Fibrin degradation products, fibrin monomer and soluble fibrin in disseminated intravascular coagulation.

Disseminated intravascular coagulation (DIC) is characterized by activation of hemostasis and fibrinolysis resulting in the formation of thrombin and plasmin, and the characteristic effects of these enzymes on plasma fibrinogen can be useful in diagnosis. Thrombin cleaves fibrinopeptides from fibrinogen, forming fibrin monomer that rapidly polymerizes to form a clot. Small amounts can circulate in plasma as "soluble fibrin," which may have a complex composition and include fibrinogen and a variable amount of cross-linking. Plasmic degradation of cross-linked fibrin forms a heterogeneous group of degradation products reactive in assays for D-dimer, and their levels provide a measure of the amount of fibrin formation and lysis. Caution should be exercised in comparing quantitative results using different assays because of problems with standardization and variable reactivity with different molecular forms. Marked elevations of fibrin(ogen) degradation products are a constant finding in experimental animal models of DIC. In human models of DIC resulting from endotoxin infusion, D-dimer is elevated early and high levels persist, reflecting lysis of microvascular fibrin deposits. Elevated levels of D-dimer and soluble fibrin are very sensitive for the diagnosis of DIC, and a normal level has a high negative predictive value. Serial monitoring of soluble fibrin or D-dimer assays may be of value in evaluating the response to therapy and possibly in identifying at-risk patients.     

Elevated plasma levels of fibrin degradation products by granulocyte-derived elastase in patients with disseminated intravascular coagulation.

Plasma levels of granulocyte-derived elastase (GE-XDP), D-dimer, and soluble fibrin (SF) were examined in 177 patients with disseminated intravascular coagulation (DIC) of various etiologies. Plasma levels of GE-XDP and D-dimer, but not SF, were significantly high in patients with sepsis and solid cancer. The ratio of GE-XDP/ D-dimer was significantly high in patients with trauma, burn, and sepsis, suggesting that fibrinolysis due to GE-XDP may be dominant in DIC. Plasma levels of GE-XDP and D-dimer, but not SF, were significantly high in patients with overt DIC and correlated with DIC score. Plasma levels of GE-XDP, but not SF, correlated significantly with D-dimer. Plasma levels of D-dimer, but not SF, correlated significantly with plasmin plasmin inhibitor complex (PPIC). Plasma levels of GE-XDP and D-dimer, but not SF, were significantly high in nonsurvivors. Plasma levels of GE-XDP, but not SF, correlated significantly with sepsis-related organ failure assessment (SOFA) score. These results suggest that GE-XDP is a potentially useful marker for the diagnosis of overt-DIC and as a predictor of organ failure-related outcome.     

The specific activity of plasminogen activator inhibitor-1 in disseminated intravascular coagulation with acute promyelocytic leukemia.

In disseminated intravascular coagulation (DIC) with acute promyelocytic leukemia (APL) in the absence of severe infection, marked fibrinolysis was noted in comparison with normal levels of antithrombin III, which is a major inhibitor of the coagulation system. Increased plasminogen activator inhibitor-1 (PAI-1) antigen levels in plasma from patients with septicemia decreased the ratio of the plasma clot lysis rate induced by an anti-alpha 2-plasmin inhibitor monoclonal antibody to the tissue-type plasminogen activator (t-PA) concentration. This decrease was not as prominent in plasma from patients with DIC, especially those with APL. To explore the character of PAI-1 in these plasmas, we measured the specific activity of PAI-1 by determining the ratio of active PAI-1 antigen to t-PA-unbound PAI-1 antigen. To calculate the amount of active PAI-1 antigen, the amount of t-PA/PAI-1 complex before and after the addition of a fixed amount of t-PA to the sample was measured by a sandwich solid-phase enzyme-linked immunosorbent assay using anti-PAI-1 and anti-t-PA monoclonal antibodies. The assay to measure total PAI-1 antigen used three monoclonal anti-PAI-1 antibodies and had similar sensitivities to free active, latent, vitronectin-bound and t-PA-bound PAI-1. The specific activity of PAI-1 decreased in patients with DIC (43.7% +/- 30.6%) and in DIC cases with APL (10.3% +/- 6.0%) in comparison to patients with septicemia (83.7% +/- 20.2%) or normal controls (85.8% +/- 27.3%). In DIC associated with APL, degraded forms of PAI-1 were detected in plasma by immunoblotting. These results suggest that a decrease in the specific activity of PAI-1 and an increase in secondary fibrinolysis result in a hyperfibrinolytic state in DIC patients with APL.     

