Diagnostic utility of bleeding assessment tools in congenital fibrinogen deficiencies

Background

The assessment of clinical history is crucial before referring a patient for further laboratory testing. Bleeding assessment tools (BAT) are developed to standardize clinical evaluation. A small number of patients with congenital fibrinogen deficiencies (CFDs) have been evaluated with these tools without definitive results.

Aims

We compared the adequacy of the ISTH-BAT and the European network of rare bleeding disorders bleeding score system (EN-RBD-BSS) to identify patients with CFDs. The correlation between the two BATs and fibrinogen levels and patient clinical grade severity was further analyzed.

Methods

We included 100 Iranian patients with CFDs. Routine coagulation and fibrinogen-specific tests (fibrinogen antigen [Fg:Ag] and activity [Fg:C]) were performed. The ISTH-BAT and EN-RBD-BSS were used to assess the bleeding score (BS) of all patients.

Results

The ISTH-BAT and EN-RBD-BSS median (range) were 4 (0–16) and 2.21 (−1.49 to 6.71), with a statistically significant moderate correlation between the two systems (r = .597, P < .001). In patients with quantitative deficiencies (afibrinogenemia and hypofibrinogenemia), the correlation between Fg:C and the ISTH-BAT was moderately negative (r = −.4, P < .001), while the correlation between Fg:C and the EN-RBD-BSS was weakly negative (r = −.38, P < .001). Overall, 70% and 72% of patients with fibrinogen deficiencies were correctly identified by both the ISTH-BAT and EN-RBD-BSS, respectively.

Conclusion

These results suggest that in addition to the ISTH-BAT, the EN-RBD-BSS may also be useful in identifying CFD patients. We found a significant level of sensitivity for detecting fibrinogen deficiency in the two BATs, and bleeding severity classification correctly identified severity grades in almost two-thirds of patients.     

Tranexamic acid without prophylactic factor replacement for prevention of bleeding in hereditary bleeding disorder patients undergoing endoscopy: a pilot study

The risk of bleeding in patients with hereditary bleeding disorders (HBD) undergoing gastro‐intestinal (GI) endoscopic procedures is unknown but guidelines generally recommend correction of factor deficiency. Investigate the safety of oral tranexamic acid (TA) without prophylactic factor replacement to prevent bleeding complications in patients with HBD undergoing elective GI endoscopic procedures. A prospective single‐arm pilot study testing the feasibility of using TA, without prophylactic factor replacement or desmopressin preprocedure, for prevention of bleeding complications following elective standard risk (<1% risk of bleeding) endoscopic procedures in patients with HBD. Baseline factor levels, haemoglobin and iron studies (IS) were measured preprocedure. Primary outcome of bleeding (NCI CTCAE v3.0 Bleeding Scale) was undertaken by patient review and repeat Hb, IS on day 21. Twenty‐eight patients underwent 32 GI endoscopic procedures from September 2010 until June 2012. The median age was 53 years (range 24–75 years) and disease types included mild haemophilia A/B (n = 12), severe haemophilia A/B (n = 9), von Willebrand disease (n = 5), FXI deficiency (n = 1) and FVII deficiency (n = 1). Procedures performed included 11 gastroscopies, 12 colonoscopies, 8 gastroscopies and colonoscopies and 1 flexible sigmoidoscopy. Fourteen standard risk procedures and two high risk procedures were performed. Two patients experienced Grade 1 bleeding and one patient experienced Grade 2 bleeding. This study suggests that TA without prophylactic factor replacement may be a safe approach for mild and moderate HBD patients undergoing standard risk endoscopic procedures, particularly where no biopsy is performed. These findings should be confirmed in a larger study.     

The estimated pulmonary artery pressure can be elevated in Behçet's syndrome

Objectives

To determine the frequency of elevated systolic pulmonary artery pressure (sPAP) estimated by echocardiography in Behçet’s syndrome (BS) patients with pulmonary artery involvement (PAI), in healthy controls and in diseased controls with systemic sclerosis (SSc), as well as in BS patients without PAI.

