Cross-linked Fibrin Degradation Products Research Articles

Fibrin degradation product (FnDP) assays: analysis of standardization issues and target antigens in plasma

The in vivo formation of fibrin and its subsequent secondary fibrinolytic digestion yields a variety of crosslinked fibrin degradation products (XL/FnDP). One of these is known as D-dimer and a variety of ELISA-type commercial kits using monoclonal antibodies to D-dimer have been developed. We have investigated the possibility of establishing a standard such that these various kits might indicate the same levels of D-dimer in the same samples. We have concluded that because it seems that each individual monoclonal antibody to D-dimer targets a unique and distinct epitope in the FnDP fraction the notion of introducing a standard D-dimer which will respond uniformly to each D-dimer monoclonal antibody is not feasible. Using various monoclonal and polyclonal antibodies in conjunction with gel exclusion chromatography we have examined human plasma derived from patients with disseminated intravascular coagulation (DIC) which contained high levels of fibrin degradation products (FnDP). The data suggested that the FnDP fraction in plasma contained mostly high molecular weight (> 2 x 10(6) daltons) crosslinked fragments which contain high levels of fibrinopeptide A. Many of these crosslinked fragments crossreact with antibodies to D-dimer because they each contain D-dimer as a structural component. On the basis of this data, a novel sequence of events is proposed which may occur during the aggregation of fibrin in vivo.

Fibrinogen/fibrin degradation products and D-dimer in clinical practice: interpretation of discrepant results.

In clinical practice, occasionally some patients show dissociated values of fibrinogen/fibrin degradation products (FDP) and D-dimer (cross-linked fibrin degradation products). In an attempt to assess the frequency, clinical backgrounds, and hemostatic states of these cases, FDP and D-dimer were simultaneously measured together with other hemostatic parameters in 371 samples from patients with various diseases. As a whole, FDP were elevated in parallel with the progress of activation of blood coagulation and fibrinolysis. However, in patients with elevated FDP and/or D-dimer, 11.5% of samples showed relatively lower D-dimer values than those expected from FDP levels, and these were regarded as an apparently dissociated group. In the dissociated group, activation of coagulation and fibrinolysis occurred to a lesser extent than others. Analysis of these samples suggested that the possible reasons for the dissociation between FDP and D-dimer values were accelerated fibrinogenolysis with or without secondary fibrinolysis, accelerated fibrinogenolysis by non-plasmic proteinases, elevated soluble fibrin, and possibly false-positive FDP levels due to unclottable fibrinogen remaining in the serum samples. In practice, simultaneous measurements of FDP and D-dimer are useful for more accurate estimation of hyperfibrinolytic states.

Relationship between elevation in the plasma concentration of elastase-alpha 1 proteinase inhibitor complex (E-alpha 1 PI) and haemostatic parameters during haemodialysis.

To investigate the relationship between changes in plasma concentrations of polymorphonuclear elastase (PMN-E) and haemostatic effects during haemodialysis (HD), changes in the plasma concentrations of elastase-alpha 1 proteinase inhibitor complex (E-alpha 1 PI) and fibrinogen (Fbg), cross-linked fibrin degradation products (XDP), thrombin-antithrombin III complex (TAT), plasmin-alpha 2 plasmin inhibitor complex (PIC) and soluble thrombomodulin (TM) in 49 patients with end-stage chronic glomerulonephritis maintained on chronic HD were measured. Plasma concentrations of TAT, PIC, TM and E-alpha 1 PI significantly increased during a single HD. There was a statistically significant correlation between change in plasma E-alpha 1 PI concentration and changes in plasma concentrations of TAT, PIC and TM during a single HD, as well as between changes in plasma concentrations of TM and TAT during a single HD. These observations suggested that activation of coagulation and fibrinolysis, endothelial cell damage, and activation of polymorphonuclear cells occur during HD. Activation of polymorphonuclear cells may induce activation of coagulation and fibrinolysis, leading to endothelial cell damage, augmented by release of proteases such as elastase.

