Chika Uotani

Hypercoagulability and high lipoprotein(a) levels in patients with type II diabetes mellitus

Diabetes mellitus is associated with disturbances in hemostasis that could contribute to the development of diabetic vascular disease. We investigated the changes in parameters of blood coagulation and the fibrinolytic system and in plasma levels of lipoprotein(a)(Lp(a)) in 124 patients with type II diabetes mellitus and 44 healthy control subjects matched for age and body mass index (BMI) to determine whether hemostatic disturbances may lead to increased cardiovascular mortality. Median levels of fibrinogen (P < 0.0001), thrombin-antithrombin III complex (TAT) (P < 0.005), and plasminogen activator inhibitor-1 (PAI-1) activity (P < 0.05) in plasma were significantly elevated in diabetic patients compared with controls. The median concentration of Lp(a) was significantly higher in diabetic patients than in normal controls (18.2 vs. 12.6 mg/dl. P < 0.0005). Lp(a) levels tended to be elevated in patients with a prolonged history of diabetes. There was no evidence that Lp(a) levels were affected by metabolic control or by type of treatment. Twenty-two diabetics with coronary heart disease (CHD) had significantly higher levels of fibrinogen (P < 0.05), TAT (P < 0.05), and Lp(a) (24.7 vs. 13.7 mg/dl, P < 0.01) than the 51 patients without diabetic angiopathy. Our data indicate that impaired hemostatic balance in diabetes may cause hypercoagulability and may thus contribute to the increased cardiovascular mortality in diabetes.

Role of tissue factor in disseminated intravascular coagulation

We examined plasma antigen levels of tissue factor (TF) in 95 cases of disseminated intravascular coagulation (DIC), to investigate the role of TF in DIC. A significant elevation of plasma antigen levels of TF was observed in cases of DIC associated with cancer. However, no such significant elevation was observed in cases of DIC associated with acute promyelocytic leukemia (APL), acute leukemia except APL, blastic crisis of chronic myelogenous leukemia, non-Hodgkin lymphoma (NHL), sepsis or fulminant hepatitis. No significant elevation of TF was observed in patients without DIC, except 4 cases of cancer who developed DIC thereafter. Plasma antigen levels of TF were higher in both cases of DIC with renal failure and chronic renal failure without DIC than its levels in those without renal failure. Therefore, plasma antigen levels of TF in DIC patients with renal failure were considered to be carefully estimated. The levels of TF were decreased with the clinical improvement in some cases of DIC but were further increased or remained at high levels in patients who showed no improvement of DIC. Thus, plasma antigen levels of TF is an important marker to predict the development and/or prognosis of DIC, especially in patients with cancer.

Quantitative estimation of elastase-α1-proteinase inhibitor (E-α1PI) complex in leukemia: Marked elevation in cases of acute promyelocytic leukemia

Abstract The concentrations of elastase- α 1 -proteinase inhibitor (E- α 1 PI) complex were assayed in 43 patients with various types of leukemia. Marked to moderate elevation of E- α 1 PI complex levels was observed in patients with acute myelocytic leukemia (AML), acute promyelocytic leukemia (APL), acute myelomonocytic leukemia (AMMoL), or chronic myelocytic leukemia (CML) at diagnosis. The ratio of E- α 1 PI complex concentrations in plasma to leukocyte counts markedly elevated in the patients with APL, especially. During the course of remission induction therapy, levels of E- α 1 PI complex decreased in parallel with decline of leukocyte counts in the patients with leukemia other than APL, however the E- α 1 PI complex was persistently elevated regardless of leukopenia in some patients with APL. In APL, concentrations of fibrin/ fibrinogen degradation products (FDP) markedly increased even when levels of plasmin- α 2 -antiplasmin complex were within normal limits. However, levels of E- α 1 PI complex usually increased in these cases. From these results it is strongly suggested that promyelocytis contain markedly elevated amounts of elastase which participates in degradation of fibrin or fibrinogen in some cases of APL.

