title: Reactive coagulation induced by plasmin in patients treated with recombinant tissue-type plasminogen activator.
abstract: BACKGROUND
  We and others have demonstrated that administration of thrombolytic agents causes the generation of thrombosis-promoting agents. At present, we have studied whether formation in vivo of excessive amounts of plasmin is responsible for the activation of coagulation in patients treated with recombinant tissue-type plasminogen activator.
  
  
  METHODS
  Modified crossed immunoelectrophoresis was used for determination of the plasminogen-binding form of alpha 2-antiplasmin. Enzyme-linked immunosorbent assay methods were used for determination of hemostatic reaction products.
  
  
  RESULTS
  The association between the generation of hemostatic reaction products and the exhaustion of the plasminogen-binding form of alpha 2-antiplasmin (PB alpha 2AP) was studied in 21 patients with acute myocardial infarction and 11 patients with unstable angina pectoris who were given a 3-hour, 100-mg intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA). We observed in all patients a fall in blood concentrations of PB alpha 2AP (P < 0.01) after 2.25 hours of treatment and, simultaneously, a significant increase in fibrin degradation products (P < 0.01), D-dimer (P < 0.01), fibrinogen degradation products (P < 0.01), prothrombin fragment 1 + 2 (P < 0.01), and thrombin-antithrombin III complexes (P < 0.01). When we evaluated individual data, we observed high concentrations of the reaction products when the PB alpha 2AP concentration after 2.25 hours of treatment was lower than 25% of the pretreatment values. Also, we observed highly significant associations between the increase in the plasma concentrations of fibrin degradation products and thrombin-antithrombin III complexes (rs = 0.72; P < 0.01), the increase in plasma concentrations of fibrin degradation products and prothrombin fragment 1 + 2 (rs = 0.63; P < 0.01), the increase in plasma concentrations of D-dimer and thrombin-antithrombin III complexes (rs = 0.78; P < 0.01), and the increase in plasma concentrations of D-dimer and prothrombin fragment 1 + 2 (rs = 0.79; P < 0.01).
  
  
  CONCLUSIONS
  Generation of excessive amounts of plasmin is the main factor in producing the procoagulant response in patients who receive thrombolytic therapy with rt-PA, and intravenous heparin does not abolish this response. Plasmin inhibitors might be used in relation to thrombolytic therapy as indirect "antithrombotics."
authors.affiliation: Department of Clinical Chemistry, Ribe County Hospital, Esbjerg, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Gram
authors.forename: S
authors.initials: S
authors.lastname: Munkvad
authors.forename: F W
authors.initials: FW
authors.lastname: Leebeek
authors.forename: C
authors.initials: C
authors.lastname: Kluft
authors.forename: J
authors.initials: J
authors.lastname: Jespersen
mesh_terms: D000368:Aged; D000990:Antithrombin III / Q000032:analysis; D001777:Blood Coagulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005341:Fibrinolysin / Q000502:physiology*; D006801:Humans; D007123:Immunoelectrophoresis, Two-Dimensional; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy; D010447:Peptide Hydrolases / Q000032:analysis; D010958:Plasminogen / Q000378:metabolism; D011516:Prothrombin / Q000032:analysis; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D015912:Thrombolytic Therapy / Q000009:adverse effects*; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000627:therapeutic use; D000979:alpha-2-Antiplasmin / Q000378:metabolism
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D011516:Prothrombin; D010958:Plasminogen; D010447:Peptide Hydrolases; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin