Vitamin K-dependent Coagulation Factors Research Articles

Thrombin Generation Capacity of Prothrombin Complex Concentrate in an In Vitro Dilutional Model

BackgroundThe use of PCC for the treatment of trauma-induced coagulopathy potentially increase the risk of thromboembolism and disseminated intravascular coagulation, which is addressed to an imbalance of both pro- and anticoagulants. As PCCs differ in composition, we used an in vitro dilutional approach to assess the overall thrombin generation of five different PCCs through various laboratory assays.MethodsThe vitamin K-dependent coagulation factors, heparin, and antithrombin were assessed in five commercially available PCCs. The procoagulant potential of the PCCs was assessed in plasma and whole blood from 4 healthy donors by means of classical coagulation assays, thrombin generation assay and thromboelastometry. In order to reflect coagulopathy, whole blood was diluted to 80, 60, 40, and 20% with Ringer’s lactate solution.ResultsThe five different PCCs were characterised by comparable levels of factors II, VII, IX and X (all around 20–30 IU/mL), whereas the heparin (0 to 17.6 IU/mL) and antithrombin (0.06 to 1.29 IU/mL) levels were remarkably different between manufactures. In vitro dilution of blood induced a prolongation of the PT and aPTT, and attenuation of thrombin generation and ExTem induced thromboelastometry. Overall, non- or low-heparin containing PCCs restored the in vitro dilutional coagulopathy, whereas PCCs containing heparin have an anticoagulant effect. The thrombin generation assay showed to be the most sensitive method for assessment of PCC effects.ConclusionsThis study shows that most available PCCs are not balanced regarding their pro- and anticoagulants. The effect of measured differences in thrombin generation among different PCCs requires further investigations to elaborate the clinical meaning of this finding in the treatment of trauma induced coagulopathy.

Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study

BackgroundThe rapid reversal of the effects of vitamin K antagonists is often required in cases of emergency surgery and life-threatening bleeding, or during bleeding associated with high morbidity and mortality such as intracranial haemorrhage. Increasingly, four-factor prothrombin complex concentrates (PCCs) containing high and well-balanced concentrations of vitamin K-dependent coagulation factors are recommended for emergency oral anticoagulation reversal. Both the safety and efficacy of such products are currently in focus, and their administration is now expanding into the critical care setting for the treatment of life-threatening bleeding and coagulopathy resulting either perioperatively or in cases of acute trauma.MethodsAfter 15 yr of clinical use, findings of a pharmacovigilance report (February 1996–March 2012) relating to the four-factor PCC Beriplex P/N (CSL Behring, Marburg, Germany) were analysed and are presented here. Furthermore, a review of the literature with regard to the efficacy and safety of four-factor PCCs was performed.ResultsSince receiving marketing authorization (February 21, 1996), ∼647 250 standard applications of Beriplex P/N have taken place. During this time, 21 thromboembolic events judged to be possibly related to Beriplex P/N administration have been reported, while no incidences of viral transmission or heparin-induced thrombocytopenia were documented. The low risk of thromboembolic events reported during the observation period (one in ∼31 000) is in line with the incidence observed with other four-factor PCCs.ConclusionsIn general, four-factor PCCs have proven to be well tolerated and highly effective in the rapid reversal of vitamin K antagonists.

Haemorrhage and intestinal lymphoma

Background: The prevalence of coeliac disease is around 1% in general population but this is often unrecognised. The classical presentation of adult coeliac disease is characterized by diarrhoea and malabsorption syndrome, but atypical presentations are probably more common and are characterized by iron deficiency anaemia, weight loss, fatigue, infertility, arthralgia, peripheral neuropathy and osteoporosis. Unusual are the coagulation disorders (prevalence 20%) and these are due to vitamin K malabsorption (prolonged prothrombin time). Clinical case: A 64-year-old man was admitted to our Department for an extensive spontaneous haematoma of the right leg. He had a history of a small bowel resection for T-cell lymphoma, with a negative follow-up and he didn’t report any personal or familiar history of bleeding. Laboratory tests showed markedly prolonged prothrombin (PT) and partial-thromboplastin time (PTT), corrected by mixing studies, and whereas platelet count and liver tests was normal. A single dose (10 mg) of intravenous vitamin K normalized the PT. Several days before the patient had been exposed to a superwarfarin pesticide, but diagnostic tests for brodifacoum, bromadiolone or difenacoum were negative. Diagnosis of multiple vitamin K-dependent coagulationfactor deficiencies (II, VII, IX, X) due to intestinal malabsorption was made and coeliac disease was detected. Therefore the previous lymphoma diagnosis might be closely related to coeliac disease. Conclusions: A gluten free diet improves quality of life and restores normal nutritional and biochemical status and protects against these complications.

Vitamin K-Dependent Coagulopathy in Pediatric Osteomyelitis: A Case Report.

Thromboembolism in children is rare and is generally limited to those with genetic disorders of coagulation and diseases that induce a hypercoagulable state1. The incidence of deep vein thrombosis (DVT) in children with osteomyelitis is reported to be much higher (between 5% and 10%) 2-4. In addition to DVT, there are other coagulation abnormalities that occur with osteomyelitis that are often paradoxically “mixed” and include features of hypercoagulability (such as pulmonary embolus and cerebral infarct5) and hypocoagulability with increased risk of bleeding4,6-11. The pathophysiology behind the coagulopathy associated with osteomyelitis is unknown. Because mixed coagulopathies often result from a loss of both procoagulant and anticoagulant factors, we hypothesize that osteomyelitis induces persistent activation of the coagulation system, resulting in consumption of coagulation factors. We present a case of osteomyelitis in a fifteen-year-old boy who developed both hypercoagulable disease (DVT) and hypocoagulable disease (gastrointestinal bleed). Laboratory evaluation revealed a severe consumption of vitamin K-dependent coagulation factors, which responded rapidly to the administration of subcutaneous vitamin K. The patient and his parents were informed that data concerning the case would be submitted for publication, and they provided consent. A fifteen-year-old previously healthy boy presented with a three-day history of left knee pain after minor trauma, fever, and inability to bear weight. A summary of the laboratory findings throughout hospitalization is presented in Figure 1. Magnetic resonance imaging (MRI) of the left leg revealed a large subperiosteal abscess and osteomyelitis of the distal part of the femur (Fig. 2-A). The patient subsequently underwent irrigation and debridement. Intraoperative duplex ultrasound showed an occlusive thrombus in the left superficial femoral and popliteal veins (Figs. 2-C, 2-D, and 2-E). Methicillin-sensitive Staphylococcus aureus grew on both blood and intraoperative cultures. Fig. 1 Coagulation and inflammatory changes …

The effect of repeated freezing and thawing on levels of vitamin K-dependent coagulation factors and fibrinogen in fresh frozen plasma

Background:Fresh frozen plasma (FFP) is considered adequate for transfusion immediately after thawing or for up to 24 hours if kept at 1–6°C, and is currently used very often to replace deficient clotting factors. If factor levels in refrozen FFP are within normal limits, then this component can possibly be transfused, thus avoiding wastage of FFP.Aim:To study the fate of vitamin K-dependent coagulation factors (F II, F VII, F IX, F X) and fibrinogen activity levels in repeatedly (twice) frozen and thawed FFP.Materials and Methods:Two hundred FFP units comprising 50 units of each major blood group (A, B, AB, and O) were thawed at 37°C and 10–20 mL of FFP transferred to transfer bags with the help of a sterile connecting device (SCD). The FFP samples were taken into tubes (first sampling), and then the transfer bags were kept for 24 hours at 4°C. After 24 hours, repeat samples were taken in tubes from the transfer bag (second sampling), and then the bags were re-stored at < -18°C. One week later, the above procedure was repeated. Activity of coagulation factors and fibrinogen levels were measured by the automated coagulation analyzer.Results:The levels of F II, F VII, F IX, F X, and fibrinogen of all the 200 FFP units, at all four time points, were above the lower normal value, but well within the normal range.Conclusion:The levels of F II, F VII, F IX, F X, and fibrinogen remain stable and adequate for transfusion in twice-thawed-and-refrozen FFP. This component can be safely used for transfusion as a source of vitamin K-dependent clotting factors and fibrinogen.

Pharmacogenetics in the Era of Next Generation Sequencing

Pharmacogenetics is the study of the effects of each individual genome on drug response. Information about genetic testing is now part of drug label as for abacavir, warfarin, clopidogrel, irinotecan, maraviroc, cetuximab, imatinib [1,2]. At present a wide range of drugs are employed for treating pathological conditions and chronic disorders, like cancer, diabetes, heart disease, etc. Ideally a drug is delivered so that it achieves a blood concentration that is within the therapeutic range: a too low drug concentration is ineffective, while one that is too high can be toxic. None of the drugs known to date proved to be 100% effective in every patient: the same dose of a given medicine may cause no response in some individuals, may produce the right therapeutic response in others, and may give rise to adverse responses in another part of them. These changes in the response may result from clinical differences between individuals (for example age or the presence of other pathological conditions), from diagnostic uncertainty, and from environmental factors. Besides, genetics has been proven to modulate in a significant way inter-patients variation in drug reaction. Genes are sequences of DNA that contain information determining the amino acid sequence of proteins, which participate in every cellular process, including drug response. Polymorphisms are DNA variations that occur at a frequency of 1% or greater, while DNA mutations occur less frequently than 1%: this definition is merely statistical and it does not reflect the functional role of both kind of genetic variants. In both cases in fact, if the DNA carries a sequence variation (a mutation or a polymorphism), the proteins may not be expressed properly, or not function correctly, or not reach the appropriate site of action. Regarding pharmacogenetics, individual genetic variations in enzymes of drug metabolizing enzymes, transporters, receptors, ion channels, target enzymes and signal transduction pathways, may lead to inadequate therapeutic responses. For example the genetic information of genes CYP2C9 (encoding a member of the cytochrome P450 superfamily of enzymes, which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids) and VKORC1 (encoding the enzyme which activates vitamin K) can assist in selection of the starting dose of warfarin [3] an anticoagulant which acts by inhibiting vitaminK-dependent coagulation factors. In particular, warfarin interferes with VKORC1enzyme, and DNA variants in CYP2C9 are related to differences in the drug’s clearance. The VKORC1 G1639A polymorphism is associated with lower dose requirements and increased bleeding risk, as well as inferior initial warfarin doses have been associated with the CYP2C9*2 and CYP2C9*3 variants [46]. Algorithms for genetics-based dosing have been developed and are available online (Online calculator for initiation of warfarin dosing based on pharmacogenetic algorithms, www.WarfarinDosing.org) [7]. The history of pharmacogenetics starts in 1957 when Arno

Thrombin Generation Capacity of Prothrombin Complex Concentrate in an in Vitro Dilutional Model

AbstractAbstract 4380 Background:There is a growing use of prothrombin complex concentrates (PCCs) for the treatment of trauma-induced coagulopathy, which is addressed to their propensity to increase thrombin generation. Despite considerable differences in composition of commercially available PCCs, there is lack of data investigating the procoagulant capacity of different PCCs. Methods:The vitamin K-dependent coagulation factors, heparin, and antithrombin were assessed in five commercially available PCCs. The procoagulant potential of the PCCs was assessed in plasma and whole blood from 4 healthy donors by means of classical coagulation assays, thrombin generation assay and thromboelastometry. In order to reflect coagulopathy, whole blood was diluted with 20, 40, 60, and 80% Ringer's lactate solution. Results:The five different PCCs were characterised by comparable levels of factors II, VII, IX and X (all around 20–30 IU/mL), whereas the heparin (0 to 17.6 IU/mL) and antithrombin (0.06 to 1.29 IU/mL) levels were remarkably different between manufactures. In vitro dilution of blood induced a prolongation of the PT and aPTT, and attenuation of thrombin generation and ExTem induced thromboelastometry. Overall, non- or low-heparin containing PCCs restored the in vitro dilutional coagulopathy, whereas PCCs containing heparin has an anticoagulant effect. The thrombin generation assay showed to be the most sensitive method for assessment of PCC effects. Conclusions:This study shows that most available PCCs are not balanced regarding their pro-and anticoagulants. The effect of measured differences in thrombin generation among different PCCs require further investigations to elaborate the clinical meaning in the treatment of trauma induced coagulopathy. Disclosures:No relevant conflicts of interest to declare.

Elevated Interleukin-6 Concentration and Alterations of the Coagulation System Are Associated with the Development of Intraventricular Hemorrhage in Extremely Preterm Infants

Background: Pathogenesis of intraventricular hemorrhage (IVH) in premature infants is multifactorial. Little is known about the influence of pro-inflammatory cytokine activation on the coagulation system in extremely preterm infants and its impact on the development of IVH. Objective: To determine the interaction between serum interleukin-6 (IL-6) and the coagulation system in preterm infants predisposed to the development of IVH. Methods: Vitamin K-dependent coagulation factors were examined retrospectively in 132 extremely preterm infants prior to vitamin K administration at the first day of life. Patients were grouped according to the occurrence of IVH and serum concentration of IL-6 >/<100 pg/ml. Results: Occurrence of IVH was associated with clinical diagnosis of chorioamnionitis, low gestational age, high CRIB score, air leak, catecholamine treatment, low initial hematocrit and increased serum concentration of IL-6. Infants developing IVH showed a diminished coagulation profile. Multivariable logistic regression analysis revealed decreased activity of coagulation factor VII, development of pneumothorax and low hematocrit as independent risk factors for the development of IVH. An increased IL-6 serum concentration was associated with a significantly decreased activity of coagulation factor VII and increased levels of fibrinogen. Conclusions: The association of elevated IL-6 levels with alterations of the coagulation profile and development of IVH found in our study supports the assumption of a close pathophysiological relation between inflammation and IVH.

The Use of Bromadiolone to Potentiate Self-Mutilatory Bleeding: A Case Report

The term “superwarfarin” applies to a group of compounds that function, like warfarin, as anticoagulants, but also have properties that allow them to be effective against warfarin-resistant rodent strains. These compounds include bromadiolone, brodifacoum, difenacoum, and chlorphacinone. Absorption of these agents occurs via multiple routes, including inhalation, tactile contact, and ingestion. The superwarfarins possess lengthier half-lives than warfarin and have been estimated to be 100 times more potent at inhibiting the vitamin K-dependent clotting factors [II, VII, IX, and X]. Bromadiolone functions by inhibiting the vitamin K 2,3-epoxide reductase enzyme, leading to increased levels of the inactive form of vitamin K. This impairs the vitamin K-dependent clotting factors, disrupting the normal clotting cascade. It has been shown to have a biphasic hepatic elimination in humans. This includes an initial period lasting between 3.5 and 6 days, and a slower phase, which has a half-life of between 10 and 24 days. Commercially available as rodenticides, the superwarfarins are available to the public without a prescription and are easily obtained. Though intended for pest control, human contact with the superwarfarins does occur and may have serious effects. Contact with the superwarfarins can lead to problems with excessive or inappropriate bleeding, such as the development of ecchymosis, epistaxis, hematuria, gingival bleeding, and menometrorrhagia. Spontaneous abortion, gastrointestinal bleeding, abdominal pain, intracranial hemorrhage, melena, and hematemesis have also been reported. These cases are summarized in Table 1. In addition to these clinical observations, patients frequently present with a combination of prolonged prothrombin time (PT), partial thromboplastin time (PTT), and increased International Normalized Ratio (INR) values. Furthermore, in these patients, correction of PT and PTT following mixing studies points to

