Publications by authors named "Rajiv Pruthi"

113 Publications

Timing of venous thromboembolism diagnosis in hospitalized and non-hospitalized patients with COVID-19.

Thromb Res 2021 Oct 7;207:150-157. Epub 2021 Oct 7.

Department of Cardiovascular Diseases, Division of Vascular Medicine, Rochester, MN, United States of America; Department of Internal Medicine, Division of Hematology/Oncology, Mayo Clinic, MN, United States of America. Electronic address:

Background: The reported incidence of venous thromboembolism (VTE) in COVID-19 patients varies widely depending on patient populations sampled and has been predominately studied in hospitalized patients. The goal of this study was to assess the evolving burden of COVID-19 and the timing of associated VTE events in a systems-wide cohort.

Methods: COVID-19 PCR positive hospitalized and non-hospitalized patients ≥18 years of age tested between 1/1/2020 through 12/31/2020 were retrospectively analyzed using electronic medical records from multiple states across the Mayo Clinic enterprise. Radiology reports within 90 days before and after confirmed COVID-19 diagnosis were examined for VTE outcomes using validated Natural Language Processing (NLP) algorithms.

Results: A 29-fold increased rate of VTE compared to the pre-COVID-19 period was noted during the first week following the first positive COVID-19 test (RR: 29.39; 95% CI 21.77-40.03). The rate of VTE steadily decreased and returned to baseline by the 6th week. Among 366 VTE events, most occurred during (n = 243, 66.3%) or after (n = 111, 30.3%) initial hospitalization. Only 11 VTE events were identified in patients who did not require hospitalization (3.0% of total VTE events). VTE and mortality increased with advancing age with a pronounced increased each decade in older patients.

Conclusion: We observed a profoundly increased risk of VTE within the first week after positive testing for COVID-19 that returned to baseline levels after 6 weeks. VTE events occurred almost exclusively in patients who were hospitalized, with the majority of VTE events identified within the first days of hospitalization.
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http://dx.doi.org/10.1016/j.thromres.2021.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495042PMC
October 2021

A single-institution retrospective study of causes of prolonged prothrombin time and activated partial thromboplastin time in the outpatient setting.

Int J Lab Hematol 2021 Oct 5. Epub 2021 Oct 5.

Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: An algorithmic approach, termed the prolonged clot time profile (PROCT), consisting of initial screening with prothrombin time (PT) and activated partial thromboplastin time (aPTT), reflexive mixing studies if indicated, and follow-up assays depending on initial testing results, offers an efficient approach to delineate the etiology of a prolonged PT/aPTT. Herein, we present the outcomes of the PROCT in the outpatient setting.

Methods: In this retrospective study, we reviewed medical records of consecutive outpatients who had prolonged PT and/or aPTT noted in the routine coagulation laboratory and who had PROCT ordered in our institutional Special Coagulation Laboratory between 2010 and 2017.

Results: One hundred and six patients, median age 55 years (IQR 30-67), met our study criteria. Twenty-nine patients had normal PT/aPTT, while 77 had persistent abnormalities and underwent reflexive testing. A prolonged PT, aPTT, or PT and aPTT was noted in 27 (35%), 27 (35%), and 23 (30%) respectively. Forty-nine (64%) had an acquired condition, 17 (22%) had a congenital condition, 7 (9%) had unclear etiology, and 4 (5%) were the result of laboratory artifact. The most common known cause of an isolated prolonged PT in our study was vitamin K deficiency in 8 (10%), the most common cause of an isolated prolonged aPTT was lupus anticoagulant in 4 (5%), and the most common cause of prolonged PT and aPTT was liver disease in 11 (14%).

Conclusion: Prolonged PT/aPTT have a wide range of causes, including artifactual prolongation or abnormalities in secondary hemostasis due to both inherited and acquired conditions.
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http://dx.doi.org/10.1111/ijlh.13727DOI Listing
October 2021

Macrovascular Thrombotic Events in a Mayo Clinic Enterprise-Wide Sample of Hospitalized COVID-19-Positive Compared With COVID-19-Negative Patients.

Mayo Clin Proc 2021 07 4;96(7):1718-1726. Epub 2021 May 4.

