Pharmacokinetics and fibrin specificity of alteplase during accelerated infusions in acute myocardial infarction

Tanswell, P.; Tebbe, Ulrich; Neuhaus, Karl-Ludwig; Gläsle-Schwarz, Liane; Wójcik, Jarosław; Seifried, Erhard

doi:10.1016/0735-1097(92)90297-z

Cited by 113 publications

(76 citation statements)

References 17 publications

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“…From these data, it is not clear whether the pCPB system is potent enough to down-regulate fibrinolysis induced in undiluted plasma by therapeutic concentrations of 1-4 g/ml t-PA (27,28). Here, we show that maximal activation of pro-pCPB in plasma achieved upon clotting in the presence of TM leads to a strong (4 -5-fold) retardation of fibrinolysis at t-PA concentrations ranging from 0.2 to 2 g/ml, which is translated to a 7-8-fold increase of t-PA concentration necessary to achieve the same lysis time.…”

Section: Discussionmentioning

confidence: 76%

On the Mechanism of the Antifibrinolytic Activity of Plasma Carboxypeptidase B

Sakharov¹,

Plow

Rijken³

1997

Journal of Biological Chemistry

205

173

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The precursor of plasma carboxypeptidase B (pCPB) also known as thrombin-activable fibrinolysis inhibitor can be converted by thrombin to an active enzyme capable of eliminating C-terminal Lys-and Arg-residues from proteins. The activation is about 1000-fold more efficient in the presence of thrombomodulin (TM). We investigated the antifibrinolytic potency of maximally activated pCPB in plasma and explored the antifibrinolytic mechanism of pCPB. During clotting of plasma in the presence of 3.3 NIH units/ml thrombin and 1 g/ml soluble TM, more than 80% pro-pCPB was converted into the active form causing an increase of plasma carboxypeptidase activity from 100 units/liter (constitutive activity ascribed to plasma carboxypeptidase N) to 430 units/liter as measured with furoylacroleyl-alanyl-arginine substrate. Under these conditions, lysis of a plasma clot induced by a range of tissue-type plasminogen activator (t-PA) concentrations (0.2-2 g/ml) was retarded more than 4-fold. A considerable retardation of fibrinolysis was observed upon addition of as little as 12 ng/ml soluble TM, a concentration comparable with physiological concentrations of soluble TM in human plasma. The presence of Ca 2؉ appeared to be a critical requirement for effective activation of pro-pCPB by thrombin-TM in plasma. Plasminogen-binding sites (C-terminal lysines) on the surface of a plasmin-treated fibrin clot were eliminated within 1-3 min by plasma with maximally activated pCPB, as studied in a recently described model involving fluorescence microscopy. Confocal fluorescence microscopy showed that in the absence of TM plasminogen strongly accumulated on fibrin fibers during t-PA-induced lysis of a plasma clot. In the presence of TM (and a concomitant pro-pCPB activation), lysis was slow and was not accompanied by accumulation of plasminogen on the fibers. In conclusion, generation of active pCPB during clotting of plasma in the presence of Ca 2؉ and TM leads to a retardation of plasma clot lysis in a wide range of t-PA concentrations, from low to therapeutic, and to a fast elimination of plasminogenbinding sites on partially degraded fibrin. This is a likely mechanism for the antifibrinolytic effect of active pCPB.

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Section: Discussionmentioning

confidence: 76%

On the Mechanism of the Antifibrinolytic Activity of Plasma Carboxypeptidase B

Sakharov¹,

Plow

Rijken³

1997

Journal of Biological Chemistry

205

173

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“…Изучена фармакокинетика алтеплазы у здоровых доб-ровольцев, а также у пациентов с инфарктом миокарда [14]. Данные исследования показывают, что препарат быстро вы-водится из плазмы, начальный период полувыведения со-ставляет <5 мин (аналогично естественному тканевому ак-тиватору плазминогена).…”

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Factors influencing the efficiency and safety of systemic thrombolysis in patients with ischemic stroke

Шамалов

Anisimov

Кустова

et al. 2014

Neurology, Neuropsychiatry, Psychosomatics

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Системная тромболитическая терапия (ТЛТ) с ис-пользованием рекомбинантного тканевого активатора плаз-миногена (rt-PA, алтеплаза) является наиболее эффектив-ным и безопасным методом реперфузионной терапии при ишемическом инсульте (ИИ) в первые 4,5 ч от начала разви-тия заболевания [1, 2].История создания фибринолитических препаратов берет свое начало с 30-х годов XX в., когда W. Tillet и R.L. Garner была установлена способность гемолитического стрептококка продуцировать фибринолитическое вещест-во, названное ими стрептококковым фибринолизином [3]. Стрептокиназа была первым препаратом, который начали применять в клинической практике для лизиса фибрина [4], и в настоящее время препарат по-прежнему используется для лечения инфаркта миокарда, несмотря на разработку новых, более эффективных тромболитиков.Проведение ТЛТ у больных с ИИ стало возможным благодаря внедрению в клиническую практику метода ком-пьютерной томографии (КТ) что позволило достоверно ди-агностировать характер инсульта [5][6][7], хотя отдельные со-

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“…Specifically, depletion of fibrinogen and factors V and VIII may occur. As the levels of plasmin in circulating plasma increase, available supplies of · 2 -antiplasmin (endogenous neutralizer of plasmin) are depleted and the risk of a systemic fibrinolytic state increases [14,15] (fig. 2).…”

Section: Introductionmentioning

confidence: 99%

Platelets and Thrombolysis: Cooperation or Contrariety?

et al. 2001

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Fibrinolytic therapy is the established treatment for the management of patients with ST elevation acute myocardial infarction (AMI). Present thrombolytic regimens have a number of limitations, including the failure to produce early and sustained reperfusion, as well as an inability to prevent reocclusion in at least some patients. Platelets play an important role in coronary thrombosis responsible for AMI. The effect of coronary thrombolysis on platelets has been extensively debated in the literature, with controversial evidence of both platelet activation and inhibition. Among fibrinolytic agents, tissue plasminogen activator (t-PA) is considered to be the cornerstone in the treatment of acute coronary occlusion. The native t-PA molecule has been modified in an attempt to achieve improved lytic characteristics with less risk of bleeding events. Extensive research has led to a group of mutant t-PA variants referred to as third-generation plasminogen activators. TNK-t-PA is one bioengineered variant of t-PA; another is reteplase (r-PA). They have been developed to establish more rapid, complete and stable coronary artery patency, thus promising reduced mortality. Both r-PA and TNK-t-PA are effective when given as bolus therapy, a feature that may facilitate earlier treatment initiation as well as lower treatment costs. New acute coronary treatment regimens include potent antiplatelet agents on top of thrombolysis that may improve sustained reperfusion. This review summarizes the latest and often contradictory data on the interaction between fibrinolytic therapy and platelets in certain in vitro, animal and clinical scenarios.

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Pharmacokinetics and fibrin specificity of alteplase during accelerated infusions in acute myocardial infarction

Cited by 113 publications

References 17 publications

On the Mechanism of the Antifibrinolytic Activity of Plasma Carboxypeptidase B

On the Mechanism of the Antifibrinolytic Activity of Plasma Carboxypeptidase B

Factors influencing the efficiency and safety of systemic thrombolysis in patients with ischemic stroke

Platelets and Thrombolysis: Cooperation or Contrariety?

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