Coagulopathy following bites by the Papuan taipan (Oxyuranus scutellatus canni).

The mechanisms of haemostatic failure were studied in 87 patients bitten by the Papuan taipan (Oxyuranus scutellatus canni). Eighty (92%) had evidence of a coagulopathy on laboratory testing; 36 (41.4%) developed spontaneous systemic bleeding, although this was rarely of clinical significance. Coagulation assays in 48 completely defibrinated patients showed marked reductions in factors V and VIII and reductions in factors II, IX, XI, XII and XIIIA. There was a reduction in plasminogen and alpha 2-antiplasmin levels and both total and cross-linked fibrin(ogen) degradation products (FDP) levels were elevated. The mean platelet count was initially decreased and fell further during admission. Similar but less severe changes were seen in patients who were mildly defibrinated. Following treatment with antivenom, fibrinogen levels rose rapidly and coagulability was restored within 6-12 h in 93% of patients. These abnormalities may be primarily attributable to the prothrombin activator present in taipan venom, but it is likely that other uncharacterized venom components contributed.

Relationship between alcohol intake and tissue plasminogen activator antigen and other haemostatic factors in the general population

Summary Objectives — To determine the relationships between self-reported alcohol intake and levels of haemostatic and fibrinolytic factors in the general population. Design — Cross-sectional survey. Setting — Random selection from the age-sex registers of ten general practices across Edinburgh. Subjects — 1537 men and women aged 55–74 years. Main outcome measures — Plasma fibrinogen, factor VII activity, tissue plasminogen activator antigen, von Willebrand factor antigen and cross-linked fibrin degradation products (D-dimer antigen). Results — Univariate analyses showed that weekly alochol intake was correlated with increasing levels of tissue plasminogen activator antigen among men (r=0.14, p≤0.001) and women (r=0.06, p=0.08) and with decreasing levels of plasma fibrinogen (r=−0.06, p≤0.05 in men and r=−0.18, p≤0.001 in women). After adjustment for age, current smoking, body mass index, HDL cholesterol, triglycerides and systolic blood pressure, alcohol intake was independently related to tissue plasminogen activator antigen (p≤0.01) in both sexes. Strong correlations were found between serum gamma-glutamyltransferase, a marker of long term alcohol intake, and tissue plasminogen activator antigen (p≤0.001). Conclusion — Self-reported alcohol consumption is related to increased tissue plasminogen activator antigen in the general population. This may be important in relation to a protective effect of moderate alcohol intake on ischaemic heart disease.

Lipoprotein (a) and fibrinolytic system in liver cirrhosis

Several observations have suggested that lipoprotein (a) (Lp(a)) is a risk factor for coronary artery disease because of potential interference with fibrinolysis secondary to its activation of plasminogen. However, there are few data on the possible role of Lp(a) in liver cirrhosis. The present study was carried out, to better elucidate its relationship to the fibrinolytic system in liver cirrhosis. We studied the plasma levels of Lp(a) and the fibrinolytic parameters of 95 patients with liver cirrhosis (57 men, 38 women, aged 26-81). Patients in Child-Pugh class C (n = 32) had significantly lower levels of Lp(a) than those in class B (n = 45), and the class B had lower Lp(a) values than class A (n = 18) (1.4 (0.0-3.7) vs 2.9 (0.0-6.1) vs 3.4 (1.8-5.5); the data are log-transformed). Alpha-2-antiplasmin and plasminogen, had patterns similar to those of Lp(a), tissue plasminogen activator (t-PA) was significantly increased only in class C (class A: 7.5 +/- 5.8 ng/ml; class B: 10.8 +/- 7.7 ng/ml; class C: 19.1 +/- 11.3 ng/ml). Patients with systemic hyperfibrinolysis (cross-linked fibrin degradation products, XDP > 200 ng/ml) also had lower levels of Lp(a) than those without 1.6 (0.0-4.4) vs (0.0-6.1); p = 0.0002. There was a significant correlation between Lp(a) and plasminogen (r = 0.43; p = 0.001). Lipoprotein (a) progressively decreases as liver cirrhosis worsens but it appears unlikely to be involved in causing the hyperfibrinolytic state often observed in advanced liver cirrhosis, in which there are marked abnormalities of several other fibrinolytic parameters, also including increased t-PA and decreased inhibitors.

Variability of plasma IL-6 and crosslinked fibrin dimers over time in community dwelling elderly subjects.

Because obtaining multiple blood samples from individuals involved in epidemiologic studies is difficult, conclusions must be drawn on the basis of one or two samples. In this study, the authors attempted to determine the variability of two plasma markers over time, namely IL-6 levels and crosslinked fibrin degradation products (D-Dimers), in 16 elderly community-dwelling individuals. The study group included both men and women and black and white subjects (four in each group). Eight blood samples were obtained from each subject over a period of 36 days. Blood was separated within 1 hour after collection and aliquots of plasma were stored at -70 degrees C until all samples were collected. All samples from an individual were analyzed at one time. IL-6 and D-Dimers were measured by commercially available ELISA kits. The variability in the levels of plasma IL-6 and D-Dimers was assessed by means of intra-class correlation coefficient (ICC). The estimates of the ICCs for one measurement of IL-6 and D-Dimers were .87 and .86, respectively. Reliability values of this magnitude indicate excellent reproducibility in the measurement. These values indicate that obtaining a single sample from a subject is fairly representative of that individual's IL-6 and D-Dimer levels over an extended period of time.

Suppression of thrombolysis in a canine model of pulmonary embolism.

The brisk fibrinolytic response of canines has impaired efforts to develop a canine model of chronic thromboembolic pulmonary hypertension. Difficulties in retaining chronic embolic residuals were partially overcome by administration of tranexamic acid (TXA) (Circulation. 1991;83:1272-1279.). In this study, we used type 1 plasminogen activator inhibitor (PAI-1), a major inhibitor of the endogenous fibrinolytic system, to determine its efficacy in the suppression of thrombolysis in canines. Thrombus was induced in the inferior vena cava of anesthetized mongrel dogs with thrombin and a special double-balloon catheter; 2 hours later, the thrombus was embolized. In one group of dogs, activated type 1 plasminogen activator inhibitor (PAI-1) (130 micrograms) was delivered directly into the forming thrombus; in another, TXA (110 mg/kg) was given intravenously before thrombus formation; in controls, thrombus was induced without inhibitors. Cross-linked fibrin degradation product (D-dimer) appeared in the blood of control animals within 1 hour of thrombus induction (176 +/- 62.5 versus 1.02 +/- 0.39 ng/mL baseline; mean +/- SEM), was maximal by 4 hours (413 +/- 110 ng/mL) and remained elevated at 24 hours (90.8 +/- 19.5 ng/mL). Compared with controls, PAI-1 and TXA suppressed D-dimer release by 80% and 85%, respectively, over the first 24 hours. One week later, animals were killed, and residual emboli were harvested. Perfusion scan defects persisted in all animals at this time, but there were no scan defect differences among groups. However, emboli recovered from animals receiving PAI-1 still harbored immunoreactive PAI-1 and were, on average, more than twofold greater in mass (393 +/- 56 mg) than emboli recovered from either controls (183 +/- 76 mg) or animals receiving TXA (180 +/- 80 mg). Intravenous TXA and intrathrombus PAI-1 effectively suppress thrombolysis for 24 hours in canines. Thromboemboli enriched with PAI-1 appear to resist lysis for longer periods of time (up to 1 week). These findings are consistent with the hypothesis that PAI-1 remains associated with the embolus, where it continues to inhibit lysis, whereas TXA eventually diffuses out of the embolus, allowing lysis to ensue.

