabolite of the Oral Anticoagulant AZD0837, with and without Aspirin or Aspirin and Clopidogrel in Experimental Models of Venous and Arterial Thrombosis and Bleeding in Anaesthetized Rats

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5459-5459
Author(s):  
Margareta Elg ◽  
Anna Rönnborg ◽  
Magnus Kjaer
Keyword(s):  
Platelet Aggregation ◽  
Ferric Chloride ◽  
Arterial Thrombosis ◽  
Peak Concentration ◽  
Low Dose ◽  
Saline Group ◽  
Vehicle Group ◽  
Impedance Method ◽  
High Dose ◽  
Anaesthetized Rats

Abstract AR-H067637 is a direct thrombin inhibitor derived in vivo from the orally available prodrug AZD0837. AZD0837 is in development for use in thromboembolic disorders. This study investigated the additional effects of aspirin (ASA) alone and in combination with clopidogrel (Clop) on AR-H067637 in animal models of venous thrombosis (VT) and arterial thrombosis (AT). Anaesthetized rats (9–11 per treatment group) were treated with vehicle or 3 increasing (low, middle and high) doses of AR-H067637 (0.1, 0.3 and 1.0 μmol/kg/h in VT model and 0.5, 1.5 and 4.5 μmol/kg/h in AT model [predicted to obtain 25%, 50% and 75% antithrombotic effect]) given intravenously (iv) as continuous infusions. Rats were also treated with saline, ASA (10mg/kg) or ASA (10mg/kg) + Clop (25mg/kg) as iv bolus injections at the start of the experiment. In the AT model the thrombotic stimulus was ferric chloride administered to the carotid artery, while in the VT model the stimulus was ferric chloride and partial stasis of the caval vein. Thrombus size (TS) was assessed as wet weight (both models) and as protein content (AT model only). Bleeding time (BT) and blood loss (BL) were investigated by tail incision (TI) and muscle transection (MT). Activated partial thromboplastin time (APTT; AT model), thrombin coagulation time (TcT; AT model), thrombin generation (determined using the calibrated automatic thrombogram [CAT] assay variables; both models), lag time (LT), time to peak concentration (ttPeak), peak concentration (peak) and endogenous thrombin potential (ETP) were investigated. Arachidonic acid (AA) and ADP-induced platelet aggregation were measured by the whole blood impedance method in a subset of rats (n=6) to verify antiplatelet effects of ASA and Clop, respectively. Results showed that ARH067637 dose-dependently decreased TS in both models (Table). ASA+Clop, decreased TS in both models. In the VT model, ASA+Clop had no additional effect to that seen with AR-H067637 alone, but in the AT model further decreased TS with total inhibition obtained at the highest dose of AR-H067637. AR-H067637 dose-dependently prolonged TI BT and BL and MT BL (up to 2.4, 1.4 & 2.1 times the vehicle group). ASA in addition to AR-H067637 did not potentiate TI BT or MT BL but potentiated TI BL in addition to the highest dose of AR-H067637. ASA+Clop potentiated TI BT, BL and MT BL (2.6, 5.4 & 2.4 times the saline group). Only high-dose AR-H067637 reinforced this bleeding (TI BT and BL and MT BL 3.4, 17 and 9.2 times the saline group). AR-H067637 concentration-dependently prolonged TcT (2–7 times), APTT (1.3–3 times), CAT LT (up to 2.6 times), CAT ttPeak (up to 2 times), and the highest plasma concentration totally abolished CAT peak and CAT ETP. ASA or ASA+Clop had no influence on these variables. AA and ADP-induced platelet aggregation was inhibited by 96% in ASA-treated and 29% in Clop-treated animals, respectively. This investigation shows that ASA with or without ARH067637 had a small effect on TS, without increasing bleeding. ASA+Clop decreased TS: effects were more marked in the AT model, but increased bleeding was seen, especially at high AR-H067637 plasma concentrations. Pharmacodynamic markers indicate dose-dependant, increased anticoagulation with rising concentrations of AR-H067637; these markers were not influenced by ASA or ASA+Clop. Thrombus size (TS) in VT and AT models TS in VT (%) TS in AT (%) AR-H=AR-H067637; LD=low dose; MD=middle dose; HD=high dose Controls 100±8 100±9 Saline + ASA 89±9 71±10 Saline + ASA/Clop 73±7 64±11 Low dose (LD) LD AR-H 62±11 82±9 LD AR-H + ASA 72±11 77±8 LD AR-H + ASA/Clop 67±9 36±8 Middle dose (MD) MD AR-H 49±6 64±9 MD AR-H + ASA 46±10 51±6 MD AR-H + ASA/Clop 32±9 34±6 High-dose (HD) HD AR-H 12±3 23±5 HD AR-H + ASA 12±2 27±6 HD AR-H + ASA/Clop 10±1 1±1

