A study of the influence of lead pollution on the anticoagulant activity of Whitmania pigra based on pharmacodynamics and metabolomics research.

Whitmania pigra Whitman (leech, also called Shuizhi in China, abbreviated as SZ), which has been used as a traditional Chinese medicine in the treatment of blood stasis syndrome (BSS) for a long time, is vulnerable to lead pollution in aquaculture environments. SZ has good anticoagulant activity. However, there are few studies on the influence of lead pollution on it. Therefore, we carried out the following researches to explore the influence of lead pollution on the anticoagulant activity of SZ and its mechanism. Firstly, the acute blood stasis model of rats was established by subcutaneous injection of adrenaline hydrochloride and ice water bath. Then unpolluted SZ (UPS) and lead-polluted SZ (LPS) were extracted. Next, the blood stasis model rats were administrated by gavage and the rats in normal control (NC) group and blood stasis model (BM) group were given the same amount of normal saline. Finally, the blood of the rats was collected to detect the coagulation function and hemorheology indexes. The metabolomics of rat plasma was studied by ultra-high-performance liquid chromatography coupled with orbitrap mass spectrometry (UPLC-Orbitrap-MS) technology. Principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA) and Hierarchical clustering analysis (HCA) were used to perform metabolomics analysis. MetPA analysis was used to search for related metabolic pathways. The results of coagulation function and hemorheology showed that lead pollution could decrease the anticoagulant activity of SZ. The OPLS-DA score plots indicated that the plasma metabolites of rats in LPS group were close to BM group, while UPS group tended to be close to NC group both in the positive and negative ion mode. Hierarchical cluster analysis (HCA) suggested that UPS group and NC group were clustered into a branch, while LPS group and BM group were clustered into a branch. To sum up, lead pollution will reduce the anticoagulant activity of SZ. And lead pollution reduces the anticoagulant activity of SZ probably by influencing the metabolic pathways such as sphingolipid metabolism, amino acid metabolism and energy metabolism in rats.

Effect Of Justicia Adhatoda (Malabar Nut) Leaf Extract On Drug-Induced Coagulopathy In Mice And In-Vitro Platelet Aggregation Of Human Blood.

BACKGROUND: Justicia adhatoda is widely used in traditional medicine for treatment of menorrhagia, piles and bleeding disorders. Oral antiplatelet and anticoagulant drugs are routinely prescribed to patients with cardiovascular diseases. These drugs have one major adverse effect that they can cause spontaneous haemorrhage, which can be fatal. Development of a haemostatic agent can help in effective management of drug-induced haemorrhages. This study was devised to observe the effect of leaf extract of Justicia adhatoda on coagulation profile in mice and to evaluate its effect on in-vitro platelet aggregation. METHODS: The study was divided into two parts. First part was designed to evaluate the effect of J. adhatoda leaf extract on coagulation parameters. Three drugs were used to induce coagulopathy viz., warfarin, aspirin and dabigatran. Bleeding time, platelet count, PT and APTT were estimated. Second part of this study was devised to observe the effect of J. adhatoda leaf extract on in vitro platelet aggregation of human. Percent aggregation was recorded by light transmission aggregometer for three minutes. RESULTS: Leaf extract of Justicia adhatoda decreased bleeding time from 6.1±2.36 minutes in normal control to 1.9±1.03 minutes in extract treated mice. There was no effect on the coagulation parameters. Platelet count increased significantly only in the aspirin treated group that received the extract to 540±46.8x103 /µl from 436.9±37.9x103 /µl of aspirin treated group. Platelet aggregation in vitro increased in a dose dependent manner. CONCLUSION: Justicia adhatoda leaf extract is effective in controlling excessive bleeding in vivo, in mice with acquired platelet defect produced by aspirin. This haemostatic effect is probably due to increased platelet aggregation as indicated by the in vitro results.

Small intestinal bacterial overgrowth (SIBO) and vitamin K-responsive coagulopathy: a previously unrecorded association.

A 17-year-old woman, with a history of three operations on the upper gut in early life and intermittent diarrhoea, presented with a history of epistaxis and leg ecchymosis for the previous 3 months. Initial investigation revealed mild anaemia, low serum albumin, moderately elevated aminotransferases and an exceedingly prolonged prothrombin time (PT) which was promptly shortened to normal by intravenous vitamin K. Additional investigations revealed a grossly abnormal glucose hydrogen breath test, a dilated duodenum and deficiencies of vitamins A, D and E. Repeated courses of antimicrobial agents caused prompt but transient shortening of PT and eventually a duodenal-jejunal anastomosis was performed. Since then, up to 36 months later, the patient has been in good general health and PT has been consistently normal with no vitamin K supplementation. Small intestinal bacterial overgrowth has previously been associated with several conditions but this is the first description of its association with vitamin K-responsive coagulopathy.

