Increase In Fibrinogen Degradation Products Research Articles

Robust Oncolytic Virotherapy Induces Tumor Lysis Syndrome and Associated Toxicities in the MPC-11 Plasmacytoma Model

Tumor-selective oncolytic vesicular stomatitis viruses (VSVs) are being evaluated in clinical trials. Here, we report that the MPC-11 murine plasmacytoma model is so extraordinarily susceptible to oncolytic VSVs that a low dose of virus leads to extensive intratumoral viral replication, sustained viremia, intravascular coagulation, and a rapidly fatal tumor lysis syndrome (TLS). Rapid softening, shrinkage and hemorrhagic necrosis of flank tumors was noted within 1-2 days after virus administration, leading to hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, increase in plasma cell free DNA, lymphopenia, consumptive coagulopathy, increase in fibrinogen degradation products, decreased liver function tests, dehydration, weight loss, and euthanasia or death after 5-8 days. Secondary viremia was observed but viral replication in normal host tissues was not detected. Toxicity could be mitigated by using VSVs with slowed replication kinetics, and was less marked in animals with smaller flank tumors. The MPC-11 tumor represents an interesting model to further study the complex interplay of robust intratumoral viral replication, tumor lysis, and associated toxicities in cases where tumors are highly responsive to oncolytic virotherapy.

Anti‐thymocyte globulin therapy induced a spurious increase of fibrinogen degradation products in hypoplastic myelodysplastic syndrome

Anti‐thymocyte globulin therapy induced a spurious increase of fibrinogen degradation products in hypoplastic myelodysplastic syndrome

The action of Lonomia achelous caterpillar venom on some blood coagulation and fibrinolysis parameters of the rabbit

The bodily secretions of the Lonomia achelous caterpillar cause a severe and often fatal acquired bleeding diathesis in humans. The rabbit was selected as model animal in an attempt to understand the mode of action of the venom. The animals were injected subcutaneously with either hemolymph or chromatographically purified fractions. Injections of hemolymph produced a drop in fibrinogen and factor XIII levels and an increase in fibrinogen degradation products (FDP). In addition one batch of hemolymph decreased plasminogen levels. The chromatographically semipurified fraction II decreased both fibrinogen and plasminogen. The effect was dose dependent but, unlike in humans, there was a fairly rapid return to baseline values. In conclusion, the response to Lonomia achelous venom in the rabbit is similar to the response seen in humans, but with a more rapid recovery.

Pharmacokinetics and Pharmacodynamics of Saruplase, an Unglycosylated Single-chain Urokinase-type Plasminogen Activator, in Patients with Acute Myocardial Infarction

We examined in patients with acute myocardial infarction (AMI) the pharmacokinetics of saruplase, an unglycosylated, single chain, urokinase-type plasminogen activator (rscu-PA) by measuring urokinase-type plasminogen activator (u-PA) antigen and total u-PA activity, its conversion to active two-chain urokinase-type plasminogen activator (tcu-PA) and evaluated its effect on haemostatic parameters. Twelve patients were studied during and after administration of 20 mg bolus plus 60 mg continuous 1 h i.v. infusion of saruplase. For u-PA antigen and total u-PA activity (expressed as protein equivalents), where 234 U corresponds to 1 microgram, respectively, steady state plasma concentrations were 2.75 +/- 8.3 and 2.50 +/- 7.0 micrograms/ml (mean +/- standard deviation) and were reached within 20 min, t1/2 lambda 1 was 9.1 +/- 1.8 and 7.8 +/- 1.3 min, t1/2 lambda 2 1.2 +/- 0.2 and 1.9 +/- 0.5 h, and the total clearance was 393 +/- 110 and 427 +/- 113 ml/min. Inactivation of saruplase in plasma was negligible. After 15 min, tcu-PA was detected in plasma. From the ratio of the areas under the curve of tcu-PA and total u-PA activities it was calculated that 28 +/- 9.3% of the saruplase dose is converted into active tcu-PA. Systemic plasminaemia occurs as shown by a decrease in alpha 2-antiplasmin and fibrinogen and an increase in fibrinogen degradation products. Thrombin-antithrombin complex formation indicated activation of the clotting system. Saruplase is eliminated rapidly from plasma in AMI patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The fibrinolytic response to ancrod therapy: characterization of fibrinogen and fibrin degradation products

