The use of andexanet alfa vs. 4-factor prothrombin complex concentrates in the setting of life-threatening intracranial hemorrhage.

OBJECTIVE: Andexanet alfa is a targeted reversal agent for life threatening hemorrhage associated with direct acting oral anticoagulants (DOACs), but there is uncertainty regarding the benefit when compared to 4-factor prothrombin complex concentrate (4F-PCC) for this indication. We investigated the clinical outcomes and cost associated with reversal of DOACs in the setting of life-threatening intracranial hemorrhage (ICH). METHODS: A retrospective evaluation was conducted to evaluate patients with ICH in the setting of anticoagulation with DOAC from 9/1/2013 to 4/30/2020. Patients were included in the study if they received reversal with either andexanet alfa or 4F-PCC. RESULTS: Eighty-nine patients were included in the study. There was no statistically significant difference in 30-day mortality between patients who received andexanet alfa or 4F-PCC (52% vs. 35%, P  = 0.14). Radiographic stability of bleed was identified in 57% of patients receiving andexanet alfa vs. 58% of patients receiving 4F-PCC ( P  = 0.93). Median length of stay was not different between the andexanet alfa and 4F-PCC populations (7 days [IQR 6 - 12] vs. 6 days [IQR 3-12], P  = 0.66). Median cost of reversal agent was higher in patients receiving andexanet alfa compared to 4F-PCC ($15 000 [IQR 15 000-$27 000] vs. $11 650 [IQR $8567-$14 149]). CONCLUSION: Among patients with life-threatening intracranial hemorrhage in the setting of DOAC therapy, no clinical differences were observed with respect to selection of reversal agent. Prothrombin complex concentrates remain a viable alternative to reversal of DOAC therapy though multicenter, randomized, prospective studies are needed to further evaluate the role of 4F-PCC in the reversal of DOAC therapy.

COVID-19 Associated Micro-Anastomotic Thrombosis After Abdominal Free Tissue Transfer: A Case Report and Literature Review.

The hypercoagulable state of COVID-19 infection presents a challenge to microsurgeons. While the American Society of Anesthesiologists recommends deferring surgery for 4-10 weeks for COVID-19-infected patients, little else is known regarding how to mitigate thrombotic complications for patients undergoing free tissue transfer. Here, we present a presumed COVID-19-induced hypercoagulable state in a patient undergoing abdominally based free tissue transfer for breast reconstruction as a brief review of the literature to guide clinical decision making.

L'état d'hypercoagulabilité de l'infection par le virus de la COVID-19 représente un défi pour la micro-chirurgie. L'American Society of Anesthesiologists recommande de retarder la chirurgie de 4 à 10 semaines chez les patients infectés par la COVID, mais on sait peu de choses sur comment réduire les complications thrombotiques chez les patients subissant un transfert de tissu libre. Nous présentons ici un état d'hypercoagulabilité présumé induit par la COVID chez un patient subissant un transfert de tissu libre d'origine abdominale pour reconstruction mammaire comme brève revue des publications pour guider la prise de décision clinique.

Dysfibrinogenemia: discrepant results following infusion of purified fibrinogen.

Inherited dysfibrinogenemias are molecular disorders of fibrinogen that affect fibrin polymerization. The majority of cases are asymptomatic, but a significant proportion suffer from increased bleeding or thrombosis. We present two unrelated cases of dysfibrinogenemia, both of whom showed a characteristic discrepancy between fibrinogen activity and the immunologic fibrinogen. In one patient, the dysfibrinogenemia was confirmed by molecular analysis; in the other case, the diagnosis was presumptive based upon laboratory studies. Both patients underwent elective surgery. Both received a highly purified fibrinogen concentrate preoperatively and demonstrated a suboptimal laboratory response to the infusion. Three methods for determining fibrinogen concentration (Clauss fibrinogen, prothrombin-derived fibrinogen, and the viscoelastic functional fibrinogen) were utilized in the case of one patient, and these techniques showed discrepant results with the classic Clauss method giving the lowest concentration. Neither patient experienced excessive bleeding during surgery. Although these discrepancies have been previously described in untreated patients, their manifestation after infusion of purified fibrinogen is less well appreciated.

