scholarly journals Αξιολόγηση των σφαιρικών δοκιμασιών της αιμόστασης στην ex vivo μελέτη της αντιπηκτικής και αντιαιμοπεταλιακής δράσης των νεότερων από του στόματος αντιπηκτικών και της ασενοκουμαρόλης σε ασθενείς με μη βαλβιδική κολπική μαρμαρυγή

2020 ◽  
Author(s):  
Κωνσταντίνος Κατωγιάννης
Keyword(s):  
Light Transmission ◽  
Ex Vivo ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Light Transmission Aggregometry

Σκοπός: Τα δεδομένα που υπάρχουν στην κλινική πράξη για τη δράση των άμεσων από του στόματος αντιπηκτικών (DOACs) είναι περιορισμένα. Στόχος μας ήταν να εκτιμήσουμε την ισχύ της αντιπηκτικής δράσης των DOACs σε ασθενείς με μη βαλβιδικής αιτιολογίας κολπική μαρμαρυγή (NVAF). Μέθοδοι: Μελετήσαμε 80 ασθενείς με NVAF και 20 υγιείς μάρτυρες με παρόμοια χαρακτηριστικά ως προς το φύλο και την ηλικία (20 λάμβαναν dabigatran 110 mg δύο φορές την ημέρα, 20 λάμβαναν rivaroxaban 20 mg μια φορά την ημέρα, 20 λάμβαναν apixaban 5 mg δύο φορές την ημέρα, 20 λάμβαναν ασενοκουμαρόλη). Σε όλους τους 80 ασθενείς και στα 20 άτομα της ομάδας ελέγχου, πραγματοποιήθηκαν οι συμβατικές δοκιμασίες πήξης (PT/INR, APTT, FIB), οι σφαιρικές δοκιμασίες αιμόστασης (θρομβοελαστομετρία, ROTEM και δοκιμασία παραγωγής θρομβίνης, ETP) και επιπλέον η πρότυπη μέθοδος εκτίμησης της ενεργοποίησης των αιμοπεταλίων, η οπτική θολοσιμετρική συσσώρευση (Light Transmission Aggregometry, LTA) με διεγέρτη την επινεφρίνη. Τέλος, με την ειδική δοκιμασία Hemoclot Thrombin Inhibitors (HTI) μετρήθηκαν τα επίπεδα στο πλάσμα του dabigatran και με την ειδική δοκιμασία Factor Xa Direct Inhibitor (DiXaI) μετρήθηκαν τα επίπεδα στο πλάσμα των rivaroxaban και apixaban. Αποτελέσματα: Σε ασθενείς υπό dabigatran 110 mg παρατηρήθηκε οριακά σημαντική μείωση της συσσώρευσης αιμοπεταλίων σε σχέση με ασθενείς που λάμβαναν ασενοκουμαρόλη (p=0,068) και σημαντικά μειωμένη συσσώρευση συγκριτικά με ασθενείς υπό rivaroxaban (p=0,045), όπως προέκυψε από τη μέθοδο LTA. Επίσης, ασθενείς που λάμβαναν dabigatran 110 mg σε σύγκριση με αυτούς που λάμβαναν ασενοκουμαρόλη, παρουσίασαν σημαντικά χαμηλότερες τιμές όσον αφορά το δείκτη Li-60 (p=0,011), ενώ δεν παρατηρήθηκε στατιστικά σημαντική διαφορά στις τιμές του ίδιου δείκτη μεταξύ των ασθενών που λάμβαναν rivaroxaban και apixaban (p=0,499). Η ασενοκουμαρόλη επηρέασε την παραγωγή θρομβίνης περισσότερο από το dabigatran 110 mg (AUC, p<0,001), με βάση το ενδογενές δυναμικό θρομβίνης (ETP). Ανάλογα ευρήματα παρατηρήθηκαν μετά τη σύγκριση του rivaroxaban και του apixaban με την ασενοκουμαρόλη (p<0,001). Επίσης, το ενδογενές δυναμικό θρομβίνης (ETP) μειώθηκε σημαντικά σε ασθενείς υπό rivaroxaban σε σύγκριση με εκείνους που λάμβαναν apixaban (p<0,003). Το Apixaban μειώνει σημαντικά την ETP σε σύγκριση με την ομάδα ελέγχου, αλλά σε μικρότερο βαθμό σε σχέση με το rivaroxaban.Επιπλέον, ανιχνεύθηκαν σημαντικές συσχετίσεις μεταξύ των επιπέδων dabigatran 110 mg, όπως προσδιορίστηκαν με τη δοκιμασία HTI, και σχεδόν όλων των παραμέτρων της δοκιμασίας ETP (AUC, p<0,001). Παρομοίως, παρατηρήθηκαν σημαντικές συσχετίσεις μεταξύ των συγκέντρωσης του rivaroxaban στο πλάσμα, όπως προσδιορίστηκε με τη χρωμογονική μέθοδο DiXaI, και των ακόλουθων παραμέτρων της δοκιμασίας ETP (Tlag, p=0,045, Tmax, p=0,016 και Cmax, p=0,003). Τέλος, σημειώθηκε στατιστικά σημαντική, αντίστροφη συσχέτιση μεταξύ της συγκέντρωσης του apixaban στο πλάσμα, όπως προσδιορίστηκε με τη χρωμογονική μέθοδο DiXaI και του ETP (AUC, p<0,001). Συμπέρασμα: Με βάση τις δοκιμασίες ROTEM, ETP και LTA, προέκυψαν τα ακόλουθα συμπεράσματα, όσον αφορά την αντιπηκτική δράση των DOACs, όταν αυτά χορηγούνται στα συγκεκριμένα δοσολογικά σχήματα σε πραγματικούς ασθενείς με NVAF: i) το dabigatran 110 mg, πέραν της αναστολής της θρομβίνης, φαίνεται να έχει αντιαιμοπεταλιακή δράση και να ενισχύει την ινωδόλυση, γεγονός που ενδεχομένως ερμηνεύει τον αυξημένο αιμορραγικό κίνδυνο, ii) οι μετρήσεις της δοκιμασίας ETP συνιστούν ένα πιο ασφαλές προφίλ για το apixaban, σε σχέση με το υπόλοιπα DOACs, ως προς τον αιμορραγικό κίνδυνο, iii) τα μέγιστα επίπεδα των DOACs συσχετίζονται με τις παραμέτρους ETP (αλλά όχι με τις παραμέτρους ROTEM), γεγονός που υποδηλώνει έναν πιθανό ρόλο των παραμέτρων του ETP στην παρακολούθηση των επιπέδων των DOACs.

