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Abnormal bleeding is sometimes observed in patients with immunoglobulin light chain (AL) amyloidosis. Although several theories have been proposed regarding the pathological causes of the bleeding tendency in AL amyloidosis, many lacked sufficient evidence and full consensus. We conducted a retrospective survey at a single institution to assess bleeding manifestations, methods for evaluating hematological abnormalities, and treatments for bleeding in patients with systemic AL amyloidosis over the past 13 years. The participants were 10 men and 14 women, aged 39-84 years (mean 65 years). The prevalence of bleeding was 29%. Prolonged prothrombin time (PT), elevated plasmin-α2-antiplasmin complex, and factor X deficiency were distinctive to the bleeding group. Two case studies showed that tranexamic acid was effective for treating this hematological condition. However, two patients with normal PT and activated partial thromboplastin time (APTT) also had a bleeding manifestation. The rates of administration of coagulation and fibrinolytic tests were relatively low in the non-bleeding group. Therefore, a close investigation concerning coagulation and fibrinolysis should be performed in every patient with AL amyloidosis regardless of the PT/APTT values. A more careful, comprehensive, and large-scale study is required to reinforce these findings.

Acquired coagulation factor inhibitors are rare. Among them, coagulation factor V (FV) inhibitor is particularly uncommon and presents with variable clinical manifestations. Certain acquired FV inhibitor patients have only mild bleeding or, in select cases, no symptoms at all, leading to spontaneous recovery. Others have life-threatening bleeding that requires medical attention. Thus, a prompt decision regarding diagnosis and clinical intervention is crucial for such patients. In five acquired FV inhibitor cases treated in our facility, each patient had a malignancy as an underlying disease and all unexpectedly showed prolongation of both prothrombin time (PT) and activated partial thromboplastin time (APTT). They all also displayed a discrepancy between PT and Normotest (Hepaplastintest, HPT) results. All but one patient experienced no bleeding at the time of diagnosis and achieved spontaneous recovery in 1-3 weeks. The patient with bleeding symptoms received plasma exchanges and a platelet transfusion. Useful markers in diagnosing the presence of an acquired FV inhibitor were a sudden prolongation of PT and APTT, and a discrepancy between the PT/APTT and HPT assays. Spontaneous recovery can be expected for patients with only minor bleeding.

We describe a case in which uncontrolled chronic disseminated intravascular coagulation (DIC) caused by an aortic aneurysm that was exacerbated by chemotherapy for lung cancer, showed dramatic improvement when warfarin, which was being administered for atrial fibrillation, was replaced by rivaroxaban, a direct oral anticoagulant (DOAC). The present case is interesting because a DOAC was effective in treating DIC due to an aortic aneurysm, whereas warfarin, another oral anticoagulant, was ineffective. In controlling DIC, it is important to inhibit activated coagulation factors such as thrombin and activated factor X, rather than the coagulation factors, which act as substrates.

Introduction: Careful monitoring of the hypercoagulable state is required during pregnancy. However, coagulation and fibrinolysis markers are not fully utilized because there are no reference values reflective of coagulation and fibrinolysis dynamics during pregnancy, which differ from the nonpregnant state., Methods: Changes in antithrombin (AT), fibrinogen (Fbg), prothrombin fragment 1+2 (F 1+2 ), thrombin-antithrombin complex (TAT), soluble fibrin (SF), D-dimer (DD), and protein S (PS) were investigated in healthy pregnant women, and reference ranges in the early, mid, late, and end stages of pregnancy were established., Results: The AT was essentially constant throughout pregnancy. The Fbg, F 1+2 , TAT, and DD increased significantly as pregnancy progressed. In contrast, SF did not show a significant increase throughout the entire pregnancy period. Total PS antigen and total PS activity showed a corresponding decrease from early gestation. When test data in 3 cases in which deep vein thrombosis or intrauterine fetal death occurred during pregnancy were compared to the established reference ranges, all of the cases had multiple markers with values that exceeded the reference ranges., Conclusion: Establishing reference ranges for each week could potentially make it possible to evaluate abnormalities of the coagulation and fibrinolysis systems during pregnancy. Of note, SF might be a useful marker that reflects thrombus formation during pregnancy. Larger-scale studies will be required to establish reference ranges for every gestational week.

An inherited antithrombin deficiency is an autosomal dominant thrombotic disorder. We identified two pedigrees of inherited type I antithrombin deficiency and two responsible mutations in each. A novel 21-22delAA appeared to have caused a frameshift with a premature termination at amino acid +63 in one patient and a large deletion including all seven exons was identified by multiplex ligation-dependent probe amplification in the other. Some asymptomatic relatives of the second patient had the same mutation. The present findings support the value of using more than one method of gene analysis and of studying the families of probands with inherited thrombotic disorders.

Previous studies have found markedly elevated serum concentrations of proinflammatory cytokines in patients with Graves' disease (GD). We investigated the role of macrophage colony-stimulating factor (M-CSF) in GD. We assayed concentrations of M-CSF in sera from 32 patients with GD (25 untreated; 7 receiving thiamazole therapy). We also studied 32 age-matched healthy subjects as controls. Relationships between serum M-CSF and both thyroid state and serum lipids were examined. Moreover, to examine the effect of thyroid hormone alone on serum M-CSF, T3 was administered orally to normal subjects. Serum concentrations of M-CSF in GD patients who were hyperthyroid were significantly increased compared with GD patients who were euthyroid (P < 0.05) and control subjects (P < 0.0001). Serum M-CSF concentrations correlated closely with T3 levels in patients (r = 0.51, P < 0.005). Serial measurement of five individual patients revealed that serum concentrations of M-CSF were significantly decreased (P < 0.05), reaching normal control values upon attainment of euthyroidism. Furthermore, oral T3 administered to 15 volunteers for 7 days produced significant increases in serum levels of M-CSF (P < 0.05). The close correlation between serum M-CSF and serum thyroid hormone levels suggests that high circulating levels of thyroid hormones may directly or indirectly potentiate the production of M-CSF in patients with GD.

