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У статті подано сучасні рекомендації з інтенсивної терапії гострої крововтрати в акушерстві. Акушерські кровотечі залишаються провідною причиною материнської смертності в усьому світі. Нові стратегії лікування кровотеч передбачають використання гемостатичної реанімації з визначенням оптимального співвідношення для введення різних компонентів і препаратів крові. Масивні протоколи трансфузії рекомендують раннє використання продуктів крові й обмежують традиційний підхід ранньої масивної інфузійної терапії на основі кристалоїдів. За останні кілька років змінилися дані про гемостатичну реанімацію, і тепер ведуться обговорення щодо оптимальних стратегій інфузійно-трансфузійної терапії. Використання транексамової кислоти, концентрату фібриногену і концентрату протромбінового комплексу стало потенційно новою альтернативною стратегією лікування з поліпшеними профілями безпеки.

Background Reversal of warfarin with prothrombin complex concentrates (PCC) is required in cases of significant bleeding or need for urgent surgery. A weight-based regimen is commonly, but a fixed-dose approach is also feasible with clinically equivalent outcomes. The purpose of this audit is to review the clinical and laboratory outcomes of patients treated in our centre where fixed-dose PCC is used for warfarin reversal. Objectives The primary objective was to evaluate the post-reversal INR. Secondary objectives were the proportion of patients requiring repeat PCC and 30-day complication rates (death, haemorrhage and thrombosis). A subgroup analysis was also performed to compare the outcomes of those who received a dose of ≤15 IU/kg (reduced dose) to those who received >15 IU/kg (standard dose). Methods Patients who received three-factor PCC for warfarin reversal between 1st January and 31st December 2016 were identified and analysed. Clinical data and PCC dosages were extracted from electronic patient records. Results Total of 144 patients were analysed. The median INR pre-reversal was 3.25 (range 1.4-10), which reduced to 1.5 (0.9-3.0) post-reversal. 87% of patients achieved a post-reversal INR of less than 2 and 55% less than 1.5. Sixteen patients required a repeat dose. Complications occurred in 22 patients (15.3%), which consisted of 15 deaths, 7 thrombosis and 2 haemorrhage. No statistically significant differences in the primary and secondary outcomes were noted between reduced-dose and standard-dose subgroups. Conclusion Our results support the use of fixed-dose PCC for warfarin reversal in a day-to-day clinical practice in a hospital setting. This article is protected by copyright. All rights reserved.

PURPOSE OF REVIEW Major bleeding in cardiac surgery is commonly encountered, and, until recently, most frequently managed with fresh frozen plasma (FFP). However, a Cochrane review found this practice to be associated with a significant increase in red blood cell (RBC) transfusions and costs. These findings have led to off-label uses of prothrombin complex concentrates (PCCs) in cardiac surgery. The purpose of this review is to compare and contrast the use of FFP and PCC, review the components, limitations and risks of different types of PCCs, and discuss the latest evidence for the use of PCC versus FFP in cardiac surgery. RECENT FINDINGS A recent review and meta-analysis suggests that PCC administration in cardiac surgery is more effective than FFP in reducing RBC transfusions and costs. SUMMARY The current data supports the use of 4F-PCC instead of FFP as the primary hemostatic agent in cases of major bleeding in cardiac surgery. The use of PCCs is associated with reduced rates of RBC transfusions while maintaining a favorable safety profile. Clear advantages of PCC over FFP include its smaller volume, higher concentration of coagulation factors and shorter acquisition and administration times.

Background Patients receiving oral anticoagulation who experience a traumatic intracranial hemorrhage (ICH) should receive anticoagulation reversal. Four factor prothrombin complex concentrate (4FPCC) is indicated for reversal of warfarin, and is frequently used for reversal of direct-acting oral anticoagulants (DOACs). The purpose of this study is to compare the safety and efficacy of 4FPCC reversal for traumatic ICH in DOAC- and warfarin-anticoagulated patients. Methods This was a single-center, retrospective review of adult patients with traumatic ICH who received 4FPCC for reversal of anticoagulation between April 2013 and August 2018. The ICH volume on the pre- and post-reversal head CT scans was measured. The primary endpoint was the incidence of expansion of ICH volume of blood using pre-and post-4FPCC imaging. Results A total of 102 patients meeting inclusion criteria were identified with 75 patients in the warfarin group and 27 patients in the DOAC group. There were no significant differences in baseline characteristics between the groups except DOAC patients had larger ICH volumes at baseline as compared to warfarin patients (23.4 mm3 vs 3.7 mm3, p = 0.0001). There was neither a statistical difference in change in ICH volume pre-and post-4FPCC administration, nor in the rate of >20% ICH expansion between the warfarin and DOAC groups. There was no difference in the rate of adverse events compared between groups. Conclusion There was no difference in the either the change in ICH volume or the rate of >20% ICH expansion in patients receiving 4FPCC for reversal DOAC versus warfarin anticoagulation. Rates of complications were low in both groups.