Consensus recommendations on peripheral blood smear review: defining curricular standards and fellow competency.

Graduate medical education training in hematology in North America is accredited by the Accreditation Council for Graduate Medical Education (ACGME). Trainees routinely review peripheral blood smears (PBS) in providing clinical care. Competency in PBS review at graduation is required by the ACGME. However, there are no consensus guidelines on best practices surrounding PBS review, education, or competency. We describe the generation of proposed theory and the consensus recommendations developed through a multi-institutional focus group, developed using constructivist grounded theory and a modified nominal group technique. Eight academic hematologists, spanning classical and malignant hematology, enrolled and participated in 2 one-hour focus groups. All routinely worked with fellows and half had formally instructed trainees on PBS interpretation. Focus group data were analyzed using mixed-methods techniques. Tenets of emerging theory were identified through inductive coding. Consensus recommendations (CR) were generated. Participants reviewed CR in an iterative fashion until consensus was reached. Strong consensus was reached on multiple aspects of PBS education. All agreed that trainees should learn PBS review through a systematic approach. Group discussion focused on disorders of red and white blood cells. The diagnoses of acute leukemia and thrombotic microangiopathies were most commonly discussed, with specific emphasis on disorders in which prompt recognition was required to avert significant patient morbidity. These CR offer external validity to future research and curricular development for both PBS review and other visuospatial tasks in medical education.

A Case of Acquired Hemophilia A and Congenital Hemophilia B.

Congenital hemophilia B is a rare, inherited X-linked bleeding disorder caused by a deficiency of factor IX (FIX). Acquired hemophilia A is a rare, acquired bleeding disorder which presents as new onset bleeding in older adults due to the development of autoantibodies against factor VIII (FVIII). This report describes the management of a patient with congenital hemophilia B and acquired hemophilia A. We highlight the limitations in maintaining FVIII levels using factor replacement alone and the need for escalating treatment such as rituximab and prednisone in patients with acquired hemophilia A. This case demonstrates the importance of continuing to pursue alternative diagnoses when existing ones do not explain the full clinical picture and laboratory data is inconclusive.

Use of cell salvage and HBOC-201 in a pregnant Jehovah's Witness with sickle beta+thalassaemia undergoing emergency caesarean section.

Patients with severe anaemia who refuse or cannot safely receive red cell transfusion present challenges during pregnancy, delivery and the postpartum period. Strategies including HBOC-201 (Hemopure) and intraoperative use of cell salvage have been used in non-pregnant patients to improve oxygen carrying capacity; however, these products pose unique risks in pregnant patients, those with sickle cell disease (SCD) and those undergoing caesarean section (C-section). We describe a case of a pregnant sickle beta+thalasasaemia patient who presented at 27 weeks gestation with pre-eclampsia and severe anaemia. As a Jehovah's Witness, she declined allogenic blood transfusion. The patient successfully underwent emergent C-section with cell salvage and received HBOC-201 immediately after delivery, during the operative procedure. To our knowledge, this is the first published report documenting a Jehovah's Witness patient with SCD who successfully received cell salvage and then HBOC-201 immediately postdelivery.

A Rational Approach to Coagulation Testing.

Quality patient care requires the appropriate selection of laboratory tests. Irrelevant testing must be avoided, whereas pertinent testing is indispensable. The goals of this review are 3-fold: (1) to describe appropriate coagulation test selection for medical and surgical patients, (2) to describe appropriate coagulation testing specifically in individuals infected with SARS-CoV-2 causing COVID-19, and (3) to define the rational use of anticoagulant monitoring.

Clots in unusual places: lots of stress, limited data, critical decisions.

Although much less common than deep vein thrombosis of the lower extremities or lungs, clots in unusual locations, including the splanchnic, cerebral, retinal, upper-extremity, and renal locations, present with significant morbidity and mortality. In the last 2 decades, treatment of clots in these unusual locations is primarily managed medically, with interventional and surgical approaches reserved for more severe or refractory cases. The hematologist is well positioned to provide consultation to organ-specific specialties (ie, neurosurgery, hepatology, ophthalmology), especially because acquired and congenital hypercoagulability plays a major role, and anticoagulation is often the primary treatment. Historically, treatment has been based on expert opinion, but systematic reviews and meta-analyses have recently been published. Various societies have produced guidelines for the treatment of clots in unusual locations; however, randomized clinical trial data remain scarce. In the last few years, increasing data have emerged concerning the efficacy of the direct oral anticoagulants in treating clots in unusual locations. Cases have recently been described highlighting atypical thrombosis associated with COVID-19 infection as well as with the ChAdOx1 nCoV-19 (AstraZeneca) vaccine and Johnson and Johnson's Janssen Ad26.COV2.S vaccine. This article reviews clots in unusual locations with an emphasis on the splanchnic (mesenteric, portal, splenic, hepatic) and cerebral circulation. Through a case-based approach, key questions are posed, and data are presented to help guide diagnosis and treatment.

Evidence-Based Minireview: Should warfarin or a direct oral anticoagulant be used in patients presenting with thrombosis in the splanchnic or cerebral veins?

Case 1: A 23-year-old female third-year medical student who has no medical history seeks treatment for abdominal distention. She takes an estrogen-containing birth control pill and does not smoke or consume alcohol. Family history is unremarkable. Physical examination is significant for abdominal distention, and an abdominal fluid wave is detected. Complete blood count is normal. Imaging confirms occlusive thrombosis of the main portal vein. On endoscopy, grade 1 to 2 esophageal varices are noted and banded. Unfractionated heparin is begun. Subsequent workup reveals a homozygous factor V Leiden mutation. Long-term anticoagulation is planned, and she asks if warfarin can be avoided given her hectic ward rotations, erratic diet, and need for monitoring. Case 2: A 35-year-old woman who has no medical history seeks treatment for progressively worsening posterior headaches for 1 week. Magnetic resonance imaging of the brain shows dural sinus thrombosis with associated small areas of petechial cerebral hemorrhage. She is started on a continuous unfractionated heparin infusion and admitted to the hospital for further observation. Her grandmother is on warfarin for atrial fibrillation, and the patient would prefer to avoid warfarin because she does not think she can comply with the frequent monitoring that will be required. She inquires about other oral anticoagulant options for her condition.

Systems-based hematology: highlighting successes and next steps.

Systems-based hematology is dedicated to improving care delivery for patients with blood disorders. First defined by the American Society of Hematology in 2015, the idea of a systems-based hematologist arose from evolving pressures in the health care system and increasing recognition of opportunities to optimize the quality and cost effectiveness of hematologic care. In this review, we begin with a proposed framework to formalize the discussion of the range of initiatives within systems-based hematology. Classification by 2 criteria, project scope and method of intervention, facilitates comparison between initiatives and supports dialogue for future efforts. Next, we present published examples of successful systems-based initiatives in the field of hematology, including efforts to improve stewardship in the diagnosis and management of complex hematologic disorders (eg, heparin-induced thrombocytopenia and thrombophilias), the development of programs to promote appropriate use of hematologic therapies (eg, blood products, inferior vena cava filters, and anticoagulation), changes in care delivery infrastructure to improve access to hematologic expertise (eg, electronic consultation and disorder-specific care pathways), and others. The range of projects illustrates the broad potential for interventions and highlights different metrics used to quantify improvements in care delivery. We conclude with a discussion about future directions for the field of systems-based hematology, including extension to malignant disorders and the need to define, expand, and support career pathways.

Bleeding and Thrombotic Risk in Low Dose Heparin Infusion as Compared to Standard Dose Heparin Infusion.

