Thromboembolic phenomena have been described in patients with thalassaemia intermedia and major, although there are relatively few epidemiological data on the overall frequency of these complications. To obtain more insight into the risk and mechanism of venous thromboembolism in thalassaemia, the aims of this study were: (i) to establish retrospectively the prevalence of thromboembolic events in a large group of adults with thalassaemia intermedia and major during a follow up period of 10 years; (ii) to measure in subgroups of these patients sensitive markers of activation of coagulation and fibrinolysis enzymes; and (iii) to look for possible procoagulant mechanisms. A high prevalence of thromboembolic events was found, particularly in splenectomized patients with thalassaemia intermedia (29%). These patients had high plasma levels of markers of coagulation and fibrinolysis activation. Furthermore, thalassaemic red cells and erythroid precursors from splenectomized patients with thalassaemia intermedia had an enhanced capacity to generate thrombin. To evaluate the role of splenectomy per se on procoagulant activity, we evaluated the capacity to form thrombin in healthy individuals who had been splenectomized for trauma. They produced the same amount of thrombin as non‐splenectomized controls. In conclusion, the results of this study show the existence of a hypercoagulable state in splenectomized patients with thalassaemia intermedia and that their red and erythroid cells are capable of acting as activated platelets in thrombin generation.

Thromboembolic phenomena have been described in patients with thalassaemia intermedia and major, although there are relatively few epidemiological data on the overall frequency of these complications. To obtain more insight into the risk and mechanism of venous thromboembolism in thalassaemia, the aims of this study were: (i) to establish retrospectively the prevalence of thromboembolic events in a large group of adults with thalassaemia intermedia and major during a follow up period of 10 years; (ii) to measure in subgroups of these patients sensitive markers of activation of coagulation and fibrinolysis enzymes; and (iii) to look for possible procoagulant mechanisms. A high prevalence of thromboembolic events was found, particularly in splenectomized patients with thalassaemia intermedia (29%). These patients had high plasma levels of markers of coagulation and fibrinolysis activation. Furthermore, thalassaemic red cells and erythroid precursors from splenectomized patients with thalassaemia intermedia had an enhanced capacity to generate thrombin. To evaluate the role of splenectomy per se on procoagulant activity, we evaluated the capacity to form thrombin in healthy individuals who had been splenectomized for trauma. They produced the same amount of thrombin as non-splenectomized controls. In conclusion, the results of this study show the existence of a hypercoagulable state in splenectomized patients with thalassaemia intermedia and that their red and erythroid cells are capable of acting as activated platelets in thrombin generation.

With advancing age, an increasing number of healthy individuals have laboratory signs of heightened coagulation enzyme activity. Such biochemical hypercoagulability might be the basis of either the increased thrombotic tendency occurring with age or a harmless manifestation of this process. To see whether these alterations are also present in the very elderly who had aged successfully, 25 healthy centenarians were studied and results of coagulation and fibrinolysis measurements were compared with those obtained in two control groups of healthy adults, 25 ranging in age from 18 to 50 years and 25 from 51 to 69 years. Older controls had, in general, slightly higher values of several coagulation and fibrinolysis measurements than younger controls. Centenarians had striking signs of heightened coagulation enzyme activity, as assessed directly by measuring activated factor VII in plasma (P < .01, compared with either control group) or indirectly by measuring the plasma levels of the activation peptides of prothrombin, factor IX, factor X, and thrombin-antithrombin complexes (all P < .001). Heightened coagulation enzyme activity was accompanied by signs of enhanced formation of fibrin (high fibrinopeptide A, P < .001) and secondary hyperfibrinolysis (high D-dimer and plasmin-antiplasmin complex, P < .001). Plasma concentrations of fibrinogen and factor VIII were higher than in controls, whereas other coagulation factors were not elevated. In conclusion, this study shows the very elderly do not escape the state of hypercoagulability associated with aging, but that this phenomenon is compatible with health and longevity. Hence, high plasma levels of the coagulation activation markers in older populations do not necessarily mirror a high risk of arterial or venous thrombosis.