Changes in Plasma Levels of Prothrombin Fragment F1+2 in Cases of Disseminated Intravascular Coagulation

Plasma levels of prothrombin fragment F 1 + 2 (PTF) and thrombin-antithrombin III complex (TAT) were assayed in 86 cases of disseminated intravascular coagulation (DIC). A significant elevation of bot

Changes in levels of t-PA and α2PI-plasmin complex in plasma in patients with DIC

Levels of alpha 2PI-plasmin complex and tissue-type plasminogen activator (t-PA) in plasma were determined in 10 cases of acute promyelocytic leukemia (APL) with marked coagulopathy and in 10 cases of hematological malignancies with DIC to investigate relevance to fibrinolysis. In the both groups, levels of alpha 2PI-plasmin complex increased and were inversely proportional to levels of fibrinogen and alpha 2PI. Levels of t-PA in plasma increased moderately in the majority of the both groups. Serial observation of the concentrations of t-PA with corresponding changes in the levels of fibrinogen, alpha 2PI, alpha 2PI-plasmin complex and FDP could not demonstrate any significant relationship between levels of t-PA and the other parameters. From these results, it is unlikely that levels of t-PA in plasma directly influence on the degree of consumption of alpha 2PI or of formation of alpha 2PI-plasmin complex in most cases of DIC.

Plasminogen activator inhibitor in plasma and arteriosclerosis.

It has been believed that hyperlipidemia causes hypercoagulability and/or hypofibrinolysis, although the exact mechanism has not been known. Recently, the importance of plasminogen activator inhibitor-1 (PAI-l), lipoprotein(a) [Lp (a)], and/or factor VII related to hyperlipidemia has been discussed. The purpose of this study is to examine whether hypofibrinolysis and/or hypercoagulability are observed in Japanese subjects with hyperlipidemia with or without mild funduscopic findings, or outpatients with diabetes mellitus. Recently, various inhibitors of the fibrinolytic system have been discovered. These inhibitors may relate to impairment of fibrinolysis and thrombotic tendency. The first type of these inhibitors is the inhibitor of plasminogen activators that trigger the fibrinolytic system. At least three plasminogen activator inhibitors that inhibit tissue-type plasminogen activator and urokinase-type plasminogen activator are known. The most important among these is probably PAI-1 because it markedly increases reactively by various stimuli. The second type of inhibitor of fibrinolysis is cq-antiplasmin (a2AP), which inhibits proteolytic activity of plasmin and binding of plasminogen onto fibrin. Factor XI11 is a procoagulant; however, it may be called an inhibitor of fibrinolysis by its activity to bind a2AP onto fibrin. However, these inhibitors are not lipid or lipoprotein. Hence the mechanism of how hyperlipidemia causes fibrinolysis remained unsolved. The only exception is a recently discovered inhibitor of fibrinolysis, namely, Lp(a). Lp(a) is a kind of lipoprotein, and is regarded as an independent risk factor of arteriosclerosis. Lp(a) can also be regarded as a kind of inhibitor of fibrinolysis because its molecular structure is homologous to that of plasminogen. Therefore, it seems reasonable to consider that Lp(a) competitively inhibits adsorption of plasminogen onto fibrin and/or vascular endothelial surface and causes a thrombotic tendency. However, the role of Lp(a) in development of thrombosis is still a matter of speculation, because levels of Lp(a) in plasma are mainly decided by congenital factors and it has been shown that an increase in Lp(a) levels does not interfere with the effect of fibrinolytic drugs in cases of acute myocardial infarction.

Haemostatic and fibrinolytic parameters in septic patients with leukopenia or leukocytosis

Abstract: Induction of leukocytopenia by cytotoxic drugs protects against the generalized Shwartzman reaction induced by endotoxin. To elucidate the relationship between leukocyte number and in haemostatic and fibrinolytic disturbances in human sepsis, we studied 32 septic patients with abnormal leukocyte counts. Twenty patients had sepsis in the setting of leukopenia after chemotherapy for haematological malignancies. Twelve patients with leukocytosis developed sepsis associated with benign disorders. Concentrations of thrombin‐antithrombin III complex (TAT), plasminogen activator inhibitor‐1 (PAI‐1) and plasma thrombomodulin (TM) in the leukocytosis group of (12.0 ± 11.0, 40.2 ± 27.0 and 5.5 ± 2.3 ng/ml, respectively) were significantly elevated compared to the leukopenia group of (3.8 ± 2.3, 18.0 ± 15.0 and 3.1 ± 1.0 ng/ml, respectively) and controls (3.3 ± 0.4, 10.5 ± 5.3, 3.0 ± 0.5 ng/ml, respectively). On the other hand, there were no significant differences in these values between leukopenia group and controls. Thus leucocytes may play important roles in thrombin generation, PAI‐1 release and injury to endothelial cells.

