Coagulopathies in Intensive Care Medicine: Balancing Act between Thrombosis and Bleeding

Patient Blood Management advocates an individualized treatment approach, tailored to each patient’s needs, in order to reduce unnecessary exposure to allogeneic blood products. The optimization of hemostasis and minimization of blood loss is of high importance when it comes to critical care patients, as coagulopathies are a common phenomenon among them and may significantly impact morbidity and mortality. Treating coagulopathies is complex as thrombotic and hemorrhagic conditions may coexist and the medications at hand to modulate hemostasis can be powerful. The cornerstones of coagulation management are an appropriate patient evaluation, including the individual risk of bleeding weighed against the risk of thrombosis, a proper diagnostic work-up of the coagulopathy’s etiology, treatment with targeted therapies, and transfusion of blood product components when clinically indicated in a goal-directed manner. In this article, we will outline various reasons for coagulopathy in critical care patients to highlight the aspects that need special consideration. The treatment options outlined in this article include anticoagulation, anticoagulant reversal, clotting factor concentrates, antifibrinolytic agents, desmopressin, fresh frozen plasma, and platelets. This article outlines concepts with the aim of the minimization of complications associated with coagulopathies in critically ill patients. Hereditary coagulopathies will be omitted in this review.

Use of an Antifibrinolytic Agent and Vitamin K As Alternative to Platelet Transfusions in Autologous Hematopoietic Cell Transplantation

Background Managing thrombocytopenia with a prophylactic strategy was previously recommended for patients with impaired bone marrow function, hematological malignancies, and recipients of HCT when platelet counts declined to under 10,000/uL. However, the updated 2018 ASCO guidelines now suggest a place for a therapeutic i.e., after a bleeding event rather than a prophylactic platelet transfusion strategy for patients with hematologic malignancies undergoing autologous HCT. Studies show a lack of significant difference between trial groups in hemostatic outcomes, such as the number of WHO grade 2-4 bleeds, and number of days with bleeding events. Platelet transfusions increase risks of infectious and non-infectious complications as well as inducing a platelet refractory state. Our Transfusion Free Medicine Program has now performed over 200 autologous hematopoietic stem cell transplants (HCT) in Jehovah's Witnesses who due to religious convictions, do not accept red cell or platelet transfusions. Vitamin K is a fat-soluble vitamin that is required for normal blood clotting. Autologous HCT patients are at risk for vitamin K deficiency from multiple reasons including malnutrition, frequent use of antibiotics, chemotherapy induced gastrointestinal toxicity leading to malabsorption and colitis. The prothrombin test lacks the sensitivity and specificity to detect mild deficiency. A mild vitamin K deficiency may be underdiagnosed in our transplant patients adding to bleeding risk. With the effective use of antifibrinolytic agents and Vitamin K as an alternative to platelet transfusions we believe this may enhance hemostasis and prove a valuable adjunct to a therapeutic approach. Methods Patients in our study were those who were of the Jehovah's Witness faith undergoing autologous HCT for Multiple Myeloma and Lymphoma. Patients received aminocaproic acid as an alternative to platelet transfusion to enhance hemostasis at a dose of 1 g every 4 hours or prophylactically for platelet counts less than 30,000 /uL. Titration to 4 g every 4 hours intravenously was required for platelet counts less than 10,000/ul or clinical bleeding. Vitamin K 10 mg orally or subcutaneous was also started at this time. Results Table 1 illustrates the low number of bleeding events especially grade 3 or 4 that occurred. There were no Grade 3 or 4 bleeding events in patients with platelet counts above 5000/uL. No patient had residual long term effects nor was there an increase in thromboembolic events. Conclusions These data add to the body of literature supporting a therapeutic platelet transfusion strategy in an experienced center for autologous HCT patients and challenges the prophylactic platelet count of 10,000 /uL suggesting instead 5000/uL. The safety and efficacy of antifibrinolytic agents and Vitamin K as an alternative to platelet transfusions to enhance hemostasis in autologous stem cell transplant patients may prove beneficial not only in JW patients but also in those transplant centers wishing to offer a therapeutic platelet transfusion approach and as a strategy to manage platelet refractoriness. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Aminocaproic Acid is an antifibrinolytic agent approved for treatment of bleeding in surgical patients and hematological bleeding disorders. Vitamin K is approved for use in reversal of anticoagulation from Warfarin, vitamin K deficiency without liver disease and in the newborn.

