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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 two one-hour focus groups. All routinely worked with fellows and half had formally instructed trainees on PBS interpretation. Focus group data was analyzed using mixed methods techniques. Tenets of emerging theory were identified through inductive coding. Consensus recommendations (CR) were generated. Participants reviewed CRs 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 being placed on disorders in which prompt recognition was required to avert significant patient morbidity. These CRs offer external validity to future research and curricular development for both PBS review and other visuospatial tasks in medical education.

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.

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.

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.

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.

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.

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.

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.

Although less common than pulmonary embolism and deep vein thrombosis, venous thrombosis at unusual sites is a frequent reason for hematology consultation. A high index of suspicion for thrombosis in unusual locations is needed as diagnosis can be challenging due to heterogeneity in clinical presentation. Treatment and secondary prevention of recurrent thrombosis is difficult given the lack of high-quality data in this specific population. Anticoagulation with warfarin or low-molecular-weight heparin has remained the mainstay of therapy in many cases, based mostly on extrapolation from treatment of pulmonary embolism and deep vein thrombosis. Future studies are needed to determine the safety and efficacy of direct oral anticoagulants in the treatment of thrombosis in unusual locations. This chapter reviews the clinical presentation, diagnosis, and management of thrombosis in unusual sites, including thrombosis of the cerebral veins, splanchnic veins, retinal veins, upper extremity veins, and other less common locations. As the pathophysiologic underpinning of these various thrombotic events is hypercoagulobility of the blood and it’s effective long-term management is using aggressive anticoagulant therapy, it is clear that the hematologist should be highly involved especially in organ-specific thromboses such as hepatic vein thrombosis (rather than just the hepatologist) or cerebral vein thrombosis (rather than just the neurologist).

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.We report a rare case of anti-N and anti-DoAnti-N and anti-Do

Background: Fondaparinux has an increased bleeding risk in patients with a CrCl ≤ 50 mL/min and is contraindicated if CrCl < 30 mL/min. Data regarding dosing and anti-Xa monitoring are lacking in this population. Objective: To describe dosing, monitoring, and safety outcomes of prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment, including renal replacement therapy (RRT). Methods: Retrospective analysis from October 2006 to November 2012 of patients ≥ 18 years old who received fondaparinux for ≥ 72 hours with ≥ 1 dose in an intensive care unit and a CrCl ≤ 50 mL/min or RRT during therapy. Participants were divided into 4 cohorts: moderate impairment (CrCl = 30-50 mL/min), severe impairment (CrCl < 30 mL/min), hemodialysis (HD), or continuous venovenous hemofiltration (CVVH). Outcomes included the incidence of clinically significant bleeding and thromboembolic events. Fondaparinux dose, dosing frequency, and anti-Xa level monitoring are described. Pharmacokinetic modeling was performed to assess drug accumulation. Results: In all, 95 patients met inclusion criteria: 64 (67.4%) with moderate impairment, 10 (10.5%) with severe impairment, 5 (5.3%) with HD, and 16 (16.8%) with CVVH. The median defined daily doses in the moderate, severe, HD, and CVVH cohorts were 2.5, 2.5, 0.9, and 1.9 mg. Anti-Xa monitoring occurred in 19 (20%) patients, although few concentrations were peaks. Clinically significant bleeding occurred in 4 (4.2%) patients. A pharmacokinetic model demonstrated drug accumulation. Conclusions: Empirical dose adjustments may be prudent in critically ill patients with renal dysfunction; however, the optimal fondaparinux dosage in this population remains unknown. Peak anti-Xa concentrations may help guide therapy.

Articles about advances in the treatment of sickle cell crisis, the use of agents to reverse anticoagulation, and targeted treatment of immune thrombocytopenia are highlighted. A study on how long ...

Myelodysplastic syndrome (MDS) is a primary bone marrow disorder whose hallmark is the development of peripheral cytopenias and a predilection toward the development of acute myeloid leukemia (AML). Patients often have hypercellular bone marrows with dysplastic features that may involve multiple lineages. An increased awareness of MDS has led to the reporting of a number of associated autoimmune and paraneoplastic conditions in the medical literature. We present the case of an elderly man who was transferred to our institution with persistent, refractory bleeding several weeks after the resection of a sebaceous cyst. Despite reoperation, treatment with topical and intravenous hemostatic agents, and transfusion of blood products, the patient's bleeding persisted. A comprehensive evaluation for the cause of his coagulopathy was undertaken. Bone marrow evaluation was consistent with MDS. A paraneoplastic consumptive coagulopathy or fibrinolytic process in conjunction with MDS-related platelet dysfunction was felt to be the most likely etiology of the patient's bleeding.

