Hiroshi Jokaji

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.

Mechanism on Disorders of Coagulation and Fibrinolysis in Diabetes

Determination of various important parameters of coagulation and fibrinolysis, clinical characteristics, and levels of serum lipid were compared in 193 patients with NIDDM and 50 control subjects. Levels of fibrinogen, tissue factor pathway inhibitor (TFPI), thrombin-antithrombin complex, and plasminogen activator inhibitor 1 in plasma increased significantly in the diabetic patients. Levels of TFPI correlated significantly with levels of total cholesterol. In the patients with coronary heart disease or cerebral infarction, levels of lipoprotein(a) increased significantly. From these results, we have concluded that there is a thrombotic tendency or at least an imbalance between the hemostatic and thrombosis-protecting system in diabetic patients, especially in patients with angiopathy.

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

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.

Role of D Dimer in Patients with Elevated Fibrinogen Degradation Products in Serum: Further Study in Chronic Myelogenous Leukemia

We quantitatively assayed the levels of cross-linked fibrin degradation products (D dimer) in plasma at 73 points in time in 32 patients with elevated fibrin/fibrinogen degradation products (FDP) in serum. The assay of FDP was performed on serum samples prepared in test tubes containing 5 U/ml thrombin (final concentration) by a method based on latex agglutination using antifibrinogen antibodies, and the levels of D dimer in plasma were determined by a newly developed latex immunoassay using monoclonal antibodies which do not cross-react with fibrinogen. 5 patients with chronic myelogenous leukemia (CML) had highly elevated FDP levels with normal levels of D dimer. Plasma samples from such patients with CML were treated with various concentrations of thrombin (2-10 U/ml) and after the removal of fibrin clots the levels of FDP in supernatants were assayed by the FDP assay procedure described above. The levels of FDP were normalized when plasma were treated with 10 U/ml thrombin. In 2 patients with CML who had elevated levels of FDP in serum, it was impossible to remove fibrinogen completely by addition of 5 U/ml thrombin. However, FDP levels in the sera treated with 5 U/ml thrombin were almost normal in normal controls and patients with other diseases than CML. From these results it is concluded that residual fibrinogen reacted in the assay procedure as markedly increased FDP in supernatants and elevated FDP levels in serum reflected fibrinogen-related materials, which may not completely polymerize in the presence of lower concentrations of thrombin in some patients with CML. The assay of D dimer in plasma using monoclonal antibodies is recommended in cases of CML to rule out disseminated intravascular coagulation.

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.