Meera Sridharan

Periprocedural warfarin reversal with prothrombin complex concentrate

INTRODUCTION Approximately 10% of chronically anticoagulated patients require an invasive procedure annually. One in 10 procedures is emergent and requires prompt anticoagulation reversal. The study objective is to determine the safety and efficacy of a 3 factor prothrombin complex concentrate (PCC) for periprocedural anticoagulation reversal. MATERIALS AND METHODS Consecutive patients receiving 3 factor PCC for warfarin reversal for either urgent/emergent invasive procedures or major bleeding were analyzed. Primary endpoints included percent achieving INR <1.5, peri-operative major hemorrhage, thromboembolism and death during the 40day post-infusion period. RESULTS Between January 1, 2010-December 31, 2012, 52 patients were treated with PCC for pre-procedural warfarin reversal and 113 patients for major bleeding. Within the peri-procedure group, there were 24 intra-abdominal surgeries, 12 percutaneous interventions, 6 cardiothoracic surgeries, 5 orthopedic and 3 endoscopic procedures. INR values <1.5 were achieved in 51% at 2.5h post-infusion. Major bleeding (13%), thromboembolism (13%) and mortality rates (15%) were high. Within the major bleeding group, PCC therapy reversed INR values (<1.5) in 75% of patients within 4h. For this group, thromboembolism (21%) and mortality rates (16%) were likewise high. Post-PCC anticoagulation, reinitiated in 37%, had no impact on bleeding or thrombotic complications. Mortality rates were threefold higher for those patients not restarting warfarin therapy. CONCLUSIONS Although PCC therapy promptly and effectively reverses INR values for patients requiring urgent/emergent invasive procedure both thromboembolic and fatal complications are soberingly high and call for judicious use of these agents in these high risk populations.

Clinical and laboratory diagnosis of autoimmune factor V inhibitors: A single institutional experience

BACKGROUND Coagulation factor V inhibitors (FV-i) may occur in patients with congenital FV deficiency or previously hemostatically normal patients (autoimmune (AI)-FV-i). Most of the published literature is confined to case reports. OBJECTIVE Describe clinical and laboratory features of AI-FV-i identified through the Special Coagulation Laboratory at Mayo Clinic, Rochester, Minnesota. METHODS In this retrospective study individuals with FV-i screens performed from January 1999 to February 2017 were identified through the special coagulation laboratory database. Clinical presentation, management, and outcomes were collected for our institutional patients while detailed laboratory data was collected for all tested patients. RESULTS Of patients with FV-i managed at our institution, 2/8 (25%) patients experienced no bleeding. There was no correlation between inhibitor titers and/or FV activity (FV:C) levels and clinical bleeding. Hemostatic management included fresh frozen plasma, platelet transfusion, activated prothrombin complex concentrates, and recombinant factor VIIa. Only 2 patients received immunomodulatory treatment. FV-i mixing studies with normal pooled plasma (n = 26) demonstrated inhibition on immediate mix but progressive inhibition after 1 h of incubation could not be demonstrated. 71% of platelet neutralization procedures were falsely positive while 59% of DRVVT assays were indeterminate. CONCLUSION FV-i demonstrates immediate inhibition on mixing studies; however our limited data does not support a time dependent inhibition. Our clinical cohort confirms the variable clinical phenotype for individuals with FV-i and supports the notion that management of FV-i should be guided by clinical symptoms and not FV:C or FV-i titer.

Shiga Toxin as a Potential Trigger of CFHR1 Deletion-Associated Thrombotic Microangiopathy

&NA; Thrombotic microangiopathy (TMA) may result from a variety of clinical conditions, including thrombotic thrombocytopenic purpura, Shiga toxin‐producing Escherichia coli‐associated hemolytic uremic syndrome and complement‐mediated hemolytic uremic syndrome. Thrombocytopenic purpura is diagnosed when ADAMTS13 is <10%, while a diagnosis of Shiga toxin‐producing Escherichia coli‐associated hemolytic uremic syndrome is made with the evidence of infection by Shiga toxin‐producing Escherichia coli. Diagnosis of complement‐mediated hemolytic uremic syndrome is not dependent on a specific laboratory test and is a diagnosis of exclusion. TMA is a rare disease and finding individuals that have more than 1 concurrent etiology leading to TMA is even more rare. Here we describe the presentation and management of an individual with CFHR1 deletion‐associated TMA also found to have a positive stool Shiga toxin. We discuss the significance of Shiga toxin in serving as a trigger for development of TMA in an individual predisposed to development of TMA due to presence of a homozygous deletion in CFHR1.

Presentation and Significance of Venous Thromboembolism

Venous thromboembolism (VTE) leads to significant morbidity and mortality within our society. Furthermore healthcare costs related to diagnosis and management of thrombotic events and its complications are substantial. Though deep vein thrombosis (DVT) of the lower extremity and pulmonary embolism (PE) are the most common, VTE may also occur in the upper extremities, inferior vena cava, renal vein, splanchnic venous circulation, and cerebral veins. VTE risk factors include inherited and acquired conditions, and the latter can be grouped into persistent or modifiable causes. Understanding risk factors for VTE will allow us to better counsel our patients in ways to minimize risk. Furthermore, awareness of clinical signs and symptoms associated with VTE will aid in earlier recognition and treatment.

