Depletion Of Coagulation Factors Research Articles

Viscoelastic Hemostatic Assays for Orthopedic Trauma and Elective Procedures.

The application of viscoelastic hemostatic assays (VHAs) (e.g., thromboelastography (TEG) and rotational thromboelastometry (ROTEM)) in orthopedics is in its relative infancy when compared with other surgical fields. Fortunately, several recent studies describe the emerging use of VHAs to quickly and reliably analyze the real-time coagulation and fibrinolytic status in both orthopedic trauma and elective orthopedic surgery. Trauma-induced coagulopathy—a spectrum of abnormal coagulation phenotypes including clotting factor depletion, inadequate thrombin generation, platelet dysfunction, and dysregulated fibrinolysis—remains a potentially fatal complication in severely injured and/or hemorrhaging patients whose timely diagnosis and management are aided by the use of VHAs. Furthermore, VHAs are an invaluable compliment to common coagulation tests by facilitating the detection of hypercoagulable states commonly associated with orthopedic injury and postoperative status. The use of VHAs to identify hypercoagulability allows for an accurate venous thromboembolism (VTE) risk assessment and monitoring of VTE prophylaxis. Until now, the data have been insufficient to permit an individualized approach with regard to dosing and duration for VTE thromboprophylaxis. By incorporating VHAs into routine practice, orthopedic surgeons will be better equipped to diagnose and treat the complete spectrum of coagulation abnormalities faced by orthopedic patients. This work serves as an educational primer and up-to-date review of the current literature on the use of VHAs in orthopedic surgery.

Simvastatin Improves Outcomes of Endotoxin-induced Coagulopathy by Regulating Intestinal Microenvironment

ObjectiveThe systemic inflammatory response is regarded as the major cause of endotoxin-induced coagulopathy, which is a strong predictor of mortality in patients with severe sepsis. Simvastatin plays an important role in reducing inflammation. In addition, the gut has long been hypothesized to be the “motor” of critical illness, driving or aggravating sepsis by the increased intestinal permeability and bacterial translocation. Whether simvastatin plays a role in severe endotoxin-induced coagulopathy through the gut is unclear.MethodsIn this study, mice were administered 20 mg/kg simvastatin by gavage for 2 weeks and then intraperitoneally injected with 50 mg/kg endotoxin. Twelve h later, cytokine release, coagulation dysfunction, organ damage, and survival were assessed. Besides, the intestinal barrier, permeability, bacteria abundance, and translocation were evaluated.ResultsWe found that the severity of endotoxin-induced coagulopathy was significantly improved in simvastatin-pretreated mice, who showed attenuated depletion of coagulation factors and platelets, decreased plasminogen activator inhibitor-1 (PAI-1) expression, reduced organ fibrin deposition, and improved survival time. Also, simvastatin reduced epithelial apoptosis and improved intestinal barrier function by upregulating antimicrobial peptides, lysozyme, and mucins. Simvastatin increased Lactobacillales counts, while the lipopolysaccharide group showed increased Desulfovibrio and Mucispirillum, which can produce harmful toxins. Finally, the decreased intestinal permeability in the simvastatin group caused reduced bacterial translocation in the organs and blood, both in terms of quantity and species.ConclusionSimvastatin improves the prognosis of severe endotoxemia, and the intestinal microenvironment participates in this process.

Depletion of Coagulation Factors in Drug-Resistant Plasmodium Falciparum Malaria

United States soldiers with acute relapsed P. falciparum malaria had accelerated intravascular coagulation which was manifested by thrombocytopenia, a prolonged prothrombin time and partial thromboplastin time, a decrease in multiple coagulation factors, and evidence of decreased plasminogen activation with an accumulation of fibrinogen breakdown products in the blood. These changes may be important in the pathophysiology of malaria and cause the hemorrhage and thrombosis found in many organs of patients dying with falciparum malaria.

SEE Question

Article| October 2020 SEE Question ASA Monitor October 2020, Vol. 84, 11. https://doi.org/10.1097/01.ASM.0000718796.88629.91 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Search Site Citation SEE Question. ASA Monitor 2020; 84:11 doi: https://doi.org/10.1097/01.ASM.0000718796.88629.91 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll PublicationsASA Monitor Search Advanced Search A previously healthy 29-year-old man is involved in a motor vehicle collision. He arrives at your trauma center with a blood pressure of 83/42 mm Hg, a heart rate of 122 beats/min, and obvious lower extremity fractures. In addition to fresh frozen plasma (FFP), you plan on administering 4-factor prothrombin complex concentrate (4-PCC). According to a recent study comparing this combination with administration of FFP alone, which of the following outcomes was MOST likely to occur in the dual therapy group? Trauma-induced coagulopathy, consisting of the lethal triad of acidosis, hypothermia, and depletion of coagulation factors, leads to increased mortality after trauma. Prevention or reversal of coagulopathy requires a balanced transfusion strategy of PRBCs, FFP, and platelets to mimic whole blood. 4-PCC consists of the coagulation factors II, VII, IX, and X. It was initially developed for the treatment of hemophilia but is now approved by the U.S. Food and... You do not currently have access to this content.