Complete Review of Ayurvedic Management of Raktapradar w.s.r. to Brihatrayi and Laghutrayi

Raktapradar in Ayurveda is characterized by excessive or prolonged menstruation with or without intermenstrual bleeding, which is one of the most common bleeding disorders in women. Excessive bleeding from uterus either at the time of menses or in intermenstrual time is considered as Asrigdara or Raktapradar in Ayurveda. Normal menstrual bleeding including ovulation or more specifically the organized sequence of endocrine signals that characterizes the ovulatory cycle, menses regularities, predictability & consistency. It is most basic concept that control the endometrial cycle, the volume & the duration of menstrual flow. Cyclic regular menstrual bleeding which is excessive in amount & duration considered as Menorrhagia. Raktapradar can be correlated with menorrhagia. As per modern science, menorrhagia is defined as cyclic regular bleeding which is excessive in amount (>80ml) or duration (>7 days) or both. It is considered as one of the commonest leading gynecological problem. In modern medicine haemostatic, analgesic and hormonal therapies are advised for Menorrhagia, which includes hormonal therapy, antiprostaglandins & antifibrinolytic agents. These have not proven their definitive efficacy in spite of high costs; their side effects have led to hormonal imbalances hence it is need of time to have an integrated and comprehensive therapeutic intervention in Ayurveda to prevent recurrence& would overcome the modern medicine limitations. Many herbal & herbo-mineral preparations, Shodhan & Shaman Chikits as per Rugnabal are mentioned in Ayurveda to cure Raktapradar and related symptoms which can be used as per Anubandha Dosha and Lakshana.

How I treat dysfibrinogenemia

Congenital dysfibrinogenemia (CD) is caused by structural changes in fibrinogen that modify its function. Diagnosis is based on discrepancy between decreased fibrinogen activity and normal fibrinogen antigen levels and is confirmed by genetic testing. CD results from monoallelic mutations in fibrinogen genes leading to clinically heterogenous disorders. Most patients with CD are asymptomatic at time of diagnosis but the clinical course may be complicated by a tendency to bleeding and/or thrombosis. Patients with a thrombotic-related fibrinogen variant are particularly at risk and in such patients long-term anticoagulation should be considered. Management of surgery and pregnancy raise important and difficult issues. The mainstay of CD treatment remains fibrinogen supplementation. Antifibrinolytic agents are part of the treatment in some specific clinical settings. In this article, we discuss five clinical scenarios to highlight common clinical challenges. We detail our approach to establish a diagnosis of CD and discuss strategies for the management of bleeding, thrombosis, surgery and pregnancy.

Blood Loss and Transfusion in Pediatric Craniofacial Surgery in the Antifibrinolytic Era

Background : Children undergoing complex cranial vault reconstruction (CCVR) for craniosynostosis experience high rates of bleeding and blood product transfusion, increasing the risk of perioperative complications. The most severe issues relate to the rate and extent of blood loss, which can be up to several times the patient's total blood volume and is often equated to controlled massive hemorrhage. ε-Aminocaproic acid (EACA) and tranexamic acid (TXA) are antifibrinolytic agents that have been shown to reduce intraoperative hemorrhage and transfusion requirements during CCVR. However, the relative efficacy of EACA vs. TXA in CCVR has not yet been evaluated. The aim of this study was to compare perioperative blood loss and need for transfusion in children receiving EACA and TXA. We hypothesized that TXA is associated with a greater decrease in blood loss and transfusion requirements when compared to EACA. Methods: All patients who underwent CCVR from September 2015 to December 2019 at our institution were retrospectively evaluated. The primary outcome measures included intraoperative estimated blood loss (EBL), red blood cell (RBC) transfusion volume (mL/kg), and calculated blood loss (CBL) (Kearney et al., Can J Anaesth 1989). Secondary outcome measures included hematologic and coagulation parameters. Study cohort demographic and outcome data were analyzed; Fisher's exact test was used for categorical data, student's t-test was used for continuous data. A p-value of < 0.05 was considered statistically significant. Results: 104 patients were included in the study with 48 patients in the EACA cohort and 56 patients in the TXA cohort. There were slightly more patients with syndromic craniosynostosis in the EACA group, but overall no significant differences in cohort characteristics (Table 1). Mean EBL (mL/kg) was slightly higher in the EACA group vs. the TXA group (21 ± 13 vs. 17 ± 10), but not statistically significant. Intraoperative mean CBL (34 ± 21mL/kg) and intraoperative percent blood volume lost (43 ± 26%) for the cohort were high, but these were equal between groups. Likewise, postoperative DO, CBL and percent blood volume lost were similar between groups. Overall, intraoperative RBC transfusion was required in 66 (64%) of patients and was similar between groups (69% of EACA patients vs. 59% of TXA patients). Intraoperative transfusion of other products was equal between groups. Postoperatively, 23 (22%) of patients required RBC transfusion. Postoperative blood product transfusions were equal between groups (Table 2). We compared routine hematologic and coagulation parameters peri-operatively and did not find any differences between the EACA and TXA group (Table 3). In the EACA group, there were 6 reported perioperative complications, including 2 suspected seizure events, as compared to 7 complications in the TXA group, which included 2 thromboembolic events. Discussion: Pediatric CCVR is a high blood loss surgery and this can lead to a consumptive coagulopathy for which intraoperative antifibrinolytic agents have been demonstrated to improve outcomes. We found no significant difference in blood loss, transfusion requirements, or hematologic parameters between patients who received EACA and TXA in our retrospective pediatric CCVR cohort. Overall there were 4 postoperative outcomes that could have been related to antifibrinolytic use (seizure, thromboembolism), but this was equal between groups and causality was not confirmed. Further research is needed to define optimal antifibrinolytic dosing and duration of therapy. While standard hematologic and coagulation parameters were similar between groups, the mechanisms of surgically induced coagulopathy in CCVR still need to be explored. Future studies investigating coagulation-based and inflammatory assays may be useful in defining surgical-induced coagulopathy. Disclosures No relevant conflicts of interest to declare.

A Major Knowledge Gap in Women's Health: The Combined Effect of Antifibrinolytics and Estrogen on Risk of Thromboembolism - a Scoping Review

Background:Up to 30% of women of reproductive age will seek medical attention for heavy menstrual bleeding (HMB), which negatively affects health-related quality of life. Both estrogen-containing oral contraceptives and antifibrinolytic agents are essential first-line treatments for HMB. Anecdotally, these agents appear synergistically effective when used in combination. Despite the strong evidence for the independent efficacy and safety of these agents for HMB as well as the use of antifibrinolytics in other high-estrogen states such as the post-partum state, prescribers are frequently uncomfortable prescribing them in combination due to the theoretical increased risk of thrombosis. Objective:To systematically evaluate the literature that explores the combined effect of pharmacologic or high physiologic estrogen and antifibrinolytic agents on risk of thromboembolism in women of reproductive age when used for heavy menstrual or post-partum bleeding. Methods:A literature search was performed on Medline, EMBASE, CINAHL, and Scopus from inception to July 2020. References of included articles were screened and a grey literature search was conducted to identify additional sources. Studies written in English that explored the risk of thromboembolism in women of reproductive age prescribed antifibrinolytic agents alongside estrogen-containing contraceptives or with a physiologic high-estrogen state were included. A thromboembolic event was defined as formation of a blood clot/thrombus in any arterial or venous structure with or without travel to a site distal to its point of origin, confirmed by appropriate diagnostic imaging/testing (including but not limited to deep vein thrombosis, superficial vein thrombosis, pulmonary embolism, ischemic stroke, myocardial infarction, mesenteric ischemia, ischemic colitis, kidney/spleen/liver infarct, or critical limb ischemia). Screening and data abstraction were performed by two independent reviewers (DM, DL) and conflicts were adjudicated by a third reviewer (MS). Results:A total of 2389 title and abstracts were identified from the literature. Of those, a total of 33 studies with 27933 participants were extracted for full text review. Of these studies, 31 investigatedantifibrinolytic use for post-partum bleeding: 22 randomized controlled trials (RCT), 3 retrospective cohort studies, 1 combined prospective-retrospective cohort study, 2 case series, and 3 case reports. Almost all (29/31) of these studies found no increased rate/risk of thromboembolism. However, only 4 of these studies were powered to make this assessment, all of which were RCTs. The 2 studies that described thromboembolism with antifibrinolytic use in the postpartum period were a case report and case series (N=18), respectively. We found only 2 case reports published describing thromboembolism withconcomitant estrogen-containing contraceptives and antifibrinolytic use, both of which reported thromboembolism in women using both agents for less than 3 months. Conclusions:We found no clear evidence that intermittent use of antifibrinolytics in either high physiologic or pharmacologic estrogenic states results in higher rates of thromboembolism. Prospective studies are warranted, particularly in the area of combined estrogen-containing contraceptive and antifibrinolytic use, to provide an accurate assessment of risk and properly inform prescribing practices. Disclosures James: Shire/Takeda:Research Funding;Bayer:Research Funding;CSL Behring:Research Funding.Sholzberg:Amgen:Honoraria, Other: Scientific Advisory Board, Research Funding;Octapharma:Honoraria, Other: Scientific Advisory Board, Research Funding;Takeda:Honoraria, Other: Scientific Advisory Board, Research Funding;Novartis:Honoraria, Other: Scientific Advisory Board;NovoNordisk:Honoraria, Other: Scientific Advisory Board.

Anesthesia for Urgent Surgery in a Patient with Angioneurotic Oedema: A Case Report

Hereditary angioneurotic oedema is an autosomal dominant disease associated with serum deficiency of functional C1-inhibitor. It is characterized by periodic swelling of subcutaneous tissues, abdominal viscera and upper airways. Lethal acute episodes of oedema can occur during anaesthesia and surgery. It is essential to prepare such patients before surgery. This article describes a case and the various preventive measures used to avoid acute episodes during anaesthesia for urgent surgery for mesenteric ischemia. In emergency situations where C1 inhibitor concentrate is not available, fresh frozen plasma (FFP) can be used as an alternative, as it also contains C1 inhibitor, corticosteroids, antihistamines, and epinephrine can be useful adjuncts but typically are not efficacious in aborting acute attacks. Prophylactic management involves long-term use of attenuated androgens or antifibrinolytic agents (Tranexamic acid).Their various indications are discussed.