Extrinsic Coagulation Pathway Research Articles

Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) display an elevated risk of thrombosis. Thrombosis occurs in cardiovascular events, such as venous thromboembolism, stroke, and acute coronary syndrome, and is a cause of hemodialysis vascular access dysfunction. CKD leads to the accumulation of uremic toxins, which exerts toxic effects on blood and the vessel wall. Some uremic toxins result from tryptophan metabolization in the gut through the indolic and the kynurenine pathways. An increasing number of studies are highlighting the link between such uremic toxins and thrombosis in CKD. In this review, we describe the thrombotic mechanisms induced by tryptophan-derived uremic toxins (TDUT). These mechanisms include an increase in plasma levels of procoagulant factors, induction of platelet hyperactivity, induction of endothelial dysfunction/ impairment of endothelial healing, decrease in nitric oxide (NO) bioavailability, and production of procoagulant microparticles. We focus on one important prothrombotic mechanism: The induction of tissue factor (TF), the initiator of the extrinsic pathway of the blood coagulation. This induction occurs via a new pathway, dependent on the transcription factor Aryl hydrocarbon receptor (AhR), the receptor of TDUT in cells. A better understanding of the prothrombotic mechanisms of uremic toxins could help to find novel therapeutic targets to prevent thrombosis in CKD.

Tissue factor: newer concepts in thrombosis and its role beyond thrombosis and hemostasis.

For many years, the attention on tissue factor (TF) in human pathophysiology has been limited to its role as initiator of extrinsic coagulation pathway. Moreover, it was described as a glycoprotein located in several tissue including vascular wall and atherosclerotic plaque. However, in the last two decades, the discovery that TF circulates in the blood as cell-associated protein, microparticles (MPs) bound and as soluble form, is changing this old vessel-wall TF dogma. Moreover, it has been reported that TF is expressed by different cell types, even T lymphocytes and platelets, and different pathological conditions, such as acute and chronic inflammatory status, and cancer, may enhance its expression and activity. Thus, recent advances in the biology of TF have clearly indicated that beyond its known effects on blood coagulation, it is a "true surface receptor" involved in many intracellular signaling, cell-survival, gene and protein expression, proliferation, angiogenesis and tumor metastasis. Finally, therapeutic modulation of TF expression and/or activity has been tested with controversial results. This report, starting from the old point of view about TF as initiator of extrinsic coagulation pathway, briefly illustrates the more recent concepts about TF and thrombosis and finally gives an overview about its role beyond thrombosis and haemostasis focusing on the different intracellular mechanisms triggered by its activation and potentially involved in atherosclerosis.

Bariatric surgery in morbidly obese individuals affects plasma levels of protein C and thrombomodulin

Obesity is associated with a prothrombotic milieu and an increased risk for thrombotic events. Bariatric surgery is the most effective treatment for obesity resulting in dramatic weight loss and reduced inflammation and extrinsic coagulation pathway activation. Blood samples were drawn from 60 patients undergoing Roux-en-Y gastric bypass surgery before and 1 year after the intervention. Protein C (PC), activated PC (APC), soluble thrombomodulin (TM), soluble E-selectin (E-Sel), prothrombin time (PT) and activated partial thromboplastin time (aPTT) were evaluated. Both PC (187.4 ± 64.5% before surgery to 118.1 ± 48% 1 year after surgery, p < 0.001) and APC (138.7 ± 64.4% before surgery to 69.1 ± 65.7% after surgery, p < 0.001) were reduced following surgical intervention. TM showed a similar behavior with a reduction of soluble TM after the procedure from 5.7 ± 2.6 to 3.2 ± 1.4 ng/ml (p < 0.001). Similarly, soluble E-Sel was reduced after surgery from 26.6 ± 12.7 to 5.5 ± 4.1 ng/ml (p < 0.001). In contrast, aPTT was not shortened but slightly increased from 29.1 ± 4.8 s. before surgery to 31 ± 4.4 s. (p = 0.001) after surgery and levels of PT were reduced after surgery to 89.6 ± 15.5% from an initial 97.5 ± 13.5% (p < 0.001). In conclusion, we demonstrate a reduction of PC and APC 1 year after bariatric surgery accompanied by a reduction in soluble TM and soluble E-Sel. The reduction of PC and APC is not paralleled by a reduction but in contrast by a prolongation of aPTT suggesting a compensatory upregulation of PC during obesity. The reduction of TM and E-Sel might hint towards an improved endothelial function in this cohort of patients.