Acute myelogenous leukemia associated with disseminated intravascular coagulation and acute myocardial infarction at relapse]

A 71-year-old man with acute myelogenous leukemia (AML, M2) developed signs of chest oppression, and was diagnosed as having acute myocardial infarction (AMI). At the same time, his leukemia relapsed in association with disseminated intravascular coagulation (DIC). The patient's risk factors for AMI were hyperlipidemia, hyperglycemia, and a history of smoking. Coronary angiography showed occlusion of the circumflex branch. Percutaneous transluminal angioplasty (PTCA) was performed successfully, followed by administration of heparin. After chemotherapy, the patient's DIC improved and a second remission was attained. When elderly patients with AML show evidence of DIC, we should be aware of AMI as a possible complication. PTCA is a safe operation for such patients.     

Pathogenesis of disseminated intravascular coagulation in patients with acute promyelocytic leukemia,and its treatment using recombinant human soluble thrombomodulin

Acute promyelocytic leukemia (APL) is an uncommon subtype of acute myelogenous leukemia characterized by the proliferation of blasts with distinct morphology, a specific balanced reciprocal translocation t(15;17), and life-threatening hemorrhage caused mainly by enhanced fibrinolytic-type disseminated intravascular coagulation (DIC). The introduction of all-trans retinoic acid (ATRA) into anthracycline-based induction chemotherapy regimens has dramatically improved overall survival of individuals with APL, although hemorrhage-related death during the early phase of therapy remains a serious problem. Moreover, population-based studies have shown that the incidence of early death during induction chemotherapy is nearly 30 %, and the most common cause of death is associated with hemorrhage. Thus, development of a novel treatment strategy to alleviate abnormal coagulation in APL patients is urgently required. Recombinant human soluble thrombomodulin (rTM) comprises the active extracellular domain of TM, and has been used for treatment of DIC since 2008 in Japan. Use of rTM in combination with remission induction chemotherapy, including ATRA, produces potent resolution of DIC without exacerbation of bleeding tendency in individuals with APL. This review article discusses the pathogenesis and features of DIC caused by APL, as well as the possible anticoagulant and anti-leukemic action of rTM in APL patients.     

Increased plasma-soluble fibrin monomer levels in patients with disseminated intravascular coagulation

Plasma-soluble fibrin monomer (SFM) level in patients with disseminated intravascular coagulation (DIC) was significantly higher than the level in patients with pre-DIC or in non-DIC patients, and the level in patients with pre-DIC was significantly higher than that in non-DIC patients. There was no significant difference in plasma SFM levels among various diseases underlying DIC. Plasma SFM level in patients with good outcome was significantly decreased after treatment for DIC. The sensitivity of fibrin degradation products and platelet number was high for DIC, but not for pre-DIC. The sensitivity of thrombin-antithrombin III complex, plasmin-plasmin inhibitor complex, and SFM was high for both DIC and pre-DIC. The specificity of these markers was also high. Receiver operating characteristic analysis suggests that plasma SFM level could be the most useful marker for the diagnosis of both DIC and pre-DIC. © 1996 Wiley-Liss, Inc.     

Assessment of fibrin degradation products during fibrinolytic therapy for acute myocardial infarction