Molecular makers such as thrombin-antithrombin complex (TAT), prothrombin fragment 1+2 (F1+2), soluble fibrin (SF), and D-dimer, are useful markers in the diagnosis and assessment of various thrombotic conditions. These markers are measured in plasma after blood sampling. Difficult blood sampling is known to falsely elevate plasma TAT levels. However, it is not known exactly why this occurs. In the present study, we examined how levels of molecular markers of haemostatic and fibrinolytic activation change under various sampling conditions using vacuum tube samples from healthy volunteers. When blood was sampled continuously by taking 10 consecutive vacuum tube samples following application of a tourniquet, blood sampling resulted in an accurate assessment of these molecular makers. When blood was sampled continuously by taking vacuum tube samples every one minute over a total of 9 minutes to investigate possible changes in the levels of the molecular markers over time, plasma levels of TAT, SF, and F1+2 gradually increased with time. Plasma levels of TAT, F1+2, and SF increased beyond the normal range over the course of nine minutes. When blood was sampled using three alternative methods, which varied in terms of the duration of needle puncture (sampling B), duration of tourniquet use (sampling C), or both (sampling A), plasma TAT and SF levels were significantly increased with all three methods, compared to control samples. Plasma F1+2 levels were significantly increased with sampling methods A and B, compared to control samples, but not with sampling method C. On the other hand, plasma D-dimer levels were not significantly altered by any of the sampling methods. In conclusion, the results suggest that molecular markers of haemostatic and fibrinolytic activation, except for D-dimer, may be affected by sampling method, particularly the duration of needle puncturing. Therefore, care needs to be taken when using TAT, F1+2, and SF levels to diagnose and estimate activation of the coagulation system.

Background: Annexin II is a receptor for tissue-type plasminogen activator (t-PA) that converts plasminogen to plasmin. Although the fibrinolytic system is known to play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs), the relationship between annexin II and AAA development is unknown. Therefore, we examined annexin II localization in the wall of human atherosclerotic AAAs., Methods and Results: Specimens from 13 patients undergoing elective repair of an AAA were taken. Annexin II expression was evaluated by immunohistochemical analysis. Immunostaining results were semiquantitatively analyzed using histology scores and WinROOF software based on staining intensity. The expression of annexin II was increased and the histology score was higher in the shoulder region of the atheromatous plaque than in the atheroma and fibrous plaque regions. Annexin II appeared to have greater expression and the histology score was higher in regions where the media was preserved. Furthermore, there was a significant inverse correlation between AAA size and histology score in the fibrous plaque region., Conclusions: The present work demonstrates various levels of annexin II expression within the aneurysm wall. Therefore, we suggest that alteration of annexin II expression within the aortic wall may be associated with the development of an aneurysm.

Chronic disseminated intravascular coagulation (DIC) is a well-known complication of aortic aneurysm. A 63-year-old man with bleeding tendency and a large palpable abdominal aortic aneurysm (AAA) was diagnosed as having fibrinolysis dominant DIC by the excessive activation of both coagulation and fibrinolysis (plasmin -alpha2 plasmin inhibitor complex concentration is usually >4 microg/ml). Although several treatments were tried, DIC could not be controlled until the patient was given combined therapy of danaparoid (1,250 U/12 h, bolus IV) and tranexamic acid (0.5 g x 3/day, oral administration). This therapy may be beneficial when control for bleeding is required without restricting the ambulatory movement of patients by continuous drip.

In a rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC), we used urokinase (UK) in an attempt to clarify the role of fibrinolysis and to investigate changes in plasma endothelin levels. Two kinds of experiment were performed. The first one: experimental DIC was induced by sustained infusion of 30 mg/kg LPS for 4 h via the tail vein, and two doses of UK (2.0 or 10.0 IU/g/4.5 h) were administered to rats 30 min before infusion of LPS, after which UK infusion was continued for a further 4 h. The second one: experimental DIC was induced by sustained infusion of 1 mg/kg/10 min LPS for 10 min, and two doses of UK (2.0 or 10.0 IU/g/4 h) were administered to rats at 30 min after LPS infusion. The parameters described below were determined at 4 h in the first experiment, at 4 h and 8 h in the second one. The similar results were observed in both kinds of experiment. There were no significant differences in plasma thrombin-antithrombin complex, fibrinogen or platelet number among the three DIC groups, in both kinds of experiment. Plasma levels of D-dimer were significantly increased in the LPS + higher dose of UK group when compared with the LPS group. The increased plasma plasminogen activator inhibitor (PAI) activity seen in the LPS group was significantly suppressed in the groups receiving UK (especially higher dose of UK). In addition, the increased plasma levels of creatinine and alanine aminotransferase seen in the LPS group were significantly suppressed in the groups receiving UK (especially higher dose of UK). Plasma levels of endothelin, known to be a potent vasoconstrictive agent, were markedly elevated by LPS infusion, and were significantly suppressed in the groups receiving UK of both kinds of experiment, in a dose-dependent fashion compared with LPS group. Glomerular fibrin deposition was significantly suppressed in the groups receiving UK when compared with the LPS group. No manifestations of bleeding were observed in any of the groups. Enhanced fibrinolysis and depressed endothelin induced by UK thus appear to play an important role in preventing the development of organ failure in the LPS-induced DIC model.