Chronic dietary toxicity and carcinogenicity studies of dammar resin in F344 rats.

Dammar resin is a natural food additive and flavoring substance present in many foods and drinks. The present study evaluates the chronic toxicity and carcinogenicity of dietary dammar resin in F344 rats. Dietary concentrations in the 52-week chronic toxicity study were 0, 0.03, 0.125, 0.5, or 2%. The major treatment-related deleterious effects were body weight suppression, increased relative liver weight, and low hemoglobin levels in males and females. Foci of cellular alteration in the liver were observed in the male 2% group, but not in any other group. The no-observed-adverse-effect level for chronic toxicity was 0.125% for males (200.4mg/kg b.w./day) and females (241.9mg/kg b.w./day). Dietary concentrations in the 104-week carcinogenicity study were 0, 0.03, 0.5, or 2%. Dammar resin induced hemorrhagic diathesis in males and females, possibly via the inhibition of extrinsic and intrinsic coagulation pathways. Incidences of hepatocellular adenomas and carcinomas were significantly increased in the male 2% group, but not in any other group. In the 4-week subacute toxicity study, the livers of male rat-fed diet-containing 2% dammar resin had increased levels of protein oxidation and increased the expression of two anti-apoptotic and seven cytochrome P450 (CYP) genes. There was also an increased tendency of oxidative DNA damage. These findings demonstrate that dammar resin is hepatocarcinogenic in male F344 rats and underlines the roles of inhibition of apoptosis, induction of CYP enzymes, and oxidative stress in dammar resin-induced hepatocarcinogenesis.

Short chain polyphosphates as a strategic colloidal source of phosphate for parenteral admixtures

Short chain sodium polyphosphates – (NaPO3)9 – PolyP – were added to 2-in-1 pediatric parenteral nutrition (PN) formulations as new alternative phosphate sources. Solutions of PolyP and Ca2+ in the presence of Mg2+, glucose, amino acids and trace elements were analyzed by electronic absorption and 31P NMR spectroscopies, as well as by pH measurements. Additionally, to verify the biocompatibility of short chain PolyP solutions, red blood cell (RBCs) units were evaluated by analyzing hemoglobin, hematocrit, and hemolysis. The blood clotting action of the PolyP was determined through Prothrombin time. We observed that the short chain PolyP anions did not interfere in the quality control parameters for RBCs units or in the blood extrinsic coagulation pathway. The spectral changes observed in the 31P NMR confirm the association of Mg2+ and Ca2+ with PolyP in the admixtures. Compatibility diagrams showed that the PolyP-Ca/Mg systems reflect a gel behavior based on the PolyP chains interaction with the incoming cations maintaining a supramolecular equilibrium until a limiting concentration. We observed that the greater the PolyP concentration, the greater the amount of Ca2+ that could be added to the admixture without phase separation and that the increased complexity of species (glucose, amino acid, trace elements and Mg2+) in the admixture favored a still higher final Ca2+ concentration. The overall colloidal behavior of short chain PolyPs shows that these polyanions function not only as alternative and safe phosphate sources in PN formulations but also as polyanions that increase the admixture stability against phase separation by efficiently sequestering metal cations present.

Inhibition of the extrinsic or intrinsic coagulation pathway during pneumonia-derived sepsis.