Methods

We studied 3 groups of patients with BS (patients with PAI: n = 30, with vascular disease but without PAI: n = 26 and without vascular disease: n = 21), patients with SSc (n = 23) and healthy controls (n = 22). Systolic pulmonary artery pressure (sPAP) was estimated by echocardiography. The upper limit for a normal sPAP was arbitrarily set at 35 mmHg. We also evaluated cardiac function by echocardiography. Pulmonary function tests, a six-minute walking test (six-MWT) and several serum biomarkers were also studied.

Results

The frequency of patients with an elevated sPAP was significantly higher only among BS patients with PAI (17%) and among patients with SSc (26%). In addition, DL_CO was decreased and pro-BNP levels were increased in BS patients with PAI, which are similar to the results in patients with SSc. Furthermore, BS patients with PAI also had mild RV diastolic dysfunction.

Conclusions

When BS involves the pulmonary arteries, it can cause mild elevations in the estimated sPAP, decrease in DL_CO, mild cardiac dysfunction and increase in pro-BNP levels. These findings suggest that BS can also affect the small/micro vessels of the heart and the lungs in addition to the well-recognized large vessel disease.     

Biological determinants of bleeding in patients with heterozygous factor XI deficiency

Bleeding risk is not predictable in patients with factor XI (FXI; F11) deficiency. In this prospective study, our objectives were to determine the biological determinants for bleeding risk in patients with heterozygous FXI deficiency. Patients were classified as either bleeding patients or non‐bleeding patients by calculating the bleeding score (BS) described for von Willebrand disease. Primary haemostasis, thrombin generation, thromboelastometry, procoagulant proteins, inhibitors, fibrinolysis, and F11 gene mutations were compared between bleeding and non‐bleeding patients. Thirty‐nine patients were included. BS significantly correlated with clinical assessment (P = 0·001), and a score over 3 discriminated between bleeding (n = 15) and non‐bleeding (n = 24) patients (P = 0·034). Despite normal values, von Willebrand factor (VWF) and thrombomodulin (TM) plasma levels were significantly lower in bleeding patients than non‐bleeding patients [ristocetin cofactor activity (VWF:RCo) = 80·6 ± 29·7 iu/dl and 101·8 ± 29·5 iu/dl respectively, P = 0·043; and VWF antigen (VWF:Ag) = 84·0 ± 28·0 iu/dl and 106·3 ± 36·1 iu/dl respectively, P = 0·035; and TM = 17·7 ± 11·7 ng/ml and 23·6 ± 9·7 ng/ml respectively, P = 0·043]. When considering BS as a continuous variable, only VWF:RCo remained significant (P = 0·042), which accounted for 11% of the variability in BS.     

Association of D-dimer with microalbuminuria in patients with type 2 diabetes mellitus

Background Microalbuminuria has been reported to be related to incidence of cardiovascular complications in diabetes. No consistent findings have been obtained on the relationships of microalbuminuria with blood coagulation and fibrinolysis. The purpose of this study was to determine whether microalbuminuria is associated with blood markers reflecting coagulation and fibrinolysis activities in patients with type 2 diabetes. Methods The relationships of albumin excretion rate (AER) with atherosclerosis-related variables, including blood coagulation and fibrinolysis markers, were investigated in patients with type 2 diabetes who showed normoalbuminuria (AER: less than 20 μg/min) and microalbuminuria (AER: 20 μg/min or higher and less than 200 μg/min). Results AER was significantly correlated with body mass index (BMI), maximum intima-media thickness of common carotid arteries, blood HDL cholesterol, uric acid, creatinine and D-dimer. On the other hand, AER showed no significant correlation with blood platelets, fibrinogen, thrombin–antithrombin III complex, plasmin–α2 plasmin inhibitor complex and plasminogen activator inhibitor-1. In multiple regression analysis, using age, sex, BMI, pulse pressure, hemoglobin A1c, HDL cholesterol, uric acid, creatinine, D-dimer and history of anti-thrombotic therapy as explanatory variables, only D-dimer showed a significant correlation with AER. The mean level of log-converted D-dimer after adjustment for age and sex was significantly higher in subjects with microalbuminuria than in those with normoalbuminuria. Conclusions D-dimer is associated with microalbuminuria in patients with diabetes and this suggests that glomerular dysfunction is in part mediated by hypercoagulability.     