Perioperative changes in coagulative and fibrinolytic function during surgical treatment of abdominal aortic aneurysm and arteriosclerosis obliterans

To determine the factors which influence perioperative coagulative and fibrinolytic function, we studied 41 patients who underwent surgical repair of unruptured abdominal aortic aneurysm (AAA) and 30 patients who underwent arterial reconstruction for arteriosclerosis obliterans (ASO). In patients with AAA, the levels of fibrin/fibrinogen degradation products (FDP) (11.4 ± 20.1 μg/ml), thrombin-antithrombin III complex (TAT) (22.0 ± 21.8 μg/l), plasmin- α 2 plasmin inhibitor complex (PIC) (2.6 ± 2.9 μg/ml) and d-dimer of cross-linked fibrin degradation products (D-D) (8.4 ± 10.8 μg/ml) were elevated, particularly when the AAAs had a large mural thrombus surface area or were accompanied by aneurysm of the iliac or femoral artery. In arterial aneurysms, blood coagulability and secondary fibrinolytic activity were believed to be enhanced. In patients with ASO, the level of TAT (17.2 ± 24.8 μg/l) was so elevated that they were considered to show chronic hypercoagulability. Among the ASO patients with aorto-iliac lesions, those with concomitant graft occlusion or anastomotic aneurysm had significantly elevated levels of TAT. Proximal arterial occlusion or accompanying aneurysm in the ASO patients was associated with increased levels of PIC and D-D. Postoperative fluctuations in conventional hematological variables did not differ significantly among the surgical procedures. Conventional markers showed a transient decrease due to consumption during surgery, and a subsequent recovery or an actual increase within several days after surgery. Changes in the molecular markers of the coagulative and fibrinolytic systems were affected by the extent of the surgical procedure. These changes revealed that the enhanced coagulative state and the depressed fibrinolytic state increased within 3 days after surgery, and the secondary fibrinolytic state rose subsequently.

Plasma concentration of cross-linked fibrin degradation product (D-dimer) and the risk of future myocardial infarction among apparently healthy men.

Plasma levels of D-dimer, the primary degradation product of cross-linked fibrin, are elevated in several acute thrombotic disorders. However, whether elevated D-dimer levels among healthy individuals are associated with future coronary thrombosis is unknown. To evaluate whether levels of D-dimer are associated with the occurrence of future myocardial infarction (MI) among apparently healthy men, levels were measured in plasma samples collected at baseline from 296 participants in the Physicians' Health Study who later developed a first MI and from an equal number of age- and smoking status-matched control subjects who remained free of vascular disease during a mean follow-up period of 60.2 months. In univariate analyses, baseline plasma concentrations of D-dimer in the upper ranges of normal were associated with elevated risks of MI. Specifically, the relative risk of future MI for individuals with baseline D-dimer concentration exceeding the 95th percentile of the control distribution was two times higher than that of individuals with lower levels (relative risk [RR], 2.02; 95% confidence interval [CI], 1.04 to 4.02; P = .04). This association persisted in multivariate analyses controlling for nonlipid cardiovascular risk factors (RR, 2.12; 95% CI, 1.05 to 4.28; P = .04) and for lipoprotein(a) (RR, 2.02; 95% CI, 1.04 to 3.94; P = .03). In contrast, this association was attenuated and no longer statistically significant in analyses that controlled for total and high-density lipoprotein cholesterol (RR, 1.74; 95% CI, 0.78 to 3.91; P = .2) or for endogenous tissue-type plasminogen activator and its primary inhibitor, plasminogen activator inhibitor type 1 (RR, 1.58; 95% CI, 0.67 to 3.77; P = .3). Elevated levels of D-dimer are associated with increased risks of future MI, although they do not appear to be an independent predictor when other risk factors are considered. As the presence of D-dimer in plasma reflects ongoing fibrin degradation, these data support the hypothesis that activation of the endogenous fibrinolytic system occurs many years in advance of coronary arterial occlusion.