Pneumonia is the most frequent cause of sepsis, and Klebsiella pneumoniae is a common pathogen in pneumonia and sepsis. Infection is associated with activation of the coagulation system. Coagulation can be activated by the extrinsic and intrinsic routes, mediated by factor VII (FVII) and factor XII (FXII), respectively. To determine the role of FVII and FXII in the host response during pneumonia-derived sepsis, mice were treated with specific antisense oligonucleotide (ASO) directed at FVII or FXII for 3 wk before infection with K. pneumoniae via the airways. FVII ASO treatment strongly inhibited hepatic FVII mRNA expression, reduced plasma FVII to ~25% of control, and selectively prolonged the prothrombin time. FXII ASO treatment strongly suppressed hepatic FXII mRNA expression, reduced plasma FXII to ~20% of control, and selectively prolonged the activated partial thromboplastin time. Lungs also expressed FVII mRNA, which was not altered by FVII ASO administration. Very low FXII mRNA levels were detected in lungs, which were not modified by FXII ASO treatment. FVII ASO attenuated systemic activation of coagulation but did not influence fibrin deposition in lung tissue. FVII ASO enhanced bacterial loads in lungs and mitigated sepsis-induced distant organ injury. FXII inhibition did not affect any of the host response parameters measured. These results suggest that partial inhibition of FVII, but not of FXII, modifies the host response to gram-negative pneumonia-derived sepsis.

The Kv1.3 channel-inhibitory toxin BF9 also displays anticoagulant activity via inhibition of factor XIa

The Kv1.3 channel plays potential roles in immune, inflammation and coagulation system. Many studies showed that Kv1.3 channel inhibitors have immunosuppressive and anti-inflammatory activities, but no Kv1.3 channel inhibitors have been found to have anticoagulation activities. Here, based on our previous work about Kv1.3 channel toxin peptide inhibitors, we first attempt to test anticoagulation activities of four known venom-derived Kv1.3 channel inhibitors with different structural folds: BmKTX with CSα/β structural fold, OmTx3 with CSα/α structural fold, BF9 with Kuntz-type structural fold, and SjAPI-2 with Ascaris-type structural fold. Our results showed that BmKTX and OmTx3 have no activities towards both intrinsic and extrinsic coagulation pathway, SjAPI-2 just has weak activity towards intrinsic coagulation pathway, and BF9 has potent activity towards intrinsic coagulation pathway with no apparent effect on extrinsic coagulation pathway. Enzyme and inhibitor reaction kinetics experiments further showed that BF9 inhibited intrinsic coagulation pathway-associated coagulation factor XIa, but have no apparent effects on common coagulation pathway coagulation factor IIa. Structure-activity relationship showed that Gly14, Asn17, Ala18 and Ile20 of BF9 are main residues involved in the inhibiting effect on factor XIa. To the best of our knowledge, BF9 is the first anticoagulant with Kv1.3 channel inhibitory activity. Together, our present studies found the first dual functional peptides with Kv1.3 channel and coagulation factor XIa inhibitory activities, and provided a new molecular template for the lead drug discovery towards immune and thrombosis-associated human diseases.

Design and Utility of a Point-of-Care Microfluidic Platform to Assess Hematocrit and Blood Coagulation.

To develop a small volume whole blood analyzer capable of measuring the hematocrit and coagulation kinetics of whole blood. A co-planar microfluidic chamber designed to facilitate self-driven capillary action across an internal electrical chip was developed and used to measure the electric parameters of whole human blood that had been anticoagulated or allowed to clot. To promote blood clotting, select chip surfaces were coated with a prothrombin time (PT) reagent containing lipidated tissue factor (TF), which activates the extrinsic pathway of coagulation to promote thrombin generation and fibrin formation. Whole human blood was added to the microfluidic device, and voltage changes within the platform were measured and interpreted using basic resistor-capacitor (RC) circuit and fluid dynamics theory. Upon wetting of the sensing zone, a circuit between two co-planar electrodes within the sensing zone was closed to generate a rapid voltage drop from baseline. The voltage then rose due to sedimentation of red blood cells (RBC) in the sensing zone. For anticoagulated blood samples, the time for the voltage to return to baseline was dependent on hematocrit. In the presence of coagulation, the initiation of fibrin formation in the presence of the PT reagent prevented the return of voltage to baseline due to the reduced packing of RBCs in the sensing zone. The technology presented in this study has potential for monitoring the hematocrit and coagulation parameters of patient samples using a small volume of whole blood, suggesting it may hold clinical utility as a point-of-care test.

Changes in coagulation factor XII and its function during aortic arch surgery for acute aortic dissection°™a prospective observational study

Changes in the intrinsic coagulation pathway during aortic arch surgery in patients with acute aortic dissection (AAD) have not yet been reported. The aim of this study is to describe the changes in intrinsic coagulation factor XII, explore its function and find a new target for the treatment of coagulopathy during surgery. Eighty-eight patients undergoing emergent surgery for AAD were enrolled. Changes in the intrinsic and extrinsic coagulation pathways were evaluated at 5 different timepoints during the perioperative period by measuring intrinsic coagulation factor XII, extrinsic coagulation factor VII and some intrinsic upstream stimulating factors. The 88 patients were also divided into two groups according to whether reoperation for coagulopathy was required after surgery. Both coagulation factors XII and VII demonstrated a significant and similar change during the perioperative period. These factors decreased significantly during hypothermia circulation arrest (P<0.001) and recovered to normal levels by 24 hours after surgery. Among the intrinsic upstream stimulating factors, bradykinin (BK) demonstrated a similar changing trend with coagulation factors XII and VII, while other stimulating factors did not. However, compared with factor VII, factor XII demonstrated a greater decline during surgery. The proportion of decline of factor XII from anesthesia induction to hypothermia circulation arrest was 42%, whereas the proportion of decline of factor VII during the same period was 20% (P<0.001). Moreover, factor VII recovered to preoperative levels 4 hours after surgery with a relatively faster speed (P<0.001) while factor XII had not recovered (P=0.010). The independent t-test and Wilcoxon test showed that coagulation factor XII levels during hypothermia circulation arrest (P=0.002), total dosage of fibrinogen (P=0.027), total dosage of packed red blood cells (PRBCs) (P=0.006) and total dosage of fresh frozen plasma (FFP) (P=0.022) during the perioperative period were significantly different between the patients who did or did not require reoperation for coagulopathy. Multivariable logistic regression analysis suggested that the factor XII level during hypothermia circulation arrest was an independent risk factor for reoperation for coagulopathy [odds ratio (OR): 1.342, 95% confidence interval (CI): 1.058-1.570; P=0.012]. Factor XII levels are more influenced by surgery and require a longer period of time to recover to preoperative levels compared with factor VII, and the level of factor XII during hypothermia circulation arrest might be an independent risk factor for reoperation for coagulopathy. Therefore, supplementation of coagulation factor XII and its upstream stimulating factors might be a promising therapeutic modality in the future.

Extrinsic clotting pathway markers predict survival in early breast cancer

Extrinsic clotting pathway markers predict survival in early breast cancer

Adipose-derived mesenchymal stem cells release microvesicles with procoagulant activity.

Extracellular vesicles are produced by a number of different cell types, among them mesenchymal stromal/stem cells (MSC) of different sources. It has been shown that extracellular vesicles of MSC exert similar therapeutic effects as the cells themselves. Here, we isolated and characterized extracellular vesicles produced by adipose-derived MSC (adMSC) in vitro upon stimulation with the proinflammatory substances lipopolysaccharide (LPS) and tumor necrosis factor (TNF). We found that the number of vesicles produced by adMSC does not change upon stimulation of the cells with LPS and TNF. Furthermore, adMSC-derived extracellular vesicles exert procoagulant activity independent of previous stimulation with LPS or TNF. We found evidence that the vesicles induce coagulation via both the intrinsic and the extrinsic pathway of coagulation.