Little is known about the effects of newer oral anticoagulants on various coagulation factors. When presented with a case of intentional or suspected overdose with an abnormal coagulation profile, it is imperative to have a working diagnostic algorithm to narrow the cause to a specific drug or drug class. This may become more crucial and time sensitive when dealing with a case of acute hemorrhage. Here we discuss the first reported case of what appears to be a surreptitious intake of newer oral anticoagulants and the steps leading to the diagnosis.

Introduction: A subpopulation of sickle-cell disease patients, termed super-utilizers, present frequently to emergency departments (EDs) for vaso-occlusive events and may consume disproportionate resources without broader health benefit. To address the health care needs of this vulnerable patient population, we piloted a multidisciplinary intervention seeking to create and use individualized patient care plans that to 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 (7 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 (figure 1); 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: ED visits decreased by 16.5 visits/pt-yr (95% CI, -1.32 to 34.2); ED length of state (LOS) decreased by 115.3 hours/pt-yr (95% CI, -82.9 to 313.5); in-patient admissions decreased by 4.20 admissions/pt-yr (95% CI, -1.73 to 10.1); in-patient LOS decreased by 35.8 hours/pt-yr (95% CI, -74.9 to 146.7); and visits where the patient left before treatment was 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 ICU care 72 hours following discharge. Conclusion: This effort suggests that a targeted approach is both feasible and potentially effective, laying a foundation for broader study.

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.

Thrombotic thrombocytopenic purpura (TTP) is a heterogeneous disease primarily characterized by thrombocytopenia and microangiopathic hemolytic anemia. Therapeutic plasma exchange has dramatically improved mortality, allowing for emergence of refractory, relapsing, and atypical presentations. In this article, we describe four cases of TTP presenting with minimal schistocytes, mild elevation of lactate dehydrogenase, and symptoms suggestive of macrovascular arterial involvement. With increasing reports of less common presentations of TTP, clinicians should consider this diagnosis in cases of unexplained arterial thrombosis, thrombocytopenia, or hemolytic anemia. Testing for a disintegrin and metalloprotease with thrombospondin Type 1 motif, Member 13 ADAMTS13 activity was extremely useful to help confirm the diagnosis in our series of patients. J. Clin. Apheresis, 2012. © 2012 Wiley Periodicals, Inc.

Hemophilia B is a rare X-linked disorder that may cause dramatic bleeding. Women account for only 3.2% of those clinically affected. The X-linked inheritance frequently delays the diagnosis in women and may expose the patient to an increased risk of adverse events. There is limited experience with these patients during labor and delivery. A 28-year-old primiparous woman with hemophilia B (bleeding phenotype) delivered a male infant by an unplanned cesarean delivery under general anesthesia following treatment with factor IX and normalization of her coagulation parameters, guided by thromboelastography. Postpartum vaginal bleeding required transfusion of two units of packed red blood cells. Factor IX supplementation continued for one week. Once diagnosed with hemophilia B, a multidisciplinary approach and advanced antenatal planning can increase the likelihood of a safe delivery. Neuraxial approaches and cesarean delivery are recommended only after normalization of the coagulation profile. The male fetus of a hemophilia A or B patient requires special attention. Operative vaginal delivery and invasive fetal monitoring should be avoided. Thromboelastography is an excellent technique to assess parturients with bleeding disorders or peripartum hemorrhage and may be underused.

Background: Unfractionated heparin (UFH) has been used clinically for 5 decades. Despite being a cornerstone of anticoagulation, UFH is limited by its unpredictable pharmacokinetic profile, which makes close laboratory monitoring necessary. The most common methods for monitoring UFH are the activated partial thromboplastin time (aPTT) and antifactor Xa heparin assay (anti-Xa HA), but both present challenges, and the optimal method to monitor UFH remains unclear. Objective: To compare the performance of the aPTT with the anti-Xa HA for efficiency and safety of monitoring intravenous UFH infusions. Methods: This was a single-center, retrospective, observational cohort study conducted in an 852-bed academic medical center. Results: One hundred patients receiving intravenous UFH for a variety of indications were enrolled in the study; 50 were assigned to each group. The mean (SD) time to achieve therapeutic anticoagulation was significantly less in the anti-Xa HA group compared with the aPTT group (28 [16] vs 48 [26] hours, p < 0.001). In addition, a greater percentage of anti-Xa HA patients compared to aPTT patients achieved therapeutic anticoagulation at 24 hours (OR 3.5; 95% CI 1.5 to 8.7) and 48 hours (OR 10.9; 95% CI 3.3 to 44.2). Patients in the anti-Xa HA group also had more test values within the therapeutic range (66% vs 42%, p < 0.0001). A significant difference was seen between the 2 groups in the number of aPTT or anti-Xa HA tests performed per 24 hours (p < 0.0001) and number of infusion rate changes per 24 hours (p < 0.01), both favoring the anti-Xa HA group. Conclusions: Monitoring intravenous UFH infusions with the anti-Xa HA, compared to the aPTT, achieves therapeutic anticoagulation more rapidly, maintains the values within the goal range for a longer time, and requires fewer adjustments in dosage and repeated tests.

Summary 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.

Little is known about patterns of hydroxyurea (HU) use by community-based hematologist/oncologists (H/Os) for the treatment of sickle cell disease (SCD). Determination of these practice patterns pertaining to adult SCD patients was the focus of this study. A self-administered survey was mailed to H/Os in two southeastern states. Replies were received from 70% of eligible physicians. This study focuses on responses from 184 community H/Os and a comparison group of 30 university-based/affiliated H/Os providing ongoing care for at least 3 SCD patients/month. The majority of community H/O respondents saw less than 3 SCD patients/month. HU was prescribed by more than half (55%) of community H/Os in at least 10% of their patients. The most common reasons cited for prescribing HU include frequent painful crises (76%), chronic pain with frequent narcotic use (58%), and acute chest syndrome (43%). Although the majority of community H/Os care for few patients with SCD, the reported indications for HU were consistent with currently accepted recommendations. However, community H/Os reported acute chest syndrome, stroke, and pulmonary hypertension as indications for HU less often than the academic H/O group. Barriers to wider use of HU include physician concerns about carcinogenic potential, doubts about HU effectiveness, perceived patient apprehension about adverse effects, concern about lack of contraceptive use, and patient compliance. Further resources should focus on updating physicians on recently published material supporting the effectiveness of HU in symptomatic SCD as well as providing management guidelines to optimize the use of HU.

The reversal of low-molecular-weight heparins, particularly at supratherapeutic levels, remains challenging. The paucity of literature available to guide the treatment of these patients makes their management difficult for primary care providers, surgeons, and subspecialists alike. We report the case of a 34-year-old woman, who intentionally overdosed on enoxaparin (Lovenox) in a suicide attempt. Her initial antifactor Xa activity level was 8.3 IU/ml, the highest level reported in the literature to date. She was initially managed conservatively, however, within 24 h of admission she developed evidence of acute blood loss. Protamine sulfate and three doses of recombinant activated factor VII (rFVIIa) were administered in an effort to control bleeding. We report the effects of these measures and review the literature to date. Our study is one of the first to graph in-vivo antifactor Xa activity levels and to suggest a drug half-life of approximately 25 h.

Department of Pathology and Laboratory Medicine, University of Florida, Gainesville, FloridaWe describe a patient who developed a markedly prolonged PT, PTT, and thrombin time13 days after repeat exposure to fibrin sealant during coronary artery bypass grafting andaortic valve replacement. Evaluation revealed an inhibitor to bovine thrombin that cross-reacted with human thrombin. In addition an inhibitor to human coagulation factor V wasidentified. Despite coagulation abnormalities there was no evidence of bleeding. Never-theless, effective anticoagulation was required to minimize the thrombotic complicationsassociated with the patient’s prosthetic valve. We elected to take a conservative ap-proach and not utilize pharmacologic anticoagulation until there was diminution in theeffect of the acquired inhibitors. We report on our patient’s course and review the avail-able literature addressing the management of patients demonstrating inhibitors to bloodcoagulation factors after repeat exposure to fibrin sealants. Am. J. Hematol. 64:59–63,2000.

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.

Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterized by microangiopathic hemolytic anemia and thrombocytopenia with varying degrees of renal dysfunction, neurologic signs and symptoms, and fever. Evidence has supported that a large proportion of cases of acquired TTP are due to the accumulation of ultralarge von Willebrand factor (vWF) multimers due to an acquired deficiency in the vWF cleaving protease, ADAMTS-13. TTP is rare in the post-surgical setting but is best described after cardiothoracic and vascular surgeries. We present a case of postoperative TTP first presenting with microangiopathic hemolytic anemia and thrombocytopenia 9 days after emergent appendectomy for a ruptured appendix. ADAMTS-13 and factor H levels returned normal and an ADAMTS-13 inhibitor was not identified. To our knowledge, this is the first case report of postoperative TTP after an appendectomy and the first report with correlative ADAMTS-13 data. Plasma exchange with fresh frozen plasma followed by cryopoor plasma, along with steroids resulted in eventual remission of TTP in our patient. Early postoperative diagnosis and aggressive management with consideration of initiation of plasma exchange is imperative to decrease the morbidity and morality associated with TTP.

Background The management of perioperative anticoagulation therapy for patients having a high risk of thromboembolism who are receiving long-term oral anticoagulant therapy is uncertain. The prevalent approach is to discontinue oral anticoagulation therapy and initiate heparin therapy. Another potential strategy is to continue oral anticoagulation therapy with a temporary adjustment of warfarin intensity to a preoperative international normalized ratio (INR) of 1.5 to 2.0. Such moderate-dose anticoagulation therapy with warfarin has been shown to be hemostatically safe yet effective in the prevention of thromboembolism after hip or knee replacement Methods Over an 11-year period ( ie , 1993 to 2003), our hemostatic consultative service prospectively identified 100 consecutive patients for whom we continued warfarin therapy at adjusted doses during the perioperative period, targeting a goal for the INR of 1.5 to 2.0. Patients were assigned a score for venous thromboembolic risk as well as overall surgical risk using published instruments. Score assignment was based on what was deemed to be extremely high risk for thromboembolism in patients who were receiving long-term warfarin therapy. Although the patients were accrued prospectively, the final retrospective analysis was made after all patients were treated Results The most common indication (62%) for high-risk assignment was a thromboembolic event within the past 6 months. The second most prevalent reason was prior postoperative venous thromboembolism (VTE) [11%]. Indications for long-term anticoagulation therapy were recent VTE (62%), inherited thrombophilia (7%), antiphospholipid syndrome (13%), mechanical heart valves (18%), and prior cerebrovascular accident (4%). The prevalence of inherited thrombophilia probably has been grossly underestimated, as neither factor V Leiden mutation nor prothrombin 20210 mutation had been described during the bulk of the accrual time. Most surgical procedures (58%) were significantly invasive (Johns Hopkins category 3 to 5). The mean INR values were 2.1 on the day prior to surgery (SD, 0.9594; range, 1.2 to 6.5; n=65), 1.8 on the day of surgery (SD, 0.4899; range, 1.2 to 4.9; n=75), and 1.8 on the first postoperative day (SD, 0.4436; range, 1.1 to 3.3; n=70). Two patients had major bleeding, and four patients had minor bleeding. One patient developed deep venous thrombosis. Several weeks after surgery, one patient with a prosthetic heart valve died from an embolic stroke, which was associated with a failure to increase his anticoagulation to therapeutic levels Conclusions Moderate-intensity anticoagulant therapy with warfarin, targeting a goal INR of 1.5 to 2.0, appears to be a safe and feasible method for preventing thromboembolic complications in high-risk surgical patients who are receiving long-term oral anticoagulant therapy. This may be considered a reasonable method to afford thromboprophylaxis in highly selected patients who are occasionally seen in clinical practice. This observational study does not prove equality, let alone superiority, to other proposed methods of anticoagulation therapy

Marked variability is a keynote in the disease course of patients with hemoglobin SC (Hb SC) and hemoglobin S/beta(+)-thalassemia (Hb S/beta(+)-thal), with some patients having a frequency of complications and painful episodes similar to patients with homozygous sickle cell (Hb SS) disease. One possible explanation is that the higher hematocrit in these syndromes may contribute to an increase in blood viscosity, leading to vaso-occlusive pain episodes as well as an increased incidence of thromboembolic complications and retinopathy. We present a patient with Hb SC disease with an excellent baseline functional status who developed splenic infarction at a high altitude. Following splenectomy, the patient developed a sustained increase in hematocrit, an increase in the frequency of painful episodes, as well as new-onset dizziness and malaise. We initiated a therapeutic phlebotomy program in order to lower the hematocrit to pre-splenectomy values, as well as to induce iron deficiency. Repeated phlebotomy resulted in a dramatic decrease in symptoms. Our patient no longer requires narcotic analgesics for pain, has resolution of constitutional symptoms, and has not required further hospitalizations for vaso-occlusive pain crises. The correlation between symptoms and hematocrit levels supports the importance of blood viscosity in contributing to this patient's symptoms. A trial of phlebotomy to reduce viscosity in patients with higher hematocrit values should be considered as an intervention for symptomatic patients with sickle cell disease.

Background G-CSF and GM-CSF have both been shown to decrease the time to hematopoietic recovery when administered after autologous BM or peripheral stem cell re-infusion. However, few studies have compared G-CSF and GM-CSF to determine which is the preferred myeloid growth factor. Methods This study compares a prospectively accrued cohort of 22 patients receiving GM-CSF with a historical cohort of patients who received G-CSF commencing Day + 6 after autologous PBSC transplantation. Patients were matched based on disease type and stage, CD34 + cell dose/kg, conditioning regimen, and prior treatment. Time to myeloid engraftment, growth factor utilization, antibiotic utilization, fever incidence, and cost were compared. Results The median time to neutrophil and platelet engraftment was similar in the two groups (ANC > 500/mm 3 , GM-CSF 12 versus G-CSF 11, P=0.69). There was a trend towards more days of temperature > 38.0°C (six versus three, P=0.05) and febrile neutropenia (three versus two, P=0.06) in the GM-CSF arm. There was a trend towards increased use of i.v. antibiotics in the GM-CSF cohort (7.6 days versus 5.5 days, P 5 0.06). More chest X-rays (1.5 versus 1.0, P=0.03) were ordered, and more blood cultures drawn (4.2 versus 2.7, P=0.05) as part of fever evaluation in the group treated with GM-CSF. Resource utilization based on actual wholesale pricing (AWP) favored the G-CSF cohort. Applying a sensitivity analysis, GM-CSF became cost-effective when priced below $94 per 250μg, despite greater resource utilization. Discussion This study suggests that engraftment characteristics are similar with GM-CSF and G-CSF following PBSC transplantation. Resource utilization for fever treatment and evaluation may be greater with GM-CSF. Determination of which agent is more cost-effective depends on institutional acquisition costs.

An optimal platelet-count threshold for prophylactic platelet transfusion in hematopoietic stem cell transplant (HSCT) recipients has yet to be determined. Between July 1997 and December 1999, we performed the first prospective randomized clinical trial addressing this issue in 159 HSCT recipients who received a prophylactic platelet transfusion when the morning platelet count fell below a 10,000/microL (10K) or 20,000/microL (20K) threshold. Subsequent prophylactic transfusions were administered according to a predetermined algorithm. The number of prophylactic and therapeutic transfusions and the incidence of minor and major bleeding were compared between the 2 groups. The groups were matched according to patient and transplantation characteristics. There were no significant differences in bleeding incidence or severity. Fourteen percent of patients in the 10K arm compared to 17% in the 20K arm had major bleeding events. Only 3 central nervous system bleeds occurred, 2 in the 10K group and 1 in the 20K group. No deaths were attributed to bleeding. An average of 11.4 days of bleeding occurred in both groups. An average of 10.4 platelet transfusions per patient were administered in the 10K group compared to 10.2 in the 20K group (P = .94). More transfusions were given above the assigned transfusion threshold in the 10K group than in the 20K group (4.3/patient versus 1.9/patient, respectively, P=.05). Safety measures incorporated into our study may have precluded demonstration of significant differences in platelet use between the groups. In conclusion, a platelet transfusion trigger of 10K was found to be safe; however, a decrease in platelet use was not achieved because of safety measures incorporated into our study design. Biol Blood Marrow Transplant 2002;8(10):569-76.