Percutaneous Angioplasty, Endothelial Markers, and Fibrin Turnover

Purpose: A number of thrombotic mediators have been related to peripheral arterial disease in both epidemiological and pathological studies. Methods: We measured preoperative levels of fibrinogen, cross-linked fibrin degradation products (FDP), and the endothelial markers, von Willebrand factor (vWF), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAD, in the venous blood of 43 claudicants undergoing percutaneous transluminal angioplasty (PTA). Samples were repeated 4 months later, and changes in the levels of thrombotic mediators were compared with ten controls undergoing angiography alone. Additional perilesional arterial samples were obtained from 11 of the patients. Results: Arterial sampling indicated that successful PTA led to an immediate fall in tPA levels and a rise in arterial vWF (p < 0.05), together with a trend toward a significant rise in cross-linked FDP levels. Only the increase in FDP following successful PTA (36 cases) (p < 0.05) was observed in 4-month postangioplasty venous samples, whereas all variables remained unchanged in cases of restenosis (4 patients) and in controls (all comparisons made by Wilcoxon matched pairs test). Conclusions: These findings suggest that successful PTA in patients with intermittent claudication results in acute endothelial disturbance and increased fibrin turnover at the site of angioplasty and in sustained increases in fibrin turnover (as reflected by FDP levels). The observation that this increase in fibrin turnover is absent in cases of restenosis within 4 months of PTA merits further study to determine whether increases in fibrin turnover are necessary to maintain patency following PTA.

Percutaneous angioplasty, endothelial markers, and fibrin turnover.

A number of thrombotic mediators have been related to peripheral arterial disease in both epidemiological and pathological studies. We measured preoperative levels of fibrinogen, cross-linked fibrin degradation products (FDP), and the endothelial markers, von Willebrand factor (vWF), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI), in the venous blood of 43 claudicants undergoing percutaneous transluminal angioplasty (PTA). Samples were repeated 4 months later, and changes in the levels of thrombotic mediators were compared with ten controls undergoing angiography alone. Additional perilesional arterial samples were obtained from 11 of the patients. Arterial sampling indicated that successful PTA led to an immediate fall in tPA levels and a rise in arterial vWF (p < 0.05), together with a trend toward a significant rise in cross-linked FDP levels. Only the increase in FDP following successful PTA (36 cases) (p < 0.05) was observed in 4-month postangioplasty venous samples, whereas all variables remained unchanged in cases of restenosis (4 patients) and in controls (all comparisons made by Wilcoxon matched pairs test). These findings suggest that successful PTA in patients with intermittent claudication results in acute endothelial disturbance and increased fibrin turnover at the site of angioplasty and in sustained increases in fibrin turnover (as reflected by FDP levels). The observation that this increase in fibrin turnover is absent in cases of restenosis within 4 months of PTA merits further study to determine whether increases in fibrin turnover are necessary to maintain patency following PTA.

Relationship between plasma essential fatty acids and smoking, serum lipids, blood pressure and haemostatic and rheological factors

We aimed to determine whether levels of plasma fatty acids are correlated with other potential risk factors for cardiovascular disease, using a sample of patients from a cross-sectional survey of the general population, in the City of Edinburgh. 306 men and women aged 55–74 years of whom half had clinical evidence of arterial disease were tested. The main outcome measures were plasma fatty acids and potential risk factors for cardiovascular disease (age, sex, smoking, blood pressure, serum cholesterol, HDL cholesterol (HDL-C), triglycerides (TGs), lipid peroxides (LPx), plasma fibrinogen, von-Willebrand factor (vWf), β-thromboglobulin (βTG), cross-linked fibrin degradation products (FIBDP) and plasminogen activator inhibitor PAI). High levels of several known risk factors for cardiovascular diseases were associated with low levels of certain essential fatty acids. Eicosapentaenoic (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) were negatively associated with smoking and TG levels. High levels of certain haemostatic factors, including plasma fibrinogen, blood viscosity and LPx were also associated with low levels of EPA, DHA, AA and HDL-C. In conclusion, plasma fatty acids show strong correlations with many potential risk factors for cardiovascular disease, emphasising their possible importance in pathogenesis.