Activation of the contact and complement systems in C1-inhibitor deficiencies is thought to contribute to the pathogenesis of angioedema attacks by releasing kinins. Trigger stimuli of attacks may also activate coagulation. This is particularly important because experimental data suggest that thrombin, the main enzyme of the coagulation cascade, increases vascular permeability and can thus influence edema formation. We have studied 19 patients with hereditary angioedema (HAE) during remission, 5 HAE patients during acute attacks, and 6 patients with acquired angioedema (AAE) during remission and during seven attacks. Thirty normal subjects, matched for sex and age, served as controls. Generation of thrombin was measured by enzyme-linked immunosorbent assay (ELISA) as plasma levels of the prothrombin fragment 1 + 2 (F1 + 2); the initiators of the tissue factor and contact coagulation pathways were investigated by measuring plasma levels of activated factor VII (FVIIa) coagulometrically and activated factor XII (FXIIa) by ELISA. Cleavage of high molecular weight kininogen (HK) was evaluated by immunoblotting analysis. F1 + 2 was slightly increased during remission and further significantly increased during attacks in both HAE (P = .0115) and AAE. FVIIa and FXIIa, normal during remission, increased strikingly during attacks in both HAE (P = .0022 and P = .0044) and AAE. During remission, cleaved HK was normal in HAE and high in AAE; during attacks it increased in HAE (P = .0008) and remained elevated in AAE. Our data indicate that in C1-inhibitor deficient patients there is increased generation of thrombin during attacks, with signs of activation of both the contact and tissue factor coagulation pathways. In conclusion, C1-inhibitor deficiency, whether hereditary or acquired, has demonstrable activation of the coagulation and kinin-forming cascades during attacks and that thrombin should be considered a possible contributing factor in the pathogenesis of edema in HAE and AAE.

Patients with active Cushing's syndrome have an increased thrombotic tendency. We chose to reassess the mechanism underlying the thrombophilic state associated with this clinical condition using sensitive markers of coagulation and fibrinolysis activation in 17 patients with active disease. The results were compared with those obtained in 12 Cushing's patients successfully treated by surgery and in 20 normal individuals. The general pattern of results in patients with active disease was the finding of increased levels of von Willebrand factor (VWF: Ag), a marker of enhanced metabolic function of endothelial cells (VWF:Ag 181 +/- 42 vs 110 +/- 43, p<0.001 in normal subjects), accompanied by signs of heightened thrombin and plasmin generation, expressed by high levels of thrombin-antithrombin (TAT 5.59+/-3.6 vs 3.06+/-0.92 ng/ml in controls, p<0.01) and plasmin-antiplasmin complexes (PAP 407+/-176 vs 245+/-67 ng/ml in controls, p<0.01). VWF:Ag and TAT values were significantly higher in hypertensive than in normotensive patients with active disease (205+/-40 vs 155+/-26 U/dl, p<0.05 and 7.49+/-3.7 vs 3.45+/-1.8, p<0.01, respectively). Plasma levels of plasminogen activator inhibitor type 1 were higher, though not to a statistically significant extent, in patients with active disease compared to controls (12.8+/-12.3 vs 5.6+/-7.4 IU/ml, NS) and positively correlated with body mass index (r=0.66, p<0.01). After surgical control of Cushing's syndrome, there was a partial or complete reversal of the abnormalities to values similar to those found in normal individuals. Our data suggest that the thrombophilic state present in patients with active Cushing's syndrome is related to an enhanced metabolic function of endothelial cells; this in turn may be caused by an heightened production of thrombin with secondary hyperfibrinolysis. Primary prophylaxis with anticoagulants is recommended in these patients when they are exposed to a thrombophilic condition such as surgery.

The causes of thrombosis and pregnancy loss in antiphospholipid syndrome (APS) are still unknown, although several hypotheses have been proposed and hypofibrinolysis has been implicated. Anti-tissue-type plasminogen activator (tPA) antibodies may induce fibrinolytic defects and preliminary data indicate an association with thrombosis in APS. We measured plasma anti-tPA antibody levels in 91 consecutive patients with APS, 91 healthy controls, 40 patients with antiphospholipid antibodies without APS symptoms, and 23 patients with systemic lupus erythematosus (SLE) without antiphospholipid antibodies and APS symptoms. Patients with APS had anti-tPA antibody levels higher than controls (P ‫؍‬ .0001), patients with SLE (P ‫؍‬ .0001), and asymptomatic antiphospholipid patients (P ‫؍‬ .05). A subgroup of 53 patients had plasma levels of tPA antigen higher (P ‫؍‬ .0001) and tPA activity lower (P ‫؍‬ .05) than controls, with an inverse correlation (r ‫؍‬ ؊0.454; P ‫؍‬ .003) between anti-tPA antibody levels and tPA activity and no correlation with tPA antigen. The 2 patients with the highest antibody levels had tPA activity below the normal range. Their antibodies were, respectively, IgG1 and IgG3; both recognized human tPA, recombinant tPA, and the catalytic domain of tPA, but not ␤ 2 -glycoprotein I, prothrombin, or plasminogen. Our data indicate that anti-tPA antibodies specifically interacting with the catalytic domain of tPA can be found in patients with APS, representing a possible cause of hypofibrinolysis. (Blood.

Summary Advanced chronic heart failure (CHF) is associated with abnormal haemostasis and inflammation, but it is not known how these abnormalities are related, whether they are modified by oral anticoagulants (OAT), or if they persist after successful heart transplantation. We studied 25 patients with CHF (New York Heart Association class IV, 10 of whom underwent heart transplantation) and 25 age‐ and sex‐matched healthy controls by measuring their plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin–antithrombin (TAT) complexes, tissue plasminogen activator (t‐PA), plasminogen activator inhibitor‐1 (PAI‐1), D‐dimer, factor VII (FVII), fibrinogen, von Willebrand factor (VWF), tumour necrosis factor (TNF), soluble TNF receptor II (sTNFRII), interleukin 6 (IL‐6), soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble vascular cell adhesion molecule‐1 (sVCAM‐1), endothelial‐selectin (E‐selectin) and thrombomodulin. CHF patients had higher plasma levels of TAT, D‐dimer, t‐PA, fibrinogen, VWF, TNF, IL‐6, sTNFRII, sVCAM‐1 (P = 0·0001), sICAM‐1 (P = 0·003) and thrombomodulin (P = 0·007) than controls. There were significant correlations (r = 0·414–0·595) between coagulation, fibrinolysis, endothelial dysfunction and inflammation parameters, which were lower in those patients treated with OATs. Heart transplantation led to reductions in fibrinogen (P = 0·001), VWF (P = 0·05), D‐dimer (P = 0·05) and IL‐6 levels (P = 0·05), but all the parameters remained significantly higher (P = 0·01–0·0001) than in the controls. Advanced CHF is associated with coagulation activation, endothelial dysfunction and increased proinflammatory cytokine levels. Most of these abnormalities parallel each other, tend to normalize in patients treated with OATs and, although reduced, persist in patients undergoing successful heart transplantation, despite the absence of clinical signs of CHF.

SummarySince it has not been established to what extent abnormalities of hemostasis contribute to the occurrence and development of dementia, selected measurements of coagulation and fibrinolysis were obtained in elderly patients with Alzheimer’s disease (n = 22) or vascular dementia (n = 29), compared with healthy individuals in the same age range (n = 61). Hemostasis abnormalities were more frequent and marked in vascular dementia, being expressed as significant increases of plasminogen activator inhibitor type 1, von Willebrand factor, D-dimer. and activated factor VII. However, some hemostasis measurements (von Willebrand factor, activated factor VII) were abnormally high also in the patients with Alzheimer’s disease, a condition in which vascular damage is not considered to play a major pathogenetic role. It could not be established in this study whether or not these hemostatic abnormalities play a causal role in the pathogenesis of dementia, or whether they are secondary to inflammation and chronic vascular disease. Nevertheless, their presence may contribute to aggravating vascular disease.