Fibrinogenolysis in thrombotic thrombocytopenic purpura.

Coagulo-fibrinolytic factors were studied in five patients suffering from thrombotic thrombocytopenic purpura (TTP). The change in coagulation factors in the acute stage was mild compared with that found in disseminated intravascular coagulation (DIC). We observed a slight increase of fibrin-fibrinogen degradation products (FDP) in the plasma of four patients during the acute stage of TTP, but the level of the D-dimer remained within normal variation and was extremely low compared with that in 27 samples from patients with DIC showing the same level of FDP. At the same time, both antigen levels of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were elevated in three of the four patients tested. Although a similar change was recognized in DIC patients' plasma, the elevation of PAI-1 in the acute stage of TTP was far higher than in overt DIC. The antigen levels of t-PA and PAI-1 were normal in remission, and a mild elevation of PAI-1 was detected in one of the three patients during the early stage of TTP relapse. Enzymography revealed the appearance of free t-PA and an increase of a substance with a 110 kD molecule, assumed to be a t-PA and PAI-1 complex, in TTP plasma in the acute stage, but the findings were normal for plasma from cases in remission and the early stage of relapse. Enzymography also showed a decrease of urokinase-type plasminogen activator (u-PA) only in the acute stage of TTP. These changes in the coagulo-fibrinolytic factors in the acute stage of TTP suggest that fibrinogenolysis might be induced by t-PA, released through vascular reaction at an uninvolved area of vascular lesions caused by platelet agglutinates, which would then release large amounts of PAI-1 inhibiting t-PA and u-PA activities at the occlusive lesion.

Fibrinolysis in critically ill patients.

Impaired fibrinolysis may contribute to development of adult respiratory distress syndrome (ARDS). Pathologic increases in endogenous plasminogen activator inhibitor (PAI-1) may blunt normal fibrinolysis and unmask alternate fibrinolytic mechanisms, such as elastase-induced fibrin degradation. We measured PAI-1 and elastase-induced fibrin(ogen) degradation products in 69 critically ill patients in our medical intensive care unit (MICU) and in nine healthy volunteers. Factor VIII-related antigen protein (VIII:Ag), a reported marker of acute lung injury, and alpha-1-protease inhibitor (alpha-1-PI), an acute phase reactant, were also measured. MICU patients included 24 control patients with no known risk of ARDS, 35 patients with risk factors for ARDS including sepsis, pneumonia, aspiration, and shock, and 12 patients with ARDS including two patients from at-risk groups who developed ARDS. Plasma PAI-1 was determined by chromogenic assay, elastase-induced peptides by a new radioimmunoassay, VIII:Ag by immunoelectrophoresis, and alpha-1-PI by immunodiffusion. When compared to normal volunteers, MICU control patients had elevated PAI-1, VIII:Ag, elastase-induced peptides, and alpha-1-PI. Patients with ARDS had significantly higher PAI-1 and VIII:Ag than did MICU control patients; elastase-induced peptides and alpha-1-PI were not higher. However, at-risk patients who did not develop ARDS also had high PAI-1 or VIII:Ag. Although these data cannot refute the possible role of these compounds in the pathogenesis of ARDS, they demonstrate that PAI-1 and VIII:Ag may be elevated in many critically ill patients but may not be useful markers for the subsequent development of ARDS.

[Diagnosis of disseminated intravascular coagulation: the value of soluble fibrin, D-dimers and fibrin(ogen) split products]. / Diagnostik der disseminierten intravasalen Gerinnung: Aussagekraft von löslichem Fibrin, D-Dimeren und Fibrin(ogen)-Spaltprodukten.

The validity of the fibrin(ogen) derivatives 'soluble fibrin, D-dimers and fibrin(ogen) degradation products' was compared with other parameters in early and sensitive diagnosing of disseminated intravascular coagulation (DIC). In a clinical study 900 patients' samples from separate, defined groups were examined, including course observations of intensive care patients (n = 38) and patients with acute pancreatitis. The fibrin(ogen) derivatives correlated very well with the degree of blood coagulation disturbances: in particular, D-dimers and soluble fibrin proved to be more sensitive in early diagnosis of DIC than other parameters. The SF-PS-turbidimetry demonstrated a good validity and practicality in the quantitative determination of soluble fibrin, but a suitable analyzer is essential. Determination of D-dimers is preferable to that of fibrin(ogen) degradation products (both in the latex-agglutination test) because of the better sensitivity and practicality; even more sensitive results were provided by the D-dimer-ELISA, which is, however, not practical in acute diagnostics. The decrease in protein C was at least equally sensitive as the antithrombin III-levels in indicating the consumption of the hemostatic potential. The decrease of thrombocyte counts and fibrinogen levels could first be detected in a later stage of DIC. In conclusion, D-dimers and soluble fibrin can improve the DIC diagnostics, making them more reliable; additionally, antithrombin III and possibly protein C deserve further consideration, although the fibrin(ogen) derivatives are apparently of greater importance.

Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia.

In a double-blind study, 12 consecutive patients with acute promyelocytic leukaemia were randomised either to tranexamic acid (TA group) or to placebo (control group) for 6 days to see whether inhibition of fibrinolysis would reduce haemorrhage and transfusion requirements. The total study period was 14 days. In the TA group, there were fewer haemorrhagic episodes, as determined by a scoring system. Packed red cell transfusion requirements decreased; and fewer additional platelet concentrate transfusions were needed. These beneficial effects were more pronounced in the second week. There were no thromboembolic complications.

Plasma fibrinolytic activity in sickle cell disease.

Changes in plasma fibrinolytic activity, as measured by euglobulin lysis time (ELT) and serum fibrinogen degradation products (FDP) were investigated in 70 Nigerians with homozygous (HbSS) sickle cell disease (SCD), (50 in stable state and 20 in crisis state) and 75 age-matched non-sicklers. All had normal hemoglobin genotype (HbAA). The levels of ELT and FDP were significantly higher in sicklers in steady state than non-sicklers, but significantly lowered in sicklers in crisis than both non-sicklers and sicklers in stable state. Disturbances of fibrinolytic mechanism in both steady and crisis state might have a relationship to the clinical state of the individual patient.

Efficacy of antithrombin III in endotoxin-induced disseminated intravascular coagulation.

Antithrombin III (AT III) is a major modulator of the clotting cascade and is decreased in disseminated intravascular coagulation (DIC). AT III was given as a pretreatment to dogs with endotoxin-induced DIC. Significant improvement in clotting parameters (prothrombin time, fibrinogen, fibrin degradation products) was noted. There was no effect on platelets. Mean arterial blood pressure was improved, while there were no other significant changes in other measured hemodynamic, acid-base, or biochemical variables. It was concluded that AT III was effective in ameliorating endotoxin-induced changes in the clotting profile. AT III may prove to be a beneficial therapy in acquired DIC.

Fibrinolytical processes in rabbits activated by the magnetic field.

Rabbits were exposed to a constant magnetic field of 0.005 T, 0.1 T and 0.3 T induction for one hour per day each day for a period of four weeks. It was found that the magnetic field increases the rate of fibrinolytical processes. A decrease in fibrinogen concentration, an increase in the level of fibrinogen degradation products and a considerably shorter time of fibrinolysis in plasma were all noted. The magnitude of these processes was proportional to duration of exposure to the magnetic field in action. These date confirms the similar effect observed in other mammalians (guinea pigs, rats). Thus, the application of a static magnetic field of intensity as low as 0.005 T to increase a fibrinolytical processes in the thrombotic therapy seems to be justified.

Assessment of D-dimer in plasma: diagnostic value in suspected deep venous thrombosis of the leg.

D-dimer, a fibrin degradation product containing the gamma-gamma crosslink of fibrin, can now be assayed by the use of highly specific monoclonal antibodies. Such assays are not influenced by fibrinogenolysis and measurements can be performed on citrated plasma. The diagnostic values of four such assays--two based on ELISA technique and two on latex agglutination--were evaluated in 108 out of 118 consecutive patients admitted with suspected deep venous thrombosis of the leg. With cut-off limits defined by a pilot study and with venography as reference, a negative D-dimer test was confirmed in 45 of 46 patients (98%; 95% confidence limits: 88-99.9%) after ELISA-M, in 43 of 44 (98%; 88-99.9%) after ELISA-S, in 54 of 67 (81%; 69-89%) after Latex-M and in 40 of 44 (91%; 78-97%) after Latex-S. A positive D-dimer test was confirmed in 61% (48-73%), 59% (46-71%), 63% (47-78%), and 55% (42-67%) respectively. These data suggest the use of one of the ELISA assays for screening. A negative D-dimer test excludes deep venous thrombosis, whereas a positive D-dimer should be followed by venography. By this procedure a 40% reduction of venographic examinations can be expected.

The effect of glycemic control on plasma soluble fibrin monomer complexes and fibronectin in diabetic patients.

We have shown previously that increased concentrations of plasma soluble fibrin monomer complexes (SFMC) and elevated fibronectin (Fn) levels are closely related to the development of diabetic microangiopathy. The purpose of the present study was to explore whether or not changes in plasma glucose levels could have an effect on these protein constituents. Plasma glucose levels of 25 uncontrolled diabetic patients were brought under control with insulin and serial measurements of SFMC and Fn were made over a period of 4 weeks. Glucose values fell from an average of 312 mg/100 ml to 160 mg/100 ml. Ten patients with macroproteinuria (i.e. greater than or equal to 0.5 g/24 hr) showed initially elevated plasma SFMC and Fn concentrations. These levels fell significantly over the 4 week observation period: from 13.6 mg/100 ml to 9.4 mg/100 ml for SFMC and from 38.4 mg/100 ml to 34.5 mg/100 ml for Fn. The remaining 15 patients had nearly normal levels of both SFMC (7.9 mg/100 ml) and Fn (31.1 mg/100 ml) and glycemic control brought no further reduction. The data indicated that a) elevated SFMC and Fn levels are indeed associated with diabetic microangiopathy, especially in the presence of macroproteinuria; and b) adequate glycemic control is capable of normalizing the plasma concentration of these constituents.

