Massive pulmonary embolism leading to cardiac arrest is associated with consumptive coagulopathy presenting as disseminated intravascular coagulation

See also Levi M. Disseminated intravascular coagulation or extended intravascular coagulation in massive pulmonary embolism. This issue, pp 1475–6; Thachil J. DIC score predicts mortality in massive clot coagulopathy as a result of extensive pulmonary embolism: a rebuttal. This issue, pp 1657–8; Leitner JM, Janata‐Schwatzek K, Spiel AO, Sterz F, Laggner AN, Jilma B. DIC score predicts mortality in massive clot coagulopathy as a result of extensive pulmonary embolism: reply to a rebuttal. This issue, pp 1658–9. Summary. Background: A consumptive coagulopathy resembling disseminated intravascular coagulation (DIC) has been seen in patients with massive pulmonary embolism (PE). We hypothesized that a DIC‐like condition is relevant in patients whose pulmonary embolism leads to cardiopulmonary arrest and cardiopulmonary resuscitation (CPR). Methods: This hypothesis was tested by the use of a database consisting of all cases of PE diagnosed at the Department of Emergency Medicine from June 1993 to October 2007. Out of 1018 cases with PE, 113 patients underwent CPR. In this cohort study, the resuscitated patients were compared with those with PE but without CPR. Results: Patients with PE and CPR had 3‐fold higher D‐dimer, prolonged prothrombin time (PT), reduced platelet counts and lower fibrinogen and antithrombin (AT) levels compared with PE patients without cardiac arrest (P < 0.001 for all). Among patients with PE and CPR, D‐dimer was abnormal in 100%, PT in 44%, AT in 53%, fibrinogen in 19% and platelets in 25%. In comparison, PE without CPR was associated with abnormal D‐dimer in 99%, abnormal PT in 15%, low AT in 6%, low fibrinogen in 1% and low platelets in 2%. Nine per cent of the resuscitated patients had a DIC score ≥ 5, indicating overt DIC. The DIC score highly correlated with 1‐year and in‐hospital mortality. Conclusions: Massive PE leading to CPR is associated with consumptive coagulopathy and overt DIC. In resuscitated patients, DIC markers may indicate pulmonary embolism as the underlying cause of arrest.     

High sCD40L levels early after trauma are associated with enhanced shock,sympathoadrenal activation,tissue and endothelial damage,coagulopathy and mortality

Summary. Background: Severe injury activates the sympathoadrenal, hemostatic and inflammatory systems, but a maladapted response may contribute to a poor outcome. Soluble CD40L is a platelet‐derived mediator that links inflammation, hemostasis and vascular dysfunction. Objectives: To investigate the association between the sCD40L level and tissue injury, shock, coagulopathy and mortality in trauma patients. Methods: A prospective, observational study of 80 trauma patients admitted to a Level I Trauma Center. Data on demography, biochemistry, Injury Severity Score (ISS) and 30‐day mortality were recorded and admission plasma/serum analyzed for sCD40L and biomarkers reflecting sympathoadrenal activation (adrenaline, noradrenaline), tissue/endothelial cell/glycocalyx damage (histone‐complexed DNA fragments [hcDNA], Annexin V, thrombomodulin and syndecan‐1), coagulation activation/inhibition (PF1.2, TAT‐complex, antithrombin, protein C, activated protein C, sEPCR, TFPI, von Willebrand factor [VWF], fibrinogen and factor [F] XIII), fibrinolysis (D‐dimer, tissue plasminogen activator [tPA] and plasminogen activator inhibitor‐1 [PAI‐1]) and inflammation (interleukin‐6 [IL‐6] and sC5b‐9). We compared patients stratified by median sCD40L level and investigated predictive values of sCD40L for mortality. Results: High circulating sCD40L was associated with enhanced tissue and endothelial damage (ISS, hcDNA, Annexin V, syndecan‐1 and sTM), shock (pH, standard base excess), sympathoadrenal activation (adrenaline) and coagulopathy evidenced by reduced thrombin generation (PF1.2), hyperfibrinolysis (D‐dimer), increased activated partial thromboplastin time (APTT) and inflammation (IL‐6) (all P < 0.05). A higher ISS (P = 0.017), adrenaline (P = 0.049) and platelet count (P = 0.012) and lower pH (P = 0.002) were associated with higher sCD40L by multivariate linear regression analysis. High circulating sCD40L (odds ratio [OR] 1.84 [95% CI 1.05–3.23], P = 0.034), high age (P = 0.002) and low Glasgow Coma Score (GCS) pre‐hospital (P = 0.002) were independent predictors of increased mortality. Conclusions: High early sCD40L levels in trauma patients reflect tissue injury, shock, coagulopathy and sympathoadrenal activation and predict mortality. As sCD40L has pro‐inflammatory activity and activates the endothelium, sCD40L may be involved in trauma‐induced endothelial damage and coagulopathy.     

Enhanced thrombin generation in patients with cirrhosis‐induced coagulopathy

Summary. Background: Prothrombin time (PT) and the international normalized ratio (INR) are still routinely measured in patients with liver cirrhosis to ‘assess’ their bleeding risk despite the lack of correlation with the two. Thrombin generation (TG) assays are global assays of coagulation that are showing promise in assessing bleeding and thrombosis risks. Aim: To study the relationship between the INR and TG profiles in cirrhosis‐induced coagulopathy. Methods: Seventy‐three patients with cirrhosis were studied. All TG parameters were compared with those from a normal control group. Contact activation was prevented using corn trypsin inhibitor. TG was also assayed in the presence of Protac^®. The endogenous thrombin potential (ETP) ratio was derived by dividing the ETP with Protac® by the ETP without Protac®. Results: The INR (mean 1.7) did not correlate with the ETP and the velocity of TG (P > 0.05). There was no difference between the lag time and ETP of the two groups (P > 0.05). The velocity of TG was increased in cirrhosis (67.95 ± 34.8 vs. 45.05 ± 25.9 nM min^?1; P = 0.016) especially in patients with INRs between 1.21 and 2.0. Both the ETP with Protac^® and the ETP ratio were increased in cirrhosis (mean 1074 ± 461.4 vs. 818 ± 357.9 nM min, P = 0.004 and 0.80 ± 0.21 vs. 0.44 ± 0.15, P ≤ 0.0001, respectively). Conclusion: Despite a raised INR, TG parameters are consistent with a hypercoagulable profile in cirrhosis‐related coagulopathy. This confirms that the PT or INR should not be used to assess bleeding risk in these patients, and other parameters, such as TG, need to be explored as clinical markers of coagulopathy.     

Factor deficiencies in venom‐induced consumption coagulopathy resulting from Australian elapid envenomation: Australian Snakebite Project (ASP‐10)

Summary. Background: Limited information exists on the dynamics of hemostasis in patients with venom‐induced consumption coagulopathy (VICC) from snake envenomation. Objective: The aim of the present study was to investigate specific factor deficiencies and their time course in Australasian elapid envenomation. Methods: We measured coagulation parameters and factor concentrations in patients recruited to the Australian Snakebite Project, an observational cohort study. There were 112 patients with complete VICC, defined as an international normalized ratio (INR) > 3, and 18 with partial VICC. Serial citrated plasma samples were collected from 0.5 to 60 h post‐bite. INR, activated partial thromboplastin time (aPTT), coagulation factors (F)I, II, V, VII, VIII, IX, X, von Willebrand factor antigen (VWF:Ag) and D‐dimer concentrations were measured. Results: Complete VICC was characterized by near/total depletion of fibrinogen, FV and FVIII, with an INR and aPTT that exceeded the upper limits of detection, within 2 h of snakebite. Prothrombin levels never fell below 60% of normal, suggesting that the toxins were rapidly eliminated or inactivated and re‐synthesis of clotting factors occurred irrespective of antivenom. Partial VICC caused limited depletion of fibrinogen and FV, and almost complete consumption of FVIII. Onset of VICC was more rapid with brown snake (Pseudonaja spp.) venom, which contains a group C prothrombin activator toxin, compared with the tiger snake group, which contains a group D prothrombin activator toxin and requires human FVa formation. Resolution of VICC occurred within 24–36 h irrespective of snake type. Conclusions: These results suggest that Australasian elapid prothrombin activators have a potent but short duration of action. Antivenom is unlikely to be administered in time to prevent VICC.     

Recurrent,persistent, or late,new-onset hematologic abnormalities in Crotaline snakebite

Background.?Hematologic effects from rattlesnake envenomation exhibit a phenomenon of recurrent, persistent or late, new onset (late) abnormalities in some Fab antivenom‐treated patients 4 or more days post‐envenomation. Indicators that reliably identify or exclude those patients at risk of late hematologic effects have not been developed.

Methods.?This was a retrospective, observational case series of rattlesnake bite records at two US poison centers. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for D‐dimer, fibrinogen, platelets, platelet count trend, INR and PTT associated with late hematologic abnormalities, were determined.

Results.?Three hundred seventy six cases were reviewed. Sixty cases met inclusion criteria. Overall, 17 of 60 patients (28%) had a hematologic abnormality as a result of envenomation. Eleven of 60 patients (65% of those with a hematologic abnormality; 18% overall) developed late hematologic abnormalities 4 or more days post‐envenomation. Four patients had late, new onset hypofibrinogenemia and/or thrombocytopenia. All were associated with early D‐dimer elevation and/or platelet rise in response to FabAV treatment, respectively. Normal hematologic parameters in the first 48 h post‐envenomation and the lack of a greater than 20% rise in platelets within 4 h post‐antivenom administration had a 100% NPV for late hematologic effects.

Conclusions.?Patients with early onset hypofibrinogenemia, a positive D‐dimer, thrombocytopenia, or a 20% increase in platelet count within 4 h post‐treatment had a significant likelihood of late hematologic effects. Patients in whom fibrinogen, D‐dimer, INR, PTT, and platelet counts remained normal throughout the first 48 h post‐envenomation, and who did not exhibit a >20% increase in platelet count within 4 h post‐antivenom administration, did not develop late hematologic effects.     

Hump-nosed pit viper (Hypnale hypnale) envenoming causes mild coagulopathy with incomplete clotting factor consumption

Context. Limited information exists on the coagulopathy caused by hump-nosed pit viper (Hypnale hypnale) envenoming. Objectives. This study aimed to characterise the coagulopathy in hump-nosed pit viper bites by measuring laboratory clotting times and factor studies. Materials and methods. Cases of hump-nosed pit viper envenoming were included from a prospective cohort study of Sri Lankan snake-bite patients. Patient age, sex, snake identification, time of bite and clinical effects were recorded. Patients did not receive anti-venom because no specific anti-venom to hump-nosed vipers exists. All patients received supportive care and serial 20-min whole blood clotting tests (WBCT20). The prothrombin time (PT), international normalised ratio (INR), activated partial thromboplastin time (aPTT), coagulation factors I, II, V, VII, VIII, IX and X, von Willebrand factor (vWF) antigen and D-Dimer concentrations were measured. The median of highest or lowest test result for each patient was reported with interquartile range (IQR). Results. There were 80 hump-nosed pit viper bites, median age was 37 years (IQR: 26–51 years) and 48 were male. The WBCT20 was positive in one patient. The median highest INR was 1.9 (1.5–2.2; Range: 1.3 to > 12) and median highest aPTT was 54 s (46–72 s; Range: 35–170 s). There was low fibrinogen [median: 1.3 g/L;1, –1.8 g/L; Range: < 0.2–2.9], low factor VIII levels [median: 23%; 16–37%] and low factor V levels [median: 43%; 23–74%]. D-Dimer concentrations [median: 3.4 mg/L; 2–7.4 mg/L] were slightly elevated. Factors II, VII and X and vWF antigen concentrations were normal. Discussion and Conclusions. Hump-nosed pit viper bites result in a mild coagulopathy which is usually not detected by a WBCT20. It is characterised by mild elevation of INR, low fibrinogen and Factors V and VIII which may be consistent with the venom containing a thrombin-like enzyme.     

Evaluation of hemostatic biomarker abnormalities that precede platelet count decline in critically ill patients with sepsis

Purpose

The hemostatic biomarkers for early diagnosis of sepsis-associated coagulopathy have not been identified. The purpose of this study was to evaluate hemostatic biomarker abnormalities preceding a decrease in platelet count, which is a surrogate indicator of overt coagulopathy in sepsis.

Materials and Methods

Seventy-five septic patients with a platelet count more than 80 × 10³/μL were retrospectively analyzed. Hemostatic biomarkers at intensive care unit admission were compared between patients with and patients without a subsequent decrease in platelet count (≥ 30% within 5 days), and the ability of biomarkers to predict a decrease in platelet count was evaluated.