Phase I Study of the Proteasome Inhibitor Bortezomib in Pediatric Patients With Refractory Solid Tumors: A Children's Oncology Group Study (ADVL0015)

2004 ◽  
Vol 22 (23) ◽  
pp. 4804-4809 ◽  
Author(s):  
Susan M. Blaney ◽  
Mark Bernstein ◽  
Kathleen Neville ◽  
Jill Ginsberg ◽  
Brenda Kitchen ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Proteasome Inhibitor ◽  
Pediatric Patients ◽  
Maximum Tolerated Dose ◽  
Proteasome Activity ◽  
20S Proteasome ◽  
Intravenous Bolus ◽  
Recommended Phase Ii Dose ◽  
Dose Dependent ◽  
Dose Limiting Toxicity

PurposeTo determine the maximum-tolerated dose, dose-limiting toxicity (DLT), and pharmacodynamics of the proteasome inhibitor bortezomib (formerly PS-341) in children with recurrent or refractory solid tumors.Patients and MethodsAn intravenous bolus of bortezomib was administered twice weekly for 2 consecutive weeks at either 1.2 or 1.6 mg/m2/dose followed by a 1-week rest. The pharmacodynamics of bortezomib were evaluated by measurement of whole blood 20S proteasome activity.ResultsFifteen patients, 11 assessable, were enrolled between November 2001 and February 2003. Dose-limiting thrombocytopenia, which prevented administration of a complete course (four doses in 2 weeks) of therapy, occurred in two of five assessable children enrolled at the 1.6 mg/m2dose level. There were no other DLTs. Inhibition of 20S proteasome activity seemed to be dose dependent. The average inhibition 1 hour after drug administration on day 1 was 67.2% ± 7.6% at the 1.2 mg/m2/dose and 76.5% ± 3.3% at the 1.6 mg/m2/dose. There were no objective antitumor responses.ConclusionBortezomib is well tolerated in children with recurrent or refractory solid tumors. The recommended phase II dose of bortezomib for children with solid tumors is 1.2 mg/m2/dose, administered as an intravenous bolus twice weekly for 2 weeks followed by a 1-week break.

Is Increased Platelet Aggregation Is a Risk Factor for Cardiovascular Disease in Women With Idiopathic Central Precocious Puberty

2021 ◽  
Author(s):  
Ahmet Bolat ◽  
CENGİZ Zeybek ◽  
ORHAN GÜRSEL ◽  
MEHMET EMRE TAŞÇILAR
Keyword(s):  
Platelet Aggregation ◽  
Precocious Puberty ◽  
Cardiovascular Events ◽  
Platelet Rich Plasma ◽  
Central Precocious Puberty ◽  
Adenosine Diphosphate ◽  
Control Group ◽  
Time Value ◽  
Idiopathic Central Precocious Puberty ◽  
Increased Risk

Abstract BackgroundEarly menarche in girls is associated with an increased risk of cardiovascular events later in life, but the role of platelets in this risk has not been investigated during puberty. Here, we evaluated the effects of idiopathic central precocious puberty (ICPP) on platelet aggregation in platelet-rich plasma samples from female patients. MethodsThe study included 40 girls diagnosed with ICPP between February 2012 and June 2016, and a control group consisting of 30 healthy females. Adenosine diphosphate (ADP) and collagen-induced platelet aggregation were studied with photometric aggregometry. ResultsThere was no difference in the platelet count or volume between girls with ICPP and the control group. In addition, the ADP-induced maximum aggregation time, value, and slope did not significantly differ between the study and control groups (p > 0.05). However, the collagen-induced maximum aggregation time, value, and slope were significantly higher in the study group (p < 0.001). ConclusionsIncreased collagen-induced platelet aggregation was detected in girls with ICPP. Thus, early treatment of ICPP may be important because of the increased risk of cardiovascular events later in life. Extensive studies with more patients are needed to determine the mechanisms of platelet dysfunction in girls with ICPP.

