Plasma Fibrin Degradation Products Research Articles

Coagulation defects of aflatoxin intoxicated rabbits.

Twelve New Zealand white rabbits were intoxicated with aflatoxin B1. Most rabbits developed a coagulation defect near the time of death. Immediately prior to death there were significant decreases in factors V, VII, and VIII coagulant activities and fibrinogen concentration without a change in plasma fibrin(ogen) degradation product concentration, platelet number, and detectable plasma fibrin monomers. Microscopic evidence of disseminated intravascular coagulation was present in one rabbit with marked, diffuse hepatic necrosis. Terminal serum albumin concentration was significantly correlated to plasma factors V and VII activities and fibrinogen concentration. The coagulation defect of aflatoxicosis is primarily due to diminished hepatic synthesis of coagulation factors except when hepatic necrosis is severe enough to initiate intravascular coagulation and consumption of coagulation factors.

Rapid detection of cross-linked fibrin degradation products in plasma using monoclonal antibody-coated latex particles.

Conformational and structural changes on conversion of fibrinogen to fibrin and its cross-linking by Factor XIIIa lead to the development of new antigenic determinants that permit differentiation between their plasminolytic cleavage products. A monoclonal antibody (DD-3B6/22) that is specific for cross-linked fibrin derivatives containing the D dimer configuration has been used in developing a latex agglutination procedure that can detect fibrin degradation products in either plasma or serum. Fibrinogen or its degradation products do not cross-react with this antibody. Results were calibrated with an enzyme immunoassay, which used a purified D dimer standard. Plasmas from 40 normal subjects, all having D dimer levels below 250 ng/mL measured by enzyme immunoassay, were all negative by latex assay. In contrast, positive latex agglutination titers were obtained with 87 of 88 patients with demonstrated deep venous thrombosis, pulmonary embolism, or disseminated intravascular coagulation. Compared to enzyme immunoassay, latex agglutination assay is less sensitive, but this latex procedure provides a rapid and less elaborate test for elevated levels of cross-linked fibrin degradation products in patients with thrombosis. Plasma assays for fibrin degradation products are preferable to those using serum.

Specific identification of fibrin polymers, fibrinogen degradation products, and crosslinked fibrin degradation products in plasma and serum with a new sensitive technique

A new method is described for identifying low concentrations of circulating derivatives of fibrinogen and fibrin, even when present in heterogeneous mixtures. This technique is applicable to plasma and serum and uses electrophoresis in 2% agarose in the presence of sodium dodecyl sulfate (SDS) followed by immunological identification of separated derivatives, using radiolabeled antifibrinogen antiserum and autoradiography. Unique electrophoretic patterns distinguish plasmic derivatives of crosslinked fibrin from those of fibrinogen and also identify crosslinked fibrin polymers produced by the combined action of thrombin and factor XIII on fibrinogen. The assay is sensitive to a concentration of 0.1 micrograms/mL of fibrinogen in serum or plasma. Fibrin polymers, plasmic degradation products of fibrinogen, and plasmic degradation products of crosslinked fibrin were detected in the plasma or serum of a patient with disseminated intravascular coagulation. Plasmic derivatives of both fibrinogen and crosslinked fibrin appeared in serum in the course of fibrinolytic therapy for pulmonary embolism, whereas during acute myocardial infarction a marked increase in the proportion of fibrin polymers in plasma was found in comparison with normal controls. Thus, the procedure can distinguish between the simultaneous processes of fibrin polymer formation, fibrinogenolysis, and fibrinolysis, and is sufficiently sensitive to detect relevant quantities of derivatives in pathologic conditions.

Specific Identification of Fibrin Polymers, Fibrinogen Degradation Products, and Crosslinked Fibrin Degradation Products in Plasma and Serum With a New Sensitive Technique

A new method is described for identifying low concentrations of circulating derivatives of fibrinogen and fibrin, even when present in heterogeneous mixtures. This technique is applicable to plasma and serum and uses electrophoresis in 2% agarose in the presence of sodium dodecyl sulfate (SDS) followed by immunological identification of separated derivatives, using radiolabeled antifibrinogen antiserum and autoradiography. Unique electrophoretic patterns distinguish plasmic derivatives of crosslinked fibrin from those of fibrinogen and also identify crosslinked fibrin polymers produced by the combined action of thrombin and factor XIII on fibrinogen. The assay is sensitive to a concentration of 0.1 micrograms/mL of fibrinogen in serum or plasma. Fibrin polymers, plasmic degradation products of fibrinogen, and plasmic degradation products of crosslinked fibrin were detected in the plasma or serum of a patient with disseminated intravascular coagulation. Plasmic derivatives of both fibrinogen and crosslinked fibrin appeared in serum in the course of fibrinolytic therapy for pulmonary embolism, whereas during acute myocardial infarction a marked increase in the proportion of fibrin polymers in plasma was found in comparison with normal controls. Thus, the procedure can distinguish between the simultaneous processes of fibrin polymer formation, fibrinogenolysis, and fibrinolysis, and is sufficiently sensitive to detect relevant quantities of derivatives in pathologic conditions.

