Plasminogen activator inhibitor type 1 deficiency

Summary. Plasminogen activator inhibitor type 1 (PAI‐1) is an important component of the coagulation system that down‐regulates fibrinolysis in the circulation. Reduced PAI‐1 levels may result in increased fibrinolysis and an associated bleeding diathesis. Clear documentation of PAI‐1 deficiency as a cause of a bleeding disorder has been rare. PAI‐1 was initially identified in the 1980s, and the first reported case of PAI‐1 deficiency appeared in 1989. Several reports followed, although only two identified an underlying genetic defect. These reports of PAI‐1 deficiency suggest that affected individuals exhibit mild to moderate bleeding symptoms, including epistaxis, menorrhagia, and delayed bleeding after trauma or surgical procedures. Affected individuals rarely exhibit spontaneous bleeding events commonly seen in other procoagulant deficiencies. The majority of bleeding events are controlled with antifibrinolytic agents, such as tranexamic acid and ε‐aminocaproic acid. A major issue that contributes to difficulty in establishing an accurate diagnosis of PAI‐1 deficiency is that the activity assay is accurate in detection of elevated levels but not at the lowest range. Reported normal ranges begin at zero, thereby making a deficiency state because of a dysproteinaemia difficult to distinguish from that of a normal unaffected individual. Although the antigen assay may be helpful in some circumstances, it assists only with complete quantitative disorders. Because of lack of standardized commercially available PAI‐1 activity assay sensitive in the lowest range, the true prevalence of this rare condition has not been established.     

Haemostatic management of intraoral bleeding in patients with congenital deficiency of α2-plasmin inhibitor or plasminogen activator inhibitor-1

Haemostatic management of intraoral bleeding was investigated in patients with congenital alpha2-plasmin inhibitor (alpha2-PI) deficiency or congenital plasminogen activator inhibitor- 1 (PAI-1) deficiency. When extracting teeth from patients with congenital alpha2-PI deficiency, we advocate that 7.5-10 mg kg(-1) of tranexamic acid be administered orally every 6 h, starting 3 h before surgery and continuing for about 7 days. For the treatment of continuous bleeding, such as post-extraction bleeding, 20 mg kg(-1) of tranexamic acid should be administered intravenously, and after achieving local haemostasis 7.5 mg kg(-1) of tranexamic acid should be administered orally every 6 h for several days. In addition, when treating haematoma caused by labial or gingival laceration or buccal or mandibular contusion, haemostasis should be achieved by administering 7.5-10 mg kg(-1) of tranexamic acid every 6 h. Tranexamic acid can also be used for haemostatic management of intraoral bleeding in patients with congenital PAI-1 deficiency, but is less effective when compared with use in patients with congenital alpha2-PI deficiency. Continuous infusion of 1.5 mg kg(-1) h(-1) of tranexamic acid is necessary for impacted tooth extraction requiring gingival incision or removal of local bone.     

Urokinase‐type plasminogen activator system and human cationic antimicrobial protein 18 in serum and induced sputum of patients with chronic obstructive pulmonary disease

Background and objective: There is increasing evidence that the innate immune system plays an important role in the pathogenesis of COPD. The objective of this study was to quantify several innate immune biomarkers in serum and induced sputum of COPD patients, and healthy non‐smokers and smokers. Methods: Serum and induced sputum levels of urokinase‐type plasminogen activator (uPA), urokinase‐type plasminogen activator receptor (uPAR), urokinase‐type plasminogen activator inhibitor (PAI‐1) and human cationic antimicrobial protein 18 (CAP18) were measured by ELISA, in 13 patients with stage I or stage II COPD (COPD I + II), 15 patients with stage III or stage IV COPD (COPD III + IV), 18 healthy non‐smokers and 14 healthy smokers. In addition, membrane‐bound uPAR in peripheral blood and induced sputum was assessed by flow cytometry. Results: Levels of uPAR, PAI‐1 and CAP18 were elevated in induced sputum of COPD I + II and COPD III + IV patients, compared with healthy non‐smokers (P < 0.05) and healthy smokers (P < 0.05). uPAR, PAI‐1 and CAP18 levels were significantly higher in COPD III + IV patients compared with COPD I + II patients (P < 0.05). The expression of uPAR on induced sputum neutrophils and macrophages was significantly higher in COPD patients compared with healthy non‐smokers (P < 0.05) and healthy smokers (P < 0.05). Sputum uPAR and CAP18 levels showed significant inverse correlations with FEV₁% and 6MWD, and significant positive correlations with St. George's Respiratory Questionnaire scores. Conclusions: In COPD patients, increased induced sputum levels of uPAR, PAI‐1 and CAP18 were associated with airflow limitation, health status and exercise tolerance, suggesting that these biomarkers may be implicated in the pathogenesis of COPD.     

Relationship between elevated cerebrospinal fluid levels of plasminogen activator inhibitor 1 and neuronal destruction in patients with neuropsychiatric systemic lupus erythematosus

Objective

A homeostatic imbalance between coagulation and fibrinolysis might occur intrathecally in neuropsychiatric systemic lupus erythematosus (NPSLE). However, there are no published data on levels of fibrinolytic factors in the cerebrospinal fluid (CSF) of patients with NPSLE. The present study was undertaken to assess CSF levels of fibrinolytic molecules, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), D‐dimer, and plasminogen activator inhibitor 1 (PAI‐1), in SLE patients with clinically verified neuropsychiatric involvement and to compare these levels with those in SLE patients without neuropsychiatric involvement and in healthy subjects.

Methods

Levels of uPA, tPA, and PAI‐1 were assessed in CSF from 94 patients with SLE (33 who had NPSLE, 56 who did not have NPSLE, and 5 who were positive for antiphospholipid antibody [not included in the NPSLE or non‐NPSLE group]) and from 53 age‐matched controls. Patients were evaluated clinically, with magnetic resonance imaging of the brain, analyses of neuronal/glial degradation products in CSF, and neuropsychiatric testing.

Results

In the group of patients with NPSLE, intrathecal PAI‐1 levels were significantly elevated compared with levels in SLE patients without overt neuropsychiatric involvement (P < 0.05) and in healthy controls (P < 0.001). In contrast, intrathecal levels of uPA did not differ significantly. Intrathecal levels of PAI‐1 correlated significantly with CSF levels of interleukin‐6 (IL‐6) (r = 0.34, P < 0.001) and IL‐8 (r = 0.33, P < 0.001). Importantly, increased PAI‐1 and D‐dimer levels were observed in SLE patients who had pathologically elevated levels of glial fibrillary acidic protein, neurofilament triplet protein, and tau protein in CSF.

Conclusion

Intrathecal release of PAI‐1 is increased in patients with NPSLE. This results in impaired fibrinolysis, which might contribute to neuronal and astrocytic damage in NPSLE.

     

REVIEW: Plasminogen Activator Inhibitor‐1 (PAI‐1): A Key Factor Linking Fibrinolysis and Age‐Related Subclinical and Clinical Conditions

Introduction: The close relationship existing between aging and thrombosis has growingly been studied in this last decade. The age‐related development of a prothrombotic imbalance in the fibrinolysis homeostasis has been hypothesized as the basis of this increased cardiovascular and cerebrovascular risk. Fibrinolysis is the result of the interactions among multiple plasminogen activators and inhibitors constituting the enzymatic cascade, and ultimately leading to the degradation of fibrin. The plasminogen activator system plays a key role in a wide range of physiological and pathological processes. Methods: Narrative review. Results: Plasminogen activator inhibitor‐1 (PAI‐1) is a member of the superfamily of serine‐protease inhibitors (or serpins), and the principal inhibitor of both the tissue‐type and the urokinase‐type plasminogen activator, the two plasminogen activators able to activate plasminogen. Current evidence describing the central role played by PAI‐1 in a number of age‐related subclinical (i.e., inflammation, atherosclerosis, insulin resistance) and clinical (i.e., obesity, comorbidities, Werner syndrome) conditions is presented. Conclusions: Despite some controversial and unclear issues, PAI‐1 represents an extremely promising marker that may become a biological parameter to be progressively considered in the prognostic evaluation, in the disease monitoring, and as treatment target of age‐related conditions in the future.     