Increased platelet sensitivity among individuals with aspirin resistance – Platelet aggregation to submaximal concentration of arachidonic acid predicts response to antiplatelet therapy

2008 ◽  
Vol 100 (07) ◽  
pp. 83-89 ◽  
Author(s):  
Sasidhar Guthikonda ◽  
Kirankumar Mangalpally ◽  
Rajnikant Patel ◽  
Timothy DeLao ◽  
Angela L. Bergeron ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Antiplatelet Therapy ◽  
Light Transmission ◽  
Ex Vivo ◽  
Platelet Inhibition ◽  
Aspirin Resistance ◽  
Light Transmission Aggregometry ◽  
Uncertain Etiology ◽  
Cox 1

SummaryAspirin ‘resistance’ (AR) is a phenomenon of uncertain etiology describing decreased platelet inhibition by aspirin. We studied whether (i) platelets inAR demonstrate increased basal sensitivity to a lower degree of stimulation and (ii) platelet aggregation with submaximal stimulation could predict responses to aspirin. Serum thromboxane B2 (TxB2) levels and platelet aggregation with light transmission aggregometry (LTA ) were measured at baseline and 24 hours after 325 mg aspirin administration in 58 healthy subjects. AR was defined as the upper sixth of LTA (≥ 12%) to 1.5 mM AA. Baseline platelet aggregation with sub-maximal concentrations of agonists [ADP 2 µM, arachidonic acid (AA) 0.75 mM, collagen 0.375 and 0.5 µg/ml] was greater in AR subjects compared with non-AR subjects, but not with higher concentrations (ADP 5 µM and 20 µM, AA 1.5 mM and collagen 1 µg/ml). Post-aspirin platelet aggregation was elevated in AR subjects with both submaximal and maximal stimulation. Baseline and post-aspirin serumTxB2 were higher inAR subjects and decreased further with ex-vivo COX -1 inhibition, suggesting incompletely suppressed COX -1 activity. Pre-aspirin platelet aggregation to 0.75 AA demonstrated a dichotomous response with 29/58 subjects having aggregation ≤15% and 29/58 subjects having aggregation ≥75%. In the high aggregation group 28% had AR compared to 6% in the non-AR group (p=0.04). In conclusion, platelets in AR subjects demonstrate increased basal sensitivity to submaximal stimulation, which could predict responses to antiplatelet therapy.

