Lance A. Williams

Pathology Consultation on the Diagnosis and Treatment of Thrombotic Microangiopathies (TMAs)

OBJECTIVES Pathologists specializing in transfusion medicine, apheresis medicine, and/or coagulation are often consulted by clinicians to reach a diagnosis for patients with thrombotic microangiopathy (TMA), so that disease-specific, often life-saving therapy can be initiated as promptly as possible. METHODS This article describes how to proceed when treating a patient with TMA. The differential diagnosis is broad and potentially very challenging. Thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and typical hemolytic uremic syndrome (HUS) are three such TMAs that require timely diagnosis and treatment. RESULTS TTP is treated with daily therapeutic plasma exchange (TPE) and commonly with adjunctive immunosuppressive therapy, while aHUS may initially be managed with TPE but is best controlled with eculizumab once a presumptive diagnosis is made. TPE has no proven role in typical HUS, which is most commonly treated with supportive measures only. CONCLUSIONS Prompt and accurate diagnosis of TMA subtypes optimizes treatment and improves patient outcomes.

Cryoprecipitate AHF vs. fibrinogen concentrates for fibrinogen replacement in acquired bleeding patients – an economic evaluation

Fibrinogen repletion in patients with acquired bleeding disorders can be accomplished by transfusing cryoprecipitate AHF (cryo) or fibrinogen concentrate (FC); thus, we undertook an economic evaluation from the transfusion service perspective regarding the use of cryo vs. FC in patients with acquired bleeding.

Discovery of 2-pyridylureas as glucokinase activators.

Glucokinase (GK) is the rate-limiting step for insulin release from the pancreas in response to high levels of glucose. Flux through GK also contributes to reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can allosterically activate GK may address this issue. Herein we report the identification and initial optimization of a novel series of glucokinase activators (GKAs). Optimization led to the identification of 33 as a compound that displayed activity in an oral glucose tolerance test (OGTT) in normal and diabetic mice.

Human neutrophil peptides and complement factor Bb in pathogenesis of acquired thrombotic thrombocytopenic purpura

Acquired thrombotic thrombocytopenic purpura is primarily caused by the deficiency of plasma ADAMTS13 activity resulting from autoantibodies against ADAMTS13. However, ADAMTS13 deficiency alone is often not sufficient to cause acute thrombotic thrombocytopenic purpura. Infections or systemic inflammation may precede acute bursts of the disease, but the underlying mechanisms are not fully understood. Herein, 52 patients with acquired autoimmune thrombotic thrombocytopenic purpura and 30 blood donor controls were recruited for the study. The plasma levels of human neutrophil peptides 1–3 and complement activation fragments (i.e. Bb, iC3b, C4d, and sC5b-9) were determined by enzyme-linked immunosorbent assays. Univariate analyses were performed to determine the correlation between each biomarker and clinical outcomes. We found that the plasma levels of human neutrophil peptides 1–3 and Bb in patients with acute thrombotic thrombocytopenic purpura were significantly higher than those in the control (P<0.0001). The plasma levels of HNP1-3 correlated with the levels of plasma complement fragment Bb (rho=0.48, P=0.0004) and serum lactate dehydrogenase (rho=0.28, P=0.04); in addition, the plasma levels of Bb correlated with iC3b (rho=0.55, P<0.0001), sC5b-9 (rho=0.63, P<0.0001), serum creatinine (rho=0.42, p=0.0011), and lactate dehydrogenase (rho=0.40, P=0.0034), respectively. Moreover, the plasma levels of iC3b and sC5b-9 were correlated (rho=0.72, P<0.0001), despite no statistically significant difference of the two markers between thrombotic thrombocytopenic purpura patients and the control. We conclude that innate immunity, i.e. neutrophil and complement activation via the alternative pathway, may play a role in the pathogenesis of acute autoimmune thrombotic thrombocytopenic purpura, and a therapy targeted at these pathways may be considered in a subset of these patients.

