Increased Bleeding Tendency Research Articles

Frequency of acquired von Willebrand’s disease in children with congenital heart disease

Objective — Bleeding tendency of paediatric patients with congenital heart disease has been well recognized.The underlying pathologies of this bleeding tendency have been studied extensively and many causes were identified. Among these causes, we aimed to find the frequency of acquired von Willebrand’s disease (AvWD) in children with congenital heart disease.Material and methods — Forty-nine children with different forms of congenital cardiopathies who were assigned for surgery, are included in the study. Serum von Willebrand factor antigen level as well as ristocetin cofactor agglutination ratios were determined preoperatively and at one week and 6 months postoperatively.Results — Six patients (12.2%) were found to have AvWD. However, we found no relation between bleeding tendency and AvWD status.Conclusion — Although frequency of von Willebrand factor deficiency is higher in children with congenital heart disease than in the normal population, this condition does not result in adverse clinical outcomes like increased bleeding tendency during operation.

Choix de l'analgésie systémique selon le terrain

A concept of balanced analgesia using nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol (acetaminophen), opioids, and corticosteroids can also be used in patients with pre-existing illnesses. NSAIDs are the most effective treatment for acute pain of moderate intensity in children; however, these drugs should be avoided in patients at increased risk for serious side effects, e.g. patients with renal impairment, bleeding tendency, or extreme prematurity. NSAIDs can be given with minimal risks to the younger child with mild to moderate asthma, and, in these patients, the use of steroids can be encouraged; in addition to their antiemetic and analgesic action, a beneficial effect on asthma symptoms can be expected. In the non-intubated child with cerebral trauma, exaggerated sedation caused by opioids and increased bleeding tendency caused by NSAIDs must be avoided. In neonates and small infants, the oral administration of sucrose or glucose is helpful to minimize pain reaction during short uncomfortable interventions.

Procedure‐induced Inflammation and Endothelial Cell Activation in an Artificially Ventilated and Circulated Porcine Double‐Lung Model

Systemic inflammation is induced during extracorporeal circulation, resulting in an increased bleeding tendency and endothelial cell activation. Lungs from seven piglets were perfused by autologous blood in an extracorporeal circuit, where the lungs and the left atrium were attached to polyvinyl chloride (PVC) tubings and the blood circulated by a roller pump. The trachea was intubated and attached to a ventilator. The lungs maintained good gas exchange, despite a slight increase in lactate levels. Plasma tPA increased slightly over time, suggesting endothelial cell activation. Activation of inflammatory systems was reflected in increased levels of plasma interleukin (IL)-6 and IL-10. A model for the study of lung endothelial activation during extracorporeal circulation has been shown to be reproducible. The lung tissue was shown to be capable of gas exchange and activation of endothelial cells and procedure-induced inflammation were noted.

Routine Measurement of Endogenous Thrombin Potential (ETP) To Assess Hemostatic Function in Patients with Liver Cirrhosis.

The maintenance of hemostasis through the production of most of the coagulation proteins is a basic liver function. In patients with cirrhosis of the liver the decrease in these proteins is one of the contributory factors to an increased bleeding tendency. Normally the hemostatic capacity of the liver is measured through routine clotting tests as the activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT). In the Child classification for liver cirrhosis the coagulation as expressed by the PT is one of the determinants.Recently a test has become available which will make it possible to routinely measure the endogenous thrombin generation potential (ETP) which may be a better alternative. In this test according to the method first described by Hemker (1993) thrombin generation is continuously measured by use of a chromogenic substrate. Results are calculated as area under the curve and as a percentage of normal.We analysed 110 patients with liver cirrhosis classified according to the Child classification, 79 patients with stage A, 19 stage B and 12 stage C, without known pre-existing coagulation abnormalities like inherited bleeding disorders, or anticoagulant drugs. In these patients ETP, APTT, PT/INR, FV, FVII and FXI were measured. We used a fully automated assay for the determination of the endogenous thrombin potential (ETP) on the BCS® System (both Dade Behring, Marburg, Germany).The results for the mean PT were 81% (CI95 77 - 85) for Child A patients, 53% (CI95 44 - 63) for Child B, and 41% (CI95 33 - 50) for Child C. For the mean INR the results were 1.11 (CI95 1.08 - 1.14) for Child A patients, 1.65 (CI95 1.22 - 2.08) for Child B, and 1.82 (CI95 1.34 - 2.31) for Child C. The results for the mean normalized ETP were 0.87 (CI95 0.84 - 0.90) for Child A patients, 0.78 (CI95 0.68 - 0.88) for Child B, and 0.58 (CI95 0.51 - 0.64) for Child C (p<0.001). While the normalized ETP correlated well with both PT and INR for Child B (P<0.05) and C (p<0.01), there were significant differences within the child A patients where no significant correlation could be identified (Pearson correlation 0.203, R2=0.04, p=0.075.We conclude that the fully automated assay for the determination of the endogenous thrombin potential (ETP) on the BCS® System (both Dade Behring, Marburg, Germany) is a potentially interesting test to measure the coagulation abilities in patients with liver cirrhosis which in the future may supersede the PT/INR in classification systems for hepatic disease.