In a group of 39 patients who received fibrinolytic therapy for acute myocardial infarction, serum crosslinked fibrin degradation products (XLDP) were quantitated by an enzyme-linked immunosorbent assay (ELISA) using an antibody reactive with a site near the gamma gamma crosslink of fibrin, and characterized by a gel electrophoretic method to distinguish fibrinogen degradation products (FDP) from XLDP. After coronary artery reperfusion, 63 of 81 (69%) serum samples showed XLDP by gel analysis, whereas the incidence of positive samples before reperfusion, 53 of 144 (37%), was significantly less (p less than .0001). The first appearance of serum XLDP by gel analysis was most often in the 15 min interval immediately before or after angiographic documentation of reperfusion, and the elapsed treatment time required to produce a positive test was shorter with more intensive treatment regimens. However, the appearance of serum XLDP was not a specific indicator of reperfusion in individual patients, since one or more serum samples was positive in five of eight patients who did not show reperfusion as well as in 27 of 29 patients who did show reperfusion. Furthermore, the concentration of serum XLDP as measured by ELISA showed no significant difference in samples from patients who did or did not have reperfusion or between samples taken before or after reperfusion. There was a close temporal correlation between the first appearance of serum XLDP (gel analysis) and the initial decrease in plasma fibrinogen (systemic lytic state), and the degree of elevation of serum XLDP (ELISA) was also correlated with the intensity of the systemic lytic state. In addition, electrophoretic analysis of pretreatment plasma samples demonstrated crosslinked fibrin polymers that disappeared during fibrinolytic therapy coincident with the appearance of serum XLDP and in parallel with fibrinogen conversion to degradation products (fragments X, Y, and D). Two patients without a lytic state showed no change in plasma fibrin polymers during therapy, and XLDP were not present in serum despite coronary reperfusion in one patient. Thus the results indicate that XLDP appearing in the blood during fibrinolytic therapy for acute myocardial infarction are not predictive of successful fibrinolytic therapy, but rather may reflect degradation of circulating fibrin polymers associated with the fibrinogenolysis of the systemic lytic state.     

Serum crosslinked fibrin (XDP) and fibrinogen/fibrin degradation products (FDP) in disorders associated with activation of the coagulation or fibrinolytic systems

Soluble crosslinked fibrin derivatives (XDP) in serum were determined by enzyme immunoassay utilizing monoclonal antibodies and compared with serum fibrinogen/fibrin degradation products (FDP) assayed by conventional techniques. In healthy subjects and patients with miscellaneous disorders not usually associated with activation of the haemostasis mechanism, mean XDP levels were 45 and 70 ng/ml respectively. However, elevated levels of XDP occurred in conditions commonly associated with intravascular and possibly extravascular activation of the coagulation system. Markedly raised mean XDP values (677-6900 ng/ml) occurred in treated pulmonary embolism, disseminated neoplasia, severe inflammatory disorders and complicated postoperative states, and lesser but significant elevation (mean 150-400 ng/ml) in treated venous thrombosis, uneventful postsurgical states, localized neoplasia, liver disease and symptomatic arterial disease. Levels during initial streptokinase therapy (mean 24 000 ng/ml) fell tenfold as treatment was continued. The degree of XDP elevation over normal values was significantly higher than that of FDP in conditions with a propensity for venous thrombosis (post-operative states, disseminated neoplasia and inflammatory diseases) than in liver disease, localized neoplasia or patients receiving heparin therapy for venous thromboembolism.     

Pseudo-Chediak-Higashi anomaly in promyelocytic leukaemia associated with intravascular coagulation.

Giant granules were present in the cytoplasm of marrow granulocytes and in abnormal immature leucocytes circulating in the blood of a patient with promyelocytic leukaemia associated with intravascular coagulation. These granules resembled those seen in Chediak-Higashi syndrome.     

Coincidence of acquired factor-X deficiency and disseminated intravascular coagulation in patients with acute nonlymphoblastic leukemia

Summary Systematic clotting studies were performed in 157 patients with de novo acute nonlymphoblastic leukemia (ANLL) prior to treatment. Sixteen patients had disseminated intravascular coagulation (DIC). Three of the patients with DIC (two with M3, one with M5 leukemia) had a marked isolated factor-X deficiency (factor XC 21%, 33%, and 41%, respectively). Another four patients had a mild isolated factor-X deficiency (factor XC 55%–68%). In these seven patients the remaining liver-synthesized clotting factors (factors II, VII, IX, V) as well as serum albumin and cholinesterase were within the normal range. Liver disease or vitamin-K deficiency could therefore be excluded. In none of the 141 patients without DIC was a marked isolated factor X deficiency observed; two patients had moderately reduced factor XC levels but normal liver-synthesized proteins. Induction treatment led to the control of DIC with an almost parallel increase of fibrinogen and factor X up to normal in all patients with factor-X deficiency who achieved complete remission. In one patient, recurrence of leukemia was associated with reoccurrence of DIC and marked factor-X deficiency. We conclude that there is a coincidence of isolated factor-X deficiency and DIC in some patients with ANLL. In some patients, this factor-X deficiency may be severe enough to contribute to the bleeding tendency.     