Ancrod is a purified coagulant venom which renders blood incoagulable by cleaving fibrinopeptide A (FPA) from fibrinogen, but the mechanism involved in the clearance of fibrin from the circulation is unknown. To investigate the fibrinolytic response to ancrod, and to increase understanding of clearance mechanisms, six patients with peripheral vascular disease causing claudication were infused with ancrod at 2 u/kg over 6 h followed by 2 u/kg at 12 h intervals for 38 h. Venous blood samples were taken at time 0, 3, 6, 25 and 49 h for assay of fibrinogen (Fbg), fibrinopeptide A (FPA), total fibrin(ogen) degradation products (TDP), fibrin degradation products (FbDP), fibrinogen degradation products (FgDP), cross-linked fibrin degradation products (XL-FDP), tissue plasminogen activator (tPA), urinary type plasminogen activator (u-PA), plasminogen, alpha 2 antiplasmin (alpha 2 AP) and plasminogen activator inhibitor-1 (PAI-1). Fibrinogen (median and range) was 2.3 (1.4-3.90) g/l at time 0 and thereafter was undetectable. FPA rose from 2.5 (1.8-3.6) to 600 and 188 pmol/l at 3 h and 6 h and remained elevated. TDP, FbDP and FgDP increased greatly following ancrod while there was no evidence of XL-FDP. The surprising increase in FgDP during defibrination suggests either that fibrinogen is digested following its incorporation into circulating fibrin protofibrils or that some of the fibrin subunits in the photofibril retain one of the two fibrinopeptide A's. tPA and uPA remained unchanged. Plasminogen fell from 125 (100-155)% to 79 (40-118)% at 49 h and alpha 2 AP fell from 91 (75-107)% to 24 (10-35)% at 49 h. The level of PAI-1 was depressed during defibrination, with the exception of the 6 h data. The results demonstrate that ancrod removes FPA from fibrinogen to produce non-cross-linked (soluble) fibrin. This is cleared from the circulation without evidence of an increase in the circulating activities of the plasminogen activators, tPA or UK, but with evidence of plasminogen activation and consumption.

Coagulation and fibrinolysis in the first human auxiliary partial liver transplantation in rotterdam

Coagulation and fibrinolysis parameters were extensively monitored during and after a case of auxiliary partial liver transplantation (APLT). Preoperative coagulation tests demonstrated a severe liver dysfunction. Routine coagulation tests were prolonged and low levels of fibrinogen, antithrombin III (AT-III), and ( α 2-antiplasmin ( α 2-AP) were measured. Pro-urokinase (pro-UK), total Uk-antigen and plasminogen activator inhibitor (PAI) activity were increased (6.2; 5.4 ng/ml and 12.5 IU/ml, respectively). During transplantation no major changes in haemostasis were detected by either standard coagulation tests or thrombelastography and only a minimal increase of fibrinogen degradation products (0.6–1.0 μg/ml) was seen just before graft recirculation up till the end of the operation. PAI levels remained high during the operation and neither tissue-type plasminogen activator (t-PA) nor active urokinase (u-PA) were detectable. After APLT, graft function was reflected by normalisation of coagulation parameters and increase of AT-III and α 2-AP to normal levels. Pro-Uk and PAI activity levels decreased after transplantation to normal values; a transient increase of t-PA activity (max. 1360 mIU/ml) was seen from the tenth to nineteenth day. It was demonstrated that a heterotopically placed partial liver allograft can provide synthesis of haemostasis factors and inhibitors and restore clearance which is adequate to reverse coagulopathy.