Variable bleeding manifestations characterize different types of surgery in patients with severe factor XI deficiency enabling parsimonious use of replacement therapy

Surgery performed without blood component therapy in patients with severe factor XI deficiency can be accompanied by excessive bleeding in some but not all patients. In an attempt to minimize the use of blood derivatives, we carried out a retrospective analysis of bleeding complications in 120 patients with severe FXI deficiency (level of <1-15 U dL-1) who had undergone different types of surgical procedures without replacement therapy. Procedures at tissues exhibiting fibrinolytic activity were associated with bleeding in 49-67% of the patients, while procedures involving sites with no local fibrinolytic activity were associated with bleeding in 1.5-40%. The increased bleeding tendency at fibrinolytic site was significant (P=0.0015), but was unrelated to the genotype of the patients. Thus, parsimonious use of replacement therapy is possible in patients with severe FXI deficiency undergoing surgery predicting a decrease in the risks of volume overload, transfusion related acute lung injury, transmission of infectious diseases, thrombosis, allergic reactions and development of inhibitors to FXI.

Valproate‐associated Coagulopathies Are Frequent and Variable in Children

Valproic acid (VPA) is an antiepileptic drug (AED) commonly used for generalized and focal epilepsies. The clinical relevance of coagulopathies, known as side effects of VPA therapy, especially thrombocytopenia, von Willebrand disease, and a decrease of factor XIII, is still unclear. In our institute, we noticed a high incidence of clinically relevant coagulation problems related to VPA in eight patients within 1 year only and a further seven children with significant coagulopathy were identified in the context of planned surgery. We provide an overview of these patients and all six VPA-induced coagulopathies. At this time, it cannot be recommended to control all hemostatic parameters in every patient. Whenever an increased bleeding tendency is observed, or before surgical procedures, a platelet count, thrombelastography, prothrombin time, activated partial thromboplastin time, TT, fibrinogen, von Willebrand factor, and factor XIII should be examined. With 385 VPA-treated patients per year and 15 cases of coagulation disorders in this period, we estimate the incidence of coagulation disorders related to VPA in children to be nearly 4%.

Behandlung der Blutung unter Antikoagulation

The increased incidence in cardiovascular diseases has initiated research that finally led to improvements in prophylactic therapies that aim to prevent the occurrence of occlusive thromboses. Nowadays, the post interventional prophylaxis in the arterial system is mainly achieved by using antiplatelet drugs; in this setting, the combination of drugs with different mechanisms allow to achieve a maximum effect. This is important since patients with cardiovascular diseases often use multiple medications which by themselves can already induce a platelet dysfunction, increasing the potential for bleeding due to side effects. Prophylaxis for venous thromboembolism or in patients with heart valve replacements is still performed with coumarin derivatives in most instances. It is crucial to target an INR of 2.5 as close and as stable as possible, since INRs below 2.0 are associated with increased incidences of thromboses and those above 3.0 show an increased bleeding tendency. In cancer patients, prophylaxis of thromboembolism with low molecular weight heprin seems more efficient than with coumarin derivatives; this might be due to the fact that low molecular weight heparin not only seems to have an antithrombotic but also an anti-tumor effect. From a pharmacokinetic point of view, renal insufficiency is always to be considered and looked for in (especially elderly) patients undergoing LMWH therapy in order to avoid cumulation. In patients suffering from a thrombotic event during heparin therapy or in patients with a significant drop in platelet count during heparin therapy, heparin-induced thrombocytopenia should be considered as a differential diagnosis; in his case, vitally important diagnostic or therapeutic steps might have to follow. This review discusses the most frequent indications for anticoagulant therapy, potential side effects of this therapy and the management of these side effects.