Relationship between elevated plasma levels of crosslinked fibrin degradation products (XL-FDP) and the clinical presentation of patients with myocardial infarction.

To assess whether the intense thrombotic state known to occur early after the onset of acute myocardial infarction is further exacerbated by impaired intrinsic fibrinolysis, we compared the intensity of fibrinolysis as measured by the level of crosslinked fibrin degradation products (XL-FDP) in plasma with the intensity of thrombosis as assessed by fibrinopeptide A (FPA) in 98 patients with transmural and 14 patients with non-Q wave infarction. Patients without complications of infarction such as shock, mural thrombi, or malignant arrhythmias requiring countershock generally had normal plasma levels of XL-FDP, less than or equal to 300 ng/ml (81% of those presenting less than 8 hours after onset and 66% of those presenting greater than 8 hours after onset) on admission despite elevated FPA indicative of ongoing thrombosis. In contrast, patients with complications generally had elevated levels of XL-FDP greater than 300 ng/ml (80% of those presenting early and 62.5% of those presenting late) and 50% of these patients had marked elevations to greater than 1000 ng/ml. FPA was markedly elevated in patients with complications whether they presented early or late after onset of infarction. Our direct measurements at the time of infarction support previous data indicating that intrinsic fibrinolysis is impaired in patients with acute infarction, despite marked thrombin activity, when complications are not present. However, when complications are present initially, a more exuberant fibrinolytic response is observed perhaps due to thrombosis associated with the complications themselves.

High-dose, brief-duration intravenous infusion of streptokinase in acute myocardial infarction: description of effects in the circulation.

The effects in the circulating blood of a 1-hour intravenous infusion of 1.5 X 10(6) units of streptokinase (SK) were measured during the subsequent 24-hour period in 7 patients with acute myocardial infarction. At the end of the infusion, the activator activity, expressed in SK units, averaged 65 U/ml, all of the plasminogen had disappeared, only a small amount of free plasmin was still present and functionally active alpha 2 antiplasmin had been reduced to 21% of the preinfusion level. All of the native fibrinogen had been degraded and the thrombin-coagulable protein was composed entirely of fragment X species, but the circulating plasma also contained significant amounts of the more extensively degraded fragments Y, D and E. The biologic half-life of the SK-induced activator activity was 23 minutes and that of the fibrinogen degradation products was 6.3 hours. The lytic effects persisted for 4 hours before any signs of recovery from the hemostatic defect were evident; considerable recovery was present at 25 hours.

Fluidity of cadaveric blood after sudden death: Part III. Acid-base balance and fibrinolysis.

In rats, fibrinolytic activity and acidosis increased rapidly after death. Postmortem fibrinolysis and the pH, base excess (BE), and [HCO3-] levels were affected by the method of sacrifice: the lower the pH, BE, and [HCO3-] levels, the higher the fibrinolytic activity. Conversely, in experiments using the vascular perfusion technique, low pH, BE, and [HCO3-] levels of the perfusate induced abundant release of plasminogen activator from the vascular wall.

Histidine-rich glycoprotein and changes in the components of the fibrinolytic system after streptokinase therapy in patients with pulmonary thromboembolism.

Although the biological function of histidine-rich glycoprotein (HRG) is unknown, it may serve as an antifibrinolytic agent by interfering with the binding of plasminogen to fibrin. To define the role of HRG, plasma titers were measured by single radial immunodiffusion in eleven patients with thromboembolism before and after streptokinase (SK) therapy and were found unchanged (84.7 +/- 6.2%, M +/- SEM before, and 99.5 +/- 6.3% after 12 hr of SK therapy). The HRG peaks on crossed immunoelectrophoresis before and after SK infusion were also unchanged. Alpha 2-plasmin inhibitor fell during SK infusion as measured immunologically (102.0 +/- 15.0% before and 28.0 +/- 1.6% after 12 hr of therapy) and fibrinogen-fibrin degradative products appeared (mean titer of 1:2,048 after 12 hr of therapy), indicating that the infused SK was biologically active. Plasminogen levels before therapy were normal, as measured functionally and immunologically (105.4 +/- 4.9% and 96.0 +/- 5.6%, respectively), and both decreased after 12 hr of SK therapy (15.2 +/- 5.6% and 50.8 +/- 4.3%). No changes in functional antithrombin III titer, Hageman factor antigen level, or fibrinogen concentration, as measured turbidimetrically, were observed. Thus, although these data do not allow one to make any firm conclusions regarding the physiologic role of this protein in fibrinolysis, they do not exclude its increased catabolism, compensated by increased production, in patients undergoing fibrinolytic therapy.