The role of leukotoxin (9, 10-epoxy-12-octadecenoate) in the genesis of coagulation abnormalities

This study was designed to clarify whether or not leukotoxin (9,10-epoxy-12-octadecenoate), which is biosynthesized by neutrophils, might be involved in the genesis of coagulating abnormalities. Twelve dogs were divided into 2 group. In the test group (n=6), 100 μmol/kg of leukotoxin was injected intravenously, and in the control group (n=6), 100 μmol/kg of linoleate was injected. In each group, a series of blood samples were collected and used for coagulation studies. After the end of the experimental period, a histological study was performed on organs removed from the dogs. In the leukotoxin group, fibrin and fibrinogen degradation products (FDP) was increased time-dependently. Fibrinogen was decreased, and prothrombin time and activated partial thromboplastin time were prolonged in parallel with the increase in FDP. A decrease in number of platelets was also observed. Intravascular coagulation was observed in sections of lung. These data were compatible with a diagnosis of disseminated intravascular coagulation (DIC). No significant changes in these parameters were observed in the linoleate group. Leukotoxin has been confirmed to show antifungal and antibacterial activity, and its production might be a defensive response to infection. Over-production of leukotoxin associated with severe infection might therefore account for infection-induced DIC.

Coronary arterial thrombolysis with low-dose synergistic combinations of recombinant tissue-type plasminogen activator (rt-PA) and recombinant single-chain urokinase-type plasminogen activator (rscu-PA) for acute myocardial infarction

The effect of combined intravenous infusion of 10 mg of recombinant tissue-type plasminogen activator (rt-PA) and 10 mg of recombinant single-chain urokinase-type plasminogen activator over 1 hour on coronary artery recanalization and on the blood fibrinolytic system was studied in 9 patients with acute myocardial infarction and angiographically confirmed coronary artery occlusion. In 3 of these patients, prior infusion of 10 mg of rt-PA over 1 hour before the first angiogram had not produced coronary artery reperfusion. Complete recanalization was achieved in 7 patients and transient recanalization with reocclusion in 1 patient, whereas coronary artery occlusion persisted in 1 patient. At the end of the infusion, the fibrinogen level remained unchanged and no increase in fibrinogen degradation products was observed, whereas the α 2 antiplasmin level had decreased to 61 ± 16 % (mean ± standard deviation) of the preinfusion level. Thus, combined intravenous infusion of rt-PA and recombinant single-chain urokinase-type plasminogen activator induces fibrin-specific coronary thrombolysis at approximately one-fourth of the dose currently used for each agent alone, which further documents the pharmacologic synergism of these agents.

Endogenous anticoagulation during extracorporeal perfusion: generation of a heparinlike inhibitor.

Studies were done to define the coagulation defect that develops in hemodynamically stable anesthetized dogs perfused on our arteriovenous extracorporeal system without added heparin. After 45 min, the dogs developed whole blood clotting times (WBCT) greater than 24 h. There was an associated decrease in ADP-induced platelet aggregation and a drop in factor V, VIII, and X levels of 75.8, 33.5, and 46.8%, respectively. Despite an increase in fibrinogen degradation products, there was no significant change in fibrinogen level or platelet count. An inhibitor of thrombin and factor Xa clotting of plasma appeared that was "heparinlike", because it stimulated the inactivation of factor Xa by antithrombin III (ATIII) but not by O-methyl isoureamodified ATIII. Thrombin inhibition by ATIII was also stimulated. The inhibitor was heat stable, adsorbed by BaSO4, and neutralized by protamine. Infusion of protamine sulfate into two perfused dogs neutralized the inhibitor and brought the WBCT from greater than 24 h to less than control. Six dogs developed inhibitor levels equivalent to 0.98 to 6.15 U/ml heparin. Five eviscerated dogs in which the hepatic artery was ligated developed peak plasma inhibitor levels of 3.2 +/- 1.0 U/ml. Thus, the endogenous heparinlike inhibitor is a major contributor to the anticoagulated state induced with our perfusion system and may have an extrahepatic origin.

