scholarly journals Studies on a Novel Circulating Anticoagulant in a Female with Bleeding Diathesis

1977 ◽  
Author(s):  
Harry L. Messmore ◽  
J. Fareed ◽  
Roberta L. Chang ◽  
Gerald M. Gawlik ◽  
Gerald F. Kozuh
Keyword(s):  
Serine Proteases ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Surgical Trauma ◽  
Thrombin Time ◽  
At Iii ◽  
Life Threatening ◽  
History Of ◽  
Induced Aggregation ◽  
Hydrolysis Of

A 42 year old Caucasian female has had a history of bleeding from surgical trauma since the age of 3. She has bled massively from surgical trauma and has had life threatening postpartum hemorrhages. Laboratory tests showed marked prolongation of thrombin time, prothrombin time, partial thromboplastin time, low α1 antitrypsin and lipoprotein lipase activity. Fibrinogen level was normal. Mixing of patient’s plasma and serum with citrated normal plasma suggested the presence of a potent antithrombin (AT) substance. Heating of both the plasma and serum at 56°C for 2 hours failed to destroy the AT activity. The AT activity of the patient’s plasma was quantitated to be equivalent to 0.75–0.9 u/ml heparin. Platelets aggregated normally with ADP, collagen, epinephrine, but not with Ristocetin and thrombin (0.5–5.0 u/ml). Her plasma and serum blocked thrombin induced aggregation of normal platelets. Her plasma also inhibited the factor Xa induced hydrolysis of S-2222 (Bz-Ile-Glu-[γ-OR]-Gly-Arg-pNA) and the action of thrombin on S-2160 (Bz-Phe-val-Arg-pNA). The inhibitor was not adsorbed with barium sulfate or reduced in activity by protamine sulfate, toluidine blue or heparinase. It was chromatographed on Sephadex G-100 and G-50, and eluted in the void volume and a low molecular (10–20,000) fraction. Incubation of the patient’s plasma with chymotrypsin and trypsin destroyed the anticoagulant activity. Although anti-AT-III serum totally neutralized the anticoagulant activity of heparin-ized plasma, it failed to neutralize the patient’s plasma anticoagulant activity. Albumin partially neutralized the anticoagulant activity. These studies suggest that this AT substance is a potent inhibitor of serine proteases and behaves as activated AT-III.

A NEW ASYMPTOMATIC TYPE III VARIANT OF ANTITHROMBIN III WITH DECREASE HEPARIN COFACTOR ACTIVITY : AT III AMIENS

1987 ◽  
Author(s):  
B ROUSSEL ◽  
J DIEVAL ◽  
S GROSS ◽  
J F CLAISSE ◽  
J DELOBEL
Keyword(s):  
Factor Xa ◽  
Normal Range ◽  
Normal Pattern ◽  
Type Iii ◽  
Crossed Immunoelectrophoresis ◽  
At Iii ◽  
History Of ◽  
Routine Laboratory Examination ◽  
Slow Moving ◽  
Cofactor Activity

A qualitative abnormality of AT III suggested by the discrepancy between a normal level of AT III antigen (0,33 g/1) and a decreased heparin cofactor activity (60 % of normal) was discovered in a 37 years old woman during a routine laboratory examination for oral contraceptive. The propositus was asymptomatic as she did not developpe any thrombo-embolic disease during three previous pregnancies. There was no familial history of thrombo-embolism. The AT III level measured by radial immuno-diffusion was within the normal range. The progressive anti factor lia and anti factor Xa activities (chromogenic substrates CBS 3 447 and CBS 3 139) were normal (92 % and 100 %). Plasma and serum crossed immunoelectrophoresis (CIE) showed a normal pattern. In the presence of heparin, anti factor Xa and anti factor Xa activities were decreased (60 % and 45 %); Plasma and serum crossed immunoelectrophoresis showed an abnormal slow moving peak exhibiting the inhability of the molecule to bind completely to heparin. CIE with various other glycosaminoglycans are on experiments.Familial study revealed that the daughter of the propositus was carrying the same molecular abnormality.We conclude that AT III Amiens is an hereditary type III variant.

A Comparison of Anticoagulation Activity of a Potent Heparin Preparation in Different Test

1979 ◽  
Author(s):  
A.S. Bhargava ◽  
J. Heinick ◽  
Chr. Schöbel ◽  
P. Günzel
Keyword(s):  
Blood Clotting ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Thrombin Time ◽  
Beagle Dogs ◽  
Clotting Time ◽  
Relative Potencies ◽  
Heparin Preparation

The anticoagulant effect of a new potent heparin preparation was compared with a commercially available heparin in vivo after intravenous application in beagle dogs. The anticoagulant activity was determined using thrombin time, activated partial thromboplastin time and whole blood clotting time after 5, 10 and 30 minutes of application. The relative potency of the new heparin preparation (Scherinq) was found to be 1.62 to 2.52 times higher than heparin used for comparison (150 USP units/mg, Dio-synth). The anticoagulant properties of both preparations were also studied in vitro using dog and human plasma. The relative potencies in vitro correlated well with those obtained in vivo. Further characterization with amidolytic method using chromogenic substrate for factor Xa and thrombin (S-2222 and S-2238 from KABI, Stockholm) showed that heparin (Schering) contains 243 to 378 USP units/raq depending upon the test systems used to assay the anticoagulation activity and in addition, proves the validity of the amidolytic method.

Isolation and Partial Characterization of a Novel Circulating Antithrombin

1979 ◽  
Author(s):  
Harry Messmore ◽  
Zaheer Pervez ◽  
Jawed Fareed
Keyword(s):  
Protease Inhibitor ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Serine Protease Inhibitor ◽  
Chromogenic Substrates ◽  
Inhibitor Activity ◽  
Antithrombin Activity ◽  
Life Threatening ◽  
Hydrolysis Of

We have previously reported on a novel circulating anticoagulant (Clin. Res. 22:396 A, 1974. Thromb. and Haem. 38:77, 1977 (abstr) in a 42 year old female who has had repeated episodes of life threatening hemorrhage since the age of 3. Our preliminary studies showed it to be a protein with some of the properties of a heparin activated antithrombin III. This report is on additional studies to further characterize the Inhibitor«The patient’s plasma was fractionated on Sephadex G-200, and the fraction showing immediate acting antithrombin activity was further purified on heparin-sepharose and conconavalin A-sepharose affinity columns. The patient’s inhibitor did not bind to heparin sepharose, and was thus separable from her antithrombin III. It did bind to conconavalin A, and was eluted from the conconavalin A with α - D (+) methylglucoside. It has very broad serine protease inhibitor activity, blocking the hydrolysis of synthetic chromogenic substrates by thrombin, factor Xa, plasmin and trypsin. It did not inhibit Reptilase.Immunochemical assays show it to be α1 antitrypsin. Isoelectric focusing shows it to he a variant of normal, with its isoelectric point being different from a normal control, and pure α1 antitrypsin (commercial, human).The total α1 antitrypsin level in this patient is about 50% of normal, and It has potent immediate acting antithrombin activity. It appears to be similar to a phenotype previously reported as Antithrombin Pittsburgh (Blood 51: 129, 1978).

In Vitro Evaluation of Apixaban, a Novel, Potent, Selective and Orally Bioavailable Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4130-4130 ◽  
Author(s):  
Joseph M. Luettgen ◽  
Tracy A. Bozarth ◽  
Jeffrey M. Bozarth ◽  
Frank A. Barbera ◽  
Patrick Y. Lam ◽  
...  
Keyword(s):  
Human Plasma ◽  
Serine Proteases ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Competitive Inhibitor ◽  
Rat Plasma ◽  
Reversible Inhibitor ◽  
Antithrombotic Agent

