Kazuya Kodama

Clinical study of Japanese spotted fever and its aggravating factors.

Abstract Twenty-eight patients with Japanese spotted fever were clinically investigated. The diagnosis was determined by confirming an increase of specific antibody. All patients were treated with minocycline, and all recovered, excluding one patient with a fulminant course. Fever and exanthema were observed in all patients, and an eschar was pointed out in 20 (71%) patients. The platelet count was 10 × 104/μl or lower in 8 (28%) patients. The fibrin degradation product (FDP)-level was abnormally high, 10 μg/ml or more, in 16 (57%) patients. The creatine kinase (CK) value was high in 14 of 22 patients, suggesting the presence of myositis. The leukocyte count, FDP, C-reactive protein, and soluble interleukin 2 receptor (sIL2-R) levels were significantly higher in severe cases. In the group without concomitant steroid therapy, mean times of 54.7 h and 101.4 h were required to reduce the temperature to 38°C and 37°C or lower, respectively, after the initiation of tetracycline treatment. There were 6 severe cases: 1 with disseminated intravascular coagulation, 2 with multiorgan failure, 1 with acute respiratory distress syndrome, and 2 with meningoencephalitis. These severe cases formed a group that required 6 or more days to initiate therapy after the onset (P < 0.005 vs non-severe group), showing that delay in diagnosis and therapy is the major cause of aggravation. In the 2 patients complicated by multiorgan failure, the sIL2-R level, produced by activated lymphocytes, was 10 000 U/ml or higher, suggesting that an sIL2-R level of more than 10 000 U/ml can be used as a marker of poor prognosis. It may be better that moderate to severe cases are treated with minocycline plus short-term steroid therapy.

Prophylactic antithrombin III administration during pregnancy immediately reduces the thrombin hyperactivity of congenital antithrombin III deficiency by forming thrombin-antithrombin III complexes

We examined the changes of haemostatic molecular markers after antithrombin III (AT III) administration in a 22-year-old woman with congenital AT III deficiency in the third trimester of pregnancy who did not have thrombosis. Various markers including fibrinopeptide A (FPA), thrombin-antithrombin III complex (TAT), prothrombin fragment F1 + 2 (F1 + 2), plasmin-alpha 2antiplasmin, D-dimer, beta-thromboglobulin, and platelet factor 4 were measured before and just after 3,000 U of AT III concentrate, which was given three times per week from the 34 week of pregnancy until delivery. Just after AT III administration, F1 + 2 and FPA levels decreased on most occasions, while TAT sometimes increased. Plasma FPA levels were markedly decreased on all 8 occasions when the plasma FPA levels was above 2.0 ng/ml before AT III administration. Plasma FPA levels were always greater than or equal to 6.4 ng/ml before AT III administration on the 4 occasions when TAT increased to above 115%. The changes of plasma F1 + 2 levels were significantly correlated with the AT III level. These results suggest that prophylactic AT III administration in the third trimester immediately inactivates intravascular thrombin to form TAT and reduce the plasma FPA level. Thus, the transient TAT elevation following AT III administration may not only be due to extraction of thrombin from the fibrin clots of thrombi but also to intravascular thrombin which is not attached to thrombi. FPA is the best molecular marker for thrombin hyperactivity and it should be monitored in AT III-deficient pregnant women in the third trimester.

Preferential consumption of heparin cofactor II in disseminated intravascular coagulation associated with acute promyelocytic leukemia