Increased levels of tPA antigen and tPA/PAI-1 complex in myotonic dystrophy

Abstract. Johansson Å, Boman K, Cederquist K, Forsberg H, Olsson T (Umeå University Hospital, Umeå, Skellefteå County Hospital, Skellefteå, and Boden Hospital, Boden, Sweden). Increased levels of tPA antigen and tPA/PAI‐1 complex in myotonic dystrophy. J Intern Med 2001; 249 : 503–510. Objective. To assess the fibrinolytic system in myotonic dystrophy (DM1), a disease connected to features of the metabolic syndrome, including a prominent insulin resistance, increased body fat mass, and hypertriglyceridaemia. We hypothesized that abnormalities in the fibrinolytic system are linked to metabolic dysfunction in DM1. Design. Circulating morning levels of tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI‐1) antigens, tPA/PAI‐1 complex, lipids and insulin were determined. Genetic analyses, including calculation of allele size, were performed in all patients. Body fat mass was estimated with bioelectrical impedance analysis. Setting. Out‐patient clinic in collaboration with Umeå University Hospital. Subjects. A total of 42 otherwise healthy patients with DM1 (22 men, 20 women; median age 41.5 years) and 50 controls (27 men, 23 women; median age 42.0 years). Main outcome measures. The tPA and PAI‐1 antigens, tPA/PAI‐1 complex, blood lipids and body fat mass. Results. The tPA antigen and tPA/PAI‐1 complex levels were significantly increased in DM1 patients (P < 0.001 and P < 0.05, respectively) whilst levels of PAI‐1 did not differ from controls. Triglyceride levels were increased (P < 0.001) whereas HDL cholesterol levels were lower in DM1 patients (P < 0.05). Body fat mass was increased in DM1 patients (P < 0.001). Conclusions. The fibrinolytic system is disturbed in DM1 patients, with increased levels of tPA and tPA/PAI‐1 complex but paradoxically unaltered levels of PAI‐1, in spite of a severely increased body fat mass. This may imply an abnormal function of adipose tissue in DM1, and calls for further studies of the fibrinolytic system in this disease.     

Glucocorticoid replacement therapy and fibrinolysis in patients with hypopituitarism

Background Hypopituitarism is associated with increased cardiovascular mortality, and it has been suggested that unphysiological glucocorticoid replacement regimens might contribute to this risk. Traditional glucocorticoid replacement regimens have often led to excessive serum cortisol levels. The hypercortisolaemia of Cushing’s syndrome is associated with an increased risk of thromboembolism. Objective To examine whether short‐term higher‐dose hydrocortisone replacement regimens adversely affect the fibrinolytic system. Design Crossover study comparing tailored low‐dose (LD) glucocorticoid regimen (mean, 17·5 mg hydrocortisone daily), with a traditional high‐dose (HD, 30‐mg hydrocortisone daily) regimen for 2 weeks. Patients Ten patients with hypopituitarism and ACTH deficiency – median (range) age, 59 (41–75) years – and 10 age‐ and sex‐matched controls. Nine patients had growth hormone deficiency (five replaced), nine patients had TSH deficiency (nine replaced), eight had gonadotrophin deficiency (five replaced). During the study, other pituitary hormone replacement therapy remained unchanged. Patients with acromegaly and Cushing’s syndrome were excluded. Measurements Hourly serum cortisol for 11 h, plasminogen activator inhibitor‐1 (PAI‐1), tissue plasminogen activator (tPA) and fibrinogen levels after 2 weeks of treatment with both LD and HD regimens. Results No overall significant differences were found between the three groups using the Kruskal–Wallis test: PAI‐1: [median (range)] HD, 25 (5–53) ng/ml; LD, 21 (4–56) ng/ml; controls, 27 (8–51); P = 0·3; tPA: HD, 10 (5–15) ng/ml; LD, 10 (4–13) ng/ml; controls 10 (3–13); P = 0·46; and fibrinogen: HD, 2·5 (1·8–3·5) g/l; LD, 3·0 (2·3–4·4) g/l; controls, 2·6 (1·6–3·2): P = 0·97 In addition, no significant differences between HD and LD using Wilcoxon’s paired test; PAI‐1 (P = 0·91), tPAag (P = 0·47) and fibrinogen (P = 0·09). Conclusions An increased dose of hydrocortisone for 2 weeks creates excessive glucocorticoid exposure, but does not significantly affect fibrinolytic‐coagulation parameters.     

Four cases of bleeding diathesis in children due to congenital plasminogen activator inhibitor-1 deficiency

Congenital plasminogen activator inhibitor-1 (PAI-1) deficiency is an extremely rare disorder characterized by a bleeding diathesis that begins in childhood due to hyperfibrinolysis as a result of decreased PAI-1 activity. We now present 4 unrelated pediatric cases of congenital PAI-1 deficiency. All 4 patients had a history of recurrent episodes of subcutaneous bleeding beginning in early childhood. These episodes were characterized by abnormal prolonged bleeding after trauma, tooth extraction, and surgical procedures, as well as by rebleeding following initial hemostasis. The 2 female patients both had symptoms compatible with hypermenorrhea. The family history was positive in 2 of the 4 patients. Hemostatic screening studies in all 4 patients revealed no abnormalities. Testing for factor XIII antigen, von Willebrand factor antigen, ristocetin cofactor activity, alpha(2)-plasmin inhibitor (alpha2PI) activity, and plasminogen activity was normal. The euglobulin lysis times were shortened in all cases as compared with those in normal control subjects. None of the patients had elevated tissue plasminogen activator (tPA) antigen levels, but PAI activity was markedly decreased in all cases. Three of the patients also had reduced levels of PAI-1 antigen. There tended to be a reduction in tPA-PAI-1 complex in all cases. In addition, 2 patients had elevated PIC (plasmin-alpha2PI complex). Tourniquet tests were performed in 2 patients, with no appreciable rise in PAI-1 activity or PAI-1 antigen levels. The administration of tranexamic acid clearly improved hemorrhagic symptoms in these patients. We considered PAI-1 deficiency to be the likely etiology of the congenital bleeding diatheses in these 4 cases.     

Successful arthroscopic treatment of pigmented villonodular synovitis of the knee in a patient with congenital deficiency of plasminogen activator inhibitor-1 and recurrent haemarthrosis.

We report the arthroscopic treatment of pigmented villonodular synovitis (PVNS) in a 13-year-old Japanese boy with congenital partial deficiency of plasminogen activator inhibitor-1 (PAI-1). He was admitted to our hospital with recurrent haemarthrosis of his right knee. Characteristic abnormalities of fibrinolysis included shortened euglobulin lysis time, low PAI-1 activity and low PAI-1 antigen levels. In addition, levels of "active PAI" in the plasma, which is a measure of total PAI bound to exogenous plasminogen activator, were very low. These parameters remained low after venous occlusion. The diagnosis of PVNS was established by synovial membrane biopsy, and arthroscopic synovectomy was performed with adjuvant administration of intravenous tranexamic acid. Subsequent bleeding episodes have been well controlled by oral administration of tranexamic acid on demand.     

Low PAI-1 activity in relation to inflammatory parameters, insulin profile and body mass index

Background and objective. High plasminogen activator inhibitor type 1 (PAI‐1) activity is associated with inflammatory reactions and insulin resistance, but it is unclear what regulates PAI‐1 activity at the low end. The purpose of this study was to investigate if patients with low PAI‐1 activity have a lack of inflammatory response or a low insulin level. Design. Retrospective cohort study with internal controls. Subjects. Sixty‐three patients referred for investigation of bleeding tendency and with low PAI‐1 activity were compared with 118 patients with normal or high PAI‐1 activity. Outcome. Levels of C‐peptide, proinsulin, high‐sensitivity C‐reactive protein (hs‐CRP) and interleukin‐6 (IL‐6). Adjustments were made for body mass index (BMI), oral oestrogens and age. Low PAI‐1 activity was defined as less than 1 U mL^?1. Results. Body mass index in the low normal range, oral oestrogens, young age and low C‐peptide were significantly associated with low PAI‐1 activity and there was a trend for association with IL‐6 in univariable analysis. The effect of age disappeared after correction for oral oestrogens and the effect of C‐peptide and IL‐6 disappeared after further adjustments. Low BMI remained as the strongest predictor of low PAI‐1 activity. Conclusion. Patients with bleeding tendency and low PAI‐1 activity have inflammatory and insulin profiles similar to those with normal or high PAI‐1, whereas BMI seems to be the most important determinant.     

Pomalidomide in combination with dexamethasone results in synergistic anti‐tumour responses in pre‐clinical models of lenalidomide‐resistant multiple myeloma

Pomalidomide is an IMiD^® immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, 2004 ; San Miguel et al, 2013; Richardson et al, 2014; Scott, 2014 ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti‐proliferative and pro‐apoptotic activity in both lenalidomide‐sensitive and lenalidomide‐resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single‐agent treatment in xenografts of lenalidomide‐resistant H929 R10‐1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide‐sensitive H929 MM cell lines, were also observed in PomDex‐treated lenalidomide‐resistant H929 MM cells. Remarkably, this resulted in strong, synergistic effects on the induction of apoptosis in both lenalidomide‐sensitive and resistant MM cells. Furthermore, gene expression profiling revealed a unique differential gene expression pattern in PomDex‐treated samples, highlighted by the modulation of pro‐apoptotic pathways in lenalidomide‐resistant cells. These results provide key insights into molecular mechanisms of PomDex in the lenalidomide‐resistant setting.     

Coagulation disorders in patients with severe leptospirosis are associated with severe bleeding and mortality

Objective To determine the involvement of coagulation in bleeding and poor outcome in patients with severe leptospirosis. Methods In a prospective study, parameters of the coagulation system were measured on admission and during follow‐up in 52 consecutive patients with severe leptospirosis. Results All patients showed coagulation disorders, such as prolonged prothrombin time (PT) and activated partial thromboplastin time, marked procoagulant activity [thrombin–antithrombin (TAT) complexes, prothrombin fragment 1+2, D‐dimer], reduced levels of anticoagulant markers (protein C, antithrombin) and increased (anti‐) fibrinolytic activity [plasmin–antiplasmin (PAP) complexes, plasminogen activator inhibitor‐1]. These disorders were more pronounced in patients who died eventually. PT prolongation was associated with mortality (OR 1.4, 95% CI: 1.0–1.8, P = 0.04). Bleeding occurred in 31 subjects (60%). Of these, 24 had mild bleeding and seven had severe haemorrhages. Thrombocytopenia (platelets ≤100 × 10⁹/l) was significantly associated with clinical bleeding (OR 4.6, 95% CI: 1.3–16). A subanalysis of patients with and without severe bleeding revealed a more pronounced imbalance of the coagulation system in patients with severe bleeding, as reflected by a significant association with PT (OR 1.4, 95% CI: 1.0–1.8, P = 0.05) and the TAT/PAP ratio (OR 1.3, 95% CI: 1.0–1.6, P = 0.05), which is an indicator of the balance between coagulation and fibrinolysis. Overt disseminated intravascular coagulation (DIC) was found in 10 (22%) of the 46 patients for whom the score could be calculated. There was no significant association between DIC scores, bleeding diathesis or poor outcome. Conclusion The coagulation system was strongly activated in patients with leptospirosis. This was more pronounced in the deceased and in patients with severe bleeding than in than the survivors and in those without severe bleeding.     