Abstract Apixaban, previously known as BMS-562247, is a high affinity, highly selective, orally-active, reversible inhibitor of coagulation factor Xa (fXa), in clinical studies as a therapeutic agent for prevention and treatment of thromboembolic diseases. The in vitro characteristics of apixaban were evaluated in purified systems and in human blood from healthy volunteers. Detailed kinetic analysis of apixaban inhibition of human fXa showed that it is a readily reversible, potent and competitive inhibitor versus a synthetic tripeptide substrate with a Ki of 0.08 nM, an association rate of 2 × 107 M−1s−1and a dissociation half life of 3.4 min. Weak affinity (Ki ~3 μM) is observed for thrombin, plasma kallikrein, and chymotrypsin. Affinity for trypsin and all other serine proteases tested is negligible with Ki > 15 μM. Apixaban is an effective inhibitor of free fXa and of prothrombinase, in buffer, platelet poor plasma, and whole blood. The anticoagulant activity of apixaban was determined in platelet-poor human plasma. Apixaban causes concentration dependent prolongation of the fXa mediated clotting assays. The human plasma concentration required to produce a doubling of the clotting time is 3.6 μM for prothrombin time, 7.4 μM for activated partial thromboplastin time and 0.4 μM for HepTest. To support preclinical efficacy and safety studies purified fXa from rabbit, dog and rat plasma was also found to be inhibited by apixaban (0.17, 2.6, and 1.3 nM, respectively). In summary the in vitro properties of apixaban show that it is a highly selective and potentially potent antithrombotic agent for venous and arterial thrombotic diseases.

scholarly journals Idarucizumab for the Reversal of Dabigatran-induced Anticoagulation in the Treatment of Gastric Bleeding: a Case Report

2021 ◽  
Author(s):  
Yu Jia ◽  
Shaohua Wang ◽  
Najuan Cui ◽  
Quanxi Liu ◽  
Wei Wang ◽  
...  
Keyword(s):  
Renal Function ◽  
Bleeding Risk ◽  
Thrombin Time ◽  
Gastric Bleeding ◽  
Laboratory Findings ◽  
Transfusion Therapy ◽  
Abnormal Accumulation ◽  
Life Threatening ◽  
History Of ◽  
Short Time

Abstract BACKGROUND:The drug instruction for dabigatran recommends the does adjustment 110 mg twice-a-day for the patient with bleeding risk, and at least 1 time of renal function test per year for moderate renal impairment. However, dabigatran still can be abnormal accumulation due to the chronic insidiously progressive renal insufficiency, which requiring idarucizumab to reverse the anticoagulation on account of acute erosive gastritis with extensive gastric mucosal bleeding.CASE SUMMARY: A 76-year-old female, with a history of Atrial Fibrillation (AF), took dabigatran 110 mg twice-a-day as recommended does adjustment to reduce the risk of stroke, and admitted to the hospital for the main complaints of hematemesis and melena. The laboratory findings showed severe life-threatening blood-loss anemia with hemoglobin (Hb) 41.0g/L, and significant coagulation abnormalities with thrombin time (TT) > 180s, most likely caused by dabigatran metabolic disorder. Aggressive acid suppressive, hemostatic and blood transfusion therapy brought out a short-time bleed-controlled misconception, which situation was exactly confirmed by re-bleeding. Idarucizumab was given timely to reverse the anticoagulation effect of dabigatran. 12 hours later, TT was tested as 17.4s which belonged to the normal range. Finally, she had no active bleeding signs, with labs showing Hb 104g/L and TT 17.7s.CONCLUSION:It is recommended to monitor renal function regularly, even coagulation function and dabigatran concentration, for the elder. There is at present no general agreement on the use of Proton Pump Inhibitor (PPI)–dabigatran coadministration to prevent upper gastrointestinal bleeding.

Recombinant Human Soluble Thrombomodulin Reduces Endotoxin-Induced Pulmonary Vascular Injury Via Protein C Activation in Rats

1995 ◽  
Vol 74 (05) ◽  
pp. 1265-1270 ◽  
Author(s):  
Mitsuhiro Uchiba ◽  
Kenji Okajima ◽  
Kazunori Murakami ◽  
Katsuhico Nawa ◽  
Hiroaki Okabe ◽  
...  
Keyword(s):  
Vascular Injury ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Factor Xa ◽  
Granulocyte Elastase ◽  
Pulmonary Vascular Permeability ◽  
Soluble Thrombomodulin ◽  
Intravascular Coagulation ◽  
At Iii