scholarly journals Personalization of Aspirin Therapy Ex Vivo in Patients with Atherosclerosis Using Light Transmission Aggregometry

Diagnostics ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 871
Author(s):  
Hamzah Khan ◽  
Reid C. Gallant ◽  
Abdelrahman Zamzam ◽  
Shubha Jain ◽  
Sherri Afxentiou ◽  
...  
Keyword(s):  
Light Transmission ◽  
Clinical Symptoms ◽  
Ex Vivo ◽  
Ankle Brachial Index ◽  
Duplex Ultrasound ◽  
Arterial Disease ◽  
Arterial Stenosis ◽  
Diagnostic Features ◽  
Light Transmission Aggregometry ◽  
Peripheral Arterial

Acetylsalicylic acid (ASA), also known as aspirin, appears to be ineffective in inhibiting platelet aggregation in 20–30% of patients. Light transmission aggregometry (LTA) is a gold standard platelet function assay. In this pilot study, we used LTA to personalize ASA therapy ex vivo in atherosclerotic patients. Patients were recruited who were on 81 mg ASA, presenting to ambulatory clinics at St. Michael’s Hospital (n = 64), with evidence of atherosclerotic disease defined as clinical symptoms and diagnostic findings indicative of symptomatic peripheral arterial disease (PAD), with an ankle brachial index (ABI) of <0.9 (n = 52) or had diagnostic features of asymptomatic carotid arterial stenosis (CAS), with >50% stenosis of internal carotid artery on duplex ultrasound (n = 12). ASA compliance was assessed via multisegmented injection-capillary electrophoresis-mass spectrometry based on measuring the predominant urinary ASA metabolite, salicyluric acid. LTA with arachidonic acid was used to test for ASA sensitivity. Escalating ASA dosages of 162 mg and 325 mg were investigated ex vivo for ASA dose personalization. Of the 64 atherosclerotic patients recruited, 8 patients (13%) were non-compliant with ASA. Of ASA compliant patients (n = 56), 9 patients (14%) were non-sensitive to their 81 mg ASA dosage. Personalizing ASA therapy in 81 mg ASA non-sensitive patients with escalating dosages of ASA demonstrated that 6 patients became sensitive to a dosage equivalent to 162 mg ASA and 3 patients became sensitive to a dosage equivalent to 325 mg ASA. We were able to personalize ASA dosage ex vivo in all ASA non-sensitive patients with escalating dosages of ASA within 1 h of testing.

Abstract 16899: Neutralization of Bleeding Induced by Direct Factor Xa and Thrombin Inhibitors by Prothrombin Complex Concentrates Alone and in Combination with Antifibrinolytic Agents

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Walter Jeske ◽  
Vicki Escalante ◽  
Elizabeth McGeehan ◽  
Jeanine Walenga ◽  
Jawed Fareed ◽  
...  
Keyword(s):  
Bleeding Time ◽  
Ex Vivo ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Medical Emergency ◽  
Saline Control ◽  
Direct Factor ◽  
Blood Samples ◽  
Prolonged Bleeding ◽  
Prolonged Bleeding Time