Study of brain and whole blood PK/PD of bortezomib in rat models

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12036-12036 ◽  
Author(s):  
L. J. Yu ◽  
B. Riordan ◽  
P. Hatsis ◽  
A. Brockman ◽  
S. Daniels ◽  
...  
Keyword(s):  
Whole Blood ◽  
Ex Vivo ◽  
Proteasome Inhibition ◽  
Proteasome Activity ◽  
Constant Infusion ◽  
Vehicle Group ◽  
20S Proteasome ◽  
Blood Contamination ◽  
The Brain ◽  
Brain Tissues

12036 Background: Bortezomib (Btz) is the first in class proteasome inhibitor and has been approved for treatment of multiple myeloma patients who have received at least 1 prior therapy. The potential for Btz to penetrate the CNS was examined in the rat under two conditions: intact blood brain barrier (BBB) and compromised BBB induced by middle cerebral artery occlusion (MCAO). Methods: Intact BBB: healthy rats received an iv bolus followed by a constant infusion of Btz to steady-state (SS). The blood and brain samples were collected for determination of concentration (Conc) of Btz (PK) and of 20S proteasome activity (PD). The brain samples were collected after a perfusion with saline. Inulin was included in the study in order to determine blood contamination in brain tissues. Compromised BBB: rats underwent MCAO surgery and 1 h later were administered Btz via an iv bolus of 0, 0.1, 0.2 or 0.35 mg/kg. The blood and brain samples were collected through 24 h postdose. Conc of Btz was determined by an LC/MS/MS method. The 20S proteasome activity was measured using an ex vivo assay. Results: 1) Intact BBB: at SS the mean blood Conc of Btz was 140 ng/mL, and proteasome activity in the blood was inhibited by ∼80% compared to the vehicle group (p < 0.0001). In contrast, the brain Conc of Btz was extremely low (∼3 ng/g) with the brain-to-blood ratio of ∼0.02. No difference was observed in brain proteasome activity between the vehicle and Btz-treated groups. 2)The MCAO rat: the PK/PD relationship in the blood was best described by a sigmoid Emax model with an EC50 of 110 ng/mL and gamma factor of 3.8. The model also suggests that there is no proteasome inhibition (PI) when the blood Conc is <40 ng/mL (no effective blood Conc, NOEBC). In the brain, the Cmax of Btz was 22.0 ng/g from the highest dose group, in contrast to the blood Cmax of 164 ng/mL. The increased exposure in the brain of a MCAO rat relative to a normal rat was anticipated as its BBB is impaired. However, the brain Concs were all below the NOEBC. No significant PI was observed in all brain tissues (P>0.1). Conclusion: Very poor brain penetration was observed for Btz in rats. Btz showed PI in whole blood but not in the brain either of normal or MCAO rats following administration of Btz. [Table: see text]

scholarly journals EFFECTS OF ANTIPLATELET TREATMENT ON THROMBOCYTIC AGGREGATING ABILITY IN PATIENTS WITH ISCHEMIC HEART DISEASE AND IN COMBINATION WITH TYPE 2 DIABETES

2019 ◽  
pp. 11-17
Author(s):  
Olena Karpenko
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Platelet Aggregation ◽  
Antiplatelet Therapy ◽  
Cardiovascular Events ◽  
Dual Antiplatelet Therapy ◽  
Control Group ◽  
Antiplatelet Treatment ◽  
Effective Prevention ◽  
Group I

The number of diabetes mellitus (DM) is steadily increasing and such a rapid increase will lead to an increase in cardiovascular events, mainly due to coronary heart disease (CHD), in which coronary atherosclerosis and its progression is one of the causes of mortality. The course of atherosclerosis is closely related to the state of the hemostasis system. The basis for the development of atherosclerosis is arterial thrombosis, with the activation of platelets playing a leading role in the disruption of hemostasis in coronary heart disease, increasing the risk of thrombotic complications. At present, data on the relationship of different hemostasis units in coronary heart disease in combination with diabetes are mixed, complicating the prognosis of adverse effects taking into account the status of platelet hemostasis. Given the relevance of the topic, the purpose of this study was to evaluate the spontaneous and induced platelet aggregation in patients with various forms of acute coronary heart disease (ACHD) and to identify features of platelet aggregation activity in the combination of ACHD and DM.Adequate reduction of platelet functional activity in patients with coronary heart disease receiving antiplatelet treatment is the basis for effective prevention of thrombus formation in the coronary vessels and the development of adverse cardiovascular events. However, according to the data obtained, the highest activation of platelet hemostasis was observed in the group of patients with ACHD in combination with DM, which showed a significant (relative to the control group) increase in the level of spontaneous platelet aggregation by 4.6 times. At the same time, the percentage of patients who had increased the above indicators was significantly lower in the group of patients with ACHD without disorders of carbohydrate metabolism. In patients with ACHD in combination with DM, activation of the spontaneous aggregation rate was also observed, which accelerated the formation of aggregates by 30% compared with the isolated ACHD group (p <0.05). In the study of induced platelet aggregation, it was taken into account that patients in both groups received dual antiplatelet therapy, which had a significant effect on their activity. However, the expected inhibition of aggregation potential was revealed only by the action of arachidonic acid (AA). Thus, the degree of platelet aggregation in response to AA in group I was 1.9 times significantly lower than the control values ​​of 18.8% [12,1; 26,4], in group II - 1,5 times and made 24,38% [21,5; 32.9] (p <0.001 for both cases). According to ADP-induced platelet aggregation, the effect of antiplatelet drugs was less effective. Thus, a moderate decrease in the degree of ADP-aggregation was observed only in the group of isolated ACHD, whose indicators were 1.42 times lower than in the control group (p <0.01). Thus, dual antiplatelet therapy was accompanied by an effective reduction in platelet function only in the group of patients with isolated ACHD.