Status of fibrin degradation products in leprosy.

ABSTRACTPlasmafibrinogen and fibrin degradation products (FDP) were estimated in 45 control subjects and 45 patients with various types of leprosy including 16 patients with erythema nodosum leprosum (ENL). The levels of FDP were quantified by using a suspension of Staphylococcus aureus (Newmans D2C strain). Significantly higher levels of plasma fibrinogen and FDP were observed in patients with lepromatous leprosy, especially with ENL, than in the controls. Only 3 lepromatous patients had plasma fibrinogen levels below the normal range; 2 of them had severe ENL and were suffering from nasal bleeding. Levels of D and E fragments were also estimated in another 20 control subjects and 13 lepromatous patients by haemagglutination inhibition technique and were found to be significantly elevated in the patients. It was inferred that raised FDP levels in such patients indicated an ongoing occult fibrinolysis during lepra reaction. A few lepromatous patients may show hypofibrinogenomia during severe ENL episodes.

Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy

Disseminated intravascular coagulation (DIC) is caused by a variety of underlying disorders, and criteria for diagnosis are not well defined. However, the most helpful are a low platelet count, positive plasma protamine test, and fibrinogen and fibrin degradation product levels viewed in the context of the patient's underlying disease. The cornerstone of therapy is prompt treatment of the underlying disease and elimination of the trigger mechanism. Additional treatment must be individualized, and generalizations are difficult to make. However, if the patient has low hemostatic factors and is actively bleeding or requires an invasive procedure, then replacement with the appropriate hemostatic factors should be tried. Heparin is indicated in patients with purpura fulminans and venous thromboembolism, but there is little evidence that heparin reverses organ dysfunction associated with DIC. In addition, heparin is also probably indicated in patients with retained dead fetus and hypofibrinogenemia prior to induction of labor, excessive bleeding associated with a giant hemangioma, and neoplastic disease, particularly promyelocytic leukemia. Although the use of heparin in acute forms of DIC remains controversial, the majority of studies suggest that it is not helpful. The role of antithrombin III (AT-III) concentrates is unknown, but they theoretically may be helpful when DIC is associated with very low AT-III levels, as is seen in liver disease.

Diagnosis and Management of Disseminated Intravascular Coagulation: The Role of Heparin Therapy

Abstract Disseminated intravascular coagulation (DIC) is caused by a variety of underlying disorders, and criteria for diagnosis are not well defined. However, the most helpful are a low platelet count, positive plasma protamine test, and fibrinogen and fibrin degradation product levels viewed in the context of the patient's underlying disease. The cornerstone of therapy is prompt treatment of the underlying disease and elimination of the trigger mechanism. Additional treatment must be individualized, and generalizations are difficult to make. However, if the patient has low hemostatic factors and is actively bleeding or requires an invasive procedure, then replacement with the appropriate hemostatic factors should be tried. Heparin is indicated in patients with purpura fulminans and venous thromboembolism, but there is little evidence that heparin reverses organ dysfunction associated with DIC. In addition, heparin is also probably indicated in patients with retained dead fetus and hypofibrinogenemia prior to induction of labor, excessive bleeding associated with a giant hemangioma, and neoplastic disease, particularly promyelocytic leukemia. Although the use of heparin in acute forms of DIC remains controversial, the majority of studies suggest that it is not helpful. The role of antithrombin III (AT-III) concentrates is unknown, but they theoretically may be helpful when DIC is associated with very low AT-III levels, as is seen in liver disease.