Preparation of low molecular weight Sargassum fusiforme polysaccharide and its anticoagulant activity

Heparin has been used as an anticoagulant drug for many years, but it has significant side effects. In the search for good substitutes, low molecular weight (MW) polysaccharides from Sargassum fusiforme have been examined and confirmed to possess biological activities. Here, S. fusiforme polysaccharides (SFP) were extracted and subjected to a hydrogen peroxide (H2O2) oxidation method for the preparation of low-MW SFP (LSFP). The effects of temperature, pH, and H2O2 concentration on the degradation process were also examined. Several LSFP of 36, 9, 5.7, and 2.7 kDa were obtained under different conditions, and their anticoagulant activities studied in vitro. The results showed that SFP and LSFP prolonged activated partial thromboplastin (APTT), prothrombin (PT) and thrombin times (TT) significantly, indicating that these low MW polysaccharides possessed anticoagulant activity in the intrinsic, extrinsic, and common coagulation pathways. As these effects were related to the MW of the polysaccharides in APTT and TT but not in PT, the contents of the monosaccharide fucose and sulfate and the polysaccharide MW could have exerted combined effects. The details of this mechanism require further verification.

Pre-operative systemic coagulation factors as biomarkers in colorectal cancer

Introduction: The two-way relationship between the extrinsic clotting pathway and cancer is well established. There is a lack of biomarkers predictive for adverse histological features in patients undergoing surgery for colorectal cancer (CRC).

Effects of Plasmodium falciparum on Placental Expression of Inflammatory and Coagulation Factors

Plasmodium falciparum infection during pregnancy, which can develop into placental malaria (PM), is estimated to cause over 200,000 infant deaths annually. PM is characterized by sequestration of parasite infected red blood cells (iRBCs) and deposition of hemozoin (HZ) in the maternal blood (intervillous) space of the placenta. HZ is an insoluble, iron‐containing by‐product of the parasite's digestion of hemoglobin. Additionally, accumulation of maternal immune cells and excessive deposition of fibrin are seen in the intervillous space. The role of the syncytiotrophoblast (ST), the outermost cell layer of the placenta, during PM pathogenesis remains unclear. It is hypothesized that the ST responds to iRBCs, HZ, and inflammatory cytokines like tumor necrosis factor (TNF) produced by maternal immune cells to attenuate infection. However, it is ultimately harmed by its own response. Mechanistically, it is predicted that TNF leads to activation of tissue factor (TF), the initiator of the extrinsic coagulation pathway, which ultimately results in fibrin deposition. In addition to TNF, HZ released from iRBCs may also upregulate TF. Downstream coagulation factors activate protease activated receptors (PARs), which are G‐protein coupled receptors highly expressed on the ST. Activated PARs increase expression of TNF, propagating what is known as “the inflammation‐coagulation cycle”. The cycle's propagation adversely affects nutrient and gas exchange between the maternal blood and the ST, resulting in growth restriction, low birth weight, and occasionally death of the fetus. Using a human choriocarcinoma cell line, BeWo, and isolated human trophoblast cells, in vivo host (ST)‐parasite interactions are simulated. BeWos and human trophoblasts are left unstimulated or stimulated over a physiologically relevant time‐course with (1) lipopolysaccharide (LPS; positive control), (2) natural HZ, (3) TNF, or (4) natural HZ/TNF. RNA isolation is followed by cDNA generation and qPCR for TF, PAR‐1, and PAR‐2. Results indicate that BeWos respond to LPS and HZ with a modest upregulation of TF and PAR‐1 between 2 to 4 hours. Response to TNF occurs at 2 hours with a modest upregulation of TF. Gene expression of PAR‐2 was not found to be significant over the time‐course. qPCR results with cDNA generated from time‐course experiments using human trophoblast cells are forthcoming. Identifying the extent to which the ST is involved in PM pathogenesis will advanced the understanding of how this syndrome impacts fetal development and outcome.Support or Funding InformationThis work is supported by National Institutes of Health grant 1R21AI111242 to Dr. Julie M. Moore.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Extrinsic pathway markers predict survival in Early Breast Cancer

Introduction: Extrinsic clotting pathway factors thrombin and tissue factor (TF) promote tumour progression through protease-activated receptors PAR1 and PAR2 respectively. We have previously demonstrated upregulation of epithelial, stromal and plasma extrinsic clotting factors and association with aggressive breast cancer phenotypes in a large prospective cohort.

