Pharmacokinetics of perioperative FVIII in adult patients with haemophilia A: An external validation and development of an alternative population pharmacokinetic model.

INTRODUCTION: Haemophilia A patients require perioperative clotting factor replacement to limit excessive bleeding. Weight-based dosing of Factor VIII (FVIII) does not account for inter-individual pharmacokinetic (PK) variability, and may lead to suboptimal FVIII exposure. AIM: To perform an external validation of a previously developed population PK (popPK) model of perioperative FVIII in haemophilia A patients. METHODS: A retrospective chart review identified perioperative haemophilia A patients at the University of North Carolina (UNC) between April 2014 and November 2019. Patient data was used to externally validate a previously published popPK model proposed by Hazendonk. Based on these validation results, a modified popPK model was developed to characterize FVIII PK in our patients. Dosing simulations were performed using this model to compare FVIII target attainment between intermittent bolus (IB) and continuous infusion (CI) administration methods. RESULTS: A total of 521 FVIII concentrations, drawn from 34 patients, were analysed. Validation analyses revealed that the Hazendonk model did not fully capture FVIII PK in the UNC cohort. Therefore, a modified one-compartment model, with weight and age as covariates on clearance (CL), was developed. Dosing simulations revealed that CI resulted in improved target attainment by 16%, with reduced overall FVIII usage by 58 IU/kg, compared to IB. CONCLUSION: External validation revealed a previously published popPK model of FVIII did not adequately characterize UNC patients, likely due to differences in patient populations. Future prospective studies are needed to evaluate our model prior to implementation into clinical practice.

Role of caplacizumab in the treatment of acquired thrombotic thrombocytopenic purpura.

Acquired thrombotic thrombocytopenic purpura is a rare blood disorder with a high early mortality rate, if untreated. Standard of care plasma exchange and glucocorticoids have dramatically improved survival. However, additional advancements are necessary to further decrease mortality. Caplacizumab-yhdp (Cablivi®) is the first Food and Drug Administration-approved treatment indicated for adult patients with acquired thrombotic thrombocytopenic purpura, in combination with plasma exchange and immunosuppressive therapy. However, there are considerable risks associated with the use of caplacizumab and they must be weighed against the benefits of the medication.

Importance of pharmacokinetic studies in the management of acquired factor X deficiency.

Up to 14% of individuals with systemic AL amyloidosis develop acquired factor X deficiency, which occurs due to adsorption of factor X onto amyloid fibrils. Although baseline factor X levels are not predictive of bleeding risk in these patients, serious hemorrhagic complications can occur, particularly during invasive procedures. Optimal management strategies to attenuate bleeding risk in these patients are unknown. We describe our experience in the management of acquired factor X deficiency, secondary to systemic AL amyloidosis, in a case series of three patients who received prothrombin complex concentrates (PCCs) for treatment and prevention of bleeding events. We performed a retrospective review extracting information on baseline demographics, laboratory data, pharmacokinetic (PK) studies, and clinically documented bleeding events. Our case series demonstrates that individuals with acquired factor X deficiency secondary to amyloidosis have variable laboratory and clinical responses to PCCs. This is likely due to distinct amyloid loads and fibril sequences, leading to different binding avidities for factor X. Our data emphasize the importance of performing PK testing prior to any invasive procedures to determine the dose and frequency interval to achieve adequate factor X levels for hemostasis, given the variable response between individuals.

Evaluation of a Multimodal Heparin Laboratory Monitoring Protocol in Adult Extracorporeal Membrane Oxygenation Patients.

BACKGROUND: Anticoagulation monitoring practices vary during extracorporeal membrane oxygenation (ECMO). The Extracorporeal Life Support Organization describes that a multimodal approach is needed to overcome assay limitations and minimize complications. OBJECTIVE: Compare activated clotting time (ACT) versus multimodal approach (activated partial thromboplastin time (aPTT)/anti-factor Xa) for unfractionated heparin (UFH) monitoring in adult ECMO patients. METHODS: We conducted a single-center retrospective pre- (ACT) versus post-implementation (multimodal approach) study. The incidence of major bleeding and thrombosis, blood product and antithrombin III (ATIII) administration, and UFH infusion rates were compared. RESULTS: Incidence of major bleeding (69.2% versus 62.2%, p = 0.345) and thrombosis (23% versus 14.9%, p = 0.369) was similar between groups. Median number of ATIII doses was reduced in the multimodal group (1.0 [IQR 0.0-2.0] versus 0.0 [0.0 -1.0], p = 0.007). The median UFH infusion rate was higher in the ACT group, but not significant (16.9 [IQR 9.6-22.4] versus 13 [IQR 9.6-15.4] units/kg/hr, p = 0.063). Fewer UFH infusion rate changes occurred prior to steady state in the multimodal group (0.9 [IQR 0.3 -1.7] versus 0.1 [IQR 0.0-0.2], p < 0.001). CONCLUSION: The incidence of major bleeding and thrombosis was similar between groups. Our multimodal monitoring protocol standardized UFH infusion administration and reduced ATIII administration.