Vitamin E and a-Lipoic Acid Supplementation Increase Bleeding Tendency via an Intrinsic Coagulation Pathway

Vitamin E and alpha-lipoic acid are potent nutritional antioxidants, and when used together, their antioxidant capabilities are improved as alpha-lipoic acid recycles vitamin E. Supplementation of vitamin E has been shown to prolong platelet aggregation but the effects of vitamin E and alpha-lipoic acid supplementation on bleeding tendency have yet to be reported. Young, male rats consumed either control diet (n=5) or vitamin E and alpha-lipoic acid-supplemented diet (n=5) for 14 weeks. Activated partial thromboplastin time (APTT) and prothrombin time (PT) were measured as markers of intrinsic and extrinsic coagulation pathways respectively in addition to lipid peroxidation (malondialdehyde). Supplementation significantly prolonged APTT (23.8+/-1.5 vs 31.4+/-1.2s, p<0.05) compared to the control diet; however, there was no significant difference in PT (27.8+/-1.5 vs 26.6+/-0.9s, p>0.05). While vitamin E was increased (p<0.05), there was no significant difference in plasma levels of malondialdehyde (p>0.05). Dietary supplementation of vitamin E and alpha-lipoic acid increases bleeding tendency via inhibition of the intrinsic coagulation pathway with no change in markers of lipid peroxidation. Such supplementation could benefit patients with cardiovascular disease who exhibit elevated levels of coagulation and oxidative stress.

Labor analgesia for the parturient with herbal medicines use: what does an obstetrician need to know?

The use of herbal medicines in the developed world is widespread, and increasing. Herbal medicines, which include a wide spectrum of substances ranging from home-made teas to the national regulatory bodies-approved medicinal substances, are defined as plant-derived products that are used for medicinal and/or nutritional purposes. The use of herbal self-therapy is common in pregnancy, with many parturients consuming more than one agent at a time. Despite widespread use there has been surprisingly little research into the outcomes or the potential risks of using herbal therapies during pregnancy. As epidural analgesia is the most popular form of pain relief in labor, the potential for herbal remedies-related alterations in maternal hemodynamics (e.g., hypertension, tachycardia), and increased bleeding tendencies (e.g., spinal-epidural hematoma) remain a significant concern. Obstetricians and obstetric anesthesiologists must be familiar with the effects of herbal medicines and should specifically inquire about the use of herbal medicines during prenatal/preanesthetic assessment. This review article attempts to summarize current data on special considerations for labor analgesia in parturients with herbal medicines use.

Evaluation of a Rapid Automated Assay for Analysis of von Willebrand Ristocetin Cofactor Activity

A commercially available turbidometric assay has been evaluated for the measurement of von Willebrand factor ristocetin cofactor activity (VWF:RCo). The assay is simple, rapid, and can be cost-effectively performed on automated coagulation analyzers. This study's aim is to illustrate the performance of the automated VWF:RCo assay and its capacity to identify patients with von Willebrand disease (VWD). By direct comparison with a conventional VWF:RCo assay, performed on an aggregometer, the concordance between the two assays was 96%. With minor modifications, the automated assay showed a detection level of 0.03 kIU/L with linearity to 2.00 kIU/L. The imprecision of the automated assay was reduced compared to the conventional assay procedure with CV of 6.8% at the 1.00 kIU/L level and 8.6% at the 0.30 kIU/L level. The automated VWF:RCo assay was also suitable as a screening test to detect VWD in patients investigated for the cause of an increased bleeding tendency. In this situation the automated VWF:RCo assay was tested simultaneously with an automated immunoassay for von Willebrand antigen. Receiver operating curves for the diagnosis of VWD showed a greater area under the curve for the automated VWF:RCo assay compared to the immunoassay, 0.98 vs. 0.94, although the difference did not reach significance. In conclusion, the modified automated VWF:RCo assay shows better precision, lower detection limit, is faster to perform with a lower cost per test compared to the conventional aggregometer based VWF:RCo activity method and is an alternative to an antigen immunoassay as a screening test for VWD.

Evaluation of low PAI-1 activity as a risk factor for hemorrhagic diathesis.