Effectiveness and Safety of Treatment with Direct Oral Anticoagulant Rivaroxaban in Patients with Slow-Flow Vascular Malformations: A Case Series.

BACKGROUND: Slow-flow vascular malformations (VM) can be associated with localized intravascular coagulopathy (LIC) that is characterized by elevated D-Dimer levels and low fibrinogen and platelets. This can lead to bleeding and clotting tendencies, which can give rise to functional limitations such as pain and swelling and even progress to disseminated intravascular coagulopathy. METHODS AND RESULTS: We conducted a chart review of four patients with evidence of LIC who were started on rivaroxaban. We found an improvement of D-Dimer and/or fibrinogen levels in all four patients. They also had an improvement of pain and functionality. CONCLUSIONS: We report on four patients in whom anticoagulation with a direct oral anticoagulant, rivaroxaban, was effective in controlling signs and symptoms of consumptive coagulopathy with no evidence of bleeding from the use of rivaroxaban.

Prolonged coagulopathy after brodifacoum exposure.

PURPOSE: A case of brodifacoum exposure leading to coagulopathy lasting for approximately one year despite treatment with large doses of phytonadione is reported. SUMMARY: A 36-year-old man was diagnosed with severe coagulopathy. He was treated and discharged on 40 mg of oral phytonadione daily. The cause of the coagulopathy remained unknown at discharge, but the hematologist theorized that exposure to a vitamin K antagonist was likely the source of the patient's condition. The patient was rehospitalized one week later with an International Normalized Ratio (INR) of 5.9 despite self-reported medication compliance. Oral phytonadione was increased to 80 mg daily. The patient was seen at an outpatient hematology clinic for several months and continued on tapering dosages of oral phytonadione. A coagulopathy panel from the original hospitalization confirmed the presence of brodifacoum, though the method of exposure remained unclear. He was lost to follow-up until approximately nine months later, when he reported taking 10 mg daily of oral phytonadione and had an INR of 1. Oral phytonadione was discontinued. Two months later, his INR was greater than 9, despite an undetectable level of brodifacoum. He was rehospitalized with oropharyngeal hematoma approximately 1 year after the initial coagulopathy diagnosis. The patient was discharged on 40 mg oral phytonadione daily with outpatient follow-up. CONCLUSION: A patient with brodifacoum exposure ingested brodifacoum had coagulopathy that lasted approximately one year despite long-term treatment with large dosages of oral phytonadione. The coagulopathy persisted even when brodifacoum was undetectable in the serum. Long-term treatment with high-dose phytonadione is expensive, which may influence medication compliance.

[Evaluate activating blood circulation and dissipating blood stasis effect mechanism of foshousan on acute blood stasis rats on basis of metabolomic approach].

Ice water bath and subcutaneous injection of adrenaline were used to establish the acute blood stasis model of rats. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to study the urine metabolic changes of acute blood stasis rats. Potential biomarkers were selected by variable importance projection, and identified on basis of MS information and databases. The metabolic pathways were predicted via MetPA database. To study the effect of Foshousan on endogenous metabolites of acute blood stasis model rats, find potential biomarkers, and explore the effect mechanism of Foshousan on activating blood circulation and dissipating blood stasis. Eleven potential biomarkers were identified with multivariate statistical analysis of urine metabolite profiles, and which also were used to explain the phenylalanine metabolism, tryptophan metabolism and sphingolipid metabolism. Those disturbed metabolic pathways in acute blood stasis rats could be regulated closely to normal state after Foshousan administration. Metabolomics has a bright prospect in the efficacy evaluation and effect mechanism elucidation of the traditional Chinese medicines.

Special Care Dentistry: Part 2. dental management of patients with drug-related acquired bleeding disorders.

UNLABELLED: The first of this series of three articles discussed the dental management of patients with inherited bleeding disorders. This paper will discuss and outline the dental management of patients with acquired bleeding disorders that can result from drug therapy. These may be associated with vascular defects, platelet defects or coagulation defects. In an age when people are living longer, and medical interventions are continually becoming more advanced, clinicians will need to be aware of systemic disorders and treatments that may cause complications in the dental setting. According to National Statistics, the UK population is projected to increase by 0.7% by 2016. This trend is shared with other European countries which also have ageing populations. The proportion of people aged over 65 is predicted to increase from 16% in 2006 to 22% in 2031. CLINICAL RELEVANCE: Being able to recognize which drugs may cause bleeding problems at an early stage will lead to good patient management, particularly in planning and delivering treatment following invasive procedures such as dental extractions. Whilst most patients can be successfully treated in general dental practice, the clinician may need to make a decision on whether or not to refer a patient to specialist services for all dental treatment, or to share care between primary care and specialist services for selected procedures.