A prospective observational study of acute traumatic coagulopathy in traumatic bleeding from the battlefield.

Acute trauma coagulopathy (ATC) after military trauma has not been comprehensively studied. ATC is defined as a prolonged prothrombin time ratio (PTr) or reduced clot amplitude (A5) in viscoelastic testing. Compared to civilian trauma, military trauma has more injuries from explosions and gunshot wounds (GSWs), potentially leading to a different pathophysiology for traumatic coagulopathy. This study aimed to characterize military ATC on admission to a military hospital in Afghanistan and to explore any differences due to the mechanism of injury. Severely injured military casualties were enrolled in the study. Blood samples were taken on admission and after routine testing, waste plasma was prepared, frozen, and transported to the United Kingdom for in-depth hemostatic analysis. Seventy-seven percent of casualties had ATC defined by a PTr greater than 1.2 and 19% when defined by rotational thromboelastometry (ROTEM) A5 less than 36 mm. Coagulation factor depletion correlated with degree of shock, particularly factor V (p < 0.01), factor X (p < 0.01), and fibrinogen levels (p < 0.01). Thrombin generation was well preserved. Fibrinolytic biomarkers were raised correlating with the degree of shock (p < 0.01), and 8% of casualties had hyperfibrinolysis on ROTEM analysis. Plasmin-antiplasmin complexes (p < 0.01) and d-dimer levels (p = 0.01) were higher and clot firmness lower (p = 0.02) in those injured by explosion compared to GSW's. ATC was present and correlated with shock, similar to civilian trauma. Thrombin generation remained adequate. Fibrinogen and factor V levels were disproportionately low but still sufficient to allow clot formation. Fibrinolysis is a key feature, probably due to a tissue plasminogen activator surge at the time of injury. Blast injuries are associated with a greater activation of fibrinolysis than GSWs.

Trauma induced clotting factor depletion in severely injured children: a single center observational study

BackgroundCoagulopathy following severe trauma contributes significantly to mortality. Impaired clotting factors have been observed in adult trauma patients, but in pediatric trauma victims their activity has not yet been investigated.MethodsSixteen pediatric trauma patients were evaluated according to the ISS and assigned to two cohorts. An additional control group (CO; n = 10) was formed. Routine coagulation parameters and the soluble clotting factors (F) were tested. Nonparametric data was analyzed using the Mann-Whitney U test. Results are reported as median and interquartile range.ResultsThe ISS of severely (SI, n = 8) and mildly (MI, n = 8) injured children differed significantly (25 [19–28] vs. 5 [4–6]; p < 0.001). INR was elevated in the SI cohort only when compared to the CO (1.21 [1.04-1.58] vs. 0.96 [0.93-1.00]; p = 0.001). Differences between SI and MI were found for FII (67 [53-90] vs. 82 [76-114] %; p = 0.028), FV (76 [47-88] vs. 92 [82-99] %; p = 0.028), and FXIII (67 [62-87] vs. 90 [77-102] %; p = 0.021). Comparison of the SI with the CO (FII 122 [112-144] %; p < 0.001; FV 123 [100-142] %; p = 0.002; and FXIII 102 [79-115] %; p = 0.006) also revealed a reduction in the activity of these factors. Furthermore, fibrinogen (198 [80-242] vs. 296 [204-324] mg/dl; p = 0.034), FVII (71 [63-97] vs. 114 [100-152] %; p = 0.009), FIX (84 [67-103] vs. 110 [90-114] %; p = 0.043), and FX (70 [61-85] vs. 122 [96-140] %; p = 0.001) were reduced in the SI in comparison with the CO. Finally, FVIII was considerably, yet not significantly, increased in both patient cohorts (235 [91-320] % and 197 [164-238] %, respectively).ConclusionsThis study proves that children suffer a depletion of clotting factors following severe injury which basically reflects the findings for adult trauma patients. Attempts to correct the impaired clotting factor activity could be based on a specific hemostatic therapy involving administration of coagulation factors. Nevertheless, therapeutic implications need to be investigated in future studies.