Solving coagulation conundrums: comparing prophylaxis strategies in adult patients receiving PEG-asparaginase.

PEG-asparaginase is a key component in treatment regimens for acute lymphoblastic leukemia (ALL). Major side effects include thrombosis and bleeding; however, there is currently no consensus on methods to prevent these complications. In this multi-center retrospective cohort study of 101 adults, we compared two prophylaxis strategies: cryoprecipitate and fresh frozen plasma (Cryo/FFP) versus cryoprecipitate and antithrombin (ATIII). The overall incidence of venous thromboembolism (VTE) was not significantly different between the two groups (19.7% for Cryo/FFP and 8.6% in Cryo/ATIII, p = 0.17), and neither was grade ≥3 bleeding (3% for Cryo/FFP and 11.4% for Cryo/ATIII, p = 0.18). Given the significant cost associated with ATIII without a clear benefit, a careful benefit and risk analysis should be considered before utilizing ATIII as a prophylaxis strategy to prevent thrombosis or bleeding following asparaginase administration.

Impact of a multidisciplinary workflow on safety and management of patients with heparin-induced thrombocytopenia.

PURPOSE: Heparin-induced thrombocytopenia (HIT) is a serious complication of heparin administration. Management strategies are complex and include discontinuing heparin products, initiating alternative anticoagulants, interpreting laboratory test results, documenting heparin allergies, and providing patient education. Medication error reports and a retrospective review conducted at an academic medical center revealed an opportunity for a quality improvement initiative and led to the creation of a multidisciplinary workflow for the management of HIT. In a pre-post study, the impact of the multidisciplinary workflow on the safety and management of HIT was evaluated. METHODS: The preimplementation group consisted of adult patients tested for suspected HIT from April 4, 2014, through May 31, 2016; the postimplementation group consisted of adult patients tested from November 1, 2016, through October 31, 2018. The primary outcome was the incidence of heparin product administration while HIT testing was ongoing. The secondary outcome was the rate of appropriate heparin allergy documentation. RESULTS: The incidence of heparin product administration while HIT testing results were pending was significantly reduced, from 54.2% to 20.0% (P < 0.001), after workflow implementation. The rate of appropriate heparin allergy documentation significantly increased, from 95.0% to 100% (P < 0.001). CONCLUSION: Implementation of a multidisciplinary workflow for the management of HIT significantly reduced the incidence of heparin administration while testing was ongoing and improved the rate of appropriate heparin allergy documentation.

Minimizing cost associated with management of heparin-induced thrombocytopenia: A cost analysis of various laboratory testing models.

INTRODUCTION: Management of patients with suspected heparin-induced thrombocytopenia (HIT) can lead to significant costs. Reported cost-saving initiatives have focused on minimizing inappropriate testing in low-risk patients and optimizing alternative anticoagulant selection. We sought to further investigate how utilizing various HIT laboratory testing models would impact total cost of testing and alternative anticoagulant use. METHODS: Utilizing a retrospective cohort of adult patients tested for HIT over three years within our institution, we evaluated how utilization of four distinct laboratory models impacted total number of HIT test combinations completed, time to HIT testing finalization, percentage of patients discharged from the hospital prior to HIT testing finalization, total alternative anticoagulant days, and total anticipated major bleed events. Additionally, we calculated cost of laboratory testing and alternative anticoagulant associated with each model. RESULTS: A total of 482 patients were included in our cohort. A laboratory testing model that utilized an in-house platelet factor 4 (PF4)-heparin enzyme-linked immunosorbent assay (ELISA) completed three days weekly, and reflex serotonin release assay (SRA) with a five-day turnaround resulted in the shortest mean time to HIT testing finalization, lowest percentage of patients discharged prior to HIT testing finalization, and lowest total alternative anticoagulant days. CONCLUSIONS: Institutions should evaluate current HIT laboratory testing practices and assess for opportunities for optimization. Testing models utilizing a PF4-heparin antibody ELISA with a reflex SRA for positive results may improve testing metrics and lead to lower utilization of alternative anticoagulants.