Dependency of phenprocoumon dosage on polymorphisms in the VKORC1 and CYP2C9 genes

Objectives Polymorphisms in the vitamin K epoxide–reductase-complex-1 (VKORC1) and the cytochrome-P450-isozyme (CYP2C9) genes account for therapeutic responses to vitamin K antagonists (VKA). This study aimed to investigate the prevalence of VKORC1 and CYP2C9 polymorphisms among patients under phenprocoumon and its influence on the VKA dosage. Methods Patients under phenprocoumon were screened for the polymorphisms −1639G > A and 3730G > A in the VKORC1 gene and 430C > T and 1075A > C in the CYP2C9 gene by means of a StripAssay. Baseline clinical and laboratory parameters were registered. Results Among 53 patients (28 females, mean age 72.5 years), VKORC1 polymorphisms were found in 34 [−1639G > A: homozygote (n = 11), heterozygote (n = 23)] and 28 [3730G > A: homozygote (n = 7), heterozygote (n = 21)] patients. Thirteen patients were compound heterozygote. CYP2C9 polymorphisms were found in 12 [430G > T: homozygote (n = 1), heterozygote (n = 11)] and 7 [1075A > C: homozygote (n = 0), heterozygote (n = 7)] patients. Seventeen patients had at least one VKORC1 and one CYP2C9 polymorphism. Mean phenprocoumon dosage per week to achieve therapeutic anticoagulation was lower (higher) in patients with than without the VKORC1 polymorphism −1639G > A (3730G > A) or the CYP2C9 polymorphisms. Despite the presence of VKORC1 or CYP2C9 polymorphisms, mean International Normalized Ratio was not significantly different between patients with and without polymorphisms. Conclusions Though VKORC1 and CYP2C9 polymorphisms influence the phenprocoumon dosage necessary to achieve therapeutic anticoagulation, anticoagulation is therapeutic if carefully monitored.     

Hypercoagulability in Cushing’s syndrome: the role of specific haemostatic and fibrinolytic markers

Objective Hypercoagulability is a commonly described complication in patients with Cushing’s syndrome. Recent clinical studies have indicated various abnormalities of coagulation and fibrinolysis parameters which may be related to that phenomenon. The aim of this study was to investigate the mechanisms underlying the hypercoagulable state in patients with Cushing’s syndrome. Research methods and procedures A wide range of serum markers involved in the processes of blood coagulation and fibrinolysis was measured in a group of 33 patients with Cushing’s syndrome and 31 healthy controls. No participant was taking medication which could influence the result or had known diseases, except hypertension and diabetes, which could affect blood coagulation or fibrinolysis parameters. Results Patients with Cushing’s syndrome had higher levels of clotting factors II (P = 0.003), V (P < 0.001), VIII (P < 0.001), IX (P < 0.001), XI (P < 0.001) and XII (P = 0.019), protein C (P < 0.001), protein S (P < 0.001), C1-inhibitor (P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) (P = 0.004). The activity of fibrinolytic markers, plasminogen (P < 0.001), antithrombin (P < 0.001) and antithrombin antigen (P = 0.001) was also increased in the patient group. Conclusion The study has demonstrated hypercoagulability in patients with Cushing’s syndrome manifest as increased prothrombotic activity and compensatory activation of the fibrinolytic system. We propose the introduction of thromboprophylaxis in the preoperative and early postoperative periods, combined with a close follow-up in order to prevent possible thromboembolic events in patients with Cushing’s syndrome.     

Erectile and endothelial dysfunction in Type II diabetes: a possible link

Aims/hypothesis: The aim of this study was to evaluate the relation between erectile dysfunction and endothelial functions, coagulation activation, peripheral and autonomic neuropathy in men with Type II (non-insulin-dependent) diabetes mellitus. Methods: We studied 30 Type II diabetic patients with symptomatic erectile dysfunction and 30 potent diabetic patients matched for age and disease. Endothelial functions were assessed with the l-arginine test, plasma thrombomodulin and cell adhesion molecules circulating concentrations. Haemostasis was evaluated with markers of thrombin activation and fibrinolysis. Quantitative sensory testing (vibratory, warming, and heat-pain thresholds), cardiovascular reflex tests and 24-h blood pressure monitoring were used to assess peripheral or autonomic neuropathy. Results: Mean erectile score and HbA_{1 c} were 10.5 ± 5.8 and 8.3 ± 1.6 % in patients with erectile dysfunction, and 24.0 ± 0.7 and 6.8 ± 1.4 % in those without erectile dysfunction, respectively (p < 0.001); there was a significant relation between HbA_{1 c} and erectile function score in patients with erectile dysfunction (r = –0.45, p = 0.02). The decrease in blood pressure and platelet aggregation in response to l-arginine was lower (p < 0.05–0.02) in patients with erectile dysfunction, whereas soluble thrombomodulin, P-selectin and intercellular cell ahhesion molecule-1 concentrations were higher (p < 0.05–0.02). Indices of coagulation activation (F1 + 2 and d-dimers) and reduced fibrinolysis (PAI-1) were also found to be higher in erectile dysfunction patients. Heat-pain and warm perception thresholds, as well as cardiovascular reflex tests, were most commonly abnormal in patients with erectile dysfunction (p < 0.05). In multivariate analysis, HbA_{1 c}, MBP response to l-arginine, P-selectin, indices of coagulation, and quantitative sensory testing were independent predictors of erectile function score. Conclusion/interpretation: Erectile dysfunction in diabetic men correlates with endothelial dysfunction. A reduced nitric oxide activity might provide a unifying explanation. [Diabetologia (2001) 44: 1155–1160] Received: 18 April 2001 and in revised form: 21 April 2001     

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.     

Obstructive Sleep Apnea Severity and the Risk of Occupational Injury: A Prospective Observational Cohort

Objective

To determine whether patients with obstructive sleep apnea (OSA) are at increased risk of occupational injury (OI)

Methods

Working patients (aged 18 to 65 who reported more than 10 h of work per week) who were referred to the University of British Columbia Sleep Laboratory for suspected OSA for polysomnogram (PSG) were recruited from 2003 to 2011. Patients completed an extensive survey the night of their PSG. Validated OI was obtained by linking patient data to Workers Compensation Board Claims Data.

Results

1109 workers were studied; mean age was 47.1 years, median AHI was 15.0/h, median BMI was 30 kg/m², 70.2% were male and 29% of patients worked in physical or manual related occupations. 78 patients (7.03%) suffered 140 OI in the 5 years after PSG. In a multivariate logistic regression model, OSA severity [defined as a log(AHI + 1)] was a significant predictor of OI (p = 0.04) after controlling for age, sex, BMI, and physical or manual related occupations. Patients with moderate and severe OSA had approximately two times the odds of an OI compared to patients without OSA (OR 1.99, 95% CI 0.96–4.44 and 2.00, 95% CI 0.96–4.49 for moderate and severe OSA groups, respectively).

Conclusions

In this prospective study, OSA severity was independently associated with an increased risk of OI.

     

Neurological complications of ankylosing spondylitis: neurophysiological assessment

Studies examined the neurological involvement of ankylosing spondylitis (AS) are limited. This study aimed to assess the frequency of myelopathy, radiculopathy and myopathy in AS correlating them to the clinical, radiological and laboratory parameters. Included were 24 patients with AS. Axial status was assessed using bath ankylosing spondylitis metrology index (BASMI). Patients underwent (a) standard cervical and lumbar spine and sacroiliac joint radiography, (b) somatosensory (SSEP) and magnetic motor (MEP) evoked potentials of upper and lower limbs, (c) electromyography (EMG) of trapezius and supraspinatus muscles. Patients’ mean age and duration of illness were 36 and 5.99 years. Bath ankylosing spondylitis metrology index mean score was 4.6. Twenty-five percent (n = 6) of patients had neurological manifestations, 8.3% of them had myelopathy and 16.7% had radiculopathy. Ossification of the posterior (OPLL) and anterior (OALL) longitudinal ligaments were found in 8.3% (n = 2) and 4.2% (n = 1). About 70.8% (n = 17) had ≥1 neurophysiological test abnormalities. Twelve patients (50%) had SSEP abnormalities, seven had prolonged central conduction time (CCT) of median and/or ulnar nerves suggesting cervical myelopathy. Six had delayed peripheral or root latencies at Erb’s or interpeak latency (Erb’s-C5) suggesting radiculopathy. Motor evoked potentials was abnormal in 54% (n = 13). Twelve (50%) and five (20.8%) patients had abnormal MEP of upper limbs and lower limbs, respectively. About 50% (n = 12) had myopathic features of trapezius and supraspinatus muscles. Only 8.3% (n = 2) had neuropathic features. We concluded that subclinical neurological complications are frequent in AS compared to clinically manifest complications. Somatosensory evoked potential and MEP are useful to identify AS patients prone to develop neurological complications.     

Acute in-vivo evaluation of bleeding with GelfoamTM plus saline and Gelfoam plus human thrombin using a liver square lesion model in swine

Background Management of post-operative bleeding has historically used topical bovine thrombin. However, possible harm through activation of coagulation inhibitors has encouraged investigation with other hemostatic agents. This study utilized a novel ordinal bleeding model to test whether a Gelfoam + human thrombin solution is superior at controlling bleeding when compared to Gelfoam + saline solution at different time intervals. Study design Four swine underwent open laparotomy after receiving unfractionated heparin. Twenty open liver biopsies were performed in each swine; ten biopsies treated with Gelfoam + human thrombin solution and 10 biopsies treated with Gelfoam + saline solution. Three, 6 min, and 12 min after the procedure, bleeding was objectively graded by a four-point model. Results There was a significant (P < 0.017), treatment effect on each success/failure outcome (success = bleeding score ≤ 1; failure = bleeding score > 1) at 3 (P < 0.001), 6 (P < 0.001), and 12 (P = 0.003) min, based on a 2 × 2 Fisher’s exact test. Similarly, there was a significant treatment effect on each success/failure outcome and four-point bleeding score based on a multiple logistic regression analysis controlling for pig, lesion weight, and initial bleeding taking into consideration repeated measures at three time points. Conclusions The results demonstrate a superior treatment effect for control of bleeding using human thrombin compared to a saline solution. Future studies should compare bovine thrombin versus human thrombins ability to control bleeding as well as the hazard of each in activating coagulation inhibitors.     

Blood coagulation and fibrinolysis in patients with acromegaly: increased plasminogen activator inhibitor-1 (PAI-1), decreased tissue factor pathway inhibitor (TFPI), and an inverse correlation between growth hormone and TFPI