Системные гемостатические и гемостазиологические эффекты низкой дозы фибрин-мономера на фоне действия варфарина в эксперименте

Введение. Ранее было показано, что фибринмономер (ФМ) в низких дозировках обладает системным гемостатическим действием в условиях дозированной травмы. Авторами выдвинута гипотеза, согласно которой ФМ способен оказывать регулирующее гемостатическое действие in vivo на фоне сниженного гемостатического потенциала. Цель исследования: изучение системных гемостатических и гемостазиологических эффектов ФМ на фоне дозированной травмы печени при гипокоагуляции, обусловленной приемом варфарина. Материалы и методы. В работе использовали 40 кроликов породы Шиншилла. Для индукции кумаринобусловленной гипокоагуляции животным per os вводили варфарин в дозе 0,4 0,5 мг/кг 14 дней до достижения международного нормализованного отношения (МНО) более 2,0. Далее животным в краевую вену уха вводили концентрат факторов протромбино вого комплекса (КФПК) в дозе 40 ЕД/кг, ФМ в дозе 0,25 мг/кг или плацебо. Через 1 ч после введения препаратов наносили травму печени и оценивали кровопотерю (в процентах от объема циркулирующей крови). Исследовали число тромбоцитов, активированное парциальное тромбопластиновое время, МНО, содержание фибриногена и Ддимера, оценивали результаты тромбоэластографии крови. Результаты. Объем кровопотери в группах животных после внутривенного введения ФМ и КФПК на фоне приема варфарина был в 9,1 раза и 6,7 раза меньше, соответственно, по сравнению с группой плацебо, получавшей тот же антикоагулянт. Вместе с тем ФМ не влиял на параметры коагулограммы (отсутствие видимого гемостазиологического эффекта) и тромбоэластограммы, тогда как применение КФПК в качестве антидота варфарина сопровождалось нормализацией параметров тромбоэластометрии и коррекцией гипокоагуляционного сдвига по МНО. Заключение. Установлено, что ФМ способен проявлять свое системное гемостатическое действие в условиях сниженного тромбинообразования, обусловленного нарушением синтеза витамин Кзависимых факторов свертывания крови. Данное действие реализуется без признаков восстановления гемостатического равновесия. Introduction. It was shown earlier that fibrinmonomer (FM) in low doses had a systemic hemostatic effect in a controlled injury condition. The authors suggest that FM is able to exert a regulating hemostatic effect in vivo under reduced hemostatic potential. Aim: to study the systemic hemostatic and hemostasiological effects of FM under controlled liver injury during hypocoagulation caused by warfarin administration. Materials and methods. In this study 40 Chinchilla rabbits were used. For the induction of coumarinmediated hypocoagulation, animals were administered per os warfarin at a dose of 0.4 0.5 mg/kg for 14 days, until an international normalized ratio (INR) was more than 2.0. Subsequently, a prothrombin complex concentrate (PCC) at a dose of 40 U/kg, FM at a dose of 0.25 mg/kg or placebo were administered into the marginal ear vein of the animals. An hour later, a liver injury was inflicted and blood loss was assessed (in percents of the circulating blood volume). The number of platelets, activated partial thromboplastin time, INR, levels of fibrinogen and Ddimer were studied and the results of blood thromboelastography were evaluated. Results. Blood loss volume in animals groups after intravenous administration of FM and PPC, under warfarin reception, was 9.1 times and 6.7 times less, respectively, compared to the placebo group receiving the same anticoagulant. However, FM did not affect on coagulogram parameters (no visible hemostasiological effect) and thromboelastogram, whereas the use of PPC as warfarin antidote was accompanied by the normalization of thromboelastometry parameters and hypocoagulation shift correction according to INR. Conclusion. It was found that FM able to manifest its systemic hemostatic effect in conditions of reduced thrombin formation caused by impaired synthesis of vitamin Kdependent blood coagulation factors. This effect is implemented without any signs of recovery of hemostatic balance.

Complement depletion and Coombs positivity in pneumococcal hemolytic uremic syndrome (pnHUS). Case series and plea to revisit an old pathogenetic concept