The Impact of Cigarette Smoking on 24‐Hour Blood Pressure,Inflammatory and Hemostatic Activity,and Cardiovascular Risk in Japanese Hypertensive Patients

The aim of the study was to assess the impact of current smoking on 24‐hour blood pressure (BP) and inflammatory and hemostatic activity and thereby the incidence of cardiovascular disease (CVD) in Japanese hypertensive patients. A total of 810 hypertensive patients (mean age 72 years; 38% men) were prospectively followed‐up (2799 person‐years). During the follow‐up, 66 cases of CVD occurred (stroke, 55; myocardial infarction, 7; both, 4). At baseline, the current smokers (n=166) had higher levels of high‐sensitivity C‐reactive protein (hs‐CRP) (0.21 mg/dL vs 0.14 mg/dL) and plasminogen activator inhibitor‐1 (PAI‐1) (46.1 ng/mL vs 37.8 ng/mL; both P=.001), but not of 24‐hour BP, compared with nonsmokers. Using a Cox regression analysis, current smoking was independently associated with an increased risk of CVD (hazard ratio [HR], 2.6; P<.01), and the risk was substantially higher in women (HR, 6.1; P<.001) than in men (HR, 1.4; P=.41). The CVD risk of current smokers was magnified when it was accompanied with high hs‐CRP (highest quartile range, ≥0.40 mg/L) or PAI‐1 levels (≥58.9 ng/mL) compared with that in smokers with low hs‐CRP or PAI‐1 levels (both P<.05). Among hypertensive patients, current smokers had increased risk of CVD events, and the increase was more prominent when accompanied by circulatory inflammatory and hemostatic abnormalities. J Clin Hypertens (Greenwich). 2012;00:00–00. ©2012 Wiley Periodicals, Inc.     

Clinical and laboratory characteristics of children with venous thromboembolism and protein C‐deficiency: an observational Israeli‐German cohort study

Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0·1–19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty‐five of 338 children (7·4%) had PCD. Mean age at first TE onset was 10 years (range 0·1–18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7·4%; 1·5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high‐risk population.     

Increased levels of tissue plasminogen activator with a low plasminogen activator inhibitor-1 in a patient with postoperative bleeding

Recurrent postoperative bleeding in a previously healthy man with a moderate prolongation of PT and PTT which did not correct with vigorous fresh-frozen plasma infusion was identified as a unique abnormality of the fibrinolytic system: a combination of an excess of tissue plasminogen activator (t-PA) at 300% of normal activity accompanied by a concurrent deficiency of plasminogen activator inhibitor-1 activity (PAI-1) of 10-20% of normal activity. This observation underscores the potentially important regulatory role of PAI-1 in the degree to which clinical manifestations of bleeding tendencies may occur in patients in whom an excess amount of t-PA is expressed.     

Bleeding disorders,menorrhagia and iron deficiency: impacts on health‐related quality of life

von Willebrand disease (VWD) is a bleeding disorder that occurs in up to 1% of the general population. The great majority of females with VWD experience menorrhagia. The morbidity burden in females with VWD may relate to iron deficiency resulting from menorrhagia. To explore relationships between bleeding disorders, menorrhagia, iron deficiency and the outcomes of health‐related quality of life (HRQL) and educational attainment. All subjects with VWD, and females with other bleeding disorders, in the Canadian national registry who were more than 12 years of age were eligible for survey. Survey measures included the HEALTH UTILITIES INDEX^®; abridged Clinical History Assessment Tool; socio‐demographic questions and serum ferritin. Statistical analyses included testing differences among groups of means using analysis of variance and of proportions using chi‐squared test. Significant size differences in mean HRQL scores were detected between VWD females and both females with other bleeding disorders [diff = (?0.08); P = 0.017] and VWD males [diff = (?0.07); P = 0.039]. Mean HRQL scores differed between females with and without menorrhagia (P < 0.001). Mean HRQL scores were not significantly different between females with and without iron deficiency. Educational attainment was not associated with disease group, menorrhagia status or iron status. Females with VWD have a greater morbidity burden than females in the general population, females with other bleeding disorders and males with VWD. Menorrhagia is associated with low HRQL scores in females with bleeding disorders, including VWD. Further investigation should assess how menorrhagia impacts HRQL in females with bleeding disorders.     