Obesity in pregnancy: problems and potential solutions.

Recent years have witnessed an increase in the prevalence of maternal obesity during pregnancy in the United States and worldwide. Obese women have increased risks for gestational problems, such as diabetes, hypertension, and pre-eclampsia. Further, gestational obesity can adversely impact fetal growth and result in macrosomia, congenital abnormalities, and even fetal death. Measures must be taken to reduce maternal adiposity, as even a modest weight loss during pregnancy is beneficial for the health of mothers and fetus. Calorie restriction and moderate exercise are proven safe methods of stopping weight gain and/or inducing white-fat loss in these subjects. Additionally, therapeutic drugs that activate the AMP-activated protein kinase signaling pathway may be effective in ameliorating pathological conditions in obese patients. Finally, dietary supplementation with L-arginine or its effective precursor (L-citrulline) may be beneficial for managing overweight or obese gestating women by reducing white-fat accretion. Because of ethical concerns over human studies, animal models (e.g., sheep, pigs, baboons, rats, and mice) are warranted to test novel hypotheses with enormous biological significance and clinical applications.

Role of orally available antagonists of factor Xa in the treatment and prevention of thromboembolic disease: focus on rivaroxaban.

Interpatient variability in the safety and efficacy of oral anticoagulation with warfarin presents several challenges to clinicians, thus underscoring the emergent need for new orally available anticoagulants with predictable pharmacokinetic and pharmacodynamic profiles and ability to target circulating clotting factors. Seven compounds including rivaroxaban, apixaban, betrixaban, and eribaxaban are orally available direct inhibitors of activated factor X currently in development for the prevention and treatment of venous thromboembolism and for thromboprophylaxis in patients with atrial fibrillation or following an acute coronary syndrome. At doses used in phase 2 and 3 clinical trials, rivaroxaban and apixaban demonstrated a predictable onset of effect, maximal plasma concentration, and half-life that was unaffected by age, renal, or hepatic disease. In clinical trials for the treatment and prevention of venous thromboembolism, rivaroxaban and apixaban produced equivalent or superior reductions in the development or progression of venous thromboembolism compared with either low molecular weight heparin or warfarin. Trials comparing the efficacy of rivaroxaban or apixaban to standard therapy for stroke prophylaxis in patients with atrial fibrillation are in process. Rivaroxaban, the sentinel compound in this class, is already approved in the European Union and Canada. It is likely to be approved for use in the United States in 2010.

Cerebral venous thrombosis associated with iron deficiency anemia.

A 55-year-old man presented with generalized seizures and postictal left hemiparesis. Computed tomography scanning of his head showed a low density area in the right frontal lobe. Cerebral angiography demonstrated a partial defect in the superior sagittal sinus and cortical veins, indicating the presence of cerebral venous thrombosis. He had bleeding from a peptic ulcer and the laboratory data revealed iron deficiency anemia concomitant with an elevation of D-dimer and thrombin-antithrombin III complex (TAT). After the anemia resolved with the treatment of the peptic ulcer and iron supplementation, the TAT and D-dimer levels were normalized, and the occluded veins were recanalized. In a cerebral venous thrombosis associated with iron deficiency anemia, treatment for the anemia may improve hypercoagulable state without antithrombotic therapy, although the long-term monitoring of TAT and D-dimer levels is required.

Therapeutic effect of traditional Chinese medicine on coagulation disorder and accompanying intractable jaundice in hepatitis B virus-related liver cirrhosis patients.

AIM: To observe the therapeutic effects of new traditional Chinese medicine (TCM) therapy on coagulation disorder and accompanying intractable jaundice in HBV-related liver cirrhosis patients. METHODS: Using stratified random sampling according to fibrinogen (Fib) levels, 145 liver cirrhosis patients due to hepatitis B complicated by coagulation disorder were treated. Of them, 70 in research group were treated with TCM by "nourishing yin, cooling blood and invigorating blood circulation" and Western medicine, 75 in control group were treated with conventional Western medicine. The indexes of liver function, coagulation function and bleeding events were observed and compared. RESULTS: The prothrombin time (PT) was shorter and the fibrinogen (Fib) level was higher in the research group than in the control group (Fib = 1.6-2.0 g/L, 1.1-1.5 g/L, and < or = 1.0 g/L). The total bilirubin (TBIL) level was significantly lower in the research group than in the control group, except for the subgroup of FIB < or = 1.0 g/L. CONCLUSION: TCM therapy can improve coagulation fuction and decrease TBIL.