Zusammenfassung Hintergrund und Fragestellung Proximale Femurfrakturen stellen mit ca. 100.000 Betroffenen/Jahr in Deutschland ein häufiges Krankheitsbild dar. Durch eine zeitnahe Versorgung ( Material und Methoden Die Daten der externen vergleichenden Qualitätssicherung Nordrhein-Westfalen für die Jahre 2015 und 2016 wurden ausgewertet. Dabei wurden ausschließlich Fälle analysiert, bei denen eine hüftgelenknahe Femurfraktur osteosynthetisch versorgt wurde. Insgesamt wurden 24.786 Fälle hüftgelenknaher Femurfrakturen in die Studie eingeschlossen. Ergebnisse Von den Patienten mit einer antithrombotischen Dauertherapie (ATDT) wurden in der größten Subgruppe mit ASS-Medikation (n = 4005) 17 %, in der zweitgrößten Gruppe mit Vitamin-K-Antagonisten-Einnahme (n = 2157) 44,6 % und in der drittgrößten Gruppe mit Einnahme von direkten oralen Antikoagulanzien (DOAKs, n = 994) 18,2 % verzögert operiert. Schlussfolgerungen Das größte Potenzial zur Verkürzung der präoperativen Verweildauer ergibt sich in der Gruppe der Patienten, die ASS (17 % auffällig) oder einen Vitamin-K-Antagonisten (VKA, 44,6 % auffällig) einnehmen. Eine Antagonisierung der Wirkung von VKA lässt sich innerhalb kurzer Zeit durch die Gabe von Prothrombinkomplex (PPSB) erreichen. Auch unter der Einnahme von DOAKs muss das noch gängige Prozedere einer verzögerten operativen Versorgung kritisch hinterfragt werden. Die Etablierung eines Gerinnungsmanagements ist zu fordern. Neben der medizinischen Intervention (Gabe von Antidota) müssen Strukturen geschaffen werden, die eine zeitnahe Versorgung ermöglichen.

Background Prothrombin complex concentrates (PCCs) are frequently used. Objective To elucidate practices and perceptions of proprietary and nonproprietary PCCs use. Methods An electronic pretested cross-sectional survey e-mailed thrice to 1 critical care pharmacist at 1170 US institutions. Questions addressed hospital and pharmacy characteristics, use of PCCs, and perceptions of effectiveness and safety. Results 429 (39.5%) of 1086 eligible institutions completed the questionnaire. PCCs were used several times per month to several times per week (62.6%). An order set was routinely or always used to direct PCCs usage at 66.4% of institutions. Four-factor PCCs were preferred by 93% of institutions. The most common perceived indications for 4-factor PCCs were hemorrhage related to warfarin (92.1%) or oral Xa inhibitors (81.8%), intracranial hemorrhage (78.4%), trauma hemorrhage (66.2%), surgical hemorrhage (61.1%), and refractory hemorrhage (57.3%). The most common perceived contraindications were heparin-induced thrombocytopenia (42%), disseminated intravascular coagulopathy (39.2%), and active thromboembolism (38.9%). Most institutions considered patient weight (78.8%), indication (77.6%), and International Normalized Ratio (76.9%) when dosing PCCs. Only 43.8% of institutions used fixed dose, only 19.6% compounded PCCs at the bedside, and only 11.9% administered PCCs by rapid infusion. Compared to standard blood products, respondents believed PCCs acted more rapidly, were less likely to cause volume issues, and were more expensive. Respondents were neutral about PCCs acting longer, being more effective at preventing or treating hemorrhage, or causing thromboembolism. Conclusions Off-label use of PCCs is common. Differing perceptions surrounding indications, contraindications, and comparisons to blood products/procoagulants likely contribute to variable practices.

Acquired factor V deficiency (AFVD) is a rare autoimmune bleeding disorder. Unlike acquired hemophilia, bypass therapies with recombinant activated factor VII and activated prothrombin complex concentrates are ineffective for severe bleeding due to AFVD. Although several treatment strategies have been attempted, a standard of care for severe hemorrhage induced by AFVD is lacking. Herein, we report a case of AFVD with severe bleeding that responded to plasma exchange (PE) combined with immunosuppression. We also reviewed previously reported AFVD cases with severe hemorrhage and suggest that PE may be an effective initial treatment for AFVD-induced severe hemorrhage.

Massive obstetric hemorrhage is one of the most threatening complications of pregnancy, delivery and early postpartum period, which are part of the triad of leading causes of maternal mortality both in the world and in the Russian Federation. In recent years, to stop coagulopathy, which is one of the clinical manifestations of massive obstetric hemorrhage, recombinant and plasma factors of the blood coagulation system are successfully used, which include a concentrate of prothrombin complex and activated coagulation factor VII (eptacog alfa activated). The authors present results of successful consistent use of the blood coagulation system factors within comprehensive intensive care of coagulopathy in a patient with massive obstetric hemorrhage.

Factor VII deficiency is one of the hereditary coagulation disorders that has autosomal reccessive inheritance and is observed relatively frequently (1/500 000). It is clinically heterogeneous, and may be asymptomatic or lead to life-threatening bleeding. Thus, there is no correlation between FVII activity and clinical findings. Plasma-derived and recombinant FVII concentrates are currently used for treatment. In countries where access to these products is lacking, fresh frozen plasma and prothrombin complex concentrates are also used, though they contain low amounts of factor FVII. In this study, we present the clinical properties, treatments, and surgical interventions used in patients followed up in our clinic with a diagnosis of factor FVII deficiency.Patients who were diagnosed as FVII deficiency in Division of Pediatric Hematology and Oncology between July 1997 and July 2018, were included in the study. The patients' demographic characteristics, symptoms at presentation, PT, aPTT, and FVII values, types of bleeding, and treatments and surgical interventions used, were recorded. The bleedings observed in the patients were classified by severity as asymptomatic, minor, and major.A total of 18 patients (7 girls and 11 boys) with a mean age of 9.64±9.63 years were included in the study. The mean follow-up time was found as 78.06±54.4 months. When the bleedings were classified clinically, no bleeding was observed in eight patients (44.4%). The factor FVII level was found as10% in three of these eight asymptomatic patients and above 20% in the others. Minor bleeding was observed in nine patients (50%) and major bleeding was observed in one patient. When the patients were classified as asymptomatic and symptomatic, there was no significant difference between the two groups in terms of FVII level (p=0.57). A total of 21 surgical interventions were performed in 14 (78%) of 18 patients who were being followed up.FVII deficiency has a very wide spectrum both clinically and in terms of approach to surgical interventions. Therefore, patients with factor FVII deficiency should be followed up and treated by comprehensive care centers with close collaboration of multiple disciplines.Faktör VII eksikliği otozomal çekinik kalıtılan ve nispeten sık görülen (1/500 000) kalıtsal pıhtılaşma bozukluklarındandır. Klinik olarak heterojendir, asemptomatik seyredebildiği gibi yaşamsal kanamalara da yol açabilmektedir. Nitekim FVII aktivitesi ile klinik bulguların arasında korelasyon bulunmamaktadır. Tedavisinde, plazma kaynaklı ve rekombinan FVII konsantreleri kullanılırsa da, bunlara erişimin olmadığı ülkelerde düşük miktarda FVII içermelerine rağmen taze donmuş plazma ve protrombin kompleks konsantreleri de kullanılmaktadır. Bu çalışmada, kliniğimizde izlenen FVII eksikliği tanısı almış hastaların klinik özellikleri, tedavileri ve uygulanan cerrahi girişimler sunulmaktadır.İstanbul Üniversitesi Onkoloji Enstitüsü, Çocuk Hematolojisi ve Onkolojisi Bilim Dalı’nda Temmuz 1997- Temmuz 2018 tarihleri arasında FVII eksikliği tanısı alan hastalar çalışmaya alındı. Hastaların demografik özellikleri, başvuru yakınmaları, PT, aPTT ve FVII değerleri, kanama tipi, tedavileri ve uygulanan cerrahi girişimler kaydedildi. Hastalarda görülen kanamalar ağırlıklarına göre asemptomatik, minör ve majör olarak sınıflandırıldı.Ortalama tanı yaşları 9,64±9,63 olan 7’si kız 11’i erkek toplam 18 hasta çalışmaya alındı. Hastaların ortalama izlem süresi 78,06±54,4 ay idi. Kanamalar klinik olarak sınıflandırıldığında; sekiz hastada (%44.4) herhangi bir kanama gözlenmezken, asemptomatik seyreden sekiz hastanın üçünde FVII düzeyi10, diğerlerinde %20’nin üzerinde idi. Dokuz (%50) hastada minör kanama, ve bir hastada major kanama kaydedildi. Hastalar asemptomatik ve semptomatik olarak sınıflandırıldığında iki grup arasında FVII düzeyi açısından anlamlı farklılık yoktu (p=0,57). İzlenen 18 hastanın 14’üne (%78) toplam 21 cerrahi girişim uygulandı.FVII eksikliği gerek klinik olarak gerekse cerrahi girişimlere yaklaşım olarak çok geniş bir yelpazede yer almaktadır. Bu nedenle, FVII eksikliği tanısı almış hastaların, uzmanlaşmış bir kanama bozukluğu merkezi ve birden çok bilim dalı ile yakın işbirliği içinde izlem ve tedavi edilmesi gerekmektedir.

Direct acting oral anticoagulants (DOAC) are now commonly prescribed medications. Urgent reversal of their anticoagulant effect is sometimes required in emergency situations. In Australia, a specific reversal agent for factor Xa (FXa)-inhibitor DOAC is not available. Instead, two non-specific haemostatic agents, activated prothrombin complex concentrate (aPCC) and 3 factor-prothrombin complex concentrate (3F-PCC), are used off-label despite a paucity of evidence for their effectiveness or safety.To provide further insight into the efficacy and safety of 3F-PCC and aPCC for the reversal of the anticoagulant effect of FXa inhibitor DOACs.We conducted a single-centre retrospective cohort study to investigate the use of aPCC and 3F-PCC for patients on FXa-inhibitor DOAC who present with a significant bleeding event or who require urgent surgery. The primary outcome was haemostatic efficacy according to prespecified criteria. Safety outcomes included the thromboembolic event rate and all-cause mortality during the hospital admission.A total of 51 patients was included in the study (36 patients who had a spontaneous bleeding event and 15 non-bleeding patients who required urgent perioperative management). Thirty-one patients received aPCC and 20 patients received 3F-PCC. Haemostasis was adjudicated as effective in all assessable patients (n = 50; 100%). Thromboembolic events occurred in three patients who received aPCC and one patient who received 3F-PCC. All-cause mortality was 7.8% (four patients).Both aPCC and 3F-PCC are useful adjuncts for the management of patients who require urgent reversal of the anticoagulant effect of FXa-inhibitor DOAC. However, the risk of thromboembolism in this patient group requires careful consideration. Prospective, comparator studies are needed along with the development of guidelines that reflect the availability of haemostatic agents in Australia.

The aim of this retrospective study was to compare andexanet alfa and 4-factor prothrombin complex (4F-PCC) for reversal of factor Xa (FXa)-inhibitor bleeding. Patients that received andexanet alfa for reversal were included. An equivalent number of patients administered 4F-PCC for FXa-inhibitor bleeding were randomly selected as historical controls. The primary outcome was effective hemostasis achievement within 12 h, defined using ANNEXA-4 criteria. Thromboembolic events and mortality within 30 days were also evaluated. A total of 32 patients were included. Baseline characteristics were not statistically different between andexanet alfa (n = 16) and 4F-PCC (n = 16). Intracranial bleeding was the primary reversal indication in 43.8% versus 62.5% of patients, respectively. Effective hemostasis was reached in 75.0% of andexanet alfa patients compared to 62.5% of 4F-PCC patients ( P = .70). Thromboembolic events occurred in 4 (25.0%) patients and 3 (18.8%) patients, respectively ( P = .99). Mortality incidence was 12.5% and 31.3%, respectively ( P = .39). Andexanet alfa and 4F-PCC attained hemostasis in a majority of patients. A high, but a similar rate of thromboembolic events was seen with both treatments. Prospective studies are needed to elucidate comparative risks and benefits of the 2 agents.

BACKGROUND/OBJECTIVES Prothrombin complex concentrates (PCC) are increasingly administered off-label in the United States to treat bleeding in cardiovascular surgical patients and carry the potential risk for acquired thromboembolic side-effects after surgery. Therefore, we hypothesized that the use of low-dose 3-factor (3F) PCC (20-30 IU/kg), as part of a transfusion algorithm, reduces bleeding without increasing postoperative thrombotic/thromboembolic complications. MATERIALS/METHODS After IRB approval, we retrospectively analysed 114 consecutive, complex cardiovascular surgical patients (age > 18 years), between February 2014 and June 2015, that received low-dose 3F-PCC (Profilnine® ), of which seven patients met established exclusion criteria. PCC was dosed according to an institutional perioperative algorithm. Allogeneic transfusions were recorded before and after PCC administration (n = 107). The incidence of postoperative thromboembolic events was determined within 30 days of surgery, and Factor II levels were measured in a subset of patients (n = 20) as a quality control measure to avoid excessive PCC dosing. RESULTS Total allogeneic blood product transfusion reached a mean of 12·4 ± 9·9 units before PCC and 5·0 ± 6·3 units after PCC administration (P