Intravenous unfractionated heparin (UFH) remains one of the most commonly used anticoagulants in the hospital setting. The optimal protocol for initiation and maintenance of UFH has been difficult to determine. Over the past two decades, weight-based nomogram protocols have gained favor. Herein, we present a retrospective study of 377 patients at a single tertiary academic center treated with low intensity (LI) and standard intensity (SI) UFH protocols for therapeutic anticoagulation. UFH levels are measured by anti-Xa assay activity with therapeutic levels of 0.30 to 0.70 IU/mL for SI and 0.25 to 0.35 IU/mL for LI.  Patients treated on the LI protocol were more likely to have had a previous history of bleeding and lower baseline hemoglobin. Incidence of new or worsening thrombus while on UFH was comparable between both protocols (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.29-2.98, p=0.899). Patients on LI protocol had higher incidence of bleeding while on UFH (OR 1.21, 95% CI 0.51-2.89, p=0.667). Our study thus suggests that the LI protocol may have comparable efficacy to the SI protocol in treating venous thromboembolism (VTE) and that target anti-Xa levels of 0.25 to 0.35 IU/mL may be more optimal in high-risk patients.

A case study of 10 patients administered HBOC-201 in high doses over a prolonged period: outcomes during severe anemia when transfusion is not an option.

BACKGROUND: Hemoglobin-Based Oxygen Carriers (HBOCs) can act as an "oxygen bridge" in acute severe anemia when transfusion is indicated, but not possible. We present data on 10 Expanded Access (EA) patients treated with high cumulative doses of Hemopure (HBOC-201), to assess the ability of HBOC-201 to safely treat life threatening anemia in situations where high volumes of product were administered over an extended period of time. STUDY DESIGN AND METHODS: Inclusion in this study required that the patient receive at least 10 units of HBOC-201 between 2014 and 2017 under the FDA-sanctioned EA program. Depending on a patient's geographical location, treatment with HBOC-201 was obtained through either a single patient emergency Investigational New Drug (IND) application, or an intermediate size population IND. Of the 41 patients who were treated during this period, 10 patients received 10 or more units of the product. Data were obtained from medical records. RESULTS: Treatments with HBOC-201 started within 24 hours of signing consent and were administered at an average rate of 1.99 (SD 0.17) units per day over a mean of 8.2 days (SD 2.9), during which patients received on average 16.2 units (SD 5.7 units) of HBOC-201. The median pre-treatment nadir corpuscular hemoglobin (Hb) concentration was 3.3 (SD 0.9) g/dL and post-treatment Hemoglobin was 7.3 (SD 1.7) g/dL. Common side effects included methemoglobinemia, gastrointestinal symptoms, and hypertension. However, no product-related serious adverse events (SAEs) were noted. All patients survived. CONCLUSIONS: Administration of HBOC-201 over an extended period is a feasible and safe oxygen bridge for severely anemic patients who cannot be transfused with RBC.

Anti-N and anti-Doa immunoglobulin G alloantibody-mediated delayed hemolytic transfusion reaction with hyperhemolysis in sickle cell disease treated with eculizumab and HBOC-201: case report and review of the literature.

BACKGROUND: Delayed hemolytic transfusion reaction (DHTR) with hyperhemolysis is a potentially fatal complication resulting from alloimmunization that can cause severe hemolysis of both transfused and intrinsic red blood cells (RBCs). Patients with sickle cell disease often receive multiple RBC units during their lifetime and thus are likely to develop alloantibodies that increase the risk for DHTR. Treatment to decrease hemolysis includes intravenous immunoglobulin (IVIG), steroids, eculizumab, rituximab, and plasmapheresis in addition to erythropoietin (EPO), intravenous (IV) iron, vitamin B12, and folate to support erythropoiesis. RBC transfusion is preferably avoided in DHTR due to an increased risk of exacerbating the hemolysis. CASE REPORT: We report a rare case of anti-N and anti-Doa immunoglobulin (Ig)G alloantibody-mediated life-threatening DHTR with hyperhemolysis in a patient with hemoglobin SS after RBC transfusion for acute chest syndrome who was successfully treated with eculizumab and HBOC-201 (Hemopure) in addition to steroids, IVIG, EPO, IV iron, and vitamin B12. HBOC-201 (Hemopure) was successfully used as a RBC alternative in this patient. CONCLUSION: Anti-N and anti-Doa IgG alloantibodies can rarely cause severe life-threatening DHTR with hyperhemolysis. HBOC-201 (Hemopure) can be a lifesaving alternative in this scenario. Our report also supports the use of eculizumab in DHTR; however, prospective studies are needed to determine the appropriate dose and sequence of eculizumab administration.