SummaryAdult respiratory distress syndrome (ARDS) is a serious complication of disseminated intravascular coagulation (DIC) or multiple organ failure. To determine whether recombinant soluble human thrombomodulin (rsTM) may be useful in treating ARDS due to sepsis, we investigated the effect of rsTM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intravenous administration of rsTM prevented the increase in pulmonary vascular permeability induced by LPS. Neither heparin plus antithrombin III (AT III) nor dan- syl Glu Gly Arg chloromcthyl ketone-treated factor Xa (DEGR-Xa), a selective inhibitor of thrombin generation, prevented LPS-induced vascular injury. The agents rsTM, heparin plus AT III, and DEGR-Xa all significantly inhibited the LPS-induced intravascular coagulation. Recombinant soluble TM pretreated with a monoclonal antibody (moAb) that inhibits protein C activation by rsTM did not prevent the LPS-induced vascular injury; in contrast, rsTM pretreated with a moAb that does not affect thrombin binding or protein C activation by rsTM prevented vascular injury. Administration of activated protein C (APC) also prevented vascular injury. LPS-induced pulmonary vascular injury was significantly reduced in rats with leukopenia induced by nitrogen mustard and by ONO-5046, a potent inhibitor of granulocyte elastase.Results suggest that rsTM prevents LPS-induced pulmonary vascular injury via protein C activation and that the APC-induced prevention of vascular injury is independent of its anticoagulant activity, but dependent on its ability to inhibit leukocyte activation.

Isolation and Partial Characterization of A Novel Circulating Antithrombin

1979 ◽  
Author(s):  
Harry Messmore ◽  
Zaheer Parvez ◽  
Jawed Fareed
Keyword(s):  
Protease Inhibitor ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Serine Protease Inhibitor ◽  
Chromogenic Substrates ◽  
Inhibitor Activity ◽  
Antithrombin Activity ◽  
Life Threatening ◽  
Hydrolysis Of

We have previously reported on a novel circulating anticoagulant (Clin. Res. 22:396 A, 1974. Thromb. and Haem. 38:77, 1977 (abstr) in a 42 year old female who has had repeated episodes of life threatening hemorrhage since the age of 3. Our preliminary studies showed it to be a protein with some of the properties of a heparin activated antithrombin III. This report is on additional studies to further characterize the inhibitor.The patient’s plasma was fractionated on Sephadex G-200, and the fraction showing immediate acting antithrombin activity was further purified on heparin-sepharose and conconavalin A-sepharose affinity columns. The patient’s inhibitor did not bind to heparin sepharose, and was thus separable from her antithrombin III. It did bind to conconavalin A, and was eluted from the conconavalin A with α - D (+) methylglucoside.It has very broad serine protease inhibitor activity, blocking the hydrolysis of synthetic chromogenic substrates by thrombin, factor Xa, plasmin and trypsin. It did not inhibit Reptilase.Immunochemical assays show it to be α1 antitrypsin. Isoelectric focusing shows it to be a variant of normal, with its isoelectric point being different from a normal control, and pure α1 antitrypsin (commercial, human).The total α1 antitrypsin level in this patient is about 50% of normal, and it has potent immediate acting antithrombin activity. It appears to be similar to a phenotype previously reported as Antithrombin Pittsburgh (Blood 51:129, 1978).

Design and characterization of dipetacompinR10H, a dipetalogastin II-derived, classical competitive thrombin inhibitor

2007 ◽  
Vol 97 (01) ◽  
pp. 139-145
Author(s):  
Mercedes López ◽  
Goetz Nowak ◽  
Thomas Bitter
Keyword(s):  
Serine Proteases ◽  
Anticoagulant Activity ◽  
Tight Binding ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Coagulation Assays ◽  
Competitive Kinetics ◽  
Inhibition Of Thrombin

SummaryThe design of small chimeric thrombin inhibitors based on the structure of dipetalogastin II has been previously described. These proteins are effective inhibitors of thrombin showing slow binding or slow, tight-binding kinetics. We report here about dipetacompinR10H, a new dipetalogastin II-derived chimeric thrombin inhibitor, which exhibits classical competitive kinetics. The dissociation constant Ki of dipetacompinR10H was determined to be 17.1 ± 0.8 pM. In various coagulation assays it showed a comparable anticoagulant activity like r-hirudin and r-dipetalogastin II. DipetacompinR10H’s inhibition of thrombin was specific, since no inhibition of other serine proteases like factor Xa, plasmin, trypsin or chymotrypsin has been observed.