Uncontrolled bleeding in trauma secondary to a combination of surgical bleeding and trauma-induced complex coagulopathy is a leading cause of death. Prothrombin complex concentrates (PCCs), recombinant activated factor seven (rFVIIa) and recombinant human prothrombin act as procoagulants by increasing thrombin generation and fibrinogen concentrate aids stable clot formation. This review summarizes the current evidence for procoagulant use in the management of bleeding in trauma, and data and evidence gaps for routine clinical use.Retrospective and prospective studies of PCCs (±fibrinogen concentrate) have demonstrated a decreased time to correction of trauma coagulopathy and decreased red cell transfusion with no obvious effect on mortality or thromboembolic outcomes. PCCs in a porcine model of dilutional coagulopathy demonstrated a sustained increase in thrombin generation, unlike recombinant human prothrombin which showed a transient increase and has been studied only in animals. In other retrospective studies, there is a suggestion that lower doses of PCCs may be effective in the setting of acquired coagulopathy.There is increasing evidence that early correction of coagulopathy has survival benefits, and the use of procoagulants as first-line therapy has the potential benefit of rapid access and timely treatment. This requires confirmation in prospective studies.

Prothrombin complex concentrates (PCCs) are used to manage bleeding in critically ill children. We performed a repeat cross-sectional study using the Pediatric Health Information System registry to describe PCC utilization in the U.S. children's hospitals over time and determine the relationship between PCC use and specific risk factors for bleeding. We included children

Study Objective: Summarize the studies evaluating the use of 4-factor prothrombin complex concentrates in the management of apixaban and rivaroxaban associated intracranial hemorrhages. Methods: A PubMed literature search was conducted for articles published between 2013 and 2020 which contained the following terms in their title: (1) apixaban, rivaroxaban, or factor Xa inhibitor*, and (2) prothrombin complex concentrate*. Results: Eighteen observational studies were included. When a ∼25 units/kg (range: 25-26.9 units/kg) non-activated 4 factor prothrombin complex concentrate dose was administered, the hemostatic effectiveness rates were ≥ 79% in 2/4 studies that utilized the Sarode et al criteria, in comparison to 4/5 studies that administered a 50 units/kg dose. The mortality rates were < 20% in 7/9 studies with hemostatic effectiveness rates ≥ 79%. Mortality rates were lower in the studies demonstrating higher hemostatic effectiveness rates and including patients with higher Glasgow coma scale scores and lower intracerebral hemorrhage volumes. Overall, the thromboembolic event rates were 0-18%, with 16/18 studies demonstrating rates ≤ 10%. The thromboembolic event rates were not dose or agent dependent. Conclusion: Rates of hemostatic effectiveness were influenced by the definition of hemostatic effectiveness, dose administered, and patient severity. Studies suggest that higher doses may result in higher hemostatic effectiveness rates without increasing the risk of experiencing a thromboembolic event. This review may be used by providers to modify or validate their reversal strategy approach until well designed studies are available.

Excessive bleeding is an important cause of morbidity and mortality after cardiac surgery. Bleeding after cardiac surgery is multifactorial. Adherence to the proverbial 6 Ps remains the cornerstone of any strategy for management of postoperative bleeding after cardiac surgery. Recent years have seen a surge in the number of patients who have been prescribed novel oral anticoagulants (NOACs) for the prevention and treatment of thromboembolic events. This phenomenon has significant repercussions particularly for patients presenting for emergency cardiac surgery. The published evidence guiding management of such patients is limited and in the form of expert consensus. Plasma levels of NOAC >30 ng/ml necessitate specific therapeutic interventions to tackle excessive bleeding attributed to NOAC intake. Current recommendation is to consider using specific reversal agent if available. Otherwise, use of prothrombin complex concentrates is recommended.

In patients following aortic surgery, the prevention and treatment of bleeding requires a multimodal approach that includes targeting fibrinogen and platelet repletion, the use of anti-fibrinolytic agents, and evaluating surgical sources of bleeding. Prothrombin complex concentrates, and fibrinogen concentrates are becoming increasingly important components of treatment algorithms. With major hemorrhage, specific protocols for massive transfusion in conjunction with pharmacologic agents should be considered. Bleeding management algorithms using viscoelastic testing to guide targeted replacement are being used increasingly in complex cardiac surgical patients.