Hemolytic uremic syndrome is a rare complication of invasive pneumococcal infection (pnHUS). Its pathogenesis is poorly understood, and treatment remains controversial. The emerging role of complement in various forms of HUS warrants a new look at this “old” disease.We performed a retrospective analysis of clinical and laboratory features of three sequential cases of pnHUS since 2008 associated with pneumonia/pleural empyema, two due to Streptococcus pneumoniae serotype 19 A. Profound depletion of complement C3 (and less of C4) was observed in two patients. One patient was Coombs test positive. Her red blood cells (RBCs) strongly agglutinated with blood group compatible donor serum at 0 °C, but not at 37 °C. All three patients were treated with hemodialysis, concentrated RBCs, and platelets. Patient 2 received frozen plasma for hepatic failure with coagulation factor depletion. Intravenous immunoglobulin infusion, intended to neutralize pneumococcal neuraminidase in patient 3, was associated with rapid normalization of platelets and cessation of hemolysis. Two patients recovered without sequelae or disease recurrence. Patient 2 died within 2½ days of admission due to complicating Pseudomonas aeruginosa sepsis and multiorgan failure.Our observations suggest that pnHUS can be associated with dramatic, transient complement consumption early in the course of the disease, probably via the alternative pathway. A critical review of the literature and the reported cases argue against the postulated pathological role of preformed antibodies against the neuraminidase-exposed Thomsen-Friedenreich neoantigen (T antigen) in pnHUS. The improved understanding of complement regulation and bacterial strategies of complement evasion allows to propose a testable, new pathogenetic model of pnHUS. This model shifts emphasis from the action of natural anti-T antibodies toward impaired Complement Factor H (CFH) binding and function on desialylated membranes. Removal of neuraminic acid residues converts (protected) self to non-self surfaces that supports membrane attack complex (MAC) assembly. Complement activation is potentially exacerbated by decreased CFH availability following tight CFH binding to pneumococcal evasion proteins and/or by the presence of genetic variants of complement regulator proteins. Detailed clinical and experimental investigations are warranted to better understand the role of unregulated complement activation in pnHUS. Instead of avoidance of plasma, a new, integrated model is evolving, which may include short-term therapeutic complement blockade, particularly where genetic or functional APC dysregulation is suspected, in addition to bacterial elimination and, potentially, neuraminidase neutralization.

Principal component analysis of coagulation assays in severely injured children

BackgroundTrauma-induced coagulopathy is common and associated with poor outcome in injured children. Our aim is to identify patterns of coagulation dysregulation after injury and associate these phenotypes with relevant clinical outcomes. MethodsWe performed principal components analysis on prospectively collected data from children with the highest-level trauma activation June 2015–June 2016. Parameters included admission international normalized ratio, platelet count and thromboelastograms. Variables were reduced to principal components; principal component scores were generated for each subject and used in logistic regression with outcomes including mortality, disability, venous thromboembolism, and blood transfusion in the first 24 hours. ResultsWe included 133 subjects with median interquartile range age =10 (5–13 years), median interquartile range Injury Severity Score =17 (9–25), 73.5% boys, 70.8% blunt trauma. principal component analysis identified 3 significant principal components accounting for 75.0% of overall variance. Principal component 1 reflected clot strength; principal component 2 reflected abnormal fibrinolysis, both hyperfibrinolysis and fibrinolysis shutdown; principal component 3 reflected global clotting factor depletion. High principal component 1 score was associated with increased mortality (odds ratio =1.63) and blood transfusion (odds ratio 1.36). Principal component 2 score was correlated with Injury Severity Score (rho 0.4) and associated with venous thromboembolism (odds ratio 1.84), functional disability (odds ratio 1.66), mortality (odds ratio 2.07) and blood transfusion (odds ratio 2.79). PC3 score was associated with increased mortality (odds ratio 1.92) and blood transfusion (odds ratio 1.25). ConclusionPrincipal component analysis detects 3 patterns of coagulation dysregulation using widely available laboratory parameters: (1) abnormalities in clot strength; (2) abnormalities in fibrinolysis, and (3) clotting factor depletion. While all were associated with mortality and transfusion, fibrinolytic dysregulation was associated with injury severity and portends particularly poor outcome including venous thromboembolism and disability.