Results

Forty-two patients (56.0%) developed a subsequent decrease in platelet count. Severity of illness, incidence of organ dysfunction, and 28-day mortality rate were higher in patients with a subsequent decrease in platelet count. There were significant differences between patients with and patients without a subsequent decrease in platelet count in prothrombin time–international normalized ratio, fibrinogen, thrombin-antithrombin complex, antithrombin, protein C (PC), plasminogen, and α₂-plasmin inhibitor (α₂-PI). Receiver operating characteristic curve analysis showed that PC (area under the curve, 0.869; 95% confidence interval, 0.699-0.951) and α₂-PI (area under the curve, 0.885; 95% confidence interval, 0.714-0.959) were strong predictors of a subsequent decrease in platelet count.

Conclusions

Decreased PC and α₂-PI activity preceded a decrease in platelet count in intensive care unit patients with sepsis.     

Protein C concentrate to restore physiological values in adult septic patients

OBJECTIVE: To describe the efficacy and safety of protein C (PC) concentrate to restore physiological values in adult septic patients having clinical contraindications to activated PC. DESIGN: Case series (pilot study). SETTING: Three adult ICUs of a University Hospital. PATIENTS AND PARTICIPANTS: Twenty adult patients affected by severe sepsis or septic shock with plasma values of PC < 50%. INTERVENTIONS: Patients were treated with PC concentrate (Ceprotin ((R))--Baxter) with a starting bolus followed by a continuous infusion for 72 h [3 IU/(kg h)]. MEASUREMENTS AND RESULTS: PC activity, WBC, platelets, D: -Dimer, fibrinogen, PT, aPTT, AT III, lactate, Sepsis-related Organ Failure Assessment (SOFA), Disseminated Intravascular Coagulation (DIC) score, adverse events, and mortality were measured. Baseline plasma PC activity was 34.5 +/- 9.1%. PC concentrate normalized the PC activity in all patients within 48 h, and then remained stable for the following days. At baseline, several patients showed abnormal PT, aPTT, platelets values, and lactate levels. During the study period, there was a significant increase of platelets, fibrinogen, PT, AT III, and a significant decrease of D: -Dimer, aPTT, DIC score, and lactate. No adverse reactions (hemorrhage or thrombosis) were observed. Mortality at 28 days was 35%. CONCLUSIONS: Our pilot study shows that the administration of PC concentrate to patients having contraindications to the treatment with activated PC was safe and possibly useful to control the coagulopathy triggered and sustained by sepsis. A randomized, double blind study in patients with severe sepsis and contraindications to activated PC administration would be advisable to state the safety and the possible role of this product in the treatment of severe sepsis.     

Correlations between rotational thromboelastometry (ROTEM) and standard coagulation tests following viper snakebites

BackgroundA high prevalence of venom-induced consumption coagulopathy has been reported in individuals with viper snakebites. Rotational thromboelastometry (ROTEM) is a rapid technique that could be advantageous in assessing and monitoring coagulation disorders.PurposeTo explore correlations between ROTEM and standard coagulation tests.Patients and methodsThis prospective observational study was performed among 41 patients with viper envenomation admitted to the Vietnam Poison Control Center from April 2016 to October 2017. Standard coagulation measurements [platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level] and ROTEM indicators [clotting time (CT), amplitude (at set time: 5 and 10 minutes), clot information time (CFT) and maximum clot firmness (MCF) for extrinsic (EXTEM), intrinsic (INTEM), and fibrin based (FIBTEM) ROTEM] were obtained.ResultsFor INTEM, EXTEM, the FIBTEM, proportions of patients with prolonged CT were 34.1%, 63.4%, and 61.0% respectively and the proportions of patients with decreased MCF were 62.2%, 62.2%, and 35.5%, respectively. Moderate correlations were observed between PT and EXTEM CT (r = 0.627), aPTT and INTEM CT (r = 0.626), fibrinogen and FIBTEM MCF (r = 0.723), and platelet count and EXTEM MCF (0.60).ConclusionROTEM indicated a hypocoagulation state in patients with viper snakebite and was moderately correlated with standard coagulation parameters.     

Direct effects of protein S in ameliorating acute lung injury

Summary. Objective: Protein S may exert an anticoagulant activity by enhancing the anticoagulant activity of activated protein C and/or by directly inhibiting the prothrombinase complex. Protein S itself may also directly regulate inflammatory responses and apoptosis. The role of protein S in acute lung injury (ALI) was unknown. This study evaluated the effect of protein S on ALI in the mouse. Methods: Animal ALI was induced in C57/BL6 mice by intratracheal instillation of lipopolysaccharide (LPS). Mice were treated with protein S or saline by intraperitoneal injection 1 h before LPS instillation. Results: Activated protein or protein S alone and combined activated protein C + protein S therapy decreased inflammatory markers and cytokines in mice with acute lung injury. In LPS‐treated mice compared with controls ALI was induced as shown by significantly increased levels of total protein, tumor necrosis factor‐α, interleukin‐6 and monocyte chemoattractant protein‐1 in the bronchoalveolar lavage fluid. Mice with ALI treated with protein S had significantly decreased concentrations of tumor necrosis factor‐α and interleukin‐6 in the lung compared with untreated animals. Thrombin‐antithrombin III, a marker of the activity of the coagulation cascade, was unchanged. Protein S inhibited the expression of cytokines in vitro and increased activation of the Axl tyrosine kinase pathway in A549 epithelial cells. Conclusion: Protein S protects against LPS‐induced ALI, possibly by directly inhibiting the local expression of inflammatory cytokines without affecting coagulation.     

Effects of replacement fluids on coagulation system used for therapeutic plasma exchange.

Therapeutic apheresis is a widely used treatment alternative for several diseases. In 29 patients with different diseases, we have monitored the PT, aPTT, thrombin time (TT), fibrinogen, D-dimer, factor VIII, IX, X, XI, XII, VWF, Protein C, S, Active Protein C Resistance (APCR) and Antithrombin-III during TPE. Patients were divided into four groups based on the replacement fluids used: 3% VARIHES or ISOHES + 4% albumin (1:1) (group 1), fresh frozen plasma (FFP) (group 2), 3% VARIHES or ISOHES (group 3) and 4% albumin (group 4). In our study, the fibrinogen level decreased to 83% of the base line level after the end of 48 h therapy. The APTT, PT, and TT increased during TPE. However no statistical difference was observed between the groups. We found a significant change in factor levels with time, only the difference in factors IX and XI between the groups was significant. In addition, factor levels measured at 48 h were close to the levels measured before aphereses. In our study, time the related change in AT-3 values was significant. Time-related changes of the Protein S and APCR were not statistical significant significant but on the other hand, we found a significant difference in AT-III and Protein C values between groups. The side effects of HES on coagulation factors and tests were comparable to those of other replacement fluids. Its low cost makes it favourable.     

Complete clinical course of envenomation by Protobothrops mangshanensis: delayed coagulopathy and response to Trimeresurus albolabris antivenom

Introduction: Protobothrops mangshanensis, the Mangshan pit viper, is a rare pit viper native to the area surrounding Mount Mang in China’s Hunan province. Toxicity from envenomation is not well characterized. Case details: A 33-year-old male presented to an emergency department (ED) after being bitten on the forearm by his P. mangshanensis. He complained of mild swelling and pain at the bite site. He was admitted for observation and toxicology consultation. Following initially normal coagulation studies including platelets, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and D-dimer, fibrinogen decreased to 121?mg/dL and D-dimer concurrently rose to 377?ng/mL over 24?h. On hospital day 2 fibrinogen stabilized at 109?mg/dL and he was discharged with outpatient laboratory monitoring. Three days later, he returned with bruising to the contralateral arm. Fibrinogen was undetectable (<40?mg/dL) and PT was 14.6?s. He declined admission but returned 2 d later with bruising to the nose. Bloodwork revealed immeasurably prolonged PT, aPTT, and thrombin time, but he eloped. Late that evening he returned and was treated with three vials of Green pit viper (Trimeresurus albolabris) antivenom. Within 24 h coagulopathy improved markedly; at five days, coagulation abnormalities resolved. Discussion: Mangshan pit viper envenomations may cause isolated hemotoxicity, despite molecular studies suggesting additional neurotoxicity and myotoxicity. T. albolabris antivenom appears effective in treating the resultant coagulopathy. Conclusion: We report the natural history of envenomation by the Mangshan pit viper. A delayed coagulopathy, apparently fibrinolytic in nature, is unaccompanied by local tissue destruction and responsive to Green pit viper antivenom.     