Prothrombin fragment 1 + 2 measures treatment effect in patients with antiphospholipid syndrome

Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis. The anticoagulant management of APS thrombosis remains controversial. Few reports on markers of in vivo activation of coagulation have been reported. To determine whether plasma levels of prothrombin fragment 1 + 2 (F1 +2) correlate with thrombotic risk and treatment effect in patients with APS, plasma F1 + 2 levels were followed in 57 patients with this syndrome for more than 2 years. Clinical findings were also observed in these patients. Plasma levels of F1 + 2 in patients with APS were significantly higher when compared with control subjects (p<.05). These results suggest patients with APS are in a hypercoagulable state. Plasma levels of F1 + 2 significantly decreased following treatment with either aspirin, or aspirin plus warfarin (p<.05 and p<.01, respectively). Recurrent thromboses or spontaneous abortions occurred in all eight patients whose plasma levels of F1 + 2 remained higher than 1 nmol/l after treatment with either aspirin alone or no anticoagulants. These patients were subsequently treated with warfarin as well as aspirin, and plasma levels of F1 + 2 decreased to less than 1 nmol/l, with no additional thrombotic events over the remainder of the 2-year follow-up. No fatal bleeding was observed in treated patients. Our results suggest plasma levels of F1 + 2 are useful indicators of successful treatment. It is also suggested that warfarin plus mini-dose aspirin therapy is effective for patients with APS to protect from recurrent thromboses without harmful side effects. Further, prospective cohort studies are needed to substantiate these associations.

A survey about further work-up for cases with positive sputum cytology during lung cancer mass screening in Ishikawa Prefecture, Japan: a retrospective analysis about quality assurance of lung cancer screening

OBJECTIVE In cancer screening programs, performing appropriate further work-up is essential. In order to elucidate whether the further work-up for the subjects with positive screening results by sputum cytology was performed appropriately, the present study was conducted as the first large-scale thorough survey in Japan. METHODS All of the lung cancer screening records from 2007 to 2012 in Ishikawa Prefecture were reviewed. Additional investigations about the further work-up were performed. RESULTS In total, 2 234 984 people were invited to undergo lung cancer screening, and 494 424 people participated in the screening. Of these, 25 264 people underwent sputum cytology, and 68 positive cases were identified. Three of these 68 cases did not undergo further work-up, and another three cases had already been diagnosed to have lung cancer. Forty-five of the remaining 62 cases did not have suspicious chest shadows, and bronchoscopic examinations were performed in 36 cases. Seventeen of these 36 cases were diagnosed as having cancer, whereas none of the nine cases who did not receive the examination was diagnosed (P = 0.038). A bronchoscopic examination was not performed due to other medical conditions in three cases, due to the patients refusal in another three cases and in the remaining three cases, the reasons were unknown. CONCLUSION The participation rate for further work-up was very high. However, there are some issues to be resolved regarding the transmission of information. With our new registered hospital system, the quality assurance of our screening program will be improved.

Plasma Levels of Thrombomodulin and Active Plasminogen Activator Inhibitor Increase in Disseminated Intravascular Coagulation with Multiple Organ Failure

Disseminated intravascular coagulation (DIC) is a serious clinical condition, but its pathophysiology is very different according to the underlying diseases responsible for DIG, For example, a marked activation of the coagulation and fibrinolytic system is present in most cases of acute promyelocytic leukemia. On the contrary, a little activation of the fibrinolytic system is present in most cases of sepsis with DIC1–4. Therefore, it is important to investigate these pathologic condithions separately according to the underlying disease responsible for DIC.