111 A LUPUS NEPHRITIS PATIENT WITH BREATHLESSNESS FOLLOWING PLASMA EXCHANGE

Category: Other Presenter: Dr WAN HASNUL HALIMI WAN HASSAN Keywords: SLE, lupus nephritis, plasma exchange, fluid overload A 17 years old girl, diagnosed with Lupus nephritis since 2014. She had Lupus Nephritis class III , in partial remission following treatment with t.mycophenolate mofetil (MMF). She was transferred to high dependency ward requiring non invasive ventilation after 4th cycle of plasmapharesis. This is due to fluid overload and her condition improves after hemodialysis and ultrafiltration. She initially presented with symptoms of facial puffiness and leg swelling for 2 weeks. She was admitted was started on high dose prednisolone (60mg OD) and t.MMF 1g BD. Progressive worsening renal function was noted (urea 29/creat 190; baseline renal function was normal urea/creat) Renal biopsy results shows Crescentric Lupus Nephritis, ISN/RPS class IV-G (A/C). activity index 15/24, chronicity index 4/12. (57% cellular crescent, 15% global sclerosis). IV cyclophosphamide induction and plasma exchange was initiated. She completed total of 10 plasmapheresis cycle and is currently still ongoing 3rd cyclophosphamide induction. Her renal profile shows improvement (urea 15.7/creatinine 116). Plasma Exchange is a recognized modality of treatment in more severe and/or resistant lupus nephritis, moreover for crescentic glomerulonephritis. The complication rate of is not high. The Swedish registry reported no fatalities during 20,485 procedures, and an overall adverse incidence rate of only 4.3% of all exchanges (0.9% for severe adverse events) of which 27% were paresthesias, 19% transient hypotension, 13% urticaria, and 8% nausea. An overall complication rate of 1.4% has been reported in more than 15,000 treatments in patients receiving albumin, and 20% in patients receiving FFP. There's increases the risk of bleeding as a result of depletion of coagulation factors in patients receiving albumin as sole replacement colloid. A study in Japan looking at 53 kidney transplant recipients receiving plasma exchange for desensitization, recorded the were no severe adverse event, milder events were pruritus 53%, numbness 40% and mild dyspnea 5%. The incidence of numbness during plasma exchange was less in patients receiving combined hemodialysis. In our case, fluid overload was noted as a major complication requiring non invasive ventilation and hemodialysis. This is due to the large volume exchange and associated renal impairment. Although uncommon, fluid overload and other complication related to large volume plasma exchange is needed to be taken under account in a renal impaired patient.

Platelet Count and Transfusion Requirements During Moderate or Severe Postpartum Haemorrhage

(Anaesthesia. 2016;71:648–656) Postpartum hemorrhage is a leading cause of maternal morbidity and mortality worldwide. Depletion of coagulation factors and platelets can occur during obstetric hemorrhage. Reduction in coagulation factors and its management by replacement with fresh frozen plasma, cryoprecipitate, and fibrinogen concentrate have been addressed in earlier studies. However, there are few data addressing the need for platelet transfusion during postpartum hemorrhage. Current guidelines suggest transfusion may be indicated when the platelet count is &lt;75×109/L. This study evaluated data from a previous study investigating the effect of fibrinogen on postpartum hemorrhage progression to assess the association between baseline platelet count and the need for platelet transfusion during postpartum hemorrhage.

Acute traumatic coagulopathy: The elephant in a room of blind scientists.

Acute traumatic coagulopathy (ATC) is the failure of coagulation homeostasis that can rapidly arise following traumatic injury, hemorrhage, and shock; it is associated with higher injury severity, coagulation abnormalities, and increased blood transfusions. Acute traumatic coagulopathy has historically been defined by a prolonged prothrombin time, although newer, more informative measurements of hemostatic function have been used to improve diagnosis and support clinical decision making. The underlying biochemical mechanisms of and best practice therapeutics for ATC remain under active investigation because of its significant correlation to poor outcomes. The wide range of hypothesized mechanisms for ATC results from the large number of symptoms, phenotypes, and altered states in these patients as observed by multiple research groups. Much like the ancient fable of blind men describing an elephant from their limited perspectives, the limited nature of clinical and laboratory tools used to diagnose coagulopathy or evaluate hemostatic function has made finding causation difficult. The prolonged prothrombin time, degree of fibrinolysis, depletion of coagulation factors and inhibitors, and general failure of the blood have all been identified as being primary indicators for ATC. Therapeutic interventions including recombinant coagulation factors, antifibrinolytics, and blood products have been used with varying degrees of success as they are used to address specific symptoms. To truly understand the causes of ATC, research efforts must recognize the complexity of the hemostatic system and get to the heart of the matter by answering the question: "Is ATC a pathological condition that develops from the observed deficiencies in coagulation, fibrinolysis, and autoregulation, or is ATC an adaptive response generated as the body attempts to restore perfusion and avoid massive organ failure?" Because patient management must proceed without definitive answers regarding the entire causative chain, the current therapeutic focus should be on using what knowledge has been gained to the patient's advantage: control hemorrhage, maintain appropriate homeostatic balances of coagulation proteins, and restore oxygen perfusion.

In vitro effects of different sources of fibrinogen supplementation on clot initiation and stability in a model of dilutional coagulopathy.