[Recombinant activated factor VII as a life-saving therapy for severe postpartum haemorrhage unresponsive to conservative traditional management]. / Intérêt du facteur VII activé recombinant dans l'hémorragie de la délivrance sévère réfractaire à la prise en charge conservatrice conventionnelle.

Postpartum haemorrhage remains the main cause of maternal morbidity and mortality. Treatment aims at maintaining hemodynamic circulation and preventing shock by stopping blood loss both medically and surgically. We report two cases of major postpartum haemorrhage due to uterine atony. Patients developed haemorrhagic shock and severe coagulation disorders (nadir values of PTT were <10% and fibrinogen was <0.1 g/l). Well-codified medical (ocytocin, sulprostone) and surgical management (ligation of both hypogastic arteries in the two cases completed by staged uterine ligation in one case) failed to stop bleeding. Recently, several case reports described successful use of recombinant activated factor VII (rFVIIa) in scheduled surgery, trauma and major postpartum haemorrhage. Thus, after transfusion of more than one blood mass and failure of surgical haemostasis to stop bleeding, rFVIIa (60 microg/kg) was given. A single iv bolus injection stopped ongoing diffuse haemorrhage in the two cases. No further transfusion was required afterwards in both patients. RFVIIa might thus be a strong complementary agent in the management of major postpartum haemorrhage. Optimal dose, timing and safety characteristics of rVIIa administration remain to be determined. One patient developed four weeks later thrombosis of both ovarian veins, a complication that can be related to either rFVIIa or to the staged uterine ligations performed during surgery.

[Effect of Kampo medicines on the peripheral blood flow rate of betamethason-induced Oketsu syndrome mice by laser Doppler flow meter].

Stagnation of peripheral blood flow is the cause of various diseases. Changes in peripheral blood flow after oral administration of Kampo medicines in mice with betamethasone-induced oketsu syndrome and normal mice were examined using a laser Doppler blood flow meter. The Kampo medicines used were: Toki-shakuyaku-san; Kami-shoyo-san; Keishi-bukuryo-gan; Daio-botanpi-to; Tokaku-joki-to; Goshuyu-to; and Hange-koboku-to. In the oketsu mice, blood flow was improved by single-dose administration of Toki-shakuyaku-san, Kami-shoyo-san, Keishi-bukuryo-gan, Daio-botanpi-to, Tokaku-joki-to, and Goshuyu-to, but only Toki-shakuyaku-san increased blood flow significantly in normal mice. In addition, blood flow decreased after single-dose administration of Keishi-bukuryo-gan, Daio-botanpi-to, and Tokaku-joki-to in normal mice.

[Haemostaseological aspects of perioperative blood management]. / Hämostaseologische Aspekte des perioperativen Blutmanagements.

Recent studies in humans have shown that tissue factor on the surface of endothelial cells, monocytes, or subendothelial structures sparks plasmatic coagulation. In vivo, there is no functional separation of an "endogenous" and "exogenous" pathway of the coagulation cascade. However, global laboratory tests run along such pathways due to preincubation with specific activators and, hence, allow localization of inherited coagulation defects. Coagulation inhibitors such as antithrombin or activated protein C are accelerated in their activity by cell surface glycoproteins and almost completely inactivate procoagulant activity in the microcirculation. Antithrombin binds to endothelial glycosaminoglycans and then significantly increases anticoagulant activity. Protein C is activated by the thrombin-thrombomodulin-complex and inactivates factors V a and VIII a, respectively. Additionally, activated protein C has a profibrinolytic effect. Both systems physiologically counteract the procoagulant transformation of endothelial and monocyte cell surfaces which occurs in critically ill patients due to induction of tissue factor, suppression of thrombomodulin, and removal of glycosaminoglycans from the cell surface. The distinction of static and dynamic coagulation disorders is useful since static disorders seldom require therapeutic interventions although global laboratory tests may continuously deteriorate. Dynamical disorders are symptoms of an underlying disease, and consumption coagulopathy with disseminated fibrin deposition and oozing occurs when coagulation turnover cannot be stopped. Antithrombin substitution is a well documented therapeutic option along with fresh frozen plasma and erythrocyte concentrate transfusion for blood substitution. Recent case reports in patients with irreversible bleeding complications favour the application of a recombinant factor VII concentrate. A rising perspective to decrease the use of heterologous blood and blood products may be intraoperative plasma retransfusion. The quality of such plasma undergoing consecutive filtration steps has to be clinically studied. The application of a synthetic platelet substitute, the "plateletsome", containing platelet glycoproteins led to significantly improved haemostasis without generating systemic procoagulant activity. In a far future, procoagulant cell surface transformation may be influenced by topic application of inhaled thrombomodulin loaded liposomes or by sense or antisense oligonucleotides inducing thrombomodulin expression or suppressing tissue factor expression, respectively.