Ketorolac and Enoxaparin Affect Arterial Thrombosis and Bleeding in the Rabbit 

1998 ◽  
Vol 88 (5) ◽  
pp. 1310-1317 ◽  
Author(s):  
Sonia Delaporte-Cerceau ◽  
Charles-Marc Samama ◽  
Bruno Riou ◽  
Philippe Bonnin ◽  
Jean-Jacques Guillosson ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
Treatment Effect ◽  
Common Carotid Artery ◽  
Arterial Thrombosis ◽  
Bleeding Time ◽  
Median Number ◽  
Control Group ◽  
Enoxaparin Group ◽  
Group 2

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) may interfere with hemostasis during the perioperative period, and the combination of NSAID and enoxaparin could increase this effect. The aim of this prospective, blinded experimental study was to assess these effects using a model of arterial thrombosis and bleeding in the rabbit. Methods After anesthesia was induced and monitors placed, the common carotid arteries were exposed, and 60% stenosis of the right common carotid artery was produced. Twenty minutes later, a compression injury of the artery was produced that triggered a series of cyclic episodes of thrombosis and clot lysis. This was manifested as cyclic flow reductions (CFR; measured with an electromagnetic flow meter). After the first flow reduction was noted, the rabbits were immediately and randomly assigned to one of four groups (n = 10 each) that received intravenous infusions: control, ketorolac (2 mg/kg), enoxaparin (0.5 mg/kg), and ketorolac plus enoxaparin (2 mg/kg and 0.5 mg/kg, respectively). The number of CFRs that occurred in the subsequent 20-min period was used as a measure of treatment effect. The contralateral common carotid artery was exposed, and both stenosis and injury were produced. The ability of the administered drug to prevent thrombosis was assessed as the number of CFRs that occurred during the first 20-min period after vessel injury. In addition, both before and after group assignment and drug injection, bleeding times were noted and a platelet aggregation test was performed. Laparotomy was followed by a spleen section, and the extent of the wound and the amount of splenic bleeding were measured. Results The treatment effect was indicated by the median number of CFRs, which was 5.5 in the control group, 1 in the ketorolac group, 2 in the enoxaparin group, and 0 in the ketorolac + enoxaparin group. The prevention effect was indicated by the median number of CFRs, which was 4 in the control group, 0 in the ketorolac group, 2 in the enoxaparin group, and 0.5 in the ketorolac + enoxaparin group. Bleeding time was significantly lengthened in the enoxaparin and in the ketorolac + enoxaparin groups. Splenic and wound bleeding was greater in the ketorolac group. Platelet aggregation was completely inhibited in the ketorolac and the ketorolac + enoxaparin groups. Conclusions Ketorolac had an important antithrombotic activity. The association of enoxaparin with ketorolac seemed to lengthen the bleeding time observed with ketorolac.