To analyse which fibrinogen source may improve coagulation using an in vitro 33% dilutional coagulopathy model. Uncritical volume resuscitation in the context of trauma haemorrhage contributes to the iatrogenic arm of the acute trauma-induced coagulopathy through dilution and depletion of coagulation factors, with fibrinogen reaching critical levels first. By using an experimental model of 33% dilutional coagulopathy, we have analysed which fibrinogen source may exert superior effects on improving haemocoagulative capacities and correcting depleted fibrinogen levels. As fibrinogen sources, we supplemented (i) fresh frozen plasma (FFP), (ii) fibrinogen concentrate low-dose (Fiblow ) and (iii) fibrinogen concentrate high-dose (Fibhigh ), the latter both in the presence and absence of additional FXIII. The dilution was associated with decreased haemoglobin and haematocrit levels. Fibrinogen supplementation with fibrinogen-containing formulations led to increased fibrinogen levels (FFP: 172·2 ± 17·4 mg dL-1 ; Fiblow : 211·5 ± 20·61 mg dL-1 ; Fibhigh : 255·8 ± 21·4 mg dL-1 ) than in a diluted-only sample (155·5 ± 19·7 mg dL-1 ). Extrinsically activated assay with tissue factor (EXTEM) clot formation times, α-angles and maximum clot firmness significantly improved in the groups of Fiblow + FXIII (79 ± 12·2 s; 74·3 ± 2·4°; 62 ± 2·3 mm), Fibhigh (70·8 ± 10·6 s; 76·2 ± 2·7°; 64·3 ± 2·3 mm) and Fibhigh + FXIII (69·8 ± 11·5 s; 77·5 ± 2·7°; 64·33 ± 2·5 mm) compared with the dilution groups (104·2 ± 19 s; 69·7 ± 2·9°; 56·5 ± 3·1 mm). In contrast, rotational thromboelastometric trace (ROTEM) measures of samples supplemented with FFP largely remained unchanged. Fibrinogen concentrates corrected and improved haemodilution-induced changes in blood clotting in vitro. High-dose fibrinogen supplementation was associated with correction and improvement in clot dynamics and stability.

Strategies for Pharmacological Organoprotection during Extracorporeal Circulation Targeting Ischemia-Reperfusion Injury.

Surgical correction of congenital cardiac malformations or aortocoronary bypass surgery in many cases implies the use of cardiopulmonary-bypass (CPB). However, a possible negative impact of CPB on internal organs such as brain, kidney, lung and liver cannot be neglected. In general, CPB initiates a systemic inflammatory response (SIRS) which is presumably caused by contact of blood components with the surface of CPB tubing. Moreover, during CPB the heart typically undergoes a period of cold ischemia, and the other peripheral organs a global low flow hypoperfusion. As a result, a plethora of pro-inflammatory mediators and cytokines is released activating different biochemical pathways, which finally may result in the occurrence of microthrombosis, microemboli, in depletion of coagulation factors and haemorrhagic diathesis besides typical ischemia-reperfusion injuries. In our review we will focus on possible pharmacological interventions in patients to decrease negative effects of CPB and to improve post-operative outcome with regard to heart and other organs like brain, kidney, or lung.

Assessment of Hemostasis after Plasma Exchange Using Rotational Thrombelastometry (ROTEM).

BackgroundTherapeutic plasma exchange (TPE)-based protocols immediately before cadaveric donor kidney transplantation have been extensively used in highly sensitized recipients. Plasma is generally preferred over human albumin as replacement fluid to avoid depletion of coagulation factors and perioperative bleeding. The aim of this study was to estimate bleeding risk after TPE replaced with albumin using rotational thromboelastography (ROTEM).MethodologyTen patients without overt coagulation abnormalities underwent TPE. Standard laboratory coagulation tests (thromboplastin time, activated partial thromboplastin time (aPTT), international normalized ratio (INR), thrombin clotting time, fibrinogen levels and antithrombin activity) were compared with thrombelastometry analysis (EXTEM and INTEM tests) before and after TPE.Principal FindingsTPE significantly reduced fibrinogen levels (482 ± 182 vs. 223 ± 122 mg/dL), antithrombin activity (103 ± 11 vs. 54 ± 11 %), and prolonged aPTT (28 ± 3 vs. 45 ± 8 s), thromboplastin time (108 ± 11 vs. 68 ± 11 %), INR (0.95 ± 0.06 vs. 1.25 ± 0.16), and thrombin clotting time (18 ± 2 vs. 20 ± 3 s). INTEM and EXTEM analyses revealed significantly prolonged clot-formation time and reduced maximum clot firmness.Conclusions/SignificanceTPE replaced with albumin induces significant changes in global hemostasis parameters thus potentially increasing bleeding risk. Therefore, pretransplant TPE should be considered carefully in indicated patients before kidney transplantation. The role of the ROTEM point-of-care test to estimate the risk of bleeding in renal transplantation needs to be evaluated in further studies.