Reference intervals for coagulation tests in adults with different ABO blood types

IntroductionCoagulation tests are affected by many factors, such as age, race, and gestation. Although coagulation test results vary by ABO blood type, reference intervals of different ABO blood groups remain to be determined. This study aims to investigate the reference ranges of coagulation tests for different ABO blood groups in the Han population in South China.MethodsA retrospective study was conducted in the First Affiliated Hospital of Shantou University Medical College. In all, 9600 individuals aged between 20 and 79 years were included. Coagulation tests, including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time, and fibrinogen, were performed.ResultsThere was a significant difference in PT, INR, and aPTT among ABO blood groups. PT and INR varied slightly between ABO blood groups. There was a higher aPTT value in individuals in the O blood group than in those in non‐O blood groups, in both males and females across the included age range. No differences were found in thrombin time and fibrinogen between the ABO blood groups.ConclusionThe study provides reference data on coagulation tests from ABO blood groups in South China. The established reference intervals specific to ABO blood type, sex, and age may improve clinical decisions based on coagulation tests.     

Thromboelastography (TEG®) compared to conventional coagulation tests in surgical patients – a laboratory evaluation

Abstract

Background. Several methods exist for evaluation of hypocoagulation in patients with perioperative bleeding, e.g. thromboelastography (TEG^®) and conventional methods (platelet count, aPTT, INR and fibrinogen). Considering the vast experience of conventional methods it is important to investigate how well the methods correspond. Methods. Sixty surgical patients were included prospectively and blood samples were taken perioperatively. TEG^® and conventional parameters were analyzed simultaneously. An assessment of coagulopathy, based on a synthesis of the conventional methods, was done by two experienced coagulation specialists, blinded from the results of TEG^® and from the results of each other. Hypocoagulation, defined by TEG^® parameters; reaction time (R-time), angle, maximal amplitude (MA) and fibrinolysis, was evaluated according to a commonly used algorithm. Results. To detect a platelet count below 150 × 10⁹ L^?1, the sensitivity of TEG was 17% (95% CI, 7–36%) with angle and 25% (95% CI, 11–45%) with MA. The sensitivity to detect fibrinogen below 2 g/L was 11% (95% CI, 3–29%) with angle and 21% with MA (95% CI, 8–43%). To detect aPTT more than 40 s and INR more than 1.2 with R-time, the sensitivity was 19% (95% CI, 8–37%) and 0% (95% CI, 0–69%) respectively. The agreement of the evaluator's assessments of hypocoagulation was 100%, but the agreement with the overall TEG^® analysis was poor with a sensitivity of 33% and a specificity of 95%. Conclusion. The agreement between conventional laboratory tests and TEG is poor, but it remains uncertain which type of coagulation tests that best reflects the actual bleeding risk.     

Pre-operative coagulopathy management of a neonate with complex congenital heart disease: a case study

Severe coagulation defects often develop in neonates undergoing cardiac surgery, both as a result of the surgical intervention, and as pre-existing defects in the hemostatic mechanisms. The following case report describes a newborn patient with complex congenital heart disease and respiratory failure whose pre-operative coagulopathy was aggressively managed prior to surgical correction. A 5-day-old, 2.5 kg child presented with interrupted aortic arch, ventricular septal defect, atrial septal defect, and patent ductus arteriosus. On admission, he was in respiratory arrest suffering from profound acidemia. In addition, the child was hypothermic (30.1 degrees C), septic (Streptococcus viridans), and coagulopathic (disseminated intravascular coagulation-DIC). The patient was immediately intubated and initial coagulation assessment revealed the following: prothrombin time (PT) 48.9 s (international normalized ratio (INR) 15.7), activated partial thromboplastin time (aPTT) >106 s, platelet count 30,000 mm(3), fibrinogen 15 mg dL(-1) and antithrombin III (AT-III) 10%. Before cardiac surgery could be performed, the patient's DIC was corrected with the administration of cryoprecipitate (15 ml), fresh frozen plasma (300 ml), and platelets (195 ml). In spite of the large transfusion of fresh frozen plasma, the AT-III activity, measured as a percentage, remained depressed at 33. Initial thromboelastographic (TEG) determination revealed an index of +2.02, and following 100 IU administration of an AT-III concentrate, declined to -2.32. Sequential TEG profiles were performed over several days, with the results used to guide both transfusion and medical therapy. The congenital heart defect correction was subsequently performed with satisfactory initial results, but the patient developed a fungal infection and expired on the 16th post-operative day. The present case describes techniques of coagulation management for a newborn with both a severe hemostatic defect and congenital heart disease.     