Introduction: Concerns remain over bleeding with direct factor Xa and thrombin inhibitors in cases of overdose or medical emergency. This study tested the ability of PCCs to reverse bleeding induced by apixaban, rivaroxaban or dabigatran in a standardized rat tail resection model. Methods: Individual groups of anesthetized rats (8-10) were anticoagulated with apixaban, rivaroxaban or dabigatran and subsequently treated with vehicle, 3-factor (Profilnine), 4-factor (Beriplex) or activated 4-factor PCC (FEIBA). Five minutes post-PCC administration, a tail snip was performed and bleeding time was measured. Upon cessation of bleeding, a blood samples were collected for ex vivo analysis and the rat was humanely euthanized. Results: In comparison to saline control (6.8 + 1.1 sec) apixaban (300μg/kg) prolonged bleeding time (17.1±5.6; p=0.024). Beriplex at doses ≤10U/kg did not shorten bleeding time while 10U/kg Profilnine did. FEIBA prolonged bleeding beyond that seen with apixaban alone (22.6±11.4 and 37.5±5.2 min for 5 and 10U/kg doses; p<0.001 apixaban + 10U/kg FEIBA vs. apixaban). 100 and 300μg/kg rivaroxaban prolonged bleeding time (20.8±2.5, p=0.002 vs. saline; 25.0±10.0 min, p<0.001 vs. saline). Profilnine was more effective than Beriplex or FEIBA in reversing rivaroxaban-induced bleeding. Dabigatran-induced bleeding was prevented by Beriplex or Profilnine but enhanced by FEIBA (50.3±8.3 vs. 15.9±1.2 min; p<0.001). Treatment of apixaban or rivaroxaban anticoagulated rats with FEIBA + 10mg/kg epsilon aminocaproic acid, produced bleeding times comparable to those of non-anticoagulated rats (apixaban: 6.7±5.0 min; rivaroxaban: 7.7±6.4 min). Ex vivo analysis of blood samples did not show any relevance with the observed bleeding or its modulation. Discussion: PCCs appear useful for neutralizing bleeding induced by direct factor Xa and thrombin inhibitors, but each PCC exhibits a distinct neutralization profile. Co-administration of a fibrinolytic inhibitor may enhance effectiveness of hemorrhage reversal by PCCs.

The uncalibrated prothrombinase-induced clotting time test

2010 ◽  
Vol 30 (04) ◽  
pp. 212-216 ◽  
Author(s):  
R. Jovic ◽  
M. Hollenstein ◽  
P. Degiacomi ◽  
M. Gautschi ◽  
A. Ferrández ◽  
...  
Keyword(s):  
Factor Xa ◽  
Heparin Therapy ◽  
Thrombin Inhibitors ◽  
Coagulation Cascade ◽  
Diagnostic Tools ◽  
Direct Thrombin Inhibitors ◽  
Functional Assay ◽  
Clotting Time ◽  
Coagulation Time ◽  
Time Test

SummaryThe activated partial thromboplastin time test (aPTT) represents one of the most commonly used diagnostic tools in order to monitor patients undergoing heparin therapy. Expression of aPTT coagulation time in seconds represents common practice in order to evaluate the integrity of the coagulation cascade. The prolongation of the aPTT thus can indicate whether or not the heparin level is likely to be within therapeutic range. Unfortunately aPTT results are highly variable depending on patient properties, manufacturer, different reagents and instruments among others but most importantly aPTT’s dose response curve to heparin often lacks linearity. Furthermore, aPTT assays are insensitive to drugs such as, for example, low molecular weight heparin (LMWH) and direct factor Xa (FXa) inhibitors among others. On the other hand, the protrombinase-induced clotting time assay (PiCT®) has been show to be a reliable functional assay sensitive to all heparinoids as well as direct thrombin inhibitors (DTIs). So far, the commercially available PiCT assay (Pefakit®-PiCT®, DSM Nutritional Products Ltd. Branch Pentapharm, Basel, Switzerland) is designed to express results in terms of units with the help of specific calibrators, while aPTT results are most commonly expressed as coagulation time in seconds. In this report, we describe the results of a pilot study indicating that the Pefakit PiCT UC assay is superior to the aPTT for the efficient monitoring of patients undergoing UFH therapy; it is also suitable to determine and quantitate the effect of LMWH therapy. This indicates a distinct benefit when using this new approach over the use of aPPT for heparin monitoring.

Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors

1990 ◽  
Vol 63 (02) ◽  
pp. 220-223 ◽  
Author(s):  
J Hauptmann ◽  
B Kaiser ◽  
G Nowak ◽  
J Stürzebecher ◽  
F Markwardt
Keyword(s):  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Factor Xa Inhibitors ◽  
Venous Stasis ◽  
Clotting Time ◽  
Thrombosis Model ◽  
Activity Factor ◽  
Antithrombotic Effects

SummaryThe anticoagulant effect of selected synthetic inhibitors of thrombin and factor Xa was studied in vitro in commonly used clotting assays. The concentrations of the compounds doubling the clotting time in the various assays were mainly dependent on their thrombin inhibitory activity. Factor Xa inhibitors were somewhat more effective in prolonging the prothrombin time compared to the activated partial thromboplastin time, whereas the opposite was true of thrombin inhibitors.In vivo, in a venous stasis thrombosis model and a thromboplastin-induced microthrombosis model in rats the thrombin inhibitors were effective antithrombotically whereas factor Xa inhibitors of numerically similar IQ value for the respective enzyme were not effective at equimolar dosageThe results are discussed in the light of the different prelequisiles and conditions for inhibition of thrombin and factor Xa in the course of blood clotting.

Inhibition of Thrombin Generation in Plasma by Inhibitors of Factor Xa

1997 ◽  
Vol 78 (04) ◽  
pp. 1215-1220 ◽  
Author(s):  
D Prasa ◽  
L Svendsen ◽  
J Stürzebecher
Keyword(s):  
Thrombin Generation ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Thrombin Generation Assay ◽  
Ic50 Values ◽  
Fxa Inhibitor ◽  
20 Nm ◽  
Tick Anticoagulant Peptide ◽  
Inhibition Of Thrombin

SummaryA series of inhibitors of factor Xa (FXa) were investigated using the thrombin generation assay to evaluate the potency and specificity needed to efficiently block thrombin generation in activated human plasma. By inhibiting FXa the generation of thrombin in plasma is delayed and decreased. Inhibitor concentrations which cause 50 percent inhibition of thrombin generation (IC50) correlate in principle with the Ki values for inhibition of free FXa. Recombinant tick anticoagulant peptide (r-TAP) is able to inhibit thrombin generation with considerably low IC50 values of 49 nM and 37 nM for extrinsic and intrinsic activation, respectively. However, the potent synthetic, low molecular weight inhibitors of FXa (Ki values of about 20 nM) are less effective in inhibiting the generation of thrombin with IC50 values at micromolar concentrations.The overall effect of inhibitors of FXa in the thrombin generation assay was compared to that of thrombin inhibitors. On the basis of similar Ki values for the inhibition of the respective enzyme, synthetic FXa inhibitors are less effective than thrombin inhibitors. In contrast, the highly potent FXa inhibitor r-TAP causes a stronger reduction of the thrombin activity in plasma than the most potent thrombin inhibitor hirudin.

Adenosine Diphosphate (ADP)-Induced ⍺-Granules Release from Platelets of Native Whole Blood Is Reduced by Ticlopidine but Not by Aspirin or Dipyridamole

1986 ◽  
Vol 56 (02) ◽  
pp. 147-150 ◽  
Author(s):  
V Pengo ◽  
M Boschello ◽  
A Marzari ◽  
M Baca ◽  
L Schivazappa ◽  
...  
Keyword(s):  
Whole Blood ◽  
Light Transmission ◽  
Ex Vivo ◽  
Early Stage ◽  
Shape Change ◽  
Adenosine Diphosphate ◽  
Dose Dependent ◽  
Plateletderived Growth Factor ◽  
Platelet Shape

SummaryA brief contact between native whole blood and ADP promotes a dose-dependent release of platelet a-granules without a fall in the platelet number. We assessed the “ex vivo” effect of three widely used antiplatelet drugs, aspirin dipyridamole and ticlopidine, on this system. Aspirin (a single 800 mg dose) and dipyridamole (300 mg/die for four days) had no effect, while ticlopidine (500 mg/die for four days) significantly reduced the a-granules release for an ADP stimulation of 0.4 (p <0.02), 1.2 (p <0.01) and 2 pM (p <0.01). No drug, however, completeley inhibits this early stage of platelet activation. The platelet release of α-granules may be related to platelet shape change of the light transmission aggregometer and may be important “in vivo” by enhancing platelet adhesiveness and by liberating the plateletderived growth factor.