The genetic mechanisms of warfarin resistance in Rattus rattus found in the wild in Japan

Warfarin is commonly used worldwide as a rodenticide. It inhibits blood coagulation by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity leading to hemorrhage. However, it has been reported that repeated or long-term treatment with warfarin results in resistance emerging in wild rodents. Such resistance may explain why it is difficult to control rodents in many regions in Japan. In this report, we studied mutations in the VKOR gene (including the VKOR complex subunit 1 (VKORC1)), while also analyzing VKOR and clotting factor activity in black rats (Rattus rattus) in order to understand better the mechanism of warfarin resistance in this species.We sequenced the VKORC1 gene from 275 rats living in the wild in Japan. We found several types of novel base substitutions, some of which conferred warfarin resistance.There was no difference in coagulation times between warfarin-sensitive and resistant rats measured under physiological conditions. However, after warfarin administration, no effect was noted in warfarin-resistant rats, although a prolonged coagulation time was noted in warfarin-sensitive rats.We also determined the kinetic differences in hepatic microsomal VKOR-dependent activity between warfarin-resistant and sensitive rats. Warfarin-resistant rats showed 2–3-fold lower Vmax/Km values than did sensitive rats. In addition, we report that resistant rats found in the Tokyo area had a VKOR activity which was poorly inhibited by warfarin.Finally, we conclude that reduced VKOR activity and warfarin resistance in the Japanese black rat might be due to mutations in the VKORC1 gene. However, further study is needed to clarify how such rats can maintain adequate vitamin K-dependent clotting factor levels, while simultaneously exhibiting low VKOR activity and warfarin resistance.

Vascular calcification: The price to pay for anticoagulation therapy with vitamin K-antagonists

Vitamin K-antagonists (VKA) are the most widely used anti-thrombotic drugs with substantial efficacy in reducing risk of arterial and venous thrombosis. Several lines of evidence indicate, however, that VKA inhibit not only post-translational activation of vitamin K-dependent coagulation factors but also synthesis of functional extra-hepatic vitamin K-dependent proteins thereby eliciting undesired side-effects.Vascular calcification is one of the recently revealed side-effects of VKA. Vascular calcification is an actively regulated process involving vascular cells and a number of vitamin K-dependent proteins. Mechanistic understanding of vascular calcification is essential to improve VKA-based treatments of both thrombotic disorders and atherosclerosis. This review addresses vitamin K-cycle and vitamin K-dependent processes of vascular calcification that are affected by VKA. We conclude that there is a growing need for better understanding of the effects of anticoagulants on vascular calcification and atherosclerosis.

Multivessel Thromboembolism Associated with Dysfunction of Protein S

Protein S is a vitamin K-dependent coagulation factor that acts as an anticoagulant. Deficiency of protein S increases the risk of thromboembolic events. We report a case of isolated protein S deficiency in a 39-year-old woman suffering arterial occlusion in both lower legs. She underwent a surgical procedure using thrombectomy and balloon angioplasty of her left lower extremity. Later, she had right trans-tibial amputation because of the reperfusion injury. Throughout the evaluation of thromboembolic events, we diagnosed a large thrombus in the right atrium and an asymptomatic pulmonary thromboembolism. The patient was successfully treated with right atrial thrombectomy and systemic anticoagulation. Careful evaluation for protein S levels may be necessary in patients with arterial thromboembolic events, especially young adults.