Prospective studies of the epidemiology and clinical significance of low plasminogen activator inhibitor type 1 (PAI-1) activity are lacking. To evaluate the prevalence of low PAI-1 activity in patients with a bleeding tendency in comparison with a normal population. In 586 consecutive patients, referred because of bleeding symptoms, we added analyses of PAI-1 activity and tissue plasminogen activator complex with PAI-1 (t-PA-PAI-1) to the routine investigation, consisting of platelet count, bleeding time, prothrombin time, activated partial thromboplastin time, fibrinogen, factor VIII, von Willebrand factor activity, and antigen. Controls were 100 blood donors and 100 age- and sex-matched healthy individuals. The latter were also evaluated regarding the previous bleeding episodes. The bleeding history was classified as clinically significant or not, and the criteria were fulfilled in 75% of the patients and 18% of the healthy controls. The routine laboratory investigation of the patients was negative in 57%. Low PAI-1 activity, defined as <1.0 U mL(-1), was found in 23% of the patients and in 13% and 10% of the blood donors and healthy controls, respectively (odds ratio and 95% CI, 2.04; 1.11-3.77 and 2.75; 1.39-5.42, respectively). The difference remained statistically significant after the adjustment for body mass index, use of estrogens, sex and age (odds ratio for patients vs. healthy controls 3.23; 95% CI, 1.22-8.56, P = 0.019). The distribution of the 4G/5G genotypes in the patients was not different from that of two control populations. No specific symptom predicted for low PAI-1, which did not aggravate the clinical picture in association with the other hemostatic defects. Low tPA-PAI-1 was not associated with the increased bleeding tendency. Low PAI-1 activity is common in patients with a bleeding diathesis, but it is a risk factor of minor clinical importance and not associated with specific bleeding manifestations.

Aspirin Induces Platelet Receptor Shedding via ADAM17 (TACE)

Aspirin is effective in the therapy of cardiovascular diseases, because it causes acetylation of cyclooxygenase 1 (COX-1) leading to irreversible inhibition of platelets. Additional mechanisms can be suspected, because patients treated with other platelet COX inhibitors such as indomethacin do not display an increased bleeding tendency as observed for aspirin-treated patients. Recently, aspirin and other anti-inflammatory drugs were shown to induce shedding of L-selectin in neutrophils in a metalloproteinase-dependent manner. Therefore, we investigated the effects of aspirin on the von Willebrand Factor receptor complex glycoprotein (GP) Ib-V-IX, whose lack or dysfunction causes bleeding in patients. As quantified by fluorescence-activated cell sorting analysis in whole blood, aspirin, but not its metabolite salicylic acid, induced dose-dependent shedding of human and murine GPIbalpha and GPV from the platelet surface, whereas other glycoproteins remained unaffected by this treatment. Biotinylated fragments of GPV were detected by immunoprecipitation in the supernatant of washed mouse platelets, and the expression level of GPIbalpha was decreased in these platelets as measured by Western blot analysis. Although shedding occurred normally in COX-1-deficient murine platelets, shedding was completely blocked by a broad-range metalloproteinase inhibitor and, more importantly, in mouse platelets expressing an inactive form of ADAM17. Shed fragments of GPIbalpha and GPV were elevated in the plasma of aspirin-injected mice compared with animals injected with control buffer. These data demonstrate that aspirin at high concentrations induces shedding of GPIbalpha and GPV by an ADAM17-dependent mechanism and that this process can occur in vivo.

Increased Bleeding Tendency in a Patient with Caffey Disease Due to a COL1A1 Mutation and a Defect in Platelet Morphology and Function.