Rapid improvement of coagulopathy by all-trans retinoic acid in acute promyelocytic leukemia.

Treatment of acute promyelocytic leukemia (APL) patients with all-trans retinoic acid (ATRA) was associated with rapid improvement in hemostatic markers. We made serial analyses of various hemostatic parameters in seven newly diagnosed APL patients. In all patients at diagnosis, plasma fibrinogen/fibrin degradation product (fragment-E), cross-linked fibrin degradation product (D-dimer fragment), thrombin-antithrombin III complex and plasmin-alpha 2-plasmin inhibitor complex were elevated, indicating the presence of disseminated intravascular coagulation (DIC). Antithrombin III (ATIII) levels were normal in all patients except for the patient with congenital ATIII deficiency. In four patients subsequently treated with ATRA without anticoagulant therapy, these hemostatic markers returned to near-normal levels by day 7 of treatment, indicating that DIC was essentially resolved. By contrast, in three patients who received conventional chemotherapy with a continuous low-dose heparin, improvement of coagulopathy was slower than in patients treated with ATRA. These results suggest that ATRA therapy exerts the rapid improvement in abnormal hemostatic markers in APL patients without any anticoagulant therapies, by inducing differentiation of leukemic cells and, in turns no massive release of procoagulant or fibrinolytic substances from these cells.

Thrombosis and intrinsic fibrinolysis in percutaneous transluminal angioplasty

Coagulation and fibrinolysis were investigated in 14 claudicants undergoing percutaneous transluminal angioplasty (PTA) for femoropopliteal artery lesions. Cross-linked fibrin degradation products (XL-FDP), tissue plasminogen activator (t-PA) antigen, fibrinopeptide A (FPA), and plasminogen activator inhibitor-1 (PAI-1) activity were measured in peripheral blood. XL-FDP and t-PA increased, and FPA and PAI-1 decreased significantly after angioplasty. XL-FDP increased from baseline 266 +/- 72 ng/ml to 481 +/- 239 ng/ml (p < 0.0005) 30 min after PTA, indicating mural thrombus formation in spite of the significant fall in FPA influenced by heparin. A groin haematoma developed after PTA in 4/6 patients, who received more than 5600 IU heparin and in 1/8 patients receiving smaller dosages. The alterations in PAI-1 showed no correlation with those of t-PA, whereas heparin had a sparing effect on PAI-1 consumption. These findings may indicate that PAI-1 acts as a thrombin inhibitor following deep vessel wall injury by angioplasty. In two patients, who had signs of rethrombosis on the next day, residual FPA was relatively high, XL-FDP peaked at 3530 +/- 1170 ng/ml, and t-PA increased by 2.6 +/- 1.0 ng/ml. The corresponding values in patients with an uncomplicated course were 406 +/- 89 ng/ml (p < 0.0001) and 0.1 +/- 0.5 ng/ml (p < 0.02). We conclude that thrombin promotes activation of coagulation and fibrinolysis in femoropopliteal PTA. Instability between these counteracting systems resulting in thrombosis is not prevented by conventional heparin administration at dosages causing bleeding complications.

Importance of thrombosis and thrombolysis in silent ischaemia: comparison of patients with acute myocardial infarction and unstable angina.