Effects of the oral,direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays

Summary. Introduction: Rivaroxaban is an oral direct factor Xa inhibitor developed for prophylaxis and treatment of thromboembolic disorders. Laboratory monitoring is not necessary but the dose‐dependent effects on common reagents and assay procedures are largely unknown. Objectives: To investigate the effect of rivaroxaban on commonly used coagulation assays. Materials and Methods: Rivaroxaban was added to plasma from healthy subjects in the concentration range 0–1000 μg L^?1 and analyzed using different reagents for activated partial thromboplastin time (APTT), prothrombin time (PT), antithrombin, fibrinogen and activated protein C (APC) resistance assays. Results: At an expected peak concentration of rivaroxaban in clinical use, the APTTs were almost invariably prolonged but at lower concentrations the effect was weak. The concentration needed to double the APTT varied between 389 ± 106 and 617 ± 149 μg L^?1 for different reagents. The PT assays showed a marked degree of difference. In general, the Quick PT type assays were more sensitive compared with the Owren type PT assays. The results from antithrombin assays were dependent on the type of reagent, with the Xa‐based assay being sensitive for rivaroxaban with an estimated increase of 0.09 IU mL^?1 per 100 μg L^?1 rivaroxaban. There were only minor effects on fibrinogen assays based on thrombin reagents. The APTT‐based assay for APC resistance is affected in a dose‐dependent manner whereas an assay based on the activation of coagulation at the prothrombinase level was unaffected. Conclusions: Different assays, and even different reagents within an assay group, display variable effects by therapeutic concentrations of rivaroxaban.     

Use of polyvalent equine anti-viper serum to treat delayed coagulopathy due to suspected Sistrurus miliarius streckeri envenomation in two children

Background: Western Pygmy Rattlesnake (WPR) envenomation reportedly causes refractory and persistent coagulopathy when treated with CroFab^® (Crotalidae Polyvalent Immune Fab). We report two cases where polyvalent equine anti-viper serum (AntivipmynTRI^®) was used to treat recurrent coagulopathy in children.

Case details: The first patient was a 16-month-old male who was bitten by a confirmed WPR. The patient received a total of 18 vials of CroFab^®. His labs normalized, swelling gradually improved, and the child was discharged to home. On day 5, the child returned to the emergency department with a great deal of inguinal tenderness. Labs were obtained and the child’s INR was >13.1, while the fibrinogen was <60?mg/dL and the d-dimer was 11.72?mg/L. A decision was made to administer Antivipmyn TRI^®, and the child received a total of 10 vials. Lab values significantly improved: INR 1.2, fibrinogen 93?mg/dL, and d-dimer 4.21?mg/L. The second patient was a 20-month-old male who presented following snake envenomation. The child was administered a total of 22 vials of CroFab^® over approximately 70?h following envenomation. Physical exam continued to improve, however, lab results showed an increasing INR 1.98, decreasing platelet count 124?×?10³ per μL, fibrinogen <60?mg/dL, and d-dimer?>20 ug/mL. A total of 15 vials of Antivipmyn TRI^® were administered to this patient. Following this administration, labs and clinical exam both significantly improved. Labs revealed INR 1.16, fibrinogen 110?mg/dL, d-dimer 3.2?mg/L and platelet count 215?×?10³/μL.

Discussion: CroFab^® is still the first-line treatment for children bitten by a WPR, but in some cases patients develop a recurrent coagulopathy. The rapid response demonstrated by Antivipmyn TRI^® leads us to conclude that this is a potential therapy for this clinical situation.     