The present state of aspirin and clopidogrel resistance

2009 ◽  
Vol 29 (03) ◽  
pp. 285-290 ◽  
Author(s):  
K. E. Guyer
Keyword(s):  
Diagnostic Tests ◽  
Arterial Thrombosis ◽  
Cardiovascular Events ◽  
Treatment Success ◽  
Antiplatelet Agents ◽  
Antiplatelet Drug ◽  
Coronary Syndrome ◽  
Testing Method ◽  
Pharmacological Response ◽  
Platelet Physiology

SummaryAntiplatelet therapy has demonstrated significant clinical benefit in the treatment of acute coronary syndrome. However, as with any treatment strategy it has been unable to prevent all cardiovascular events. This is far from surprising when considering the complexity of arterial thrombosis and more specifically platelet physiology. This lack of treatment success has provoked the introduction of various diagnostic tests and testing platforms with the intent of guiding and optimizing clinical treatment. Such tests have resulted in the generation of clinical data that suggest suboptimal response to antiplatelet agents such as aspirin and clopidogrel.In the case of both aspirin and clopidogrel, this suboptimal response has been termed resistance. Drug resistance would imply a lack of pharmacological response that has not been specifically investigated in many of the clinical studies performed to date. Rather, the term resistance has been used to describe various facets of platelet activation and aggregation relative to the testing method. Many of these measured parameters are not addressed in the therapeutic intent of the antiplatelet drug in question.

Platelet Aggregation in Diabetes Mellitus and the Effect of Insulin in Vivo on Aggregation

1972 ◽  
Vol 27 (01) ◽  
pp. 114-120 ◽  
Author(s):  
A. A Hassanein ◽  
Th. A El-Garf ◽  
Z El-Baz
Keyword(s):  
Platelet Aggregation ◽  
Rapid Onset ◽  
Control Group ◽  
Diabetic Patients ◽  
Fasting State ◽  
Clotting Time ◽  
Cholesterol Levels ◽  
Platelet Disaggregation ◽  
Aggregation And Disaggregation

SummaryADP-induced platelet aggregation and calcium-induced platelet aggregation tests were studied in 14 diabetic patients in the fasting state and half an hour after an intravenous injection of 0.1 unit insulin/kg body weight. Platelet disaggregation was significantly diminished as compared to a normal control group, and their results were negatively correlated with the corresponding serum cholesterol levels. Insulin caused significant diminution in the ADP-induced platelet aggregation as a result of rapid onset of aggregation and disaggregation. There was also a significant increase in platelet disaggregation. In the calcium-induced platelet aggregation test, there was a significant shortening of the aggregation time, its duration, and the clotting time. The optical density fall due to platelet aggregation showed a significant increase. Insulin may have a role in correcting platelet disaggregation possibly through improvement in the intracellular enzymatic activity.

The Modification of Experimental Occlusive Arterial Thrombosis in the Rat by Malayan Pit Viper Venom

1968 ◽  
Vol 19 (01/02) ◽  
pp. 242-247 ◽  
Author(s):  
K. E Chan
Keyword(s):  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Arterial Occlusion ◽  
Control Group ◽  
Antithrombotic Effect ◽  
Daily Dose

SummaryThe effect of Malayan pit viper (Ancistrodon rhodostoma) venom on the fate of experimental arterial thrombosis was studied in rats. A suitable daily dose of venom (500 μg) was used to induce hypofibrinogenaemia in the treated rats for the greater part of each of three consecutive post-operative days.The treated animals showed a statistically significant overall reduction in the incidence of both red thrombus formation and thrombotic arterial occlusion when compared to a control group. This antithrombotic effect of the venom could be observed in the 7-day period following the cessation of the treatment.

The Effects of Acute Smoking on Platelet Behaviour, Fibrinolysis and Haemorheology in Habitual Smokers

1984 ◽  
Vol 51 (01) ◽  
pp. 006-008 ◽  
Author(s):  
J J F Belch ◽  
B M McArdle ◽  
P Burns ◽  
G D O Lowe ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Plasminogen Activator ◽  
Arterial Thrombosis ◽  
Plasma Viscosity ◽  
Red Cell ◽  
Cell Deformability ◽  
Red Cell Deformability ◽  
Cigarette Smokers ◽  
Smoking Group

SummaryThere is an increased frequency of arterial thrombosis in cigarette smokers. The changes in blood coagulation seen in these subjects have been studied by many workers but results have not always been in agreement. We wished to study the effects of acute .smoking on platelet behaviour, fibrinolysis and haemorheology in ten habitual smokers, and to compare these results with nonsmoking controls. Results show that the smoking group had higher plasma fibrinogen (p <0.04), lower plasminogen (p <0.02) and plasminogen activator (p <0.05), and higher plasma viscosity (p <0.003). The changes seen in cigarette smokers after smoking three cigarettes were an increase in the rate of platelet aggregation to ADP (p <0.02), an increase in α2M, (p <0.02), and factor VIII RAG (p <0.05). Plasma viscosity was decreased (p <0.02) as was red cell deformability (p >0.02).We confirm an increased tendency to hypercoagulability in smokers compared to controls which becomes more pronounced immediately after smoking three cigarettes.

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