To investigate whether plaque rupture and thrombosis have a role in silent ischaemia as well as in unstable angina. Prospective analysis of the results of haemostatic diagnostic tests at the moment of developing silent ischaemia at rest. Coronary care unit. 22 patients with acute myocardial infarction, 12 patients with symptomatic angina (unstable angina), and 10 normal volunteers (control group). Continuous cardiac monitoring detected 15 asymptomatic episodes (silent ischaemia) in 6 patients with unstable angina. Blood samples were obtained at admission and when an asymptomatic alteration was detected and 10 minutes later. Comparisons of concentrations of tissue plasminogen activator, urokinase type plasminogen activator, tissue plasminogen activator inhibitor-1, cross-linked fibrin degradation products, von Willebrand factor, and thrombin-antithrombin III complexes in patients and controls at admission; same comparisons in patients with silent ischaemia at the start of an episode and 10 minutes later. Tissue plasminogen activator concentrations were raised at admission in patients with acute myocardial infarction (mean (SD) 14.2 (6) ng/ml) and in patients with unstable angina (10.1 (2.5) ng/ml) in comparison with controls (5.1 (2.7) ng/ml, p < 0.01 and < 0.05 respectively). There was no differences between the two groups of patients, however. Similar results were observed at the start of a silent ischaemic episode (9.8 (1.9) ng/ml) and 10 minutes later (10.5 (2.9) ng/ml) compared with controls (p < 0.05). Tissue plasminogen activator inhibitor-1 concentrations were raised in patients with acute myocardial infarction (45.1 (15) ng/ml) compared with volunteers (20.6 (16) ng/ml, p < 0.01). In patients with silent ischaemia tissue plasminogen activator inhibitor-1 concentrations were slightly but not significantly increased. Concentrations of cross-linked fibrin degradation products (D dimer) increased during unstable angina (2150 (350) ng/ml) and silent ischaemia (2270 (450) ng/ml) compared with the concentrations in volunteers (340 (80) ng/ml) and patients with acute myocardial infarction (310 (120) ng/ml; p < 0.01). The results suggest that thrombosis mediates the pathophysiological mechanisms of silent ischaemia and unstable angina.

D-dieter during intra-arterial low-dose streptokinase treatment of peripheral arterial occlusive disease

In order to assess systemic and local intra-arterial levels of D-dieter, a specific degradation product of cross-linked fibrin, blood samples were obtained before and 0.5, 1.5, 4, 8, 24, and 48 hours after the start of intra-arterial low dose streptokinase treatment (3750 IU/h) in 21 patients with angiographically documented peripheral arterial occlusive disease. Blood was sampled simultaneously from the cubital vein and from the arterial catheter located close to the occlusive thrombus. Pre-treatment D-dieter levels in arterial and venous blood were 298 and 259 ng/mL (medians), respectively. During the first day of treatment D-dieter levels in arterial blood increased on average 10–20 fold and were at all times significantly higher than D-dieter levels in venous blood (artery vs vein; 0.5 h: 414 vs 266; 1.5 h: 2640 vs 411; 4 h: 2490 vs 898; 8 h: 2640 vs 906; 24 h: 6290 vs 1060 ng/mL, medians). In 13 patients in whom recanalization was achieved D-dieter levels were higher than in 8 unsuccessfully treated patients (vein: p < 0.05; artery: not significant). Significant decreases in plasminogen, α 2-antiplasmin, fibrinogen and euglobulin clot lysis time indicated fibrinolytic activation in local arterial as well as in systemic venous blood. It was concluded that higher D-dieter in the vicinity of the thrombus compared to systemic levels reflected local lysis of fibrin. Systemic levels of D-dieter might provide early information on the efficacy of the treatment.

The specificity and sensitivity of latex and ELISA methods for fibrin degradation products in the diagnosis of myocardial infarction

Several commercial antibodies for cross-linked fibrin degradation products (plasma XDP) were assessed for their sensitivity and specificity in the diagnosis of myocardial infarction (MI) in a pilot study of 20 patients with MI, 20 patients with unstable angina (UA), patients with stable angina (SA) and 20 age matched controls. The SimpliRED whole blood assay was the most sensitive (70%) in comparison to the latex and ELISA tests evaluated (p < 0.001). DIMERTEST II was the most sensitive (50%) and specific (95%) of the latex tests. DIMERTEST I was the most sensitive (35%) and specific (98%) of the ELISA tests. The sensitivity, specificity appears to depend on the technology and/or the specificity of the antibodies for cross-linked fibrin.