Objectives Antiphosphatidylserine/prothrombin complex antibodies (aPS/PT) are risk factors for thrombosis, yet further validation of their clinical relevance in different ethnic groups is required. We investigated the performance of aPS/PT of IgA/G/M isotypes among Sudanese and Swedish systemic lupus erythematosus (SLE) patients. Methods Consecutive SLE patients/matched controls from Sudan (n = 91/102) and Sweden (n = 332/163) were included. All patients fulfilled the 1982 ACR SLE classification criteria. IgA/G/M of aPS/PT, anti-cardiolipin and anti-β2glycoprotein I (anti-β2GPI) were tested in both cohorts, and lupus anticoagulant (LA) also in the Swedish cohort. Clinical antiphospholipid syndrome-related events and atherosclerosis, measured as carotid plaques were assessed for associations. Univariate and multivariate analyses adjusting for cardiovascular risk factors were performed. Results Sudanese SLE patients had higher levels of IgM aPS/PT, but using national cut-offs, the frequency of positivity was similar to Swedish patients for all isotypes. Among Swedish patients, all isotypes of aPS/PT associated with venous thromboembolism (VTE), while only IgA aPS/PT associated with arterial thrombosis (AT). aPS/PT antibodies associated strongly with LA and they were, independently, the best predictor for VTE. Double positivity for aPS/PT and anti-β2GPI associated with higher VTE risk than the conventional triple positivity. Carotid plaques did not associate with any antiphospholipid antibody. Conclusions IgA aPS/PT associated with AT, and the association of IgG/M aPS/PT with VTE outperforms LA and criteria antiphospholipid antibodies in Swedish SLE patients. Furthermore, double positivity for aPS/PT and anti-β2GPI performed better than conventional triple positivity. Future studies need to address if aPS/PT can replace LA, as this would simplify clinical procedures.

SUMMARY The 2006 Revised Sapporo Classification Criteria for Definite Antiphospholipid Syndrome included as laboratory criteria the tests for antiphospholipid antibodies whose accuracy was regarded as satisfactory according to the evidence available at that time. In practice, however, the sensitivity and specificity of these “criteria” of antiphospholipid antibodies are sometimes insufficient for identifying or ruling out antiphospholipid syndrome. It has been studied whether the accuracy of the laboratory diagnosis of the syndrome could be improved by testing for non-criteria antiphospholipid antibodies. In this work, we review evidence on the clinical associations and diagnostic value of the most commonly studied non-criteria antibodies, namely: antiphosphatidylethanolamine, anti-annexin A5, anti-prothrombin, anti-phosphatidylserine/prothrombin complex, IgA anticardiolipin, and IgG anti-domain I of the β2 glycoprotein antibodies. RESUMO A classificação de Sapporo revisada para a síndrome antifosfolipídica definida de 2006 incluiu como critérios laboratoriais aqueles testes para anticorpos antifosfolípides cuja acurácia era considerada satisfatória de acordo com a evidência então disponível. Porém, na prática, a sensibilidade e especificidade desses anticorpos antifosfolípides “critério” são por vezes insuficientes para identificar ou descartar a síndrome antifosfolípide. Tem-se estudado se a acurácia do diagnóstico laboratorial da síndrome poderia ser melhorada por meio da testagem de anticorpos antifosfolípides não critério. Neste trabalho revisamos a evidência a respeito das associações clínicas e valor diagnóstico dos anticorpos não critério mais estudados, nomeadamente: anticorpos antifosfatidiletanolamina, antianexina A5, antiprotrombina, anticomplexo fosfatidilserina/protrombina, IgA anticardiolipina e IgG antidomínio I da anti-β2 glicoproteína I.

Expert consensus and international guidelines recommend urgent co-administration of vitamin K and 4-factor prothrombin complex concentrates (4F-PCCs) to rapidly reverse VKA-related bleeding. This narrative review examined real-world evidence and strategies to optimize international normalized ratio (INR) reversal, hemostasis, and outcomes in patients receiving 4F-PCC in this setting. Key determinants for success include the appropriate use of alternative dosing and administration strategies, such as fixed dosing and increased infusion speed, adherence to institutional guidelines, and removing significant institutional barriers to reduce time to treatment. In the opinion of authors, minimizing the time to treatment with 4F-PCCs is of paramount importance when treating patients with VKA-related bleeding. Practices that safely and feasibly shorten the time to administration should be included in guidelines for institutions responsible for anticoagulant care, and adhered to in centers that perform invasive procedures on patients receiving VKA therapy. Further studies are required to optimize use of 4F-PCC, particularly in relation to the ideal dosing strategy and the role of INR.

Rivaroxaban has the most available data to support the use of prothrombin complex concentrates (PCC) as a reversal agent. However, PCC might increase the incidence of thrombotic events by shifting the haemostatic balance towards hypercoagulability. We assessed the in vitro efficacy and safety of three 4-factor PCCs for reversing rivaroxaban anticoagulant effect. Our in vitro finding indicates that 4-factor PCCs at the dose of 25 U.kg− 1 may be sufficient to reverse rivaroxaban anticoagulant effect.