We measured plasma heparin cofactor II (HC II) activity in patients with disseminated intravascular coagulation (DIC) due to various underlying diseases together with the levels of antithrombin III (AT III), pseudocholinesterase (a marker of hepatic synthesis), and various haemostatic molecular markers. Both HC II and AT III were decreased in DIC secondary to all the underlying diseases studied, except acute promyelocytic leukemia (APL), when compared with healthy subjects. The lowest HC II and AT III levels was observed in coagulopathy secondary to liver disease, the HC II level in sepsis was the second lowest. In DIC due to APL, the decrease in HC II was not accompanied by a decrease in AT III. Thus, we divided all 124 samples tested into APL and non-APL groups. The HC II level correlated positively with fibrinogen and plasminogen in both the APL and non-APL groups. In the APL group, the HC II level had a significant negative correlation with the thrombin-AT III complex (TAT), fibrinogen/fibrin degradation products, and D-dimer levels as well as the prothrombin time, while AT III showed no correlations with any of the haemostatic parameters. These results suggest that HC II may be consumed preferentially by thrombin in APL patients with DIC, and thus may spare the consumption of AT III. Accordingly, HC II seems to be a superior indicator of DIC than AT III in APL patients. Moreover, replacement therapy with HC II instead of AT III may be useful to treat DIC associated with APL. In the non-APL group, the HC II levels were positively correlated with the levels of AT III and pseudocholinesterase activity. This indicates that plasma HC II levels are closely related not only to consumption coagulopathy but also to hepatic synthetic activity, as is the case for plasma AT III.

Imbalance between Thrombin and Plasmin Activity in Disseminated Intravascular Coagulation

We investigated the imbalance between thrombin and plasmin activity in vivo with various grades of severity of disseminated intravascular coagulation (DIC) in relation to the underlying diseases. Plasma thrombin-antithrombin-III complex (TAT) and plasmin-alpha 2-antiplasmin complex (PAP) levels were measured in 133 blood samples obtained from patients with DIC. The TAT/PAP ratio was higher in patients with sepsis or solid cancer than in those with hematologic malignancies. In acute promyelocytic leukemia (APL), the TAT levels were the highest, but the PAP levels were even higher and the TAT/PAP ratio was the lowest. As for the severity of DIC, in mild DIC, both thrombin and plasmin activities were increased. In moderate DIC, the TAT/PAP ratio increased, and thrombin activity was much more predominant. However, in severe DIC, the ratio decreased, and plasmin activity became excessive. In 3 patients with acute myeloblastic leukemia, APL and pancreatic cancer, respectively, the PAP level remained high during heparin therapy although the TAT level was decreased. When tranexamic acid was given, the PAP level was selectively reduced, and the TAT/PAP ratio was markedly decreased along with clinical improvement. These results indicate that monitoring of the TAT/PAP ratio may contribute to decisions regarding the institution and performance of combination therapy for DIC using anticoagulants and antifibrinolytic agents.

Effect of Rickettsial Antigen-Specific T Cell Line on the Interaction of Rickettsia tsutsugamushi with Macrophages

The effect of rickettsial antigen‐specific T cell line on macrophages infected with Rickettsia tsutsugamushi was studied. It was suggested that the T cells could produce a factor which acts cytotoxically and selectively on infected macrophages.

Hemodialysis in acute renal failure induced by mamushi viper venom.

マムシ咬傷により横紋筋融解症から, 急性腎不全を来し, 血液透析にて救命し得た症例を経験したので報告する. 患老は71歳の女性で, 昭和63年8月13日自宅にてマムシに左足蹠を噛まれ, 本院救急外来を受診し局所処置を受け帰宅した. その後左下肢の腫脹, 黒褐色尿を見るようになり, 次第に呼吸困難, 無尿を呈し8月16日内科入院となる. 意識は傾眠状態で, 左鼠径部以下の下肢の著明な腫脹, 左足蹠に血性水疱を伴う咬傷が認められた. 入院時検査では. BUN・Crの上昇と共に, GOT, GPT, LDH, CPK, ミオグロビンなどの筋由来と考えられる酵素群の上昇がみられ, マムシ咬傷による横紋筋融解症による急性腎不全と考えられた. 第1病日より血液透析を開始し, 計13回施行, 第18病日より尿量の増加と共に, 臨床症状の軽快を見た. 同時にミオグロビンや骨格筋由来の酵素値は急速に減少し, マムシ毒による横紋筋融解症は一過性のものと思われた. また経過中一過性の血液凝固異常がみられ, 蛇毒によるものと考えられた. 以上のことより, マムシ咬傷による横紋筋融解症から生じた急性腎不全は, 発症早期からの血液透析にて急性腎不全の状態を乗り切れば予後は良好であり, また一過性の血液凝固異常に対し, 体外循環時の抗凝固剤の使用には注意が必要なことが伺われた.