Objective Growth hormone/insulin-like growth factor-1(GH/IGF-1) hypersecretion may influence risk factors contributing to the increased cardiovascular morbidity and mortality associated with acromegaly However, so far little is known about the impact of GH/IGF-1 on coagulation and fibrinolysis in acromegalic patients as possible risk factors for cardiovascular disease (CVD). To our knowledge, plasma tissue factor pathway inhibitor (TFPI) and thrombin-activatable fibrinolysis inhibitor (TAFI) levels in these patients have not been investigated. Therefore, the main purpose of this study was to evaluate the markers of endogenous coagulation/fibrinolysis, including TFPI and TAFI, and to investigate the relationships between GH/IGF-1 and these hemostatic parameters and serum lipid profile in patients with acromegaly. Research Methods and Procedures A total of 22 patients with active acromegaly and 22 age-matched healthy controls were included in the study. Fibrinogen, factors V, VII, VIII, IX, and X activities, von-Willebrand factor (vWF), antithrombin III (AT III), protein C, protein S, tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor-1 (PAI-1), TFPI and TAFI, as well as common lipid variables, were measured. The relationships between serum GH/IGF-1 and these hemostatic parameters were evaluated. Results Compared with the control subjects, fibrinogen, AT III, t-PA, and PAI-1 were increased significantly in patients with acromegaly (P < 0.0001, P < 0.05, P < 0.01, and P < 0.0001, respectively), whereas protein S activity and TFPI levels were decreased significantly (P < 0.05 and P < 0.01, respectively). Plasma TAFI Ag levels did not significantly change in patients with acromegaly compared with the controls. In patients with acromegaly, serum GH levels were inversely correlated with TFPI and apo AI levels (r: −0.514, P: 0.029 and r: −0.602, P: 0.014, respectively). There was also a negative correlation between insulin-like growth factor −1 (IGF-1) and PAI-1 (r: −0.455, P:0.045). Discussion We found some important differences in the hemostatic parameters between the patients with acromegaly and healthy controls. Increased fibrinogen, t-PA, PAI-1 and decreased protein S and TFPI in acromegalic patients may represent a potential hypercoagulable and hypofibrinolytic state, which might augment the risk for atherosclerotic and atherothrombotic complications. Thus, disturbances of the hemostatic system and dyslipidemia may contribute to the excess mortality due to CVD seen in patients with acromegaly.     

Coagulation abnormalities in type 1 Gaucher disease are due to low-grade activation and can be partly restored by enzyme supplementation therapy

In type 1 Gaucher disease a bleeding tendency occurs which is partly caused by thrombocytopenia due to massive splenomegaly. In addition, low levels of factors IX and XI have been described. The mechanism responsible for these clotting factor abnormalities is unknown.
We performed a detailed study of parameters of coagulation and fibrinolysis in 30 type 1 Gaucher disease patients (14 splenectomized) before and after treatment with enzyme supplementation therapy. Pre-treatment aPTT and PT were prolonged in 42% and 38% of patients, respectively. In 30–60% serious deficiencies (>50%) of coagulation factors XI, XII, VII, X, V and II were observed. The low levels of factor V correlated with platelet count and were inversely associated with splenic volume. Levels of inhibitors were mildly decreased. Markers for activation of coagulation (thrombin–antithrombin (TAT) complex) and fibrinolysis (PAP complex, fibrin cleavage product D-dimer) were significantly elevated, especially in the splenectomized patients, indicating ongoing activation of these processes. After 12 months of enzyme supplementation therapy partial correction occurred.
Thus, severe disorders of the coagulation system occur in Gaucher disease, contributing to the bleeding tendency. The deficiencies may be the result of consumption of coagulation factors caused by ongoing low-level coagulation activation, possibly due to mononuclear cell activation.     

Functional MRI in assessment of diabetic kidney disease in people with type 1 diabetes