Division of Hematology/Oncology, Mayo Clinic, Rochester, MN; Division of Vascular Medicine, Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.

Objective: To determine the difference in the rate of thromboembolic complications between hospitalized coronavirus disease 2019 (COVID-19)-positive compared with COVID-19-negative patients.

Patients And Methods: Adult patients hospitalized from January 1, 2020, through May 8, 2020, who had COVID-19 testing by polymerase chain reaction assay were identified through electronic health records across multiple hospitals in the Mayo Clinic enterprise. Thrombotic outcomes (venous and arterial) were identified from the hospital problem list.

Results: We identified 3790 hospitalized patients with COVID-19 testing across 19 hospitals, 102 of whom had positive test results. The median age was lower in the COVID-positive patients (62 vs 67 years; P=.03). The median duration of hospitalization was longer in COVID-positive patients (8.5 vs 4 days; P<.001) and more required intensive care unit care (56.9% [58 of 102] vs 26.8% [987 of 3688]; P<.001). Comorbidities, including atrial fibrillation/flutter, heart failure, chronic kidney disease, and malignancy, were observed less frequently with COVID-positive admissions. Any venous thromboembolism was identified in 2.9% of COVID-positive patients (3 of 102) and 4.6% of COVID-negative patients (168 of 3688). The frequency of venous and arterial events was not different between the groups. The unadjusted odds ratio (OR) for COVID-positive-patients for any venous thromboembolism was 0.63 (95% CI, 0.19 to 2.02). A multivariable logistic regression model evaluated death within 30 days of hospital discharge; neither COVID positivity (adjusted OR, 1.12; 95% CI, 0.54 to 2.34) nor thromboembolism (adjusted OR, 0.90; 95% CI, 0.60 to 1.32) was associated with death.

Conclusion: Early experience in patients with COVID-19 across multiple academic and regional hospitals representing different US regions demonstrates a lower than previously reported incidence of thrombotic events. This incidence was not higher than a contemporary COVID-negative hospitalized comparator.
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http://dx.doi.org/10.1016/j.mayocp.2021.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096191PMC
July 2021

Novel splicing (c.6529-1G>T) and missense (c.1667G>A) mutations causing factor V deficiency.

Blood Coagul Fibrinolysis 2021 Jul;32(5):344-348

Mayo Comprehensive Hemophilia Center, Special Coagulation and Molecular Hematopathology Laboratories, Mayo Clinic, Rochester, Minnesota, USA.

Congenital factor V deficiency (FVD) is a rare bleeding disorder. In this study, we investigated the genetic basis in an African American patient with factor V activity 3%. Custom sequence capture and targeted next-generation (NGS) sequencing of the F5 gene were undertaken followed by PCR and Sanger sequencing. Two novel variants were identified. In silico analyses correlated clinically with the patient's factor V activity and hemorrhagic tendency. A review of the literature regarding these genomic alterations is presented. We described two novel mutations causing moderate FVD. The first, Chr1:g.169483698C>A with cDNA change (F5):c.6529-1G>T, occurred in a conserved nucleotide at the canonical acceptor splice site of intron 24. The second, Chr1:g.169515775C>T with cDNA change (F5):c.1667G>A, was a missense variant of exon 11, affecting a highly conserved amino acid in the A2 domain. Further research into the mechanisms of F5 mutations leading to FVD and residual factor V expression are needed.
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http://dx.doi.org/10.1097/MBC.0000000000001036DOI Listing
July 2021

Coagulation Abnormalities in Light Chain Amyloidosis.

Mayo Clin Proc 2021 02;96(2):377-387

Division of Hematology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To assess the prevalence of coagulation abnormalities in patients with systemic light chain (AL) amyloidosis and their association with disease-related characteristics, disease progression, and survival.

Patients And Methods: This is a retrospective study of patients with AL amyloidosis seen at Mayo Clinic, Rochester, Minnesota, from January 1, 2006, to December 31, 2015. We studied the association between abnormal coagulation parameters and baseline characteristics and their association with survival outcomes.

Results: The study included 411 patients. Abnormalities at diagnosis included prolonged clotting times and coagulation factor deficiencies; prolonged prothrombin time (PT) and factor X (FX) deficiency were found in 19% (73 of 390) and 43% (177 of 411) of patients, respectively. The FX deficiency was associated with higher Mayo stage, involvement of more than 1 organ, liver and cardiac involvement, and greater than 10% bone marrow plasma cells. On univariate analysis, the risk for disease progression or death was higher in patients with abnormal values for PT and factor V, factor VII (FVII), FX, and factor XII compared with those with normal values. Prolonged PT and FVII and FX deficiencies were independent predictors of death after adjusting for Mayo stage and more than 1 organ involvement. Only 106 patients had repeat testing after treatment; no clear relationship was found between treatment response and changes in coagulation parameters.

Conclusion: Coagulation abnormalities occur in a significant proportion of patients with AL amyloidosis and are associated with advanced disease and inferior outcomes. Larger studies are needed to establish whether a relationship exists between treatment response and improvement in individual parameters.
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http://dx.doi.org/10.1016/j.mayocp.2020.06.061DOI Listing
February 2021

Risk of perinatal intracranial hemorrhage and role of prenatal genetic testing in individuals with type 3 von Willebrand disease.

J Thromb Haemost 2020 10;18(10):2779-2780

Special Coagulation Laboratory, Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1111/jth.15000DOI Listing
October 2020

Revisiting the effects of spectral interfering substances in optical end-point coagulation assays.

Int J Lab Hematol 2021 Oct 17;43(5):1181-1190. Epub 2021 Jan 17.

Special Coagulation Laboratory, Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Introduction: Hemolysis, icterus, and lipemia (HIL) are common pre-analytical variables in the clinical laboratory. Understanding their effects on coagulation laboratory results is essential.

Methods: HIL effects on the prothrombin time (PT), activated partial thromboplastin time (APTT), dilute Russell's viper venom time (DRVVT), thrombin time (TT), and protein C chromogenic activity (CFx) were evaluated on the ACL TOP 750 optical analyzer and STA-R Evolution mechanical analyzer (PT and APTT only) by spiking normal donor, patient, and commercial control samples with varying concentrations of hemolysate, bilirubin, or a lipid emulsion. The relative difference or bias compared to the original results was determined.

Results: Hemolysis (H) indices up to 900 mg/dL did not affect the APTT, PT, DRVVT Confirm, TT, and CFx; however, H indices above approximately 200 mg/dL resulted in a false-negative DRVVT screen and screen/confirm ratio in samples with a lupus anticoagulant. There was an artifactual prolongation of the PT and APTT when conjugated bilirubin was dissolved in aqueous solvents and not when it was dissolved in dimethyl sulfoxide. Icterus (I) indices up to 45 mg/dL did not result in significant (>15%) bias for all assays evaluated. The PT and APTT assays failed to produce a robust clot curve when the lipemia (L) index exceeded 6000 milliabsorbance units (mAbs), and the TT and DRVVT assays failed when the L index exceeded 3000 mAbs; the CFx assay was unaffected by lipemia.

Conclusions: Verification of the manufacturer's recommended interference thresholds is important since it may avoid inappropriate instrument flagging and/ or sample rejection.
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http://dx.doi.org/10.1111/ijlh.13465DOI Listing
October 2021

A Review of Pathophysiology, Clinical Features, and Management Options of COVID-19 Associated Coagulopathy.

Shock 2021 06;55(6):700-716

Division of Trauma, Critical Care, and General Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota.

Abstract: There is increasing evidence that novel coronavirus disease 2019 (COVID-19) leads to a significant coagulopathy, a phenomenon termed "COVID-19 associated coagulopathy." COVID-19 has been associated with increased rates of both venous and arterial thromboembolic events, a source of significant morbidity and mortality in this disease. Further evidence suggests a link between the inflammatory response and coagulopathy associated with COVID-19. This presents a unique set of challenges for diagnosis, prevention, and treatment of thrombotic complications. In this review, we summarize and discuss the current literature on laboratory coagulation disruptions associated with COVID-19 and the clinical effects of thromboembolic events including pulmonary embolism, deep vein thrombosis, peripheral arterial thrombosis, and acute ischemic stroke in COVID-19. Endothelial injury and augmented innate immune response are implicated in the development of diffuse macