Atherosclerotic plaque growth: presence of stimulatory fibrin degradation products.

Focal smooth muscle cell proliferation is widely perceived as a key event in the formation of stenosing atherosclerotic lesions, but the stimuli for this remain uncertain. Soluble extracts of human aortic intima from proliferative gelatinous and transitional lesions, as well as surface encrusted thrombi, have been shown by us to be mitogenic for the chick chorioallantoic membrane (CAM). They have also been shown to stimulate increase in vascularity of the CAM. When active samples were passed through anti-albumin and anti-whole-serum affinity columns, mitogenic activity in the unabsorbed, fibrin related antigen fraction remained close to the original whole extract level. In contrast, when the unabsorbed fractions from anti-whole-serum columns were passed through an antifibrinogen affinity columns, the activity was reduced to insignificant levels. Similarly, whole extracts lost activity after passing through an antifibrinogen column. This has been taken one stage further by dividing the unabsorbed fraction from an anti-whole-serum column into two equal volumes and passing one half through an antifibrinogen fragment D affinity column, and the other through an antifibrinogen fragment E affinity column. The activity of the unabsorbed fraction from the fragment D column remained the same, but that from the fragment E column was significantly reduced. Most of the fibrin degradation products (FbDP) in lesion extracts are derived from fibrin, not fibrinogen, and clotting out fibrinogen and fragment X with thrombin did not remove the activity. Whole extracts of atherosclerotic lesions clotted on the CAM surface as has previously been shown with plasma.(ABSTRACT TRUNCATED AT 250 WORDS)     

Fibrin degradation products generation and fibrinopeptide A release in normal plasma incubated with thrombolytic agents: proposed mechanisms.

Clinical data have shown that the evaluation of fibrin degradation products (FbDP) does not reflect the efficiency of thrombolytic therapy in vivo. In this study, we found that the addition of plasminogen activators to normal plasma resulted in generation of FbDP and release of fibrinopeptide A (FpA) as shown by ELISA and HPLC. This FpA release was concomitant with fibrinogen degradation, and was not inhibited by thrombin inhibition or by prothrombin depletion in plasma. Thus, the increase in FpA did not result from coagulation activation and may result from the plasmin-induced release of FpA from fibrinogen degradation product E1. The generation of cross-linked FbDP after tPA addition occurred in normal plasma as well as in factor-XIII-deficient plasma and quickly reached a plateau. It was not inhibited by hirudin. Therefore FbDP in these plasmas probably derived from the plasmin degradation of cellular transglutaminase cross-linked fibrin/fibrinogen derivatives present in plasma.     

Artificial exudate: stimulation of cell proliferation by plasma not serum is associated with fibrinolysis

Despite its abundance of cell culture growth factors, serum does not enhance growth of the in vivo test system, the chick chorioallantoic membrane (CAM). Previously we have also shown that fibrinogen (Kabi) and its degradation products do not display mitogenic activity on the CAM, but have now been surprised to find stimulation of DNA synthesis (up to 2.5-fold) 18 h after application of human plasma [incorporation of [3H]thymidine control mean +/- SEM 8442 +/- 1338 dpm/CAM (n = 8); test--20 199 = 3491 (n = 6); t-test P less than 0.01)]. Plasma (platelet-rich and platelet-poor) was freshly prepared by minicolumn removal of citrate at 16 degrees C; 0.3 ml aliquots of 10% human plasma were applied to the CAM and groups were fixed at various time intervals. Cross-sections were examined histologically, including immunoperoxidase studies with antihuman fibrinogen which does not cross react with chick fibrinogen, and autoradiography with [3H]thymidine. Initially, a layer of plasma was observed on the surface of the CAM. After 1 h a condensed fibrillar layer of fibrin was formed and was still present at 6 h. This was associated with increased [3H]thymidine labelling of the surface layer of the CAM. By 18 h the fibrin had disappeared, indicating that it had been lysed by the CAM, and widespread [3H]thymidine labelling was observed. No inflammatory cell infiltrate was apparent, but marked oedema developed. Oedema alone was observed in controls receiving serum or Dulbecco buffer. Both platelet-rich and platelet-free plasma gave stimulation of mitogenic activity, implying that platelet-derived growth factor is not involved in the stimulation of the CAM.(ABSTRACT TRUNCATED AT 250 WORDS)     

A monoclonal antibody specific to the granulocyte-derived elastase-fragment D species of human fibrinogen and fibrin: its application to the measurement of granulocyte-derived elastase digests in plasma

When granulocytes are stimulated under certain clinical conditions, elastase is released therefrom and digests fibrin(ogen) independently of the plasmin system, which may also be mobilized simultaneously. Thus, discrimination of these 2 systems becomes urgent for the diagnosis and treatment of the underlying diseases. Using as immunogen a 97-kd granulocyte-elastase digest of human fibrinogen, we raised an antibody IF-123 that specifically recognizes elastase digests of human fibrin(ogen). The 97-kd elastase fragment resembles plasmic fragment D(1), and the epitope of this antibody is located on the Aalpha (196-204) residue segment. This segment appears to be masked in fibrin(ogen) but exposed when the Aalpha Leu 204-Ile 205 peptide bond is cleaved by elastase. Cathepsin G concomitantly released from granulocytes failed to expose the epitope. By an enzyme immunoassay using IF-123 as the capture antibody, the elastase digests of fibrin(ogen) can be measured in plasma samples without interference by abundantly coexisting fibrinogen. Indeed, we found that the elastase digests were mostly elevated in patients with inflammation or malignant tumors, but remained in a normal range in patients with a benign gastrointestinal tract disease such as duodenal ulcer and polyps in the gallbladder or the colon. Like the plasmic D-dimer, the elastase digests predominantly consisted of the DD/E complex and DD/E-containing high-molecular weight derivatives apparently corresponding to the phase-3 plasmic digests of cross-linked fibrin. (Blood. 2000;95:1721-1728)     

Fibrinolysis and fibrinogenolysis in patients with thrombotic disease.

In order to assess the fibrinolytic state in thrombotic disease, plasma levels of fibrin degradation products (FbDP) and fibrinogen degradation products (FgDP) were measured in 126 patients with a variety of thrombotic diseases. Mean plasma concentrations of both FbDP and FgDP were significantly elevated in patients with thrombotic disease as compared with healthy subjects. Plasma concentrations of FgDP were positively correlated with FbDP (r = 0.667, P less than 0.001). When analysed according to the disease categories, the magnitude of elevations of FbDP and FgDP was most prominent in venous thrombotic disease such as deep vein thrombosis and pulmonary embolism. These findings indicate that fibrinolysis is accelerated in patients with thrombotic disease and that fibrinolysis is frequently accompanied by some fibrinogenolysis in these patients.     

Plasmin generation and fibrin(ogen)olysis following desmopressin infusion.

Desmopressin acetate (DDAVP) is known to stimulate the release of tissue-type plasminogen activator (t-PA) from endothelial cells, but it is unclear whether the increased t-PA actually elicits the plasmin generation and fibrin(ogen)olysis in the circulating blood. We measured plasma levels of plasmin-alpha 2-plasmin inhibitor complex, fibrinogen degradation products (FgDP) and fibrin degradation products (FbDP) following desmopressin infusion in 19 patients with bleeding disorders or thrombophilia. Administration of desmopressin (0.3-0.4 microgram/kg) produced a 4.0-fold increase in plasmin-alpha 2-plasmin inhibitor complex at 30 min, whereas neither FgDP nor FbDP was elevated significantly. These findings indicate that desmopressin infusion provokes the generation of plasmin in vivo, but most of the plasmin generated is complexed to alpha 2-plasmin inhibitor and does not degradate fibrin or fibrinogen.     

Hemostatic imbalance in active and quiescent ulcerative colitis

OBJECTIVE: In healthy conditions, factors inducing or inhibiting coagulation and factors inducing or inhibiting fibrinolysis are in balance. In ulcerative colitis, hypercoagulation is presumed, which may explain part of the clinical features of this disease. Therapy strategies affecting hemostasis may improve the course of ulcerative colitis. This study was conducted to evaluate the balance of coagulation and fibrinolysis in the course of treatment of active ulcerative colitis. METHODS: Patients with active ulcerative colitis were studied by serial determination of markers of the coagulation cascade (thrombin-antithrombin complexes and fibrin degradation products [FbDP]) and the fibrinolytic cascade (fibrinogen degradation products [FgDP]). Parameters of inflammation were also measured (C-reactive protein [CRP], erythrocyte sedimentation rate [ESR], albumin, platelet count, and fibrinogen). Disease activity was assessed by endoscopic and histopathological scores. Follow-up measurement was performed in the course of treatment at the third or fourth month after baseline. Measurements were compared with healthy controls. RESULTS: Thirty-three patients and 22 healthy controls were included. During active ulcerative colitis, inflammatory parameters (CRP, ESR, platelet count) and hemostatic parameters (thrombin-antithrombin complexes, fibrinogen, FgDP, and FbDP) were elevated in comparison with healthy controls. Albumin was decreased and antithrombin-III remained unchanged. During treatment, disease activity decreased significantly endoscopically and histopathologically (p < 0.001). CRP, ESR, platelet count, and fibrinogen also decreased significantly. The hemostatic balance, expressed as the ratio between the plasmin-dependent generation of FgDP and coagulation-dependent generation of FbDP, increased from 0.69 to 1.12 during treatment, mainly because of a decrease of FbDP. In healthy controls, this ratio was CONCLUSIONS: The coagulation and fibrinolytic cascades were activated in active ulcerative colitis, with a hemostatic imbalance in favor of coagulation. This hypercoagulability persisted in 20% (7/33) of patients with ulcerative colitis in remission. The decrease of FbDP and the increase in the FgDP/FbDP ratio during reconvalescence of ulcerative colitis showed that the coagulation cascade was more activated than the fibrinolytic cascade in active disease.     

Blood tests for the diagnosis of venous and arterial thrombosis

There are many reports in the literature of blood test abnormalities occurring in patients with venous or arterial thrombosis. Most of these have not used acceptable criteria for establishing an association between thrombosis and blood tests and, therefore, their interpretation is questionable. Recently, sensitive and specific assays have been developed for the detection of products of intravascular thrombin formation, of plasmin digests of fibrin or fibrinogen and of platelet specific proteins that are released into the plasma when platelets react with stimuli. Blood abnormalities have been sought that can either predict or detect venous thrombosis. Many of the predictive tests evaluated are nonspecific acute phase reactant responses to inflammation; of these, only reduced fibrinolytic activity has been consistently reported to be associated with postoperative venous thrombosis. Hereditary antithrombin III deficiency has been consistently shown to predispose patients to venous thrombosis. Abnormalities of the plasminogen and fibrinogen molecule have also been described in patients with familial or recurrent venous thrombosis but these are rare and the association could be coincidental. Two blood tests, the fibrinopeptide A assay and the assay for fibrin/fibrinogen fragment E are highly sensitive to acute venous thromboembolism in symptomatic patients but both are nonspecific. Elevated levels of beta thromboglobulin and platelet factor 4 have been reported in patients with arterial thromboembolism but the sensitivity and specificity of these findings is presently unknown.     

Fibrin-dependent activation of plasminogen by a proteolytic digest of streptokinase

Among four enzymatic digests of streptokinase (SK), the smallest peptide with plasminogenolytic activity was in a tryptic digest; it had a molecular weight of 29,000. A complex of this peptide, SK29, and human plasminogen hydrolysed human fibrin, but a complex of native streptokinase and human plasminogen hydrolysed both human and bovine fibrin. The complex with SK29 caused amidolysis of the synthetic substrate S-2251 in the presence of human fibrin, but was inactive in the presence of human fibrinogen, bovine fibrinogen or bovine fibrin. Analysis of the amino terminal sequence of SK29 indicated that cleavage by trypsin was on the carboxyl side of lysine, the 59th amino acid of streptokinase. These results suggest that the conformational changes caused by human fibrin formation resulted in the generation of an active site of human plasminogen by SK29.     

The effect of alcohol ingestion on the exercise-induced changes in fibrin and fibrinogen degradation products in man.

The present study examined the influence of ingesting a moderate dose of alcohol on plasminogen activator activity (t-PA), plasma fibrinogen (Fb), total degradation products (TDP) and the degradation products of fibrin (FbDP) and fibrinogen (FgDP) at rest and in response to exercise. Eleven male subjects performed two separate experimental trials at an exercise intensity corresponding to 70% maximal oxygen consumption for 35 min. Prior to trials, subjects were either given 0.5 g/kg alcohol in orange-flavoured drink or an equal volume of non-caloric non-alcoholic drink 45 min before exercise. Comparison of the levels of t-PA, Fb, TDP, FbDP, and FgDP at rest, before and 45 min after the ingestion of alcohol revealed no significant differences between alcohol and control experiments. Exercise resulted in a marked increase in t-PA, TDP, and FgDP, with no appreciable change in FbDP. Although plasma fibrinogen level showed significant decrease post-exercise when subjects ingested alcohol, this difference was small and its biological significance is questionable. While t-PA level increased similarly in response to exercise during alcohol and control trials, a significantly higher response of TDP was found during the control trial compared with alcohol trial. It was concluded that exercise with and without alcohol ingestion is followed by a substantial increase in t-PA, which coincided with an increase in TDP. The increase in TDP was mainly due to an increase in FgDP, but not to FbDP. These findings support the hypothesis that a significant fibrinogenolysis occurs in response to exercise, and moderate intoxication with alcohol prior to exercise reduced this response.     

Anticoagulant function of a 24-Kd fragment isolated from human fibrinogen A alpha chains

A fibrinogen fragment obtained by limited-plasmin proteolysis has been isolated and purified to apparent homogeneity by gel filtrations. This fragment, denoted as 24-Kd fragment, has an apparent M(r) approximately 24,000 and contains an N-terminal sequence of met-glu-leu-glu-arg-pro- gly-gly-asn-glu-ile. The fragment contains a large number of acidic amino acid residues, and its amino acid composition is similar to several fibrinogen A alpha chains degradation fragments isolated previously. It corresponds to a peptide of the fibrinogen A alpha chains, the N-terminal of which starts at alpha Met-240. This peptide delays thrombin plasma clotting time. It does not bind calcium ions and does not inhibit thrombin's amidolytic activity. It binds to immobilized fibrin but not fibrinogen. It also inhibits the polymerization of desAA and desAABB fibrin monomers by simultaneously decreasing the maximum rate and the maximum level of the polymerization reaction. However, the initial lag period of this reaction is not affected by the fragment.     

Validity of enzyme-linked immunosorbent assays of cross-linked fibrin degradation products as a measure of clot lysis

Concentrations of cross-linked fibrin degradation products (XL-FDPs) in plasma, measured by enzyme-linked immunosorbent assays (ELISAs) based on monoclonal antibodies (MAbs) raised against fragment D-dimer of cross-linked fibrin, increase when patients are given fibrinolytic agents. Whether XL-FDPs derive from circulating cross-linked fibrin polymers in plasma, compared with clot-associated fibrin, has been questioned because increases in XL-FDP are measured by some assays after fibrinolysis in vitro in the absence of clot. We characterized the source of XL-FDP immunoreactivity in plasma of patients with acute myocardial infarction and ischemic heart disease and the response to plasminogen activation in vitro induced by pharmacological concentrations of tissue-type plasminogen activator (t-PA) and streptokinase. XL-FDPs were measured with two different ELISA. One, "pan-specific tag ELISA," was based on a capture MAb specific for XL-FDP and a tag MAb that recognizes an epitope exposed in the fragment D region of both fibrin and fibrinogen, whereas the other, "fibrin-specific tag ELISA," was based on a capture and tag MAbs both specific for fibrin. After plasminogen activation was induced in vitro in plasma from patients with myocardial infarction, increased concentrations of XL-FDP were measured by the pan-specific tag ELISA; however, concentrations measured with the fibrin-specific tag ELISA were not increased. To determine the mechanism for this discrepancy, plasma was subjected to immunoadsorption with a MAb specific for fragment D-dimer before and after in vitro activation of the fibrinolytic system and immunoblotting with a fragment D-dimer-specific MAb and with the pan-specific MAb. Increased concentrations of fragment D-dimer, as well as fibrinogen fragment D at high concentrations, were recognized by the specific MAb. Non-cross-linked fragments were also shown by immunoblotting with the pan-specific MAb to coprecipitate with cross-linked fibrin fragments. This suggested the increased concentrations of XL-FDP measured by the pan-specific tag ELISA after in vitro activation of the fibrinolytic system were due to detection of non-cross-linked fibrinogen fragments. However, fibrin fragment D-dimer concentrations were found to increase in plasma of 15 patients given t-PA for acute myocardial infarction. We conclude fragment D-dimer in plasma of patients during thrombolysis does not originate from circulating soluble cross-linked fibrin but rather is a marker of solid-phase fibrin dissolution, which may be quantitated with assays based on capture and tag antibodies that do not detect fibrinogen or its degradation products.     