Introduction Fondaparinux, a selective activated Factor Xa inhibitor, is a parenteral anticoagulant primarily excreted by the kidneys. Renal insufficiency (RI), commonly encountered in the critically ill, has been shown to portend an increased risk of bleeding than in normal healthy adults. In comparison to the low molecular weight heparin dalteparin, fondaparinux has been shown to be superior for the prevention of post-surgical venous thromboembolism (VTE), however an increased rate of nonfatal bleeding has been observed. Recently, data has emerged supporting empiric dose reductions in patients with moderate RI, defined as a creatinine clearance (CrCl) between 30 and 50 mL/min. Overall, the data supporting appropriate use of fondaparinux in patients with RI is lacking. This retrospective, single center study describes our experience using prophylactic fondaparinux in critically ill patients with moderate RI. Methods We report our experience utilizing fondaparinux in a mixed medical and surgical, critically ill adult population with moderate RI. The site examined was UF Health; an 852-bed sized tertiary care hospital in Gainesville, Florida between 2006 and 2012. Moderate RI was defined as a CrCl between 30 and 50 mL/min calculated by the Cockcroft/Gault equation. Only patients treated with fondaparinux for prophylaxis of VTE were included, patients treated for other indications were excluded. Doses, dose frequency and dose adjustments were documented. If patients had anti-Xa level monitoring these values were recorded. Timing of anti-Xa levels drawn with respect to fondaparinux dosing was also noted. The primary end point of the study was the rate of clinically significant bleeding events in patients receiving at least 72 hours of fondaparinux. Clinically significant bleeding was defined as transfusion of at least two units of packed red blood cells within 48 hours of a documented bleeding event or the workup of bleeding with endoscopy or imaging. Bleeding events were screened by ICD-9 codes and validated via chart review, incidence of VTE was also noted. Results Sixty-fourpatients met inclusion criteria between October 2006 and November 2012. Two patients (3.1%) experienced clinically significant bleeding events as per our definition, both in the form of gastrointestinal bleeding. Empiric dose reductions occurred in 8 (12.5%) patients, this occurred in the form of every other day administration or dose reduction using fondaparinux 1.25mg daily. Nine (14%) patients were monitored with anti-Xa levels, none of these patients encountered bleeding events. The median anti-Xa level was 0.5 mcg/mL, which is in the target prophylactic range for in our lab. The median time interval after last dose of fondaparinux to anti-Xa level measurement was 4 hours. Seven (10.9%) patients had VTE diagnoses prior to the initiation of prophylactic fondaparinux. No patients suffered a VTE event after treatment with prophylactic fondaparinux in our data set. Conclusion We report a cohort of patients with moderate RI receiving fondaparinux for the prevention of VTE. The incidence of clinically significant bleeding was 3.1%. The risk of VTE was low, no patients suffered from a VTE after treatment with fondaparinux in our data set. The rate of bleeding is slightly higher compared to patients with normal renal function. Our experience over this 6 year period supports the notion that RI portends an increased risk of bleeding with the use of fondaparinux. Further prospective studies are needed to determine the safety and efficacy of empiric fondaparinux dose reductions in patients with RI and end stage renal disease. Anti-Xa monitoring may help reduce the risk of bleeding in this patient population by identifying those patients in whom a dose reduction may be beneficial. Disclosures: No relevant conflicts of interest to declare.

The hands of 14 normal humans were used to determine the somatotopic organization of the modulation of warmth sensation and heat pain by different forms of cutaneous stimuli. Test stimuli were 5-sec heat pulses ranging from 36 degrees to 51 degrees C, delivered to the fingerpads of digits 1, 2, 4, and 5 with a contact thermode. Conditioning stimuli (15 sec) bracketed the test stimuli and included vibration, noxious and innocuous heat, cold, and electrical pulses delivered to the fingerpads of digits that were adjacent or nonadjacent to the tested digits. Noxious (48 degrees +/- 1.3 degrees C), but not innocuous (43 degrees C), heat stimuli increased the perceived magnitude estimation of innocuous test stimuli (36-43 degrees C) by 20-37% when delivered to adjacent, but not to nonadjacent, digits. No other conditioning stimuli had any effect on the intensity of warmth perception. In contrast, both noxious and innocuous heat or electrical conditioning reduced the magnitude estimation of noxious (50-51 degrees C), but not innocuous, test pulses by 12-22% when delivered to adjacent digits. Conditioning of nonadjacent digits was significantly less effective. The analgesic effects of noxious and innocuous conditioning were approximately equal. Vibratory (120 Hz, 3.5 microns) and cold (15 degrees C) conditioning stimuli were ineffective. The results are consistent with a dermatomal somatotopic organization of tactile and heat modulatory influences on warmth sensation and heat pain. The results further suggest that the neural mechanism subserving warmth mediate a negative feedback influence on heat pain intensity.

Successful Use of Argatroban as an Anticoagulant in Burn-related Severe Acquired Antithrombin III Deficiency after Heparin Failure