Caffey disease or infantile cortical hyperostosis is characterized by hyperirritability, acute inflammation of soft tissues, and profound alterations of the shape and structure of particularly the long bones. This autosomal dominant disorder in 4 unrelated families is caused by a similar missense mutation (R836C) in the gene for the alpha1 chain of type I collagen (COL1A1; Gentile et al, JCI, 2005). The precise link between this mutation and either the localized inflammation problems or the originally described thrombocytosis and easy bruising associated with Caffey disease (Lorber et al, 1979) was not evidenced. In the present study, we studied the platelets from a 6-year-old girl with Caffey disease due to a de novo COL1A1 R836C mutation because of her increased bleeding tendency. Apart from the typical skeletal deformities she also presented with easy bruising. This COL1A1 mutation modulates normal megakaryopoiesis since the patient presented with a relatively high number of platelets (+/−450.000/mL) and a decreased MPV (7-8 fL). All other hematological parameters were normal. Electron microscopy further revealed platelets with a proliferation of the dense tubular system, a pronounced open canalicular system and a reduced number of often smaller dense granules. Platelet ATP secretion was reduced after stimulation with 5 mg/ml Horm collagen (2 mM: nl 3-7 mM). The PFA100 response with either collagen/epinephrine or collagen/ADP was within the normal range. Aggregation studies were suggestive for a selective impairment of platelet activation to collagen since the patient platelets showed a reduced and retarded response towards Horm Collagen, convulxin and the collagen related peptide (CRP-XL) but a normal aggregation with ADP, U46019 and arachidonic acid. Membrane glycoprotein (GP) profiling by flow cytometry showed a normal antibody binding to integrin beta3, integrin alpha2beta1 and GPVI. Since R to C amino acid substitutions in COL1A1 are associated with an increased disulfide crosslinking within mutant collagen fibers (Gentile et al, JCI, 2005) but also with other cysteine-containing proteins as integrins, we hypothesized that the platelet integrins might be triggered when mature megakaryocytes are in contact with the collagen type I of the extracellular matrix of the patients bone marrow. Immunoblot analysis of platelet lysates from the patient indeed showed the presence of a 190 kDa COL1A1 band, which could not be detected in control samples. In addition, beta1 integrin could be co-immunoprecipitated with an anti-COL1A1 antibody in platelet lysates from the patient. Further studies are needed to determine whether this COL1A1 R836C binding to platelet collagen receptors is responsible for the defective collagen signaling in this patient by receptor desensitization. In conclusion, we here present the first collagen type I mutation that leads to a defective platelet ultra structure and function.

Allogeneic Bone Marrow Transplantation in a Child with Hemophilia A and Severe Aplastic Anemia.

Hemophilia A is a blood clotting disorder characterized by a mutation of the factor VIII (FVIII) gene, leading to a deficiency in FVIII. It is the most common type of hemophilia. Inheritance is X-linked; hence males are affected while females are carriers or very rarely display a mild phenotype. 1:10,000 males are affected. We describe a child with a rare association of congenital hemophilia A and acquired severe aplastic anemia (SAA) who was successfully treated with allogeneic bone marrow transplantation (allo-BMT). A 6-year old male, SG, was diagnosed with hemophilia A (FVIII 3%) at 6-month old when he presented with right knee hemarthroses and psoas muscle hematoma. His maternal grandfather was hemophiliac. Since his diagnose, FVIII was infused on average once a month, generally due to hemarthroses and bleeding secondary to trauma. In July 2004, pt presented with progressive pancytopenia. In January 2005 CBC showed: Hb 7g/dl, Ht 22%, WBC 1000/μl (absolute neutrophil count 250/μl) and PLT 23,000/μl. Bone marrow aspirate and biopsy were consistent with SAA. DEB test was negative. Since then he was poly-transfused with PLT and RBC due to increased bleeding tendency, especially hematoma and petechiae. In July 2005 he underwent an allo-BMT from his HLA-identical non-hemophiliac 5-year old brother. For catheter implantation pt received PLT transfusion to achieve a PLT level greater than 50,000/mm3 and 60 units/kg of FVIII to achieve an initial level of 100% followed by 30 units/kg every 12 hours to maintain it continuously at greater than 50% for 3 days. Conditioning consisted of cyclophosphamide 50mg/day from D-5 to D-2 and thymoglobulin 5mg/kg from D-3 to D-1. Cyclosporine and a short course of methotrexate were given for GVHD prophylaxis. 3,5x108 mononuclear cells/kg were infused. Allo-BMT was uneventful. Neutrophil engrafted on D+15 and megakaryocyte (>50,000/mm3) on D+38. During the transplant PLT were kept at greater than 30,000/mm3 with PLT transfusion every 2 days. FVIII was infused when there was more than 2 cm increase in the knee perimeter or any other abnormal bleeding, especially at the catheter implantation site. 6 months after allo-BMT the child is well, with a normal CBC and coagulation tests similar to pre-BMT. Hemophilia and AA association is rare, and to our knowledge, this is the first allo-BMT in a hemophiliac patient to be reported.