Evaluation of 4Ts score inter-rater agreement in patients undergoing evaluation for heparin-induced thrombocytopenia.

The American Society of Hematology and American College of Chest Physicians heparin-induced thrombocytopenia guidelines recommend calculation of a pretest probability score prior to performing laboratory testing, and the 4Ts score is commonly used. Inter-rater agreement of the 4Ts score has been evaluated, but limited data are available regarding the reliability of the 4Ts score when performed by nonexpert clinicians. The purpose of this study was to Compare 4Ts scores calculated by medical teams to an expert. A single-center observational study was conducted in patients evaluated for heparin-induced thrombocytopenia over 24 months. The primary outcome was difference in mean 4Ts score calculated by the medical team compared with an expert. Secondary outcomes included inter-rater agreement in risk category assignment and the negative predictive value (NPV) of the 4Ts score. The mean total 4Ts score was significantly higher when calculated by the medical team compared with expert (4.16 ±â€Š1.41 versus 3.42 ±â€Š1.53; P < 0.001). There was slight agreement in risk category assignment (Cohen κ coefficient = 0.164; P = 0.005). The NPV of the 4Ts score was 0.949 (95% confidence interval 0.891-1.000) when calculated by the medical team and 0.927 (95% confidence interval 0.869-0.984) when calculated by expert. Total 4Ts scores calculated by the medical team were significantly higher with only slight inter-rater agreement compared with expert. The NPV of the 4Ts score when calculated by nonexperts may be lower than previously reported. The recommendation to forgo laboratory testing for low 4Ts score patients may need to be revisited.

Safety and Efficacy of High-Dose Unfractionated Heparin Versus High-Dose Enoxaparin for Venous Thromboembolism Prevention in Morbidly Obese Hospitalized Patients.

BACKGROUND: Venous thromboembolism is a cause of morbidity and mortality in hospitalized patients, and morbid obesity increases this risk. Various prophylaxis dosing strategies have been investigated. However, it is unclear if high-fixed dose enoxaparin or high-fixed dose unfractionated heparin thromboprophylaxis is optimal for minimizing the incidence of major bleeding and reducing hospital-acquired venous thromboembolism. METHODS: A single-center retrospective observational study was conducted in hospitalized patients who were morbidly obese (body mass index ≥40 kg/m2) and who received either high-fixed dose enoxaparin (40 mg every 12 hours) or unfractionated heparin (7500 units every 8 hours) for venous thromboembolism prophylaxis. Co-primary outcomes included incidence of major bleeding and venous thromboembolism diagnosed during hospitalization. Predictors of major bleeding were evaluated by multivariable regression. RESULTS: In the 305 patients included (n = 190 unfractionated heparin, n = 115 enoxaparin), the incidence of major bleeding was significantly higher in the unfractionated heparin group (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.07-3.13; P = 0.025), with no significant difference in the incidence of venous thromboembolism diagnosed during hospitalization. The only independent predictors of major bleeding were intensive care acuity (OR 3.32, 95% CI 1.91-5.78; P <0.001) and selection of unfractionated heparin rather than enoxaparin for venous thromboembolism prophylaxis (OR 2.16, 95% CI 1.22-3.82; P = 0.008). CONCLUSION: High-fixed dose unfractionated heparin for venous thromboembolism prophylaxis may lead to a higher risk of major bleeding events compared with high-fixed dose enoxaparin in patients who are morbidly obese.

Recombinant porcine FVIII for bleed treatment in acquired hemophilia A: findings from a single-center, 18-patient cohort.

Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired autoantibodies to endogenous factor VIII (FVIII) decrease FVIII activity and lead to a bleeding phenotype. A substantial majority of individuals who develop AHA present with severe bleeding. Effective treatment requires both immunosuppressive therapy and prompt hemostatic treatment. Bleeding is commonly treated with bypassing agents (BPAs) such as recombinant activated FVII (rFVIIa) or activated prothrombin complex concentrates Disadvantages to BPAs include the inability to monitor response with standard laboratory assays, inconsistent hemostatic efficacy, and thrombosis. Recombinant porcine FVIII (rpFVIII: Obizur, Baxter, Deerfield, IL) was approved by the US Food and Drug Administration (FDA) for bleed treatment in AHA in 2014, and has the advantage of laboratory monitoring of FVIII activity levels and known hemostatic efficacy in the presence of anti-human FVIII inhibitors and after failure of BPAs. Using an algorithm-based approach, rpFVIII has been used to successfully treat 18 patients with AHA at our center with substantially lower doses than the current FDA-recommended dosing. Additionally, data from our cohort show that the preexposure anti-porcine Bethesda titer does not reliably predict the clinical response to rpFVIII treatment and is not correlated with the anti-human Bethesda titer. We also present data showing lower total rpFVIII use for initial bleed resolution when rpVIII is used upfront, as compared with use as rescue therapy. We validated our dosing algorithm, which uses much lower than FDA-recommended doses with 14 more patients than in our previously reported patient series.

Inhaled Desmopressin for Refractory Gastrointestinal Bleeding in a Patient With a HeartMate II Left Ventricular Assist Device.

Patients with a durable, continuous-flow left ventricular assist device (LVAD) are commonly prescribed the combination of an oral anticoagulant and an oral antiplatelet agent as prophylaxis against device thrombosis and systemic embolic events. Current International Society of Heart and Lung (ISHLT) guidelines recommend warfarin with an INR goal of 2-3 and concomitant aspirin 81-325 mg daily for patients with a HeartMate II LVAD. Unfortunately, gastrointestinal (GI) bleeding is very common in these patients because of multiple factors including the development of arteriovenous malformations and acquired von Willebrand syndrome. If this bleeding cannot be corrected through interventional measures, it then requires at least temporary, and potentially permanent, cessation of antiplatelet or anticoagulant therapy. Patients who continue to bleed while off all antithrombotic therapies present a clinical challenge. We describe the successful management of a patient with refractory GI bleeding through the use of inhaled desmopressin.

Improved Organizational Outcomes Associated With Incorporation of Early Clinical Experiences for Second-Year Student Pharmacists at an Academic Medical Center.

PURPOSE: To assess the feasibility of engaging second professional year student pharmacists in the medication reconciliation process on hospital and health system pharmacy practice outcomes. METHODS: Student pharmacists in their second professional year in the Doctor of Pharmacy degree program at our institution were randomly selected from volunteers to participate. Each participant completed training prior to completing three 5-hour evening shifts. Organizational metrics, student pharmacist perception regarding quality of interactions with health care professionals, and pharmacist perceptions were collected. RESULTS: A total of 83 medication histories were performed on complex medical patients (57.0 ± 19.2 years, 51% female, 65% Caucasian, 12 ± 6 medications); of those, 93% were completed within 24 hours of hospital admission. Second professional student pharmacists completed on average 1.9 ± 0.6 medication histories per shift (range 1-3). Student pharmacists identified 0.9 medication-related problems per patient in collaboration with a pharmacist preceptor. Student pharmacists believed the quality of their interactions with health care professionals in the Student Medication and Reconciliation Team (SMART) program was good or excellent. The program has been well received by clinical pharmacists involved in its design and implementation. CONCLUSION: This study provides evidence that second professional year student pharmacists can assist pharmacy departments in the care of medically complex patients upon hospital admission.

Economic costs of hemophilia and the impact of prophylactic treatment on patient management.

Hemophilia is a rare congenital bleeding disorder characterized by spontaneous and potentially life-threatening bleeding episodes. In addition to its clinical burden on the patient, the condition also places a significant economic burden on healthcare payers, patients/caregivers, and society. Hemophilia is associated with staggering direct costs from hospitalizations, outpatient visits, and drug treatments, as well as high indirect costs from diminished work productivity and absenteeism from work and school. Additionally, hemophilia incurs tremendous intangible costs, including reduced quality of life, pain and suffering, and the emotional and physical toll on the patient and caregivers. The evolution of treatment patterns in hemophilia has transformed the once-fatal disease into a chronic but potentially well-managed condition through the use of prophylaxis treatment. However, other complications, such as development of inhibitory antibodies, have added to the complexity of managing the disease and its costs. To ensure optimal treatment outcomes and disease management, there is a critical need to understand the utilization of healthcare resources in the treatment of hemophilia and to educate patients on the importance of treatment adherence and compliance to reduce long-term effects on musculoskeletal health.