A Patient-Centered Emergency Department Management Strategy for Sickle-Cell Disease Super-Utilizers.

INTRODUCTION: A subpopulation of sickle-cell disease patients, termed super-utilizers, presents frequently to emergency departments (EDs) for vaso-occlusive events and may consume disproportionate resources without broader health benefit. To address the healthcare needs of this vulnerable patient population, we piloted a multidisciplinary intervention seeking to create and use individualized patient care plans that alter utilization through coordinated care. Our goals were to assess feasibility primarily, and to assess resource use secondarily. METHODS: We evaluated the effects of a single-site interventional study targeted at a population of adult sickle-cell disease super-utilizers using a pre- and post-implementation design. The pre-intervention period was 06/01/13 to 12/31/13 (seven months) and the post-intervention period was 01/01/14 to 02/28/15 (14 months). Our approach included patient-specific best practice advisories (BPA); an ED management protocol; and formation of a "medical home" for these patients. RESULTS: For 10 subjects targeted initially we developed and implemented coordinated care plans; after deployment, we observed a tendency toward reduction in ED and inpatient utilization across all measured indices. Between the annualized pre- and post-implementation periods we found the following: ED visits decreased by 16.5 visits/pt-yr (95% confidence interval [CI] [-1.32-34.2]); ED length of state (LOS) decreased by 115.3 hours/pt-yr (95% CI [-82.9-313.5]); in-patient admissions decreased by 4.20 admissions/pt-yr (95% CI [-1.73-10.1]); in-patient LOS decreased by 35.8 hours/pt-yr (95% CI [-74.9-146.7]); and visits where the patient left before treatment were reduced by an annualized total of 13.7 visits. We observed no patient mortality in our 10 subjects, and no patient required admission to the intensive care unit 72 hours following discharge. CONCLUSION: This effort suggests that a targeted approach is both feasible and potentially effective, laying a foundation for broader study.

Management of granulomatous lymphocytic interstitial lung disease in a patient with common variable immune deficiency.

A 61-year-old woman presented with longstanding cough and progressive dyspnoea. She underwent an extensive evaluation and was diagnosed with common variable immunodeficiency (CVID) with granulomatous lymphocytic interstitial lung disease (GLILD). She was initially treated with subcutaneous immunoglobulin therapy, having declined intravenous immunoglobulin (IVIG) therapy. She also declined treatment with oral glucocorticoids. Over several months, she became increasingly symptomatic and developed increased pulmonary infiltrates, pleural effusions, mediastinal adenopathy, splenomegaly, pancytopenia and ascites. An interdisciplinary team composed of an immunologist, pulmonologist and haematologist deliberated over a therapeutic management approach. The patient received a recently reported immunotherapy regimen with azathioprine and rituximab. The therapy led to rapid improvement of her constitutional and respiratory symptoms, with clinical and radiographic improvement in her interstitial lung disease, lymphadenopathy, pleural effusions and ascites. This case report reviews the literature surrounding the diagnosis and management of GLILD.

Patient satisfaction with extended-interval warfarin monitoring.

Extended-interval monitoring of warfarin has been proposed to reduce follow-up burden and improve patient satisfaction. We aimed to make an initial assessment of anticoagulation satisfaction before and after an extended-interval warfarin monitoring intervention. We conducted a translational prospective single-arm pilot study of extended-interval warfarin monitoring in five pharmacist-managed anticoagulation clinics. Patients meeting CHEST guideline criteria for extended-interval warfarin monitoring began progressive extended-interval follow-up (6, 8, and 12 weeks thereafter). The Duke Anticoagulation Satisfaction Scale (DASS) was administered at baseline and at end-of-study or study removal (in patients no longer appropriate for extended interval follow-up). Forty-six patients had evaluable pre- and post-intervention DASS survey data. Mean age of patients was 66.5 years, 74 % were non-Hispanic whites, and 48 % were men. Patients completed a mean ± SD of 34 ± 22 weeks of follow-up. Mean ± SD total DASS score at baseline was 45.2 ± 14.2 versus 49.1 ± 14.9 at end-of-study (mean change, +3.9 [95 % CI -0.6-8.4; p = 0.09]), indicating no benefit-and trending toward decrement-to anticoagulation satisfaction. Change in anticoagulation satisfaction varied substantially following extended-interval monitoring, with no evidence of improved satisfaction. Plausible reasons for patients not preferring extended-interval monitoring include increased anxiety and disengagement from self-management activities, both potentially related to less frequent feedback and reassurance during extended interval-monitoring. Additional research is needed to identify who is likely to benefit most from extended-interval monitoring. Anticoagulation satisfaction should be considered with clinical factors and shared-decision making when implementing extended-interval warfarin monitoring.