Spontaneous intracranial meningioma bleeding: clinicopathological features and outcome

The aim of this study was to determine the clinicopathological features of patients with intracranial bleeding from unsuspected meningioma and to relate these data to surgery-related outcome. The authors report on two cases in which hemorrhage of an unsuspected meningioma occurred in the tentorial ridge and in the falx, and they discuss the details of 143 cases described in the literature. A bleeding propensity index of the meningioma, related to the patient's age, sex, and the lesion's intracranial location and histological type was computed as a ratio between the frequencies of bleeding meningioma and all meningiomas. This was tested by independent samples t-test for proportions. A chi-square test was used to determine the correlations between several variables: location and type of bleeding; survival and type of bleeding; and consciousness and survival. Increased bleeding tendency was found to be associated with two age groups (< 30 years and > 70 years), convexity and intraventricular locations, and fibrous meningiomas. The overall mortality rate documented in cases of bleeding meningiomas was 21.1% (13.9% in the computerized tomography [CT] scanning era), and that in surgically treated cases was 9.5% (7.5% in the CT scanning era). The overall major morbidity rate was 36% (33.8% in the CT scanning era). Overall 96.2% of conscious patients survived after their meningiomas spontaneously hemorrhaged. In patients who were unconscious before surgery, overall mortality rate was 74.1%, and that in surgically treated cases was 46.2%. The mortality rate in preoperatively conscious patients (those in whom acute deterioration and irreversible brain damage were prevented by early diagnosis and definitive surgery) was similar (< 3% in the CT scanning era) to that documented in cases in which meningiomas did not bleed. In contrast, the associated morbidity rates were much higher. One-stage total removal of the hemorrhagic meningioma and hematoma is the treatment of choice in such patients.

Duration of increased bleeding tendency after cessation of aspirin therapy

Aspirin has a significant effect on hemostasis, so it is often recommended that patients taking aspirin discontinue treatment before elective surgery. While off aspirin, these patients may be at risk of thrombosis. The optimum period of time that aspirin should be withheld is controversial. The aim of this study was to establish the duration of the antihemostatic effect of prolonged aspirin therapy. In a prospective study, 51 healthy volunteers were randomly assigned into 3 groups, each receiving an identical tablet for 14 days. One group received a placebo tablet; individuals in the other two groups received either 75 mg or 300 mg of aspirin once a day. Template bleeding times and specific platelet function testing (using the PFA-100; Dade Behring) were carried out on subjects before therapy and again after its completion until they returned to baseline. Thirty-eight volunteers complied sufficiently with the protocol to provide useful results. All bleeding times normalized within 96 hours and all platelet function tests within 144 hours after stopping aspirin. There was no demonstrable hemostatic defect in any volunteer persisting by or beyond the sixth day after treatment cessation. There was no apparent difference in duration of effect between those taking either 75 mg or 300 mg of aspirin. This study uses sensitive measures of platelet function to demonstrate the duration of increased bleeding tendency after withdrawal of aspirin therapy. It supports discontinuation of aspirin therapy 5 days before elective surgery (with the operation being performed on the sixth day).

A Case of Soft Tissue Bleeding Due to a Possible Drug Interaction between Warfarin and TS-1

Warfarin is one of the most commonly used oral anticoagulant. It is well established that a wide range of drugs, including the anticancer drug 5-fluorouracil, interact with warfarin; this results in altered coagulation parameters and bleeding sequelae. To date, any drug interaction between warfarin and TS-1 has not been reported on. A 58-yr old woman visited emergency department with gross hematuria and soft tissue swelling involving her left thigh and buttock. She had been diagnosed as having advanced colon cancer (Duke's classification D); she had undergone right hemicolectomy and partial hepatectomy, and she had received 5-FU/leucovorin chemotherapy two years pri or to admission. Recurrent disease was revealed in the liver and lungs, and so 6 cycles of FOLFIRI (5-FU, leucovorin and irinotecan) chemotherapy were given. Follow-up abdominal CT scan showed progressive disease and then TS-1 oral chemotherapy was started. She took warfarin 2mg per day because of partial thrombosis in the lower inferior vena cava and left ovarian vein. The initial laboratory tests revealed a prothrombin time of 120 seconds and an international normalized ratio of 35. Fresh frozen plasma and a parenteral vitamin K injection were given. After resorption of the subcutaneous hematoma, warfarin was restarted at a dose of 1mg per day. This case shows the significant increased bleeding tendency following the combined administration of warfarin and TS-1. Because of the potential severity of this interaction, close monitoring of the coagulation parameters is recommended for patients receiving warfarin together with TS-1. (Korean J Hematol 2005;40:271-273.)