Prothrombin complex concentrates in warfarin anticoagulation reversal

Anticoagulation is very effective for primary and secondary prevention of thromboembolic events. However, questions persist about the risks and management of over-anticoagulation. The annual incidence of major bleeding in trials and cohort studies has been reported to be between 1.1% and 2.3% in patients treated with warfarin to achieve an international normalized ratio (INR) of 2.0 to 3.0. These rates are derived from carefully controlled studies, but in unselected outpatients, the risk of bleeding was found to be as high as 4.3% in patients receiving warfarin(1). For minor bleeding due to Vitamin K antagonists (VKA), discontinuation of anticoagulation therapy (with or without the administration of vitamin K) is sufficient to bring bleeding under control. However, for patients with major bleeding during VKA use, rapid reversal of anticoagulation is desirable, particularly if bleeding is life threatening or an urgent surgical procedure is required. Two products are suitable for increasing the concentration of vitamin K-dependent coagulation factors in these situations: fresh frozen plasma (FFP) and prothrombin complex concentrates (PCC)(2). Both products contain coagulation factors II, VII, IX and X, which are down-regulated during VKA therapy. PCC present several advantages over FFP, the most significant being the potential to completely reverse warfarin-induced anticoagulation in minutes, as compared with the longer periods required for the issuing of FFP from blood banks, the requirement of pre-transfusion tests, thawing and transfusion. Additional disadvantages of FFP include potential allergic reactions, transfusion-related acute lung injury (TRALI), volume overload and transfusiontransmitted diseases. For these reasons, some guidelines suggest a preferential use of PCC over FFP for warfarin reversal(3). Although all PCC contain factors II, IX and X, there is significant variability in the factor VII content. It has been argued by some that PCC with little factor VII (the so called 3-factor PCC) produce poorer correction of the INR and should not be used for warfarin reversal(3,4). The aim of the present study was to review the scientific literature on employing PCC for warfarin reversal.

Protein-Z Deficiency and/or Protein Z Polymorphisms in First Trimester Pregnancy Complications

Abstract 1221 INTRODUCTION:Protein Z (PZ) is a vitamin K-dependent coagulation factor; it is a glycoprotein that inhibits activated factor Xa, acting as a co-factor to PZ-dependent protease inhibitor, enhancing its action approximately by 1000 times. PZ levels in normal individuals vary greatly, as a result of PZ gene polymorphisms. PZ deficiency has been involved in the pathogenesis of ischemic strokes and pregnancy complications. Gris et al [Blood 2002;99(7):2606–08] first described a possible role of PZ deficiency (PZ <= 1mg/L) in women with fetal loss between the beginning of the 10th and the end of the 15th week of gestation. In a recent meta-analysis [Sofi et al, Thrombosis and Haemostasis 2010;103(4):749–56] PZ deficiency was associated with increased risk of pre-eclampsia and fetal loss, as well as with increased risk of arterial and venous thrombotic events. MATERIALS-METHODS:We studied a total of 314 women, 70 women with three or more consecutive spontaneous abortions (group A), 145 women with less than 3 early spontaneous abortions (group B) and 99 control women with at least one normal pregnancy and negative history of a thrombotic complication (group C). All women were tested for congenital and acquired thrombophilia such as antithrombin, protein C and S levels, homocysteine levels, lupus anticoagulant (PTTLa), factor V Leiden mutation, prothrombin G20210A gene polymorphism and PZ levels. We also investigated protein Z polymorphism F79A in a subgroup of our patients. Measurements were made at least 3 months apart from a thrombotic event. Differences between groups were assessed with ANOVA and chi-squared tests for continuous and categorical variables respectively. RESULTS:Statistically significant difference was found in PZ levels between the three groups. Mean PZ level was 1.23mg/dL, 1.31mg/dL και 1.61mg/dL (p<0.00001) in groups A, B, C respectively. Post-hoc Bonferroni analysis revealed a significant difference between groups A and C (p=0.0003) and between groups B and C (p=0.001). The percentage of PZ deficiency (95% condidence interval) was 40% (28%–52%), 38% (30%–46%) and 18% (11%–26%) respectively (p=0.001). Both group A (OddsRatio[OR]=3) and group B (OR=2.75) have a statistically greater PZ deficiency than control group C. The other parameters did not differ significantly between the three groups. DISCUSSION/CONCLUSIONS:Spontaneous abortions are common in women especially in first trimester. Thrombophilia has a major role in pregnancy complications. In these women that one cannot find some of the well established thrombophilic factors, searching for other possible deficiencies is necessary. The role of PZ deficiency has been investigated thoroughly in the last decade with sometimes conflicting results. To the best of our knowledge, this is the first Greek study investigating the possible role of protein Z deficiency in women with early pregnancy losses. From our study it is evident that PZ deficiency is an independent risk factor for early pregnancy losses. From our study it seems that the other thrombophic factors may play a minor role. A plausible pathophysiologic explanation is the occurrence of microthrombi due to atherosclerotic lesions soon after the development of materno-placental circulation. The role of PZ gene polymorphisms in PZ levels and in thrombotic complications remains to be investigated further. According to preliminary results from a sub-group of our patients (Topalidou et al, Thrombosis Research 2009;124:24–27), the presence of the intron F79A polymorphism was associated with significantly lower PZ levels, but was unrelated to unexplained early pregnancy losses. Disclosures:No relevant conflicts of interest to declare.