止凝血分子标志物在急性白血病合并DIC中的意义

目的 探索血浆止凝血分子标志物检测在急性白血病（AL）合并弥散性血管内凝血（DIC）诊断和预后判断中的价值.方法 采用ELISA方法检测77例AL（37例合并DIC,40例AL未合并DIC）患者血浆血小板α颗粒膜糖蛋白-140（GMP-140）、抗凝血酶-Ⅲ（AT-Ⅲ）、D-二聚体（D-D）、凝血酶-抗凝血酶复合物（TAT）、凝血酶原片段F1＋2、纤溶酶-抗纤溶酶复合物（PAP）含量,并与38例正常人对照.结果 AL合并DIC早期F1＋2、D-D、TAT含量均显著高于正常对照组（P＜0.01）,GMP-140、PAP含量明显高于正常对照组（P＜0.05）,AT-Ⅲ活性显著降低,与正常对照组比较差异有显著性意义（P＜0.05）;在DIC中晚期F1＋2、D-D、TAT、GMP-140明显升高,AT-Ⅲ活性明显降低（P＜0.01）,经直线相关分析,D-D与F1＋2、GMP-140、TAT在DIC患者中有显著性相关（r=0.871,P＜0.01;r=0.697,P＜0.05;r=0.763,P＜0.05）.AL未合并DIC者GMP-140、D-D、PAP水平明显升高,AT-Ⅲ活性明显降低（P＜0.05）,AL合并DIC患者各期GMP-140、TAT、F1＋2、D-D、PAP水平明显升高,与AL未合并DIC比较有显著性差异（P＜0.05）.结论 止凝血分子标志物是能早期反映体内凝血、抗凝及纤溶系统激活的敏感性指标,在DIC早期诊断中有着重要实用价值.止凝血分子标志物检测有助于急性白血病病情观察,可作为疗效观察的辅助指标.     

Global fibrinolytic capacity in pediatric patients with sepsis and disseminated intravascular coagulation.

There are many complex pathophysiologic changes of the coagulation system in sepsis. The fibrinolytic system was evaluated in septic children using the global fibrinolytic capacity (GFC), a new technique reflecting the overall fibrinolytic activity. The study consisted of 24 children with sepsis, 36 children with sepsis plus disseminated intravascular coagulation (DIC), and 20 healthy age-matched control individuals. Compared with controls, 86% of sepsis patients and 87% of sepsis plus DIC patients had decreased GFC levels. Between the sepsis plus DIC and sepsis groups there was no significant difference in terms of GFC levels. While 19 patients (52.7%) died in the sepsis plus DIC group, only three patients (12.5%) died in the sepsis group. When survivors and nonsurvivors were compared in terms of coagulation tests, there were significant differences for protein C, antithrombin, platelet, fibrinogen, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and white blood cell values. In conclusion, the level of GFC reduced in most of the pediatric sepsis patients but no difference was observed between patients with sepsis and patients with sepsis plus DIC. While inhibition of fibrinolysis is an important finding in sepsis, the mortality is mainly associated with the presence of end-organ damage and the status of coagulation parameters.     

Characteristics of fibrinolytic disorders in acute promyelocytic leukemia

ABSTRACT

Objectives: Catastrophic hemorrhage remains the main cause of acute promyelocytic leukemia (APL) treatment failure. This study was aimed to study the pathogenesis of coagulopathy in patients with APL.

Methods: Multiple procoagulant and profibrinolytic parameters in plasma and peripheral leukocytes from 24 patients with newly diagnosed APL accompanied by coagulopathy before and after arsenic trioxide (ATO) treatment were evaluated.