Exogenous activated protein C inhibits the progression of diabetic nephropathy

Summary. Background: Activated protein C (APC) can regulate immune and inflammatory responses and apoptosis. Protein C transgenic mice develop less diabetic nephropathy but whether exogenous administration of APC suppresses established diabetic nephropathy is unknown. Objectives: We investigated the therapeutic potential of APC in mice with streptozotocin‐induced diabetic nephropathy. Methods: Diabetes was induced in unilaterally nephrectomized C57/Bl6 mice using intraperitoneal (i.p.) injection of streptozotocin. Four weeks later, the mice were treated with i.p. exogenous APC every other day for 1 month. Results: APC‐treated mice had a significantly improved blood nitrogen urea‐to‐creatinine ratio, urine total protein to creatinine ratio and proteinuria, and had significantly less renal fibrosis as measured by the levels of collagen and hydroxyproline. The renal tissue concentration of monocyte chemoattractant protein‐1 (MCP‐1), vascular endothelial growth factor (VEGF) and the RNA expression of platelet‐derived growth factor (PDGF), transforming growth factor‐β1 and connective tissue growth factor (CTGF) were significantly lower in APC‐treated mice than in untreated animals. The percentage of apoptotic cells was reduced and the expression of podocin, nephrin and WT‐1 in the glomeruli was significantly improved in mice treated with APC compared with untreated mice. The levels of coagulation markers were not affected by APC treatment. Conclusion: Exogenous APC improves renal function and mitigates pathological changes in mice with diabetic nephropathy by suppressing the expression of fibrogenic cytokines, growth factors and apoptosis, suggesting its potential usefulness for the therapy of this disease.     

Platelet count and erythrocyte sedimentation rate are good predictors of Kawasaki disease: ROC analysis

Background and Aims: Kawasaki disease (KD) is the leading cause of acquired pediatric cardiac disease and requires a timely diagnosis. Available effective therapy is ideally administered within 10 days of illness diagnosis. Recent reports of several laboratory tests in KD have been published. In this study, we aimed to evaluate the sensitivity and specificity of several laboratory tests. Methods: We performed a retrospective study of consecutive patients diagnosed with KD from January to December 2008. We studied the sensitivity and specificity of several different tests [T‐cell subgroups, platelet count, erythrocyte sedimentation rate (ESR), and C‐reactive protein (CRP)] to predict KD using receiveroperator characteristic curve analysis. Results: No significant difference was demonstrated in T‐cell subgroups between patients with KD and referent patients (P>0.05). However, platelet count, ESR, and CRP were significantly higher in patients with KD than in referent patients (P<0.05). ESR showed a sensitivity of 93.9% and specificity of 83.3% with a cut‐off of 15 mm/hr (area under the curve [AUC], 89.1%; P=0.03). Platelet count showed a sensitivity of 70.6% and specificity of 75% with a cut‐off of 336.5×10⁹/l (AUC, 71.2%; P=0.03). Conclusions: These results indicate that platelet count and ESR are good predictors of KD. J. Clin. Lab. Anal. 24:385–388, 2010. © 2010 Wiley‐Liss, Inc.     

Effects of pentoxifylline on coagulation profile and disseminated intravascular coagulation incidence in Egyptian septic neonates

Background and objectives: Neonatal sepsis is frequently associated with pathological activation of the coagulation system, leading to microcirculatory derangement and multiple organ dysfunction syndrome (MODS). The key role in the pathogenesis of sepsis has been attributed to proinflammatory cytokines. These trigger the development of disseminated intravascular coagulation (DIC) via the tissue factor‐dependent pathway of coagulation. Pentoxifylline (PTX), a methylxanthine derivative that is used in peripheral vascular disease, has the potential to modify inflammatory response. The current work was designed to evaluate the potential protective effects of PTX against sepsis‐induced microcirculatory derangement in Egyptian neonates. Methods: A double‐blind placebo‐controlled quasi‐randomized design was used. Thirty‐seven neonates with sepsis were randomly allocated into two groups. Seventeen patients were given PTX (5 mg/kg/h for 6 h; for 6 successive days). Twenty patients received equivalent volume of normal saline and represented the placebo group. Prothrombin time (PT), Activated partial thromboplastin time (APTT), fibrinogen, d ‐dimer, C‐reactive protein (CRP), complete blood count (CBC), also hemodynamic parameters comprising arterial blood pressure, heart rate, capillary refill and urinary output were assessed in both groups before and after treatment. Results: Coagulation parameters in the two groups showed no significant differences. However, a higher incidence of DIC was observed in the placebo group neonates. PTX significantly lowered the percentage of bleeding (P = 0·0128) and less frequent use of FFP was observed in the PTX group (35·53% in PTX group vs. 80% in placebo group, P = 0·003). Incidence of MODS was significantly lower (P = 0·037) and hospital stay duration of survivors was significantly shorter (P = 0·044) in the PTX treated‐infants. Conclusion: Pentoxifylline protects against sepsis‐induced microcirculatory derangement in neonates. It significantly lowered the incidence of bleeding and MODS and shortened the length of hospital stay.