Fibrinolysis and Fibrinolytic Activity in Man

Sherry, Sol; Fletcher, Anthony P.; Alkjærsig, Norma

doi:10.1152/physrev.1959.39.2.343

Cited by 345 publications

(81 citation statements)

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“…10 First tested for efficacy more than 40 years ago, plasmin was ineffective when administered by the intravenous route 11 because it was neutralized by plasma antiplasmin. 12 However, our regional administration of plasmin by catheter directly to the thrombus avoids antiplasmin neutralization, and rabbit arterial and venous thrombolysis models clearly document thrombolytic activity of plasmin. 10,13 In addition, our studies show a significant advantage of plasmin over TPA in its safety from fibrinolytic hemorrhage.…”

Section: Introductionmentioning

confidence: 94%

Distinct dose-dependent effects of plasmin and TPA on coagulation and hemorrhage

Stewart

Kong

Novokhatny

et al. 2003

Blood

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All thrombolytic agents in current clinical usage are plasminogen activators. Although effective, plasminogen activators uniformly increase the risk of bleeding complications, especially intracranial hemorrhage, and no laboratory test is applicable to avoid such bleeding. We report results of a randomized, blinded, dose-ranging comparison of tissue-type plasminogen activator (TPA) with a directacting thrombolytic agent, plasmin, in an animal model of fibrinolytic hemorrhage. This study focuses on the role of plasma coagulation factors in hemostatic competence. Plasmin at 4-fold, 6-fold, and 8-fold the thrombolytic dose (1 mg/kg) induced a dose-dependent effect on coagulation, depleting antiplasmin activity completely, then degrading fibrinogen and factor VIII. However, even with complete consumption of antiplasmin and decreases in fibrinogen and factor VIII to 20% of initial activity, excessive bleeding did not occur. Bleeding occurred only at 8-fold the thrombolytic dose, on complete depletion of fibrinogen and factor VIII, manifest as prolonged primary bleeding, but with minimal effect on stable hemostatic sites. Although TPA had minimal effect on coagulation, hemostasis was disrupted in a dose-dependent manner, even at 25% of the thrombolytic dose (1 mg/kg), manifest as rebleeding from hemostatically stable ear puncture sites. Plasmin degrades plasma fibrinogen and factor VIII in a dose-dependent manner, but it does not disrupt hemostasis until clotting factors are completely depleted, at an 8-fold higher dose than is needed for thrombolysis. Plasmin has a 6-fold margin of safety, in contrast with TPA, which causes hemorrhage at thrombolytic dosages. (Blood.

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Section: Introductionmentioning

confidence: 94%

Distinct dose-dependent effects of plasmin and TPA on coagulation and hemorrhage

Stewart

Kong

Novokhatny

et al. 2003

Blood

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“…When intravascular coagulation is induced in the fetus, the plasminogen level does decrease (Table VI). It is not known whether the plasminogen is being activated and converted to plasmin but is present in insufficient quantity to lyse the fibrinogen or fibrin formed, or if the plasminogen is not activated but simply decreased because of adsorption onto the fibrin [101]. The ratio of inhibitor to activator in the fetus is also not known.…”

Section: Discussionmentioning

confidence: 99%

“…Boyd [19] also suggested decreased lytic activity of the fetus, and Zilliacus [117] stated that the lytic activity decreases with aging of the fetus. Some of the studies showing increased fibrinolytic activity in the newborns may well have been measuring fibrinolysis in vitro, unless the samples were collected in inhibitors of fibrinolysis such as bovine protease inhibitor [118] or c-aminocaproic acid [101]. This is particularly important when umbilical cord blood samples are used, since tissue activator of the fibrinolytic system may easily contaminate such specimens.…”

Section: Discussionmentioning

confidence: 99%

Placental Transfer of Intravascular Coagulation between Mother and Fetus

et al. 1971

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ExtractPregnant sheep of 110-140 days' gestation were used to determine the effect of intravascular coagulation in the mother upon her fetus and the effect of intravascular coagulation in the fetus upon its mother. Because fetal lambs can be delivered and left attached to the mothers via the umbilical cord without placental separation, coagulation studies on a mother and her corresponding fetus could be done simultaneously. When intravascular coagulation was induced in the mothers by administering thromboplastin infusions intravenously, the attached fetal lambs also developed intravascular coagulation with decreased levels in platelets, fibrinogen, and factor V, and prolongation of prothrombin, thrombin, and partial thromboplastin times. When intravascular coagulation was induced in fetal lambs, the dam had a drop in platelet count, a minimal drop in fibrinogen levels, and the appearance of fibrin breakdown products in serum and urine.The factor or factors that crossed the placenta initiating this transfer of coagulation abnormalities are not known. It has been demonstrated that the transfer was not due to fibrin or fibrinogen breakdown products, nor to the infused thromboplastin, and that the trauma of surgery or hypoxia did not contribute to the coagulation abnormalities. The mothers consistently developed fibrin breakdown products in the serum and urine when intravascular coagulation was induced. This was in contrast to the results observed in fetal lambs, which, with one exception, did not show evidence of fibrin breakdown products in serum or urine under identical experimental conditions. These observations suggest the fibrinolytic system of the fetus is inefficient compared with that of the adult; this could be a considerable disadvantage in the presence of intravascular coagulation. SpeculationAs a result of intravascular coagulation in the mother or the fetus a stimulus is produced on the opposite side of the placental barrier resulting in similar changes in the placental partner. This mechanism may be of significance in the etiology of fetal death in eclampsia. Introductionplacentae [4,7,29,33,39,53,69,72,76,82,87,98,111], amniotic fluid embolism [53,68,83,86,88,99, Defects in hemostasis have been described in women 102], retention of a dead fetus [36, 53, 67, 68, 70, 71, with toxemia of pregnancy with preeclampsia or 73, 89, 99, 109, 113], and sepsis [53,68,99]. The eclampsia [28,45,54,68,74,75,94,99], abruptio pathogenesis of coagulation abnormalities has been

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“…The regulatory role of the generation of plasmin in the coagulation process is suggested by the known actions of plasmin in degrading not only fibrin, but also fibrinogen and factors V and VIII. 30 These effects may help to localize the thrombus to the site of vascular injury. The conversion of plasminogen to plasmin requires the presence of activators.…”

Section: Fibrinolysismentioning

confidence: 99%