Partial growth hormone deficiency is associated with an adverse cardiovascular risk profile and increased carotid intima‐medial thickness

Objective To quantify the relative prevalence of surrogate markers of vascular risk in adults with partial GH deficiency (GH insufficiency, GHI). Context Hypopituitary adults with untreated GH deficiency (GHD) have an excess vascular mortality and demonstrate clustering of adverse vascular risk factors. The vascular risk profile of GHI adults has yet to be comprehensively studied. Design A cross‐sectional case controlled study. Patients Thirty GHD adults, 24 GHI, and 30 age‐ and sex‐matched controls. GHI adults were defined biochemically using two GH stimulation tests (peak GH 3–7 μg/l). Measurements Serum lipids and apolipoproteins, plasminogen activator inhibitor type‐I (PAI‐I), C‐reactive protein (CRP), lipoprotein (a) [Lp(a)], fibrinogen, blood pressure and carotid intima‐medial thickness (IMT). Results IGF‐I levels of GHI adults were lower than controls (373 ± 123 vs 295 ± 104 μg/l; P < 0·001). Total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C) and triglycerides (TG) values were consistently between those of, but not significantly different from, GHD and control subjects. GHI adults showed significantly elevated PAI‐I levels [80 (13–98) vs 50·5 (3–98) ng/ml; P = 0·01], although no there were differences in CRP, Lp(a), and fibrinogen levels compared with control subjects. No differences in systolic or diastolic blood pressure were shown between study groups. In parallel with the increased vascular risk profile of GH‐insufficient adults, carotid IMT was significantly increased (0·503 ± 0·08 vs 0·578 ± 0·130 mm; P = 0·02). TC, LDL‐C, Waist‐Hip Ratio (WHR), truncal fat mass, and IMT correlated with IGF‐I levels and GH status. TG, K_ITT, and PAI‐I additionally correlated with GH status, but not with IGF‐I levels. Conclusion GHI adults are at elevated vascular risk, reflected by adverse surrogate markers and increased carotid IMT. The surrogate risk marker profile parallels GHD adults, but is less divergent from that observed in healthy individuals. No data are yet available as to whether these anomalies will be reflected in an increased vascular mortality in GHI adults.     

α2‐Antiplasmin and its deficiency: fibrinolysis out of balance

Summary. Fibrinolysis serves an important role in the process of coagulation, ensuring that clots that are formed in response to injury resolve after the injured tissue is repaired. Fibrinolysis occurs because the protein plasminogen is converted to the active serine protease plasmin by its activating molecules (primarily tissue plasminogen activator). One of the inhibitors of fibrinolysis is α₂‐antiplasmin, which acts as the primary inhibitor of plasmin(ogen). Congenital deficiency of α₂‐antiplasmin causes a rare bleeding disorder because of increased fibrinolysis. Despite the rare nature of this disorder, understanding of the actions of α₂‐antiplasmin and the results of its deficiency has provided the opportunity for better understanding of the fibrinolytic system in both how it affects the risk of bleeding and its impact on other bodily systems. Here, we review the history of the discovery of α₂‐antiplasmin, our understanding of its genetics and function, and our current knowledge of its congenital deficiency. We also discuss some of the current avenues of investigation into its impact on other diseases and physiological states.     

食管癌组织中纤溶成份的表达及其意义

目的 研究肿瘤组织中纤溶成份的表达与肿瘤进展和术后生存时间的关系,方法 用Ｎｏｒｔｈｅｒｎ印迹和免疫组化法研究１０例正常食管和４１例食管癌标本中的尿激酶型纤溶酶原激活物（ｕＰＡ）,尿激酶型纤溶酶原激活物受体和纤溶激活抑制物－１（ＰＡＩ－１）。