Characterization of a novel selective factor Xa inhibitor, DJT06001, which reduces thrombus formation with low risk of bleeding

Factor Xa (FXa) is a serine protease that plays key roles in linking the intrinsic and extrinsic coagulation pathways to the final common pathway. DJT06001 is an oral, highly specific and direct FXa inhibitor for the prevention and treatment of thromboembolic diseases. We characterized the compound in vitro and studied its in vivo activity in rat thrombosis models, as well as bleeding risk and Pharmacokinetics and Pharmacodynamics (PK/PD) relationship. DJT06001 inhibited free FXa with an inhibitory constant (Ki) of 0.99 nM, and exhibited >10000-fold selectivity for FXa than for other related serine proteases. DJT06001 concentration-dependently inhibited FXa activity in the prothrombinase complex with an IC50 of 2.53 nM. The concentrations for DJT06001 to double the prothrombin time (PT) and activated partial thromboplastin time (APTT) were 0.74 and 0.57 μM, respectively. Importantly, DJT06001 did not impair platelet aggregation induced by ADP, platelet activating factor (PAF) and collagen. Furthermore, DJT06001 inhibited thrombus formation in rat thrombosis models in a dose dependent manner. And in rat tail bleeding risk test, it caused less bleeding than rivaroxaban at doses that achieve the same antithrombotic effect. PK/PD studies further demonstrated that there was a good correlation between the plasma concentrations of DJT06001and its inhibition of plasma FXa activity and prolongation of PT. In conclusion, DJT06001 was shown to be a potent and specific FXa inhibitor with excellent PK/PD profiles and it could be developed as a new anticoagulant for the management of thromboembolic diseases.

Pathophysiology of Trousseau’s syndrome

SummaryClinically relevant clotting abnormalities in cancer patients are referred to as Trousseau’s syndrome. While thrombotic complications such as venous thromboembolism are most frequent in every day’s practice, cancer patients may also experience severe bleeding symptoms due to complex systemic coagulopathies, including disseminated intravascular coagulation, haemolytic thrombotic microangiopathy, and hyperfibrinolysis. The pathophysiology of Trousseau’s syndrome involves all aspects of Virchow’s triad, but previous basic research has mainly focused on the cellular and molecular mechanisms underlying blood hypercoagulability in solid cancers and haematological malignancies. In this regard, over-expression of tissue factor (TF), the principal initiator of the extrinsic coagulation pathway, by primary tumour cells and increased shedding of TF-bearing plasma microparticles are critical to both thrombus formation and cancer progression. However, novel findings on intrinsic contact activation in vivo, such as the release of polyphosphates or DNA by activated platelets and neutrophils, respectively, have pointed to additional pathways in the complex pathophysiology of Trousseau’s syndrome.

Coagulation factor VII gene polymorphisms are not associated with the occurrence or the survival of hepatocellular carcinoma: a report of 37 cases.