Cross-linked fibrin degradation products (XL-FDP) as marker of early rethrombosis in percutaneous transluminal angioplasty

The thrombotic response to percutaneous transluminal angioplasty (PTA) was investigated in 31 patients treated for 1-10 cm femoropopliteal (n = 28) and tibial (n = 3) artery obstructions by measurement of cross-linked fibrin degradation products (XL-FDP) in peripheral blood samples drawn before and 30 min after PTA. XL-FDP increased from 400 +/- 147 ng/ml to 700 +/- 445 ng/ml (median +/- S.E., p = 0.0005). XL-FDP rose from 320 +/- 110 ng/ml to 540 +/- 102 ng/ml in 23 patients, whose ankle/brachial systolic blood pressure index (ABI) increased > 0.15 after PTA, whereas XL-FDP increased from 850 +/- 450 ng/ml to 2620 +/- 1472 ng/ml in eight patients, who failed to increase ABI in spite of preceding recanalisation. XL-FDP increased by more than 1000 ng/ml in 1/23 (4.3%) patients with uncomplicated PTA and in 6/8 (75%) patients with haemodynamic failure (p = 0.0005). Using a XL-FDP increase of 1000 ng/ml as cut-off, estimates of positive and negative predictive values (95% confidence limits) for early failure of PTA were 85.7% (42.1-99.6%) and 91.7% (73.0-99.0%), respectively. We conclude from this pilot study that femorotibial PTA produces a hypercoagulable state which may result in failure of early patency due to rethrombosis. We suggest for the first time XL-FDP as a marker of early rethrombosis in PTA, and report a sequential XL-FDP assay which may be useful for identification of high-risk patients requiring thrombolytic therapy after PTA for maintenance of early vascular patency.

Plasma D-dimer measurement as a marker of gynecologic tumors: comparison with Ca 125.

Fibrin is formed and degraded intra-abdominally in ovarian cancer, and the cross-linked fibrin degradation product, D-dimer (D-D), has been found in increased concentrations in the plasma of these patients. D-dimer and Ca 125 levels were determined simultaneously in 110 patients with gynecologic neoplasms. D-dimer and Ca 125 assays were performed using the Dimertest Stripwell EIA Kit (Ortho) and CA 125-II EIA assay (Roche), respectively. D-dimer plasma and Ca 125 serum levels were significantly higher in patients with ovarian cancer (mean +/- SE = 894.2 +/- 173.7 ng/ml and 760.5 +/- 292.7 U/ml, respectively) than in those with uterine cancer (mean DD +/- SE = 109.7 +/- 23.5 ng/ml and mean Ca 125 +/- SE = 50.0 +/- 23.1 U/ml) or those with benign disease (mean D-D +/- SE = 70.5 +/- 5.5 ng/ml and mean Ca 125 +/- SE = 6.6 +/- 2.8 U/ml). The levels of both markers increased with regard to ovarian cancer disease status. Mean D-D +/- SE was 90.0 +/- 22.8 ng/ml and mean Ca 125 +/- SE was 2.1 +/- 1.2 U/ml in patients with complete remission; mean D-D +/- SE was 143.3 +/- 33.5 ng/ml and mean Ca 125 +/- SE was 26.2 +/- 13.6 U/ml in patients with partial remission. In active disease, both markers had very high levels: D-D mean +/- SE = 1021.6 +/- 173.0 ng/ml and Ca 125 mean +/- SE = 1154.7 +/- 458.1 U/ml. In all groups of ovarian cancer patients, D-dimer sensitivity was better than that of Ca 125. In advanced ovarian cancer patients, the D-dimer concentration in ascites was up to 100 fold that in plasma. Our results suggest that D-dimer can serve as a sensitive indicator to monitor the extent and course of the disease in ovarian cancer patients. The patient follow-up is ongoing to establish the predictive value of D-dimer measurement with respect to prognosis.