Successful implementation of a packed red blood cell and fresh frozen plasma transfusion protocol in the surgical intensive care unit.

BACKGROUND: Blood product transfusions are associated with increased morbidity and mortality. The purpose of this study was to determine if implementation of a restrictive protocol for packed red blood cell (PRBC) and fresh frozen plasma (FFP) transfusion safely reduces blood product utilization and costs in a surgical intensive care unit (SICU). STUDY DESIGN: We performed a retrospective, historical control analysis comparing before (PRE) and after (POST) implementation of a restrictive PRBC/FFP transfusion protocol for SICU patients. Univariate analysis was utilized to compare patient demographics and blood product transfusion totals between the PRE and POST cohorts. Multivariate logistic regression models were developed to determine if implementation of the restrictive transfusion protocol is an independent predictor of adverse outcomes after controlling for age, illness severity, and total blood products received. RESULTS: 829 total patients were included in the analysis (PRE, n=372; POST, n=457). Despite higher mean age (56 vs. 52 years, p=0.01) and APACHE II scores (12.5 vs. 11.2, p=0.006), mean units transfused per patient were lower for both packed red blood cells (0.7 vs. 1.2, p=0.03) and fresh frozen plasma (0.3 vs. 1.2, p=0.007) in the POST compared to the PRE cohort, respectively. There was no difference in inpatient mortality between the PRE and POST cohorts (7.5% vs. 9.2%, p=0.39). There was a decreased risk of urinary tract infections (OR 0.47, 95%CI 0.28-0.80) in the POST cohort after controlling for age, illness severity and amount of blood products transfused. CONCLUSIONS: Implementation of a restrictive transfusion protocol can effectively reduce blood product utilization in critically ill surgical patients with no increase in morbidity or mortality.

Feasibility of Extended-interval Follow-up for Patients Receiving Warfarin.

AIMS: The 2012 American College of Chest Physician Evidence-Based Management of Anticoagulant Therapy guidelines suggest an international normalized ratio (INR) testing interval of up to 12 weeks, rather than every 4 weeks, for patients with consistently stable INRs while taking vitamin K antagonists. We aimed to examine the feasibility of extended-interval follow-up in a real-world setting. METHODS: Patients receiving stable warfarin therapy for ≥ 12 weeks at baseline began extended-interval follow-up with visits occurring at 6 weeks, 14 weeks, and every 12 weeks thereafter to a maximum of 68 weeks or until they were no longer suitable for extended-interval follow-up. A single INR excursion >0.3 from goal was permitted if a reversible precipitating factor was identified and the INR was expected to return to goal without dose adjustment. The primary outcome was the proportion of patients completing all study follow-up visits. RESULTS: Of 48 patients enrolled, 47 had evaluable data. The most common indication for anticoagulation was atrial fibrillation/flutter (53.2%). At baseline, mean prior warfarin treatment duration was 6.7 ± 6 years and median number of weeks on a stable regimen was 24 weeks (IQR, 19-37.5). Eleven patients (23%) completed all study follow-up visits, whereas 17 (36%) did not maintain a stable INR past the 14-week follow-up. CONCLUSION: A large proportion of patients with previously stable (≥ 3 months) INRs were not able to maintain stable INRs during extended-interval follow-up. More research is needed to identify patient characteristics predictive of success with extended-interval follow-up prior to broad implementation.