Objective: Coagulation factor VII (FVII) triggers the extrinsic pathway of blood coagulation. In our previous study, we showed that FVII plays an important role in tumorigenesis of hepatocellular carcinoma (HCC). However, the role of FVII polymorphism in HCC is still unknown. The present study aimed to investigate the relationship between HCC carcinogenesis and single nucleotide polymorphism of FVII.Methods: Thirty-seven HCC patients and 30 healthy donors were recruited in this study. Four common FVII gene polymorphisms – a decanucleotide insertion at position –323 (–323ins10-bp), a G to T substitution at position –401 (–401G/T), a G to A substitution at position –402 (–402G/A), and a T to C substitution at position –122 (–122T/C) – were analyzed by sequencing or commercialized assays using genomic DNA isolated from blood samples. Clinicopathological parameters between control and HCC subjects were compared according to the specific genotypes.Results: The most common nucleotide variation was –402G/A. However, no statistically significant difference was observed between healthy controls and HCC subjects for all four polymorphisms in terms of genotype distribution and allele frequencies, indicating that these polymorphisms may not affect HCC tumorigenesis. Furthermore, no association was found between –402G/A polymorphisms and tumor stage, recurrence, and overall survival.Conclusions: Our results indicate that FVII polymorphisms may not be a key factor that clinically impact tumorigenesis and outcomes of HCC, although further investigations should be conducted to confirm our findings.

Variations in activated partial thromboplastin time and prothrombin time in individuals of A, B, AB, and O blood groups

Background: Differences in blood group have been associated with predisposition to some diseases. Activated partial thromboplastin time (APTT) measures the efficiency of the intrinsic and common coagulation pathways, whereas prothrombin time (PT) test assesses the extrinsic and common coagulation pathways. Objective: The aim of this study was to assess the variations in PT and APTT among individuals of different ABO blood groups. Materials and Methods: A research was conducted at College of Health Sciences, Nnamdi Azikiwe University, Nnewi Campus, and a total of 200 students were recruited, consisting of 106 females and 94 males. Six milliliters of blood was withdrawn from each individual, after obtaining ethical clearance and informed consent. ABO blood grouping was done by the tile method while APTT, and PT were analyzed using the standard manual methods. Statistical analysis was carried out using Statistical Package for the Social Sciences version 21. Results: The result shows that blood group O was predominant among the test individuals (45%) followed by blood groups A (31%) and B (15%), while blood group AB has the least percentage (9%). Blood group O showed a significantly higher APTT value (44.24 ± 15.10 s) compared to blood groups A (39.35 ± 12.12 s), B (35.93 ± 9.78 s), and AB (37.22 ± 8.15 s) (P Conclusion: This study showed that APTT and PT levels differ among different ABO blood groups; therefore, variations in blood group of individuals may affect their intrinsic and extrinsic coagulation mechanisms.

Increased Thrombogenicity in Chronic Renal Failure in a Rat Model Induced by 5/6 Ablation/Infarction.

PurposeAbnormalities in hemostasis and coagulation have been suggested in chronic renal failure (CRF). In this study, we compared processes of thrombus formation between rats with CRF and those with normal kidney function.Materials and MethodsCRF was induced by 5/6 ablation/infarction of the kidneys in Sprague-Dawley rats, and surviving rats after 4 weeks were used. Ferric chloride (FeCl3)-induced thrombosis in the carotid artery was induced to assess thrombus formation. Whole blood clot formation was evaluated using rotational thromboelastometry (ROTEM). Platelet aggregation was assessed with impedance platelet aggregometry.ResultsFeCl3-induced thrombus formation was initiated faster in the CRF group than in the control group (13.2±1.1 sec vs. 17.8±1.0 sec, p=0.027). On histological examination, the maximal diameters of thrombi were larger in the CRF group than in the control group (394.2±201.1 µm vs. 114.0±145.1 µm, p=0.039). In extrinsic pathway ROTEM, the CRF group showed faster clot initiation (clotting time, 59.0±7.3 sec vs. 72.8±5.0 sec, p=0.032) and increased clot growth kinetics (α angle, 84.8±0.2° vs. 82.0±0.6°, p=0.008), compared to the control group. Maximal platelet aggregation rate was higher in the CRF group than in the control group (58.2±0.2% vs. 44.6±1.2%, p=0.006).ConclusionOur study demonstrated that thrombogenicity is increased in rats with CRF. An activated extrinsic coagulation pathway may play an important role in increasing thrombogenicity in CRF.