Thrombosis has proven to be extremely difficult to predict. Measuring the generation of thrombin is a very sensitive method to detect changes in the hemostatic system. We developed a method based on the generation of thrombin to further fingerprint hemostasis, which we have named thrombin dynamics. Via this method we are able to exactly measure the prothrombin conversion and thrombin inactivation, and any change in the coagulation cascade will be reflected in these two processes. In the current study we analyzed the importance of the members of the prothrombin complex on the dynamics of thrombin activation and inactivation. We show that prothrombin conversion is predominantly influenced by factor X and antithrombin, which will provide essential insights in complex thrombosis-related diseases, such as liver cirrhosis and kidney failure.

Anticoagulant-related bleeding carries considerable morbidity and mortality. Major or life-threatening bleeding is among the most severe of these complications. As the number of patients treated with direct oral anticoagulants (DOACs) continues to increase, so does the number of DOAC-related bleeding events. The incidence of CRNM bleeding related to DOAC therapy ranges from 15 to 18% per 100-year patients, while the incidence of major bleeding ranges from 2.71 to 3.6%. Many of these bleeding events can be prevented with tailored dosing regimens or proper peri-procedural management. When unable to be prevented, DOAC-related bleeding can lead to significant long-term disability or death. Management with newer reversal agents such as andexanet alfa and idarucizumab, as well as prothrombin complex concentrates, may improve outcomes for patients with DOAC-related bleeding. The purpose of this review is to explore strategies for preventing and treating bleeding in patients receiving DOACs for anticoagulant therapy.

Obstetrical hemorrhage is the most common cause of maternal mortality worldwide. Together with adequate surgical control and judicious transfusion of blood products, the use of pharmacological agents (e.g., tranexamic acid) and clotting factor concentrates (e.g., fibrinogen concentrates and prothrombin complex concentrates) results in improved hemostasis and decreased bleeding-associated mortality. Guidance in the administration of these agents with the use of viscoelastic testing will likely become standard of care in the near future.

Studies evaluating the use of activated prothrombin complex concentrates (aPCCs) for DOAC-associated bleeding are sparse.We conducted a retrospective study of patients receiving aPCC for DOAC-associated bleeding or for pre-operative optimization of hemostasis prior to urgent surgery. The primary efficacy outcome was hemostatic efficacy, the primary safety outcome was the 30-day thromboembolic complication rate.Eighty-two patients were included in the analysis; 14 patients on dabigatran, 39 patients on rivaroxaban and 29 patients on apixaban. Fifty-four patients received aPCC for major bleeding and 28 patients prior to urgent surgery. Mean aPCC dosing was 2974 IU (SD ± 857 IU). Hemostasis was deemed effective by ISTH criteria in 50% of cases and "Good" or "Moderate" by Sarode criteria in 45.2% and 14.3% of cases, respectively. Surgical hemostasis was rated as "Normal" in 84% of cases pre-operative administration. Median pre-aPCC INR was 1.6 (IQR 0.5) and median post-aPCC INR was 1.2 (IQR 0.2) (p 0.00001). Median pre-aPCC aPTT was 36 s (IQR 12.8), median post-aPCC aPTT was 29 s (IQR 9.8) (p = 0.0001). The 30-day thromboembolic event rate was 6.1%.Further study is needed to characterize the hemostatic effects and thromboembolic risk of aPCC among patients with DOAC-associated bleeding or for attempted normalization of hemostasis prior to urgent surgery.

Prothrombin complex concentrate (PCC) is used as an alternative to fresh frozen plasma (FFP) for emergency bleeding. The primary objective of this study was to compare the time from order to start of administration between 3-factor PCC (PCC3), 4-factor (PCC4), and FFP in the emergency department (ED). The secondary objective was to evaluate the effect of an ED pharmacist on time to administration of PCCs.This was a single center three-arm retrospective cohort study. Adult patients in the ED with bleeding were included. The primary outcome measure was the time from order to administration, which was compared between PCC3, PCC4, and FFP. The time from order to administration was also compared when the ED pharmacist was involved versus not involved in the care of patients receiving PCC.There were 90 patients included in the study cohort (30 in each group). The median age was 69years (IQR 57-82years), and 57% (n=52) were male. The median time from order to administration was 36min (IQR 20-58min) for PCC3, 34min (IQR 18-48min) for PCC4, and 92min (IQR 63-133) for FFP (PCC3 versus PCC4, p=0.429; PCC3 versus FFP, p0.001; PCC4 versus FFP, p0.001). The median time from order to administration was significantly decreased when the ED pharmacist was involved (24min [IQR 15-35min] versus 42min [IQR 32-59min], p0.001).Time from order to administration is faster with PCC than FFP. ED pharmacist involvement decreases the time from order to administration of PCC.