The effect of peptides and monoclonal antibodies that bind to platelet glycoprotein IIb-IIIa complex on the development of clot tension

The development of tension in platelet-rich clots is a manifestation of fibrin polymer binding to platelets as well as platelet contractile activity. Arg-Gly-Asp(RGD)-containing peptides of fibrinogen alpha- chain and gamma-400-411 of fibrinogen gamma chain increased clot tension considerably, especially when it developed under isometric conditions. Morphometry revealed increased confluence of oriented fibrin and platelet aggregates. Monoclonal antibodies directed against different epitopes on the glycoprotein IIb-IIIa complex had varying effects on clot tension development. Monoclonal antibodies A2A9 and 7E3 inhibited clot tension while T10 and 10E5 increased it. Since neither peptides nor antibodies affected the platelet actomyosin ATPase activity, their effect on tension must reflect the interaction between platelets and polymerizing fibrin. We conclude that gamma-400-411 and RGD-peptides increase platelet-polymerizing fibrin interaction. This suggests that clot tension requires a platelet receptor for polymerizing fibrin, which is different from the fibrinogen receptor domain required for aggregation. The results with the monoclonal antibodies support this hypothesis.     

Some Effects of Splenectomy in Thalassaemia Major

S ummary . The fibrin digestion products which appear in serum of patients having treatment with ancrod have been compared with derivatives of human fibrinogen produced by plasmin by means of immunoelectrophoresis, immunodiffusion and gel filtration techniques. In ancrod-treated patients the large molecular weight derivatives X and Y, as well as fragments D and E were seen 4 hr after the start of therapy. By 24 hr the main serum component was fragment D with low concentrations of large molecular weight derivatives still present, but fragment E had been cleared from the circulation. The identity of these fragments to the known products of fibrinogen proteolysis by plasmin has been confirmed. It is suggested that the initial degradation of fibrin micro-clots produced in the circulation during ancrod infusion is mediated by the fibrinolytic enzyme system.     

Inhibition of Human Platelet Aggregation by Plasmin Digests of Human and Bovine Fibrinogen Preparations: Role of Contaminating Factor VIII-related Material

Preparations of human fibrinogen, digested by plasmin, inhibited ADP-inducedplatelet aggregation; the inhibitory activity was confined to the small dialyzablefragments accumulating during the degradation. Purified large molecular weightfragments D and E had no effect on ADP-induced aggregation, but fragment E inhibited thrombin-induced aggregation.Extensively degraded bovine fibrinogenpreparations also inhibited platelet aggregation by ADP. Both human and bovinefibrinogen preparations were contaminated with factor VIII-related material(factor VIII-related antigen and factorVIII procoagulant activity, respectively);separation of factor VIII-related materialfrom human or bovine fibrinogen by gelchromatography and subsequent plasmindigestion of the fractions revealed thatthe inhibitory activity was mainly linkedto digested factor VIII-related material.This inhibitory activity was dialyzable.The effect of fibrinogen digests on plateletaggregation should therefore be reconsidered.

Submitted on May 4, 1973 Revised on January 17, 1974 Accepted on January 23, 1974     

An Inhibitor of Fibrin Formation in Thromboplastins Prepared by Saline Extraction of Human Brain

Human brain is a common source of thromboplastin for the prothrombin time, where the end point is the conversion of fibrinogen to fibrin. Experiments showed that human brain also contains a proteolipid which inhibits the conversion of fibrinogen to fibrin. The proteolipid is removed when brain tissue is washed with acetone, but remains as a contaminant when brain is extracted with saline. For this reason prothrombin times on the same plasma are longer when saline extracts, rather than acetone dried preparations, are the source of thromboplastin. The proteolipid explains why the prothrombin time becomes shorter when saline extracts are diluted to standardize their activity against the British comparative thromboplastin.     

Validation, calibration, and specificity of quantitative D-dimer assays

Assays for D-dimer antigen are based on monoclonal antibodies reactive with epitopes found on fibrin fragment D-dimer but not on fibrinogen fragment D, other fibrinogen degradation products, or native fibrinogen. The antibodies react with conformational epitopes generated by factor XIII-induced linkage of the C-terminal appendages of the fibrin gamma-chains of adjacent D-domains within a fibrin polymer. For some monoclonal antibodies, degradation of the cross-linked fibrin compound by plasmin is an additional requirement for the generation of the epitope. In clinical plasma samples, D-dimer antigen assays detect an array of fibrin compounds of different molecular weights, including fibrin fragment D-dimer as well as higher-molecular-weight fibrin degradation products and fibrin X-oligomers. Most D-dimer antigen represents cross-linked soluble fibrin present in circulation rather than degradation products from particulate clots. Due to differences in epitope reactivity, harmonization of D-dimer antigen assays can only be achieved with standard preparations containing a similar variety of cross-linked fibrin compounds. Assay technologies include manual latex agglutination assays, automated latex-enhanced light-scattering immunoassays, enzyme-linked immunoassays, and others.     