The clinical significance of differences between point-of-care and laboratory INR methods in over-anticoagulated patients

IntroductionPatients receiving warfarin are at increased risk of bleeding when their International Normalised Ratio (INR) >4.5. Although not standardised above 4.5 the INR is measured in over-anticoagulated patients, consequently we have examined the reliability of INR results ≥4.5. We assessed: the relationship between different prothrombin time systems for INRs >4.5; the relationships between the INR and levels of vitamin K-dependent coagulation factors (VKD-CF) and thrombin generation test (TGT) parameters; and the impact that variation in results would have on warfarin dosing. MethodsINRs were performed using a CoaguChek XS Plus point-of-care (POC) device (measuring range 0.6-8.0). For POC INRs ≥4.5, laboratory INRs were also measured using a recombinant tissue factor (rTF) and a rabbit brain (RBT) thromboplastin. ResultsThere was good correlation between POC (INR ≥4.5, <8.0) and Lab INRs (rTF n=154, rs=0.87, p<0.0001; RBT n=102, rs=0.76, p<0.0001); and significant correlations between each of the VKD-CF and the INR, the strongest being with FVII (POC INR rs=-0.53 p<0.0001; Lab rTF-INR rs=-0.70 p<0.0001). TGT peak thrombin and ETP also showed good correlations with INR values (R2>0.71). Using POC and Lab rTF-INR, 109/154 (71%), or POC and Lab RBT-INR 75/102 (74%) results exhibited dosage concordance and/or were within 0.5 INR units. In the remaining patients variation in warfarin dosing was generally slight. ConclusionsOur data suggest that CoaguChek XS Plus INRs >4.5 and <8.0 are comparable to laboratory INRs (both methods) and it is probably unnecessary to perform laboratory INRs for clinical management of patients with INRs >4.5 including those >8.0.

Vitamin K‐dependent coagulation factor deficiency in trauma: a comparative analysis between international normalized ratio and thromboelastography (CME)