Lack of fibrin formation in exercise-induced activation of coagulation

Strenuous physical exercise leads to a significant shortening of blood clotting in various test systems. Such short times are also characteristic of those observed in sedentary patients with thrombosis or disseminated intravascular coagulation, and of those observed in experimental animals after thrombin infusion. The patients exhibit an increase in circulating fibrinopeptide A, which is attributed to thrombin action on circulating fibrinogen, and to an increase of fibrinogen degradation products, which is thought to indicate reactive fibrinolysis. To check whether physical exercise leads to fibrinemia, 10 healthy male volunteers were subjected to strenuous exercise on a bicycle ergometer. Blood samples were taken immediately before and on completion of the exercise period. Despite a significant shortening of the activated partial thromboplastin time, the thrombin time, and the Reptilase time, no increase of fibrinopeptide A could be demonstrated and the ethanol gelation test remained consistently negative. Simultaneously, the euglobulin lysis time was significantly shortened, whereas the fibrin(ogen) degradation products did not increase. The results indicate that the shortening of the coagulation times associated with physical exercise must be explained by mechanisms other than thrombin-mediated conversion of fibrinogen to fibrin.

Prognostic value of urinary fibrinogen degradation products in bladder carcinoma.

In this study, the value of urinary fibrinogen degradation products as a biological marker of bladder carcinoma has been studied. An increase in fibrinogen degradation products was found in 86% of bladder cancer patients independent of the fact that they had active tumors or that they were disease free. A highly significant correlation between the amount of the increase, the grade, local invasiveness, and the risk of recurrence of the tumor has been established. One can conclude that urinary fibrinogen degradation products are of great prognostic value in patients with bladder carcinoma.

Antifibrinolytic therapy in ruptured intracranial aneurysm through repeated monitoring of fibrinolytic activity of blood.

Streptkinase euglobulin lysis time (SK-ELT), fibrin and fibrinogen degradation products (FDP) and fibrinogen in blood were measured to determine the proper dosage of tAMCHA which would not cause ischemic complications but yet would suffice to prevent rebleeding in ruptured intracranial aneurysm. SK-ELT was almost doubled (130 sec) by the administration of 6-8 g/day of t-AMCHA within 24 h in normal control. On the other hand, SK-ELT in SAH patients fluctuated markedly during ten days after first bleeding. FDP demonstrated high value soon after first bleeding in Grade IV and V patients. Increase in FDP was also observed following rebleeding, severe vasospasm, and progressive neurological deterioration. Usually the increase in FDP was most obvious between 4-14 days after SAH. Fibrinogen showed the tendency to increase gradually by the administration of t-AMCHA, and this increased fibrinogen would be one of the alarm signs to indicate development of ischemic complications. From these results, it was suggested that doses of t-AMCHA should be determined precisely according to the result of repeated monitoring, and doses should be as such that it could keep SK-ELT constant between 130-150 sec.

Analysis of protein constituents in the ascitic and pleural fluids

This investigation has been performed to detect the individual variances in protein components of the ascitic or pleural fluids obtained from 151 cases of various disorders.Quantitative determination of fibrinogen, α1-acid glycoprotein and IgG in the fluids was made by the single radial immunodiffusion method. Fibrinogen and its degradation product increased in parallel with the proliferation of cancer cells in the serous cavities, on the other hand, the increase of α1-acid glycoprotein reflected the histopathological classification of cancers.The immunoelectrophoretic analysis performed with the specific anti-human fibrinogen antiserum demonstrated the increase of fibrinogen degradation products in the ascitic and pleural fluids. The reaction patterns of fibrinogen and its derivatives were classified into five types and their relation to the morphological findings of cellular components was investigated. The majority of cancerous fluids was involved in Type 4 and 5 which revealed two distinct lines closer to the cathode. The cancer cell-negative transudates belonged to Type 1 or 2, forming very weak patterns and most of inflammatory effusions to Type 3.Fibrinolytic activity determined by the fibrin plate method showed a marked variety in each fluid. Based on the comparison of cytological pictures in active and in negative cases of fibrinolysis, it was suggested that the proliferation of macrophages correlated with the increase of fibrinolytic activity.It may be assumed that the immunological analysis and estimation of several protein components in the ascitic and pleural fluids are of help to the differentiation of cancerous and other disorders.