Incidence and Predictive Value of Thrombocytopenia in Patients with Severe Community Acquired Pneumonia

Summary Introduction. Thrombocytopenia is frequently encountered in intensive care unit (ICU) patients. The cause of thrombocytopenia is multifactorial, it develops as a result of infection, inflammation and depletion of coagulation factors. Therefore, thrombocytopenia could potentially serve as an indicator of severity of the illness and an outcome predictor in patients with severe community-acquired pneumonia (CAP). Aim of the study. To determine incidence and predictive value of thrombocytopenia in ICU patients with severe CAP. Material and methods. We carried out a retrospective study based on clinical records from patients admitted to the Pauls Stradins Clinical University Hospital Intensive Care and Reanimation Unit from 2011 to 2014. Thrombocytopenia was defined as platelet count ≤150×109/L. Results. A total of 98 patients were included in this study, 58 (59%) men and 40 (41%) women. The mean (±SD) age of patients was 61±17.9 years, 54% died and 46% survived. 57 patients (58%) developed thrombocytopenia, in 58% it was present at the admission to ICU, and 42% developed thrombocytopenia during their stay in ICU. The lowest platelet count, in survivors was on fifth day in ICU, while in non-survivors on fourth day in ICU. Platelet count on admission to ICU (ROC AUC: 0.610, p=0.095) had lower discriminative power for ICU mortality than SOFA score (ROC AUC: 0.729, p=0.001) and CURB-65 score (ROC AUC: 0.680, p=0.006). Patients with thrombocytopenia at any point of ICU stay had higher hospital mortality in comparison to patients without thrombocytopenia. (36 (63.1%) vs 17 (41.1%), p=0.041). In thrombocytopenic patients non-resolution of thrombocytopenia during the ICU stay was associated with higher mortality (OR 5.5; 95% CI, 1.6-18.7, p=0.006). After adjusting for age, gender and SOFA score, non-resolution of thrombocytopenia remained to be an independent mortality predictor (OR 8, 95% CI 1.7-37, p=0.008) Conclusions. Thrombocytopenia is frequently encountered in patients with severe CAP. Thrombocytopenia at any point of ICU stay is associated with higher hospital mortality. Resolution of thrombocytopenia is associated with better clinical outcome.

A principal component analysis of postinjury viscoelastic assays: Clotting factor depletion versus fibrinolysis

The mechanisms driving trauma-induced coagulopathy (TIC) remain to be defined, and its therapy demands an orchestrated replacement of specific blood products. Thrombelastography (TEG) is a tool to guide the TIC multicomponent therapy. Principal component analysis (PCA) is a statistical approach that identifies variable clusters; thus, we hypothesize that PCA can identify specific combinations of TEG-generated values that reflect TIC mechanisms. Adult trauma patients admitted from September 2010 to October 2013 for whom a massive transfusion protocol was activated were included. Rapid TEG values obtained within the first 6hours after injury were included in the PCA. PCA components with an eigenvalue >1 were retained, and, within components, variable loadings (equivalent to correlation coefficients) >|60| were considered significant. Component scorings for each patient were calculated and clinical characteristics of patients with high and low scores were compared. Of 98 enrolled patients, 67% were male and 70% suffered blunt trauma. Median age was 41years (interquartile range 28-55) and median Injury Severity Score was 31.5 (interquartile range 24-43). PCA identified three principal components (PCs) that together explained 93% of the overall variance. PC1 reflected global coagulopathy with depletion of platelets and fibrinogen whereas PC3 indicated hyperfibrinolysis. PC2 may represent endogenous anticoagulants such as the activation of protein C. PCA suggests depletion coagulopathy is independent from fibrinolytic coagulopathy. Furthermore, the distribution of mortality suggests that low levels of fibrinolysis may be beneficial in a select group of injured patients. These data underscore the potential of risk for concurrent presumptive treatment for preserved depletion coagulopathy and possible fibrinolysis.

VaSP1, catalytically active serine proteinase from Vipera ammodytes ammodytes venom with unconventional active site triad