Postpartum Hemolytic Uremic Syndrome

Three cases of postpartum hemolytic uremic syndrome (HUS) are presented. Symptoms of acute renal failure, hypertension and microangiopathic hemolytic anemia with thrombocytopenia occurred 10, 17 and 24 days after delivery. Despite early heparin therapy in all cases, one patient went into terminal renal failure needing chronic hemodialysis, with persistent hypertension which became uncontrollable requiring bilateral nephrectomy 6 months later. The second patient had diuresis one month after starting hemodialysis, but 3 months later developed malignant hypertension. Slight improvement in renal function with persistent hypertension occurred after hemodialysis for 20 months. The third patient showed complete clinical recovery after 2 months. Pathological examination of renal tissue showed the typical lesions of thrombotic microangiopathy (TMA). However, striking differences were observed in the lesion seen in early and late specimens. Early lesions could be differenciated from infancy TMA because the medium-dize arteries were more severely involved. Late lesions were variable, ranging from minor changes in glomeruli and blood vessels, via ischemic and sclerotic lesions in glomeruli with arteriolosclerosis, to the vascular and glomerular lesions seen in malignant nephrosclerosis. There was a good correlation between the renal pathology and the clinical outcome of the patients. HUS with renal TMA as a cuase of postpartum renal failure has been reported in 49 patients with a fatal outcome in 61%. The pathogenesis of the syndrome probably involves a primary endothelial damage. This causes local renal intravascular coagulation in the presence of the usual postpartum hypercoagulable state. This is shown by the presence of fibrin-fibrinogen in glomeruli and vessels, increased plasma fibrin degradation products, thrombocytopenia and lowered levels of coagulation factors. There is little hematological or pathological evidence fo disseminated intravascular coagulation or an immune-complex disease. Hypocomplementemia seen frequently is probably due to local C3 activation via the alternative pathway.

Coagulation Abnormalities in Dogs with Neoplastic Disease

Conventional laboratory methods were used to screen untreated tumor-bearing dogs for hemostatic abnormalities. Excluded from study were dogs with clinical evidence of bleeding. The primary site for neoplastic disease in 100 dogs studied included hemolymphatic system, skin, bone, thyroid gland, oropharynx, mammary gland, and nasal cavity. Eighty-three percent of the dogs had one or more abnormal coagulation tests. Thrombocytopenia occurred in 36 dogs and 3 had thrombocytosis. Twenty-five dogs had hypofibrinogenemia, and 25 had hyperfibrinogenemia. There were 32 dogs with prolongation of the activated partial thromboplastin time, 10 dogs with shortened prothrombin time, and 6 dogs with prolongation of the thrombin time. Sixteen dogs had positive protamine sulfate (paracoagulation) reaction, and 8% had increased plasma fibrin degradation products. The euglobulin lysis time was accelerated in 24% of the dogs, and 15% had schistocytes on blood film. These data indicate that the majority of dogs with advanced neoplasms are likely to have abnormal coagulation tests.

Precipitation of fibrin monomers and fibrin degradation products by ristocetin.

Ristocetin, at relatively low concentrations (1.0 mg/ml-1.5 mg/ml), can selectively precipitate fibrin monomers and fibrin degradation products (fdp) from plasma without effect on fibrinogen or fibrinogen degradation products (FDP). 125I-labeled fibrin monomers and fibrin degradation products were precipitated by ristocetin when their plasma concentrations were greater than 0.25 microgram/ml and 50 microgram/ml, respectively. In order to obtain a visible precipitated, 2 microgram/ml of fibrin monomers of 50 to 100 microgram/ml of fibrin degradation products were necessary. These effects were optimally observed under the following conditions: (1) temperature, 20 C to 37 C; (2) pH, 7.0 to 7.5; and (3) incubation time, 15 to 60 minutes. Late-fibrin degradation products are approximately eight times less sensitive to ristocetin-induced precipitation than early-fibrin degradation products. Plasma medium is essential for the differentiation of fibrin monomers and fibrin degradation products from fibrinogen and fibrinogen degradation products by ristocetin. These results suggest that the specific detection of fibrin monomers and fibrin degradation products in plasma may be easily performed by ristocetin.

On the origin of urinary fibrin-fibrinogen-related antigen in glomerulonephritis.

A model of antiglomerular basement membrane nephritis in the rat was used to elucidate the origin of urinary fibrin-fibrinogen-related antigen (FRA). The intrarenal distribution and excretion of 125I-rat fibrinogen was examined to determine whether there was increased filtration of bibrinogen or fibrin degradation products (FDP) or lysis of intraglomerular fibrin. 125I-protein appeared in the urine immediately after injection of 125I-fibrinogen and fell in parallel with the fall in plasma 125I-fibrinogen. Renal retention of 125I-fibrin averaged less than 0.2 percent of the administered dose of 125I-fibrinogen. The infusion of epsilon aminocaproic acid (EACA) had no significant effect on either FRA excretion or 125I-protein excretion. Plasma FDP levels and the elution patteren of 125I-protein from the urine were not significantly changed by EACA infusion. These observations support the view that ruinary FRA excretion in glomerulonephritis is derived predominantly from increased filtration of plasma fibrinogen rather than from breakdown of intraglomerular fibrin.