Bypassing agents are presently the standard of care for the treatment of bleeding episodes in patients with hemophilia and high-titer inhibitors and are also used for bleed prevention. Only two bypassing agents are available to patients, and these products trace their lineage to the 1970s (activated prothrombin complex concentrates) and the 1980s (recombinant factor VIIa). Given the limited repertoire of available products, clinicians have relied on experience, empirical observation, registry data and individualized care to improve clinical outcomes on a case-by-case basis. Research over the past two decades has culminated in a greatly improved understanding of human coagulation; resulting from this, new products have been developed that offer treatment options and mechanisms of actions that differ from current bypassing agents. The most advanced in clinical development is emicizumab, a bispecific antibody that mimics the function of FVIIIa in the intrinsic Xase complex and is indicated for once-weekly or every-other-week prophylactic dosing in inhibitor patients. Other non-traditional products in clinical development include fitusiran and antibodies directed against tissue factor pathway inhibitor. As non-factor-based therapies become more widely utilized over time, the use of bypassing agents may be expected to decrease; however, bypassing agents will remain essential for the foreseeable future. As such, clinical development of bypassing agents continues, with some products (e.g. eptacog beta) under regulatory review. In this review we examine the optimal use of bypassing agents and their mechanism of action. We also discuss newer products and how these might theoretically be administered in conjunction with traditional bypassing agents.

Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies.

Even though vitamin K antagonists (VKAs) have been employed for >50 years, there is still some uncertainty about the best strategy to reverse anticoagulation due to VKAs in cases of major bleeding. Furthermore, there is also scarce evidence about the most appropriate way to treat serious bleeding associated with non-vitamin K antagonist oral anticoagulants. This review analyses the main advantages and disadvantages of the various forthcoming therapeutic options to restore a normal coagulation status in anticoagulated patients with ongoing serious bleeding. It discusses the role of fresh frozen plasma, prothrombin complex concentrates and recombinant factor VII activated. Moreover, we report updated evidence on antidotes currently available or in development. Finally, this article proposes a comprehensive algorithm that summarizes major bleeding management during treatment with oral anticoagulants.

Traumatic coagulopathy has now been well characterized and carries high rates of mortality owing to bleeding. A 'factor-based' resuscitation strategy using procoagulant drugs and factor concentrates in lieu of plasma is being used by some, but with little evidentiary support. We sought to evaluate and compare resuscitation strategies using combinations of tranexamic acid (TXA), prothrombin complex concentrate (PCC), and fresh frozen plasma (FFP).Sixty adult swine underwent 35% blood volume hemorrhage combined with a truncal ischemia-reperfusion injury to produce uniform shock and coagulopathy. Animals were randomized to control (n = 12), a single-agent group (TXA, n = 10; PCC, n = 8; or FFP, n = 6) or combination groups (TXA-FFP, n = 10; PCC-FFP, n = 8; TXA-PCC, n = 6). Resuscitation was continued to 6 hours. Key outcomes included hemodynamics, laboratory values, and rotational thromboelastometry. Results were compared between all groups, with additional comparisons between FFP and non-FFP groups.All 60 animals survived to 6 hours. Shock was seen in all animals, with hypotension (mean arterial pressure, 44 mm Hg), tachycardia (heart rate, 145), acidosis (pH 7.18; lactate, 11), anemia (hematocrit, 17), and coagulopathy (fibrinogen, 107). There were clear differences between groups for mean pH (p = 0.02), international normalized ratio (p0.01), clotting time (CT; p0.01), lactate (p = 0.01), creatinine (p0.01), and fibrinogen (p = 0.02). Fresh frozen plasma groups had significantly improved resuscitation and clotting parameters (Figures), with lower lactate at 6.5 versus 8.4 (p = 0.04), and increased fibrinogen at 126 versus 95 (p0.01). Rotational thromboelastometry also demonstrated shortened CT at 60 seconds in the FFP group vs 65 seconds in the non-FFP group (p = 0.04).When used to correct traumatic coagulopathy, combinations of FFP with TXA or PCC were superior in improving acidosis, coagulopathy, and CT than when these agents are given alone or in combination without plasma. Further validation of pure factor-based strategies is needed.

REVIEW QUESTION The question of this review is: what is the effectiveness of Kcentra/Beriplex/Confidex compared to plasma for international normalized ratio (INR) reduction in adult patients (18 years and over) on any vitamin K antagonist therapy?