Impact of an innovative blood factor stewardship program on drug expense and patient care.

PURPOSE: An innovative pharmacist-led program to improve prescribing, dosing, and monitoring of clotting factor therapy within a large health system is described. SUMMARY: In an initiative to optimize patient outcomes and control costs associated with the use of clotting factor concentrates, the pharmacy department at University of North Carolina Medical Center (UNCMC) led the development of a "factor stewardship program" in collaboration with UNCMC hematologists. Key steps in program development and implementation included (1) selection of one formulary product within each clotting factor class, (2) establishment of guidelines on blood factor prescribing, order review, compounding, and administration, and (3) initial and ongoing education of pharmacy, nursing, and medical staff. As part of the program, a designated pharmacist rounds with hematologists daily, recommending treatment plan modifications and dosage adjustments as appropriate. Now in its fifth year, the stewardship program has enabled consistent pharmacist oversight of all aspects of clotting factor use and enhanced transitions-of-care coordination. Through optimization of product selection, dosing regimens, and infusion frequencies, the number of blood factor doses in fiscal year 2013 was reduced by 45% from the prior year despite a 22% increase in the volume of treated patients; in patients with hemophilia A, re-admissions due to bleeding episodes have declined. During the four-year period ending in July 2014, estimated cost savings attributable to the stewardship program exceeded $4 million annually. CONCLUSION: Implementation of the UNCMC stewardship program has led to improved outcomes in patients receiving clotting factor concentrates, with significant institutional cost savings.

Retrospective evaluation of the clinical use of prothrombin complex concentrate for the reversal of anticoagulation with vitamin K antagonists.

Anticoagulation reversal is a time-sensitive intervention for the prevention of life-threatening hemorrhagic events occurring with bleeding or surgery. Recommendations for the most effective and well tolerated reversal agent in these settings remain controversial. Several clinical guidelines for the management of intracerebral hemorrhage support use of prothrombin complex concentrates (PCCs) for the rapid reversal of warfarin-associated coagulopathy despite limited clinical data. The purpose of this investigation was to evaluate the efficacy and safety of PCC for the rapid reversal of anticoagulation by vitamin K antagonists for life-threatening bleeding or emergent surgery and to assess adherence to a hospital-based protocol. A retrospective chart review was conducted of adult patients receiving PCC for the reversal of anticoagulation. Patients were assessed according to indication for anticoagulation reversal. The primary outcome measure was adequacy of international normalized ratio reversal. Other outcomes included cessation of bleeding, thrombotic complications, and adherence to an institutional-based guideline for the use of PCC. ICU and hospital length of stay and 30-day mortality was assessed. There were 70 patients included in this study. Mean international normalized ratio was reduced from 3.1 to 1.6 following administration of at least one dose of PCC. Cessation of bleeding occurred in 65.7% of patients. Clinical assessment was unclear in 18.6%. Thrombotic complications were observed in 7.1% of patients. The 30-day mortality rate was found to be 14.3%. These data demonstrate that PCC is a well tolerated and effective method for anticoagulation reversal associated with a relatively high 30-day survival rate.

Early Clinical Experiences for Second-Year Student Pharmacists at an Academic Medical Center.

OBJECTIVE: To examine student outcomes associated with the Student Medication and Reconciliation Team (SMART) program, which was designed to provide second-year student pharmacists at the University of North Carolina (UNC) Eshelman School of Pharmacy direct patient care experience at UNC Medical Center. DESIGN: Twenty-two second-year student pharmacists were randomly selected from volunteers, given program training, and scheduled for three 5-hour evening shifts in 2013-2014. Pre/post surveys and reflection statements were collected from 19 students. Data were analyzed with a mixed methods approach. ASSESSMENT: Survey results revealed an increase in student self-efficacy (p<0.05) and positive perceptions of SMART. Qualitative findings suggest the program provided opportunities for students to develop strategies for practice, promoted an appreciation for the various roles pharmacists play in health care, and fostered an appreciation for the complexity of real-world practice. CONCLUSION: Early clinical experiences can enhance student learning and development while fostering an appreciation for pharmacy practice.