VaSP1, a serine proteinase from Vipera ammodytes ammodytes venom, is a glycosylated monomer of 31.5 kDa, as determined by MALDI mass spectrometry, showing multiple isoelectric points between pH 6.5 and pH 8.5. Partial amino acid sequencing of VaSP1 by Edman degradation and MS/MS analysis identified sequences which allowed its classification among the so-called snake venom serine proteinase homologues, members of the peptidase S1 family, however being devoid of the canonical catalytic triad. Only few representatives of this group have been identified so far with just two of them characterised in detail at the protein level. Despite substitution of His57 with Arg, VaSP1 possesses proteolytic activity which can be inhibited by Pefabloc, benzamidine, Zn2+ ions, DTT and trypsin inhibitor II, a Kunitz/BPTI group member. It hydrolyses Nα-benzoyl-Phe-Val-Arg-p-NA, exhibiting Michaelis–Menten behaviour with Km = 48.2 μM and Vm = 0.019 nM s−1. The pH for optimal activity on tested substrate is around 9.0. VaSP1 also cleaves insulin B-chain, digesting it at positions His10-Leu11, Ala14-Leu15 and Tyr16-Leu17. Furthermore, the novel serine proteinase is active towards wide array of proteins involved in haemostasis where its degradation of fibrinogen, fibrin, prothrombin, factor X and plasminogen in vivo probably results in depletion of coagulation factors in blood circulation. The possibility that VaSP1 possesses anticoagulant properties has been further indicated by its ability to prolong prothrombin time and activated partial thromboplastin time.

Use of ROTEM and MEA in a cardiac surgical patient with ITP

To the Editor: Perioperative management of idiopathic thrombocytopenic purpura (ITP) is challenging because the platelet count does not directly indicate platelet function. We report the use of rotation thromboelastometry (ROTEM; Tem International, Munich, Germany) and multiple electrode aggregometry (MEA) using a Multiplate analyzer (Dynabyte Medical, Munich, Germany) (Supplemental Fig. 1) to manage a 71-year-old man with an 8-year history of ITP who required an aortic valve replacement. ITP is characterized by the formation of antiplatelet antibodies that target platelet membrane glycoproteins, resulting in accelerated platelet destruction. After induction of anesthesia, the maximum clot firmness (MCF) was low in the EXTEM test but was normal in the FIBTEM test, and MEA measurements were all below the normal range, which are independent of activators (Supplemental Tables 1, 2). These results indicated a reduction in the platelet component as reflected by MCFextem–MCFfibtem [1] and slower and less dense occupation of the sensor wires on MEA, decreasing the aggregation velocity and the maximum aggregation [2]. During cardiopulmonary bypass, the MCF was reduced in EXTEM and FIBTEM tests, and these results together with all MEA measurements indicated hemodilution, coagulation factor depletion, and platelet dysfunction (Supplemental Tables 1, 2). According to the ROTEM-based algorithm, 30 U platelets and 5 U fresh frozen plasma were transfused, which normalized the ROTEM data and the unsatisfactorily corrected MEA data (Supplemental Tables 1, 2). These results reflected reduced platelet aggregation because of apheresis and storage. MEA has been reported to be useful for assessment of platelet responsiveness to antiplatelet therapy. As ROTEM is unable to evaluate primary hemostasis, use of ROTEM and MEA together might be functionally complementary. However, the patient did not require any more blood products, and the results of MEA did not affect the transfusion decision.

A principal component analysis of coagulation after trauma

Clotting factor abnormalities underlying acute traumatic coagulopathy are poorly understood, with application of traditional regression techniques confounded by colinearity. We hypothesized that principal components analysis (PCA), a pattern-finding and data reduction technique, would identify clinically predictive patterns in the complex clotting factor milieu after trauma. Plasma was prospectively collected from 163 critically injured trauma patients. Prothrombin; factors V, VII, VIII, IX, X; D-dimer; activated and native protein C; and antithrombin III levels were assayed and subjected to nonlinear PCA to identify principal components (PCs). Of 163 patients, 19.0% were coagulopathic on admission. PCA identified 3 significant PCs, accounting for 67.5% of overall variance. PC1 identified global clotting factor depletion; PC2 the activation of protein C and fibrinolysis; and PC3 factor VII elevation and VIII depletion. PC1 score correlated with penetrating injury and injury severity, predicting coagulopathy (odds ratio [OR], 4.67; p < 0.001) and mortality (OR, 1.47; p = 0.032). PC2 score correlated with injury severity, acidosis, and shock, and significantly predicted ventilator-associated pneumonia (OR, 1.59; p = 0.008), acute lung injury (OR, 2.24; p < 0.001), multiorgan failure (OR, 1.83; p = 0.002), and mortality (OR, 1.62; p = 0.006) but was not associated with international normalized ratio (INR)-based or partial thromboplastin time (PTT)-based coagulopathy (p > 0.200). PC3 did not significantly predict outcomes. PCA identifies distinct patterns of coagulopathy: depletion coagulopathy predicts mortality and INR/PTT elevation, while fibrinolytic coagulopathy predicts infection, end-organ failure, and mortality, without detectable differences in INR or PTT. While depletion coagulopathy is intuitive, fibrinolytic coagulopathy may be a distinct but often overlapping entity with differential effects on outcomes.