The use of international normalized ratio (INR) to diagnose vitamin K-dependent coagulation factor (VitK-CF) deficiency in trauma has limitations (inability to predict bleeding and long turnaround times). Thromboelastography (TEG) assesses the entire coagulation process. With TEG, reaction time (TEG-R) is used to assess global coagulation factor activity and takes less than 10 minutes. We assessed the ability of TEG-R to detect VitK-CF deficiency in trauma, compared to the INR. A total of 219 trauma patients with INR, TEG, and all VitK-CF measured at admission were included. Demographics and laboratory tests, drugs, blood transfusions, and severity scores were analyzed. Specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV) of INR (≥1.3 and ≥1.5) and TEG-R (>8 min) to diagnose VitK-CF deficits (≤50%) were calculated. Secondary outcomes included time to INR and TEG results. Overall, TEG-R performed worse than INR. TEG-R had a sensitivity of 33% (95% CI, 16%-55%), specificity of 95% (95% CI, 91%-98%), PPV of 47% (95% CI, 23%-72%), and NPV of 92% (95% CI, 87%-95%). An INR of 1.5 or greater had a sensitivity of 67% (95% CI, 45%-84%), specificity of 98% (95% CI, 96%-99.7%), PPV of 84% (95% CI, 60%-97%), and NPV of 96% (95% CI, 92%-98%). An INR of 1.3 or greater also had better sensitivity, PPV, and NPV. For patients on warfarin, the times to INR results and TEG completion were 58 (±23) and 92 (±40) minutes (p=0.07), respectively. TEG-R was abnormal in only one patient on warfarin. Our study suggests that TEG-R is not superior at identifying VitK-CF deficiency compared to INR in trauma.

Breastfeeding: More Than Just Good Nutrition

Breastfeeding: More Than Just Good Nutrition

Novel phenotype and γ‐glutamyl carboxylase mutations in combined deficiency of vitamin K‐dependent coagulation factors

HaemophiliaVolume 17, Issue 5 p. 822-824 LETTERS TO THE EDITORS Novel phenotype and γ-glutamyl carboxylase mutations in combined deficiency of vitamin K-dependent coagulation factors B. LUNGHI, B. LUNGHI Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, ItalySearch for more papers by this authorR. REDAELLI, R. REDAELLI Hemostasis and Thrombosis Unit, Department of Hematology, Ospedale Niguarda Ca’ Granda, Milan, ItalySearch for more papers by this authorT. M. CAIMI, T. M. CAIMI Hemostasis and Thrombosis Unit, Department of Hematology, Ospedale Niguarda Ca’ Granda, Milan, ItalySearch for more papers by this authorA. R. CORNO, A. R. CORNO CNR Clinical Physiology Institute, Ospedale Niguarda Ca’ Granda, Milan, ItalySearch for more papers by this authorF. BERNARDI, F. BERNARDI Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, ItalySearch for more papers by this authorG. MARCHETTI, G. MARCHETTI Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, ItalySearch for more papers by this author B. LUNGHI, B. LUNGHI Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, ItalySearch for more papers by this authorR. REDAELLI, R. REDAELLI Hemostasis and Thrombosis Unit, Department of Hematology, Ospedale Niguarda Ca’ Granda, Milan, ItalySearch for more papers by this authorT. M. CAIMI, T. M. CAIMI Hemostasis and Thrombosis Unit, Department of Hematology, Ospedale Niguarda Ca’ Granda, Milan, ItalySearch for more papers by this authorA. R. CORNO, A. R. CORNO CNR Clinical Physiology Institute, Ospedale Niguarda Ca’ Granda, Milan, ItalySearch for more papers by this authorF. BERNARDI, F. BERNARDI Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, ItalySearch for more papers by this authorG. MARCHETTI, G. MARCHETTI Department of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, ItalySearch for more papers by this author First published: 24 March 2011 https://doi.org/10.1111/j.1365-2516.2011.02524.xCitations: 3 Prof. Giovanna Marchetti, Department of Biochemistry and Molecular Biology, University of Ferrara, via Fossato di Mortara 74, 44121, Ferrara, Italy.Tel.: +39 0532 974423; fax: +39 0532 974484; e-mail: mrg@unife.it Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume17, Issue5September 2011Pages 822-824 RelatedInformation

Haplotypes of VKORC1, NQO1 and GGCX, their effect on activity levels of vitamin K-dependent coagulation factors, and the risk of venous thrombosis

Haplotypes of VKORC1, NQO1 and GGCX, their effect on activity levels of vitamin K-dependent coagulation factors, and the risk of venous thrombosis -

Treatment of vitamin K-dependent coagulation factor

Treatment of vitamin K-dependent coagulation factor