Fibrinogen and its fragment D stimulate proliferation of human hemopoietic cells in vitro.

Purified fibrinogen at concentrations of 3-30 nM has been found to stimulate continuous growth of human lymphoid and myeloid cell lines under serum-free conditions. A strong proliferative response resulted from the synergism elicited by the addition of fibrinogen to transferrin-supplemented medium. This effect was observed with the pre-B-cell line Raji, the T lymphoma-derived JM, and the monocytic cell line U 937, either at high or low cell densities. With the promyelocytic cell line HL 60, fibrinogen did not shorten the doubling time of cultures seeded at high cell densities (2 x 10(5) cells per ml). However, at cell densities lower by 2 orders of magnitude and in the same medium, it promoted growth with a doubling time similar to that obtained at high cell concentrations. Fibrinogen also was found to increase the plating efficiency and colony size when human bone marrow cells were cultured in semisolid medium containing serum. In long-term bone marrow liquid cultures without fibrinogen, colony-forming cells were no longer detected after 6 weeks. In those cultured with fibrinogen, approximately equal to 50 granulocyte-macrophage colonies per 10(5) cells were obtained after 6 weeks, and 10, after 12 weeks. Purified fibrinogen fragment D possessed a stimulating activity similar to that of the intact fibrinogen molecule. This fragment cannot form fibrin, thus eliminating fibrin as a source of the mitogenic effect.     

SDS Polyacrylamide Gel Characterization of Serum FDP Produced in Response to Ancrod and Streptokinase/Plasminogen Infusions in Man

S ummary . The serum FDP produced in response to defibrination with ancrod and to thrombolytic therapy with intermittent streptokinase/plasminogen infusion have been characterized using a method of solid phase immuno-precipitation followed by polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulphate. Using this method it is possible to distinguish between the plasmin degradation products of fibrinogen and factor XIIIa induced crosslinked fibrin. During ancrod administration, fragments of similar mobility to fibrinogen fragments X, Y, D and E are present in serum samples taken 24 h after the initiation of treatment, while subsequent samples contain mainly fragments with the same mobility as fibrinogen fiagment D. The intermittent nature of the streptokinase/plasminogen infusions produces fibrinogen fragments X, Y, D and E in the serum 1 h after each daily streptokinase/plasminogen administration. An early clearance of fragment E from the circulation of patients receiving either ancrod or streptokinase/plasminogen infusions accords with the results of other investigations. The presence of the D dimer fragment, which is produced only by plasmin lysis of factor XIIIa crosslinked fibrin, could not be conclusively confirmed in either group of patients.     

Fibrin and fibrinogen degradation products with an intact D-domain C- terminal gamma chain inhibit an early step in accessory cell-dependent lymphocyte mitogenesis

Although the low molecular weight degradation products of fibrinogen (FgDP) and fibrin (FbDP) are known to inhibit lymphocyte blastogenesis, the effect of purified macro-molecular FgDP and FbDP (molecular weight, 90 to 200 Kd) is unclear. We have examined the effect of these latter FgDP and FbDP and find that products that contain the D domain inhibit lymphocyte proliferation in response to T-cell mitogens, allogeneic mononuclear leukocytes, and anti-CD3 in vitro. Plasmic digestion of D1 in the absence of calcium with removal of the C-terminal end of the gamma chain or disruption of the gamma-gamma C-terminal cross-link site of D-dimer (DD) by puffadder venom (PAV-D) abrogates their inhibitory potential. Prior incubation of monocytes with DD or D1 inhibits subsequent lymphocyte transformation. Binding studies with radiolabeled DD and PAV-D confirm that monocytes interact only with DD. This specific binding may be competitively inhibited by monoclonal antibodies to CD11b/CD18 or by peptide analogues of the C-terminal gamma chain of fibrinogen that mimic the adhesion recognition site of integrins. We postulate that DD and D1 bind to CD11b/CD18 on adherent monocytes and modulate lymphocyte activation. These products are typically present in the plasma of patients with disseminated intravascular coagulation with sepsis and could therefore influence inflammatory processes in vivo.