AimsTo compare levels of renal hypoxia measured by Blood Oxygen Level Dependent (BOLD) magnetic resonance imaging (MRI) with measured transverse relaxation rate (R2*) and renal structural changes including apparent diffusion coefficient (ADC) and fractional anisotropy (FA) in patients with type 1 diabetes and healthy controls.MethodsCohort study comparing MRI metrics in type 1 diabetes (n = 32, GFR 105 (77, 120) ml/min.1.73m²) and controls (n = 10). Renal function and selected inflammatory renal biomarkers were also measured.ResultsFor BOLD, we found reduced cortical [14.7 (13.7,15.8) (1/s) vs 15.7 (15.1,16.6) (1/s), p < 0.001] and medullary [24.8 (21.8,28.2) (1/s) vs. 29.3 (24.3,32.4) (1/s), p < 0.001] R2*, indicating more oxygenated parenchyma, in type 1 diabetes vs. controls, respectively. We observed reduced cortical FA, indicating decreased structural integrity in type 1 diabetes ?0.04 (?0.07, ?0.01), (p = 0.02). We found reduced cortical ADC, reflecting reduced water diffusion, in non-hyperfiltering [2.40 (2.29,2.53) (10³mm²/s)] versus hyperfiltering [2.61 (2.53,2.74) (10³mm²/s)] type 1 diabetes patients. MRI parameters correlated with renal function and inflammatory renal biomarkers.ConclusionsMRI derived indices of renal function and structure differed between (i) type 1 diabetes and healthy controls, and (ii) between non-hyperfiltering and hyperfiltering type 1 diabetes patients, providing insight into the role of hypoxia and renal structural, and functional changes in DKD.     

Early changes in local hemostasis activation following percutaneous coronary intervention in stable angina patients: a comparison between drug-eluting and bare metal stents

Background Early change in local intracoronary hemostasis following drug-eluting (DES) and bare metal stent (BMS) implantation has never been assessed in stable angina patients. Methods Markers of local platelet activation (soluble glycoprotein V [sGPV] and P-Selectin [CD62P]), coagulation activation (tissue factor [TF], prothrombin fragments 1 + 2 [F1 + 2] and activated factor VII [FVIIa]) and fibrinolysis markers (D-dimers [DD], fibrinogen [FIB], tissue plasminogen activator [t-PA], and plasminogen activator inhibitor type-1 complexes [PAI-1]) were determined in 20 patients with stable angina who underwent percutaneous coronary intervention (PCI). All patients were pretreated with clopidogrel, aspirin, and enoxaparin. Systematic balloon predilation was performed before DES (9 patients) and BMS (11 patients) implantation. All blood samples were drawn 10–20 mm distal to the lesion site. Results No significant changes in levels of platelet activation markers occurred during PCI. There was a transient significant increase in TF (14%; P = 0.004), in F1 + 2 (40%; P = 0.001), and FVIIa (31%; P = 0.007) following angioplasty. Similarly, a significant 43% increase was observed in DD levels following balloon predilation, associated with an increase of 46%, 60%, and 70% in FIB, t-PA and PAI-1 levels, respectively (all P < 0.0001). All these markers returned to baseline values after stent implantation. No difference was observed between DES and BMS. Conclusions Early changes in local hemostasis activation following PCI, were related to balloon predilation. Neither DES nor BMS increased markers of platelet activation, coagulation, or fibrinolysis, under dual antiplatelet and anticoagulant pretreatment.     

Association between phenotype and genotype in carriers of haemophilia A

Summary. Female carriers of haemophilia might suffer from increased bleeding tendency therefore the assessment of the bleeding risk is very important for improving care. This single‐centre study documents the occurrence of bleedings in 46 carriers of haemophilia A including bleeding after tooth extraction (77%), easy bruising (67%), postsurgical bleeding (61%), menorrhagia (50%) or prolonged postpartum bleeding (43%). The F8 gene mutation of all 46 carriers (median age: 36.5 years, 15–80 years; mean FVIII:C activity: 59 ± 24.45%; normal range: 64–167%) was determined, and family history of haemophilia was recorded. For analysis, the bleeding tendency of the carriers was differentiated by severity into three groups. There was no statistically significant difference of FVIII:C between these groups. However, a correlation was found between the severity of bleeding tendency and the type of F8 gene mutation (P < 0.05) as well as the severity of haemophilia in affected male relatives (P < 0.0005). Results show that even carriers with a FVIII:C activity as high as 50–60% are at increased risk of bleeding. Incidence and intensity of bleeding symptoms of haemophilia A carriers are high and correlated with the phenotype of the male haemophilic relative and the underlying F8 gene mutation.     