Evaluations of deep convolutional neural networks for automatic identification of malaria infected cells

This paper studied automatic identification of malaria infected cells using deep learning methods. We used whole slide images of thin blood stains to compile an dataset of malaria-infected red blood cells and non-infected cells, as labeled by a group of four pathologists. We evaluated three types of well-known convolutional neural networks, including the LeNet, AlexNet and GoogLeNet. Simulation results showed that all these deep convolution neural networks achieved classification accuracies of over 95%, higher than the accuracy of about 92% attainable by using the support vector machine method. Moreover, the deep learning methods have the advantage of being able to automatically learn the features from the input data, thereby requiring minimal inputs from human experts for automated malaria diagnosis.

Plasma Transfusion Demystified: A Review of the Key Factors Influencing the Response to Plasma Transfusion

Many studies have suggested that inappropriate plasma usage is common. An important factor contributing to futile plasma administration in most patients is the nonlinear relationship between coagulation-factor levels and the volume of plasma transfused. In this review, a validated mathematical model and data from the literature will be used to illuminate 3 key properties of plasma transfusion. Those properties are as follows: the effect of plasma transfusion on international normalized ratio (INR) is transient; for the same volume of transfused plasma, a greater reduction in INR is observed at higher initial INRs; and the effect of plasma transfusion on INR correction (ie, the difference between initial and final INRs) diminishes as more plasma is transfused. Frequent misunderstanding of these properties may contribute to inappropriate plasma usage. Therefore, this review will assist physicians in navigating these common pitfalls. Stronger understanding of these principles may result in a reduction of inappropriate plasma transfusions, thus potentially enhancing patient safety and reducing healthcare costs.

Mathematical model and calculation to predict the effect of prophylactic plasma transfusion on change in international normalized ratio in critically ill patients with coagulopathy

Plasma transfusion is often used prophylactically in patients with coagulopathy. However, the doses transfused may not be adequate to normalize hemostatic tests, which are commonly used as surrogate markers in practice. Currently, there is no reliable way to predict the posttransfusion international normalized ratio (INR) after plasma transfusion. Therefore, our aim was to develop and validate a formula that can reliably estimate post–plasma transfusion INR.

Periprocedural Management of Patients on Anticoagulants

Every year, new studies are undertaken to address the complex issue of periprocedural management of patients on anticoagulants and antiplatelet medications. In addition, newer drugs add to the confusion among clinicians about how to best manage patients taking these agents. Using the most recent data, guidelines, and personal experience, this article discusses recommendations and presents simplified algorithms to assist clinicians in the periprocedural management of patients on anticoagulants.

ADAMTS13 test and/or PLASMIC clinical score in management of acquired thrombotic thrombocytopenic purpura: a cost-effective analysis

The ADAMTS13 test distinguishes thrombotic thrombocytopenic purpura (TTP) from other thrombotic microangiopathies (TMAs). The PLASMIC score helps determine the pretest probability of ADAMTS13 deficiency. Due to inherent limitations of both tests, and potential adverse effects and cost of unnecessary treatments, we performed a cost‐effectiveness analysis (CEA) investigating the benefits of incorporating an in‐hospital ADAMTS13 test and/or PLASMIC score into our clinical practice.

Red blood CELL exchange: 2015 American Society for Apheresis consensus conference on the management of patients with sickle cell disease

The American Society for Apheresis (ASFA) conducted a one‐day consensus conference on red blood cell exchange (RBCx) in sickle cell disease (SCD) during its annual meeting in San Antonio, TX, on May 5, 2015. The authors of this article, a subcommittee of ASFAs Clinical Applications Committee, developed several questions with regard to pathophysiology of SCD and use of RBCx in the management of various complications. These questions were provided to the seven invited speakers who are the experts in the field of SCD. Two experts in the field moderated the proceedings of the conference, which was attended by more than 150 participants. After each presentation, there was a summary of the main points by the moderators and an open discussion with questions from the audience. A video recording of the proceedings, as well as each presentation, was made available to the authors. Each authors summary was reviewed and approved by the respective speaker before submission of this manuscript. The subcommittee also developed several key questions to generate a consensus amongst the speakers on key issues for using RBCx for patients with SCD.