フィブリン・フィブリノーゲンと動脈硬化

Fibrinogen derivatives in the cryoprecipitable portion of Blombäck's fraction I-O from 50 patients, mainly with atherosclerosis, were studied by SDS-polyacrylamide gel electrophoresis. No discernible stabilized fibrinogen-fibrin complex could be detected in the electrophoresis. Although stable fibrinogen dimer, probably made by disulfide linkage, were detected in all cases of atherosclerosis and also in normal controls, fibrinogen dimers having γ-γ diads could be observed in only two cases; one with acute myocardial infarction one day prior to the study and the other five months prior to the study. Fraction I-8, clottable derivatives of fibrinogen degradation, could also be found in all cases and in controls. Serial dilution protamine sulfate test showed negative for all plasma samples except one which had acute myocardial infarction one day prior to the study and showed γ-γ diads in the electrophoresis.Plasma of the atherosclerotic patients showed the increments of plasma fibrinogen concentration and fibrin degradation products together with the shortening of the euglobulin lysis time. Concentration of the plasma fibrin stabilizing factor had no relation to the aging nor to the plasma fibrinogen concentration. Levels of plasma fibrin stabilizing factor in two cases with γ-γ diads remained normal.Plasma fibrinogen could suppress both the polymerization and crosslinking of fibrin produced in the circulation. Increased plasma fibrinogen may accelerate the suppression of the polymerization and crosslinking of fibrin produced more under the hypercoagulable state of sclerotic patients.Possible roles of fibrinogen derivatives in the mechanisms of the deposition of insoluble fibrinogen derivatives in the aortic intima (by Shainoff, J. R.) were discussed.

Distinction between fibrinogen and fibrin degradation products in plasma

Polyacrylamide (PA) gel electrophoresis in sodium dodecyl sulphate (SDS) has been shown to distinguish between the major components in the plasmin induced lysates of purified crosslinked fibrin and fibrinogen. The D dimer fragment from crosslinked fibrin separated on SDS-PA gels from the fibrinogen fragments X, Y, D g and E. Following immuno-absorption of plasmin induced lysates of plasma clots, plasma fibrinogen, and mixtures of both, the major fragments of fibrinogen and fibrin were capable of being discriminated by SDSPA gel electrophoresis. The presence of D dimer in patient plasma suggested the efficacy of heparin in the management of haemorrhage associated with amniotic fluid embolism.

Immunonephelometric determination of fibrinogen and its derivatives in plasma

An immunonephelometric method for determination of fibrinogen and fibrin degradation products in plasma is described. Test plasms are diluted 1/600 in a solution containing 17 g NaCl and 3.8 g trisodium citrate/100 ml. To 3 cm 3 of this mixture 0.2 cm 3 of a concentrated antifibrin gamma globulin preparation is added. The reading of this sample minus the γ-globulin blank in a Thorp Nephelometer is directly proportional to the fibrinogen content of the plasma or to its FDP concentration in terms of intact fibrinogen. This paper examines the mechanism, accuracy and reproducibility of this method.

Blood fibrinolytic activity during arvin therapy.

Summary:When Arvin is administered to patients, there is a rapid fall in plasma plasminogen concentration and fibrin degradation products appear in the blood which can be detected both by their anticoagulant effect and by their reaction with anti‐fibrinogen serum. There is a minimal but inconstant increase in the concentration of plasminogen activator and circulating plasmin cannot be detected. These findings are similar to those recorded in the defibrination syndrome and are explained by the assumption that both plasminogen and activator are adsorbed onto intravascular fibrin micro‐clots. Local plasmin release would then cause lysis of fibrin with the appearance of fibrin degradation products.There is no apparent reason why this mechanism should assist in the lysis of coexisting preformed thrombi. The apparent rapid lysis of thrombi which has been observed in some patients treated with Arvin can be explained if such thrombi are not static, but represent a balance between fibrin deposition and fibrinolysis. Therapeutic defibrination, by preventing extension of the thrombus, would allow the normal fibrinolytic mechanism to produce dissolution of the thrombus.