Inter-individual variability in clopidogrel inhibition effect on platelet aggregation

2018 ◽  
Vol 9 (SPL1) ◽  
Author(s):  
Hussein Ali Sahib ◽  
Bassim Irhiem Mohammed ◽  
Ban A. Abdul Majid
Keyword(s):  
Cardiovascular Disease ◽  
Platelet Aggregation ◽  
Coronary Care Unit ◽  
Light Transmission ◽  
Individual Variability ◽  
Study Group ◽  
Inhibition Effect ◽  
Light Transmission Aggregometry ◽  
Coronary Care ◽  
Skewness And Kurtosis

Despite the unmistakable beneficial effect of clopidogrel on platelet aggregation,still there are some patient poorly responds to clopidogrel that may lead to worse cardiovascular clinical events.One hundred and twenty seven patients with cardiovascular disease (ACS,stroke,or TIA) were enrolled as a study group. Patients were recruited at coronary care unit (CCU) of Al-Yarmouk Teaching Hospital. Paletlet assessment was done by using light transmission aggregometry. between the patients that enrolled in this study there are significant inter-individual variability both skewness and Kurtosis were negative (-0.450,-0.130) respectively. 24% of patient enrolled in this study were hyporesponder.

Biochemical and Pharmacological Properties of SANORG 34006, a Potent and Long-Acting Synthetic Pentasaccharide

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4197-4205 ◽  
Author(s):  
J.M. Herbert ◽  
J.P. Hérault ◽  
A. Bernat ◽  
R.G.M. van Amsterdam ◽  
J.C. Lormeau ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Therapeutic Index ◽  
Inhibitory Effect ◽  
Experimental Models ◽  
Treatment And Prevention ◽  
Long Acting

Abstract SANORG 34006 is a new sulfated pentasaccharide obtained by chemical synthesis. It is an analog of the “synthetic pentasaccharide” (SR 90107/ ORG 31540) which represents the antithrombin (AT) binding site of heparin. SANORG 34006 showed a higher affinity to human AT than SR 90107/ORG 31540 (kd = 1.4 ± 0.3 v 48 ± 11 nmol/L), and it is a potent and selective catalyst of the inhibitory effect of AT on factor Xa (1,240 ± 15 anti–factor Xa U/mg v850 ± 27 anti-factor Xa U/mg for SR 90107/ORG 31540). In vitro, SANORG 34006 inhibited thrombin generation occurring via both the extrinsic and intrinsic pathway. After intravenous (IV) or subcutaneous (SC) administration to rabbits, SANORG 34006 displayed a long-lasting anti–factor Xa activity and inhibition of thrombin generation (TG) ex vivo. SANORG 34006 was slowly eliminated after IV or SC administration to rats, rabbits, and baboons, showed exceptionally long half-lives (between 9.2 hours in rats and 61.9 hours in baboons), and revealed an SC bioavailability near 100%. SANORG 34006 displayed antithrombotic activity by virtue of its potentiation of the anti–factor Xa activity of AT. It strongly inhibited thrombus formation in experimental models of thromboplastin/stasis-induced venous thrombosis in rats (IV) and rabbits (SC) (ED50values = 40.0 ± 3.4 and 105.0 ± 9.4 nmol/kg, respectively). The duration of its antithrombotic effects closely paralleled the ex vivo anti–factor Xa activity. SANORG 34006 enhanced rt-PA–induced thrombolysis and inhibited accretion of125I-fibrinogen onto a preformed thrombus in the rabbit jugular vein suggesting that concomitant use of SANORG 34006 during rt-PA therapy might be helpful in facilitating thrombolysis and preventing fibrin accretion onto the thrombus under lysis. Contrary to standard heparin, SANORG 34006 did not enhance bleeding in a rabbit ear incision model at a dose that equals 10 times the antithrombotic ED50 in this species and, therefore, exhibited a favorable therapeutic index. We suggest that SANORG 34006 is a promising compound in the treatment and prevention of various thrombotic diseases.

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