Emboli Rate During and Early after Carotid Endarterectomy after a Single Preoperative Dose of 120 mg Acetylsalicylic Acid—A Prospective Double-Blind Placebo Controlled Randomised Trial

Purpose To investigate whether a single pre-operative dose of 120 mg acetylsalicylic acid (ASA) decreased either (1) emboli rate, as detected by transcranial Doppler (TCD), during and early after carotid endarterectomy (CEA) and (2) clinical intra- and post-operative signs suggestive of embolism or increased bleeding tendency. Design Prospective, double-blind placebo controlled trial. Patients and methods One-hundred consecutive patients were randomised to receive either 120 mg ASA ( n=48) or placebo ( n=49) by suppository on the night before CEA; three patients were excluded. Emboli were counted and expressed as emboli rate (ER). The incidence of bleeding complications was assessed. Surgeons were asked to indicate which patients had received ASA or placebo. Results There were no significant differences between the ASA and placebo groups in ER in the intraoperative and postoperative periods. ER higher than 0.9 min −1 was associated with a significantly increased risk of complications (26 vs. 0%, P<0.01). No extra bleeding complications were observed in the ASA group. Surgeon assessment of whether or not ASA had been administered had a sensitivity of 42% and a specificity of 70%. Conclusion A single pre-operative dose of ASA (120 mg) did not reduce significantly the emboli rate during and after CEA and surgeons could not correctly identify whether or not ASA had been administered.

Impedance-Based Whole Blood and Optical-Based Platelet Rich Plasma Aggregation Methods for the Assessment of Celexocib Effects on Platelet Function: A Preliminary Report.

Cyclooxygenase-2 (COX-2) is the inducible cyclooxygenase isoform expressed by cells involved in inflammation. Platelets normally lack COX-2; however, the enzyme is expressed in megakaryocytes and newly formed platelets and may play a role in clinical syndromes associated with high platelet turnover (1, 2). Selective COX-2 inhibitors (coxibs), have become the mainstay for treatment of patients with arthritis and also have been widely used in cancer chemoprevention. Coxibs were found to have a safer GI toxicity profile when compared with classic NSAIDS; however, in some patients they may increase the risk of GI bleeding (3). The underlying mechanism has not yet been elucidated. Moreover, the role of coxibs in hemostatic alterations has been a subject of controversy. The aim of the study was to investigate the possible anti-platelet effects of celecoxib (200 mg/d for 7 days) in 7 healthy volunteers (2 females, 5 males; mean age = 35.7 ± 8; mean platelet count = 230 ± 23; mean Ht = 42.3 ± 6). A very sensitive whole blood impedance platelet aggregation assay, previously unused for this purpose, was employed for the assessment of celecoxib influence on platelet function. The test was performed along with a traditional, optical-based platelet rich plasma (PRP) aggregation method. Arachidonic acid (0.5; 0.25 mM), Collagen (2; 1mg/mL) and ADP (20, 10 mM) were used as platelet agonists in both tests.Celexocib did not affect platelet function in neither whole blood nor in PRP. The preliminary results of this study indicate that the increased bleeding tendency in patients treated with celecoxib is probably not related to platelet dysfunction.AssayArachidonic AcidCollagenADP0.5[mM]0.25[mM]2[μg/mL]1[μg/mL]20[μM]10[μ M]WB Impedance17.5±4.720.9±3.825.4±3.925.9±6.114.3±2.614.1±5Aggregation: Pre-drugPost-drug18±421±527.1±4.724±418.7±6.216.3±7PRP Optical118.1±10.3118.1±6.7101.4±13.7110±2.2104±15108±8.9Aggregation: Pre-drugPost-drug119.6±6.7112.9±10.2105.4±11.5110.4±7.5102.1±18.3107.7±9.6

Venous thromboembolism and escitalopram

Selective serotonin reuptake inhibitors (SSRIs) are currently used as a first-line treatment for depression, as they have a favorable side-effect profile. Escitalopram, a new SSRI, is also well-tolerated and serious side effects are rarely associated with its use. There have been several reports that SSRIs might increase bleeding tendency in some patients by affecting platelet function. However, to our knowledge, there have been no reports about their relation to thrombosis. In this brief report, we present a case of venous thromboembolism associated with escitalopram in a patient with psychotic depression without any major risk factors for thrombosis. SSRIs might have a dual effect on platelet function. The immediate and early effect of SSRI use on platelets might be an increase be an in tendency for thrombosis, whereas the late effect after repeated dosing might be an increase in tendency to bleed, as suggested by previous literature.