Results: Prior to the treatment, the patients had elevated D-dimer and decreased fibrinogen levels. Plasma urokinase-type plasminogen activator receptor (uPAR) and plasmin–ɑ₂ antiplasmin complexes (PAP) levels, plasmin (Pn) activity, and cell surface levels of urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) were significantly higher; plasma plasminogen activator inhibitor-1 (PAI-1) levels and plasminogen (Pg) activity were significantly decreased; plasma plasminogen activator (PA) activity, uPA and tPA levels; and cell surface levels of uPAR and annexin II were not significantly different from levels in the control group. During ATO treatment, both patients’ plasma PA activity and uPAR on leukocytes gradually increased, annexin II on leukocytes increased initially and decreased afterwards, and tPA and uPA on leukocytes remained consistently higher in the patients than in the controls. Other parameters gradually tended toward normal values.

Conclusions: In APL, activated coagulation system activated fibrinolytic system, and increased uPAR levels could contribute to the hyperfibrinolysis. Annexin II might not be involved in the coagulopathy.     

Hemorrhagic necrosis of the intestinal mucosa associated with disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC), experimentally induced by endotoxin, caused severe hemorrhagic necrosis of the intestinal mucosa in dogs. Microscopic observation showed tortuous thrombus formation in the microcirculation of the villi. Ligation of the pancreatic and bile ducts, or administration of heparin protected the mucosa from hemorrhagic necrosis, while systemic administration of tranexamic acid increased the intestinal mucosal lesion. Local pretreatment of the intestinal mucosa by Trasylol or tranexamic acid reduced the degree of hemorrhagic necrosis. It is concluded that intravascular coagulation in the microcirculation of the intestinal mucosa, as well as pancreatic proteases, play a role in the pathogenesis of hemorrhagic necrosis in the intestine associated with DIC.     

Thrombomodulin in the management of acute cholangitis-induced disseminated intravascular coagulation

AIM: To evaluate the need for thrombomodulin(r TM) therapy for disseminated intravascular coagulation(DIC) in patients with acute cholangitis(AC)-induced DIC. METHODS: Sixty-six patients who were diagnosedwith AC-induced DIC and who were treated at our hospital were enrolled in this study. The diagnoses of AC and DIC were made based on the 2013 Tokyo Guidelines and the DIC diagnostic criteria as defined by the Japanese Association for Acute Medicine, respectively. Thirty consecutive patients who were treated with r TM between April 2010 and September 2013(r TM group) were compared to 36 patients who were treated without r TM(before the introduction of r TM therapy at our hospital) between January 2005 and January 2010(control group). The two groups were compared in terms of patient characteristics at the time of DIC diagnosis(including age, sex, primary disease, severity of cholangitis, DIC score, biliary drainage, and anti-DIC drugs), the DIC resolution rate, DIC score, the systemic inflammatory response syndrome(SIRS) score, hematological values, and outcomes. Using logistic regression analysis based on multivariate analyses, we also examined factors that contributed to persistent DIC. RESULTS: There were no differences between the r TM group and the control group in terms of the patients' backgrounds other than administration. DIC resolution rates on day 9 were higher in the r TM group than in the control group(83.3% vs 52.8%, P 0.01). The mean DIC scores on day 7 were lower in the r TM group than in the control group(2.1 ± 2.1 vs 3.5 ± 2.3, P = 0.02). The mean SIRS scores on day 3 were significantly lower in the r TM group than in the control group(1.1 ± 1.1 vs 1.8 ± 1.1, P = 0.03). Mortality on day 28 was 13.3% in the r TM group and 27.8% in the control group; these rates were not significantly different(P = 0.26). Multivariate analysis identified only the absence of biliary drainage as significantly associated with persistent DIC(P 0.01, OR = 12, 95%CI: 2.3-60). Although the difference did not reach statistical significance, primary diseases(malignancies)(P = 0.055, OR = 3.9, 95%CI: 0.97-16) and the non-use of r TM had a tendency to be associated with persistent DIC(P = 0.08, OR = 4.3, 95%CI: 0.84-22).CONCLUSION: The add-on effects of r TM are anticipated in the treatment of AC-induced DIC, although biliary drainage for AC remains crucial.     

Pancreatic cancer complicated by disseminated intravascular coagulation associated with production of tissue factor

Received: April 21, 2000 / Accepted: December 22, 2000