Diagnostic Utility of Complement Serology for Atypical Hemolytic Uremic Syndrome

Objective: To investigate the clinical utility of a 9‐analyte complement serology panel (COMS) covering complement function (CH50 and AH50), components (C3, C4), factor B (CFB), factor H, and activation markers (C4d, Bb, and soluble membrane attack complex) for the diagnosis of atypical hemolytic uremic syndrome (aHUS). Methods: Physician orders for COMS from January 19, 2015, through November 4, 2016, were reviewed. Demographic characteristics, patient diagnosis, and laboratory parameters were recorded. Results: There were 177 COMS orders for 147 patients. The median patient age was 44.9 years (range, 0.9‐88.0 years). Common reasons for ordering COMS included monitoring and diagnosis of C3 glomerulopathy and renal dysfunction and differentiation of aHUS from other thrombotic microangiopathies (TMAs). Forty‐four patients had COMS ordered for TMAs: 8 had aHUS and all had 1 or more abnormalities within the alternative pathway of complement. Although the sensitivity of this finding for the diagnosis of aHUS is 100%, the specificity is only 28%, with a positive likelihood ratio of 1.39. Patients with aHUS had lower CH50, C3, and CFB than did those with secondary non‐aHUS TMA (all P<.01). A combined CFB of 20.9 mg/dL or less and CH50 of 56% or less led to sensitivity of 75% with increased specificity of 88.9% and a diagnostic odds ratio of 24. Conclusion: A COMS abnormality should not be interpreted in isolation. In conjunction with clinical presentation, a decrease in both CFB and CH50 may be an important clue to support the diagnosis of aHUS.

A Patient With Hereditary ATTR and a Novel AGel p.Ala578Pro Amyloidosis

&NA; Hereditary amyloidosis represents a group of diseases in which mutant proteins are deposited in various organs leading to their dysfunction. Correct identification of the amyloid‐causing protein is critical because this will determine the optimal therapy for the patient. The most common type of hereditary amyloidosis is due to mutant transthyretin (ATTRm) deposition and often presents with heart failure or peripheral neuropathy. We report the first known case of a patient who had amyloidosis both due to a mutant transthyretin (p.Val122Ile) and due to a novel variant in the gelsolin gene (p.Ala578Pro). Both mutant proteins were identified by mass spectrometry analysis of amyloid deposits as well as sequencing of the genes. Molecular dynamic simulations suggest that the gelsolin p.Ala578Pro variant is likely amyloidogenic.

Atypical hemolytic uremic syndrome: Review of clinical presentation, diagnosis and management

Thrombotic microangiopathies (TMA) are a class of disorders characterized by microangiopathic hemolytic anemia, non-immune thrombocytopenia, and organ dysfunction. One type of TMA is atypical hemolytic uremic syndrome (aHUS) a disorder caused by hyper-activation of the alternative complement pathway due to over activation of C3 convertases and loss of complement regulatory mechanisms. The pathophysiological mechanism of aHUS involves increased continuous spontaneous hydrolysis of C3 to C3b which leads to tissue deposition of C3b, the membrane attack complex formation and subsequent tissue injury. The underlying susceptibility factors to aHUS include acquired autoantibodies or germline mutations in complement proteins or their regulators. Currently there are no clear diagnostic criteria for aHUS. Diagnosis involves ruling out other causes of TMA and incorporating complement serologic and genetic data. TPE has been used to treat aHUS; however, clinical improvement in these patents is far less than in patients with thrombotic thrombocytopenic purpura. Furthermore, there is a higher rate of progression to end stage renal disease with almost half of patients progressing despite TPE. For those, another option for treatment is eculizumab, a monoclonal antibody that blocks complement C5. Eculizumab has proven effective in aHUS and dramatically changed the prognosis of this syndrome. In this review the clinical presentation, diagnosis and management of aHUS are highlighted with three clinical cases.

The impact of eculizumab on routine complement assays

BACKGROUND Eculizumab (ECU) blocks complement C5 cleavage, preventing the formation of C5a and the cytolytic effects of the membrane attack complex. The presence of ECU in blood impacts routine complement tests used to monitor treatment. METHODS Residual serum samples with normal total complement (CH50) and residual citrate plasma with normal PT/APTT were spiked with ECU at varied concentrations ranging from 25 to 600 μg/mL. In addition, seventy-one samples from patients on ECU were obtained. Artificial and patient samples were analyzed for CH50 and C5 function (Wako Diagnostics), C5 concentration (Quidel), AH50 (Wieslab ELISA) and sMAC (Quidel). ECU concentration was measured by mass spectrometry for all patients. RESULTS Complement blockage by ECU was evident in spiked artificial samples. At 25 μg/mL ECU, partial complement blockage was observed in CH50, AH50 and C5 function in serum. Complete blockage defined by undetectable AH50 (<10%) occurred at 100 μg/mL ECU. C5 concentrations remained the same regardless of ECU. sMAC results stayed around 81% of baseline in serum and 47% in citrate plasma with 50μg/mL ECU. Patient samples had ECU ranging from <5 to 1220 μg/mL. In all patients with ECU >100 μg/mL, C5 function was <29 U/mL. CONCLUSIONS The spiked sera and patient samples showed complement blockage with CH50, AH50 and C5 function assays when ECU >100 μg/mL. CH50, AH50 or C5 function assays can serve as indicators for the pharmacodynamic effects of eculizumab. Allied to ECU concentration, laboratory studies may be helpful to tailor therapy.