The relationship between coagulation disorders and the risk of bleeding in cirrhotic patients

Introduction and ObjectivesFor long, bleeding in cirrhotic patients has been associated with acquired coagulation disorders. The aim of our study was to investigate the impact of acquired coagulation disorders on bleeding risk in cirrhotic patients.Materials and methodsBlood samples were collected from 51 cirrhotic patients with (H+) or without (H−) bleeding events and 50 controls matched by age and sex. Thrombin generation was assessed as endogenous thrombin potential (ETP). Hemostatic balance was assessed by means of ratios of pro- to anticoagulant factors and by ETP ratio with/without protein C (PC) activator (ETP ratio).ResultsBleeding events occurred in 9 patients (17.6%). Compared with controls, VIII/anticoagulant factors, VII/PC and XII/PC were significantly higher in (H+) patients. No significant difference as regards all ratios across patient groups was detected. ETP ratio was significantly higher in (H+) patients than in controls (p = 0.017). However, there was no significant difference between patient groups as regards ETP ratio.ConclusionHemostatic balance is shifted toward a hypercoagulability state even in cirrhotic patients who experienced bleeding. These findings provide evidence against traditional concept of hemostasis-related bleeding tendency in cirrhotic patients.     

Effect of fibrinolysis on bleeding phenotype in moderate and severe von Willebrand disease

Patients with von Willebrand disease (VWD), the most common inherited bleeding disorder, display large variation in bleeding tendency, which is not completely related to VWF levels. The cause of variability in clinical expression is largely unknown. The effect of plasma fibrinolytic capacity on bleeding tendency in VWD patients has not been investigated. We hypothesized that enhanced fibrinolysis may result in a more severe bleeding phenotype. Therefore, we measured the fibrinolytic potential in patients with moderate or severe VWD to investigate the contribution of fibrinolysis to the bleeding tendency. Fibrinolytic potential was measured as plasma clot lysis time (CLT) with and without addition of potato carboxypeptidase inhibitor (PCI) in 638 patients with moderate or severe VWD who participated in a nationwide multicentre cross-sectional study. Bleeding severity was measured using the Bleeding Score (BS).The CLTs were significantly longer, indicative of hypofibrinolysis, in men compared to women with VWD [106.2 (IQR 95.7-118.1) vs. 101.9 (IQR 92.8-114.0) min]. The CLTs prolonged with increasing age. No association was found between VWF or FVIII levels and CLT, or between VWF or FVIII levels and CLT(+PCI) . No association was observed for BS in a model with 10log-transformed CLT, adjusted for age, gender, VWF:Act and FVIII [b = 6.5 (95%CI -0.3 to 13.4)]. Our study showed that the plasma fibrinolytic potential does not influence bleeding tendency in VWD patients and therefore does not explain the variability in bleeding phenotype in VWD.     

Coagulation and fibrinolysis abnormalities in familial amyloid polyneuropathy

Objective: Familial amyloid polyneuropathy (FAP) is an autosomal dominant form of hereditary amyloidosis. Several studies reported coagulation factor X deficiency and excessive fibrinolysis in immunoglobulin light chain amyloidosis. However, few have investigated coagulation and fibrinolysis in FAP. The objective of this study was to determine abnormalities in plasma biomarkers of coagulation and fibrinolysis in FAP. Methods: We prospectively recruited eight FAP patients with transthyretin mutations and ten age-matched control patients with other neuropathies in our university. We examined plasma biomarkers of coagulation and fibrinolysis including prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin/fibrinogen degradation products, D-dimer, α2-antiplasmin, antithrombin, plasminogen, thrombin-antithrombin complex, plasmin-α2-antiplasmin complex, prothrombin fragment 1+2, and coagulation factor X. The Mann–Whitney U test was performed for statistical comparisons between FAP and control groups. Results: FAP patients exhibited significantly decreased levels of coagulation factor X, plasminogen and α2-antiplasmin, and significantly increased levels of prothrombin fragment 1+2 compared to control patients. Conclusion: Our results indicate abnormalities of coagulation and fibrinolysis in FAP patients.