Biochemical and Pharmacological Characterization of YM-60828, a Newly Synthesized and Orally Active Inhibitor of Human Factor Xa

1998 ◽  
Vol 79 (03) ◽  
pp. 543-548 ◽  
Author(s):  
Yumiko Sakai ◽  
Nami Hisamichi ◽  
Makoto Kayama ◽  
Yuji Mano ◽  
Kazuo Sato ◽  
...  
Keyword(s):  
Oral Administration ◽  
Human Factor ◽  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Thrombin Time ◽  
Pharmacological Characterization ◽  
Active Inhibitor ◽  
Prothrombinase Complex ◽  
Orally Active

SummaryYM-60828 was found to potently inhibit human factor Xa following oral administration. YM-60828 showed high affinity for factor Xa (Ki = 1.3 μM), but did not affect thrombin (Ki > 100 μM). YM-60828 doubled factor Xa clotting time, prothrombin time (PT) and activated partial thromboplastin time (APTT) at 0.10, 0.21, 0.24 μM, respectively. Importantly, it did not prolong thrombin time at 100 μM. YM-60828 also inhibited factor Xa in the prothrombinase complex with an IC50 value of 7.7 nM. In addition to its anticoagulant activity, YM-60828 inhibited platelet aggregation induced by various agonists (IC50 = 3 to 23 μM). Squirrel monkeys were used to study the ex vivo anticoagulant activity and pharmacokinetic properties of YM-60828. One hour after oral administration at 3 mg/kg, YM-60828 strongly prolonged PT and APTT by 4.8- and 1.9-fold, respectively, and plasma concentration reached 788 ± 167 ng/ml. Bioavailability was calculated to be 20.3%. These results strongly suggest that YM-60828 will be a valuable orally active and potent anticoagulant agent showing potential antithrombotic activity.

Do Anti-Factor Xa Levels have any Impact on Pregnancy Outcome in Women with Previous Adverse Outcomes?

2020 ◽  
Vol 224 (06) ◽  
pp. 355-359
Author(s):  
Z. Asli Oskovi-Kaplan ◽  
Kudret Erkenekli ◽  
Efser Oztas ◽  
Seda Bilir Esmer ◽  
Nuri Danisman ◽  
...  
Keyword(s):  
Pregnancy Outcome ◽  
Pregnancy Outcomes ◽  
Neonatal Intensive Care ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
First Trimester ◽  
Adverse Outcomes ◽  
Prevention Of Thromboembolic Events ◽  
History Of ◽  
Adverse Pregnancy

Abstract Objective Low-molecular-weight heparin (LMWH) is used during pregnancy in women diagnosed with thrombophilia for prevention of thromboembolic events and prevention of recurrent pregnancy loss. Prophylactic dosing does not always achieve target anti-FXa levels of 0.2–0.6 IU/ml. We aimed to determine if anti-FXa levels, measured in the first trimester, have an influence on pregnancy outcome. Material and Methods Eighty-one first-trimester women with a history of adverse pregnancy outcomes under LMWH therapy during pregnancy were enrolled in this study. Anti-FXa levels were measured in the first trimester, and fetal and maternal outcomes were recorded. Results The mean age of women was 28±4 (19–40) and mean anti-FXa level 0.44±0.93 IU/ml. No bleeding or clotting complications were associated with LMWH administration. Anti-FXa levels did not have a relationship with gestational age at birth, fetal weight, type of delivery, cesarean indications, postpartum bleeding, APGAR scores, or admission to the neonatal intensive care unit (p>0.005). Anti-FXa levels were not correlated with live birth rates. Conclusion Anti-FXa levels did not have an influence on pregnancy and fetal outcomes. The effect of LMWH on pregnancy outcomes may not be due to anticoagulant activity but other mechanisms.

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