Long-latency event-related potentials in acute hepatitis patients with severe coagulopathy.

In 19 acute hepatitis patients with severe coagulopathy who were fully alert and oriented without any changes of mood or behavior, the P300 latency and the arterial blood ketone body ratio (KBR) were assessed as predictors of fulminant hepatitis. All 5 patients developing fulminant hepatitis had a corrected P300 latency longer than 345 msec and 4 of them had a KBR below 0.6. There was a significant negative correlation between the KBR and the blood ammonia level and between the KBR and the corrected P300 latency, while there was a positive correlation between the blood ammonia level and the corrected P300 latency. These data suggest that hepatic encephalopathy develops when loss of hepatic detoxifying activity allows toxic substances to reach the brain and induce cerebral edema. Our findings also suggest the clinical value of using the P300 latency combined with the KBR as predictors of fulminant hepatitis.

[Mediators and ARDS]. / Mediatoren und ARDS.

The symptoms of adult respiratory distress syndrome (ARDS) include dyspnea, tachypnea, hypoxemia refractory to supplemental oxygen and bilateral infiltrations in the chest X-ray. Neutrophils are implicated in the pathogenesis as important effector cells acting by release of mediators. Activation of the complement system has been shown in several studies and can induce lung damage directly in animal models. Proteases and collagenase have been found in elevated concentration in bronchoalveolar lavage fluid, while the amount of protease-inhibitors has been found to be reduced. Arachidonic acid metabolites of the cyclooxygenase and lipoxygenase pathway, such as prostaglandins and leukotrienes, may play a role in the pathogenesis or perpetuation of the disease process. The same holds true for cytokines such as interleukin-1 or tumor necrosis factor. All of them have been found to be elevated either in plasma or bronchoalveolar lavage fluid of ARDS patients. Several lines of evidence implicate oxygen radicals as important mediators of lung damage in ARDS. The therapeutic implications of these new insights into the pathogenesis of ARDS are briefly discussed.

Avoiding coagulopathy in vascular surgery.

The possibility of coagulopathy can be minimized by attending to certain general perioperative details to avoid hypothermia, hypotension-shock, and multiple transfusions. In this paper, we present our protocol for avoiding coagulopathy in vascular surgery. In the past 1 1/2 years, we have used perioperative plasmapheresis in 204 patients undergoing cardiac or aortic peripheral vascular surgery. Autologous platelet-rich plasma is transfused at the completion of the operation after heparin reversal. Our data show an approximate 50% reduction in homologous blood product requirement. Seventy-five percent of patients having aortic surgery received no homologous blood products during their hospital stay. For those undergoing cardiac surgery, there has been about a 45% reduction in the use of homologous blood products. In our experience, autologous platelet-rich plasma not only decreases the risk of transmittable disease, but promotes hemostasis.

Participation of Hageman factor dependent pathways in human disease states.

Abnormalities of Hageman factor dependent pathways have been described in a wide variety of human disease states. Congenital deficiencies of factor XII (Hageman trait) prekallikrein (Fletcher trait) and high molecular weight kininogen (Williams, Fitzgerald and Flaujeac traits) although resulting in profound in vitro changes, do not cause in vivo difficulties. In contrast, deficiency of C1 esterase inhibitor (hereditary angioedema) results in significant morbidity and mortality. Acquired diseases may exhibit decreased synthesis of these three proteins in cirrhosis and dengue fever. In vivo activation of factor XII initiated pathways occur in septic shock, disseminated or localized intravascular coagulation, typhoid fever, polycythemia vera, hyperbetalipoproteinemia, coronary artery disease, nephrotic syndrome, transfusion reactions, hemodialysis and extracorporeal bypass. Activation of both the intrinsic system and tissue mediators contribute to the vasomotor phenomena in carcinoid syndrome and postgastrectomy dumping. Roles for factor XII, prekallikrein and kininogen have been suggested in gouty arthritis, allergic disorders and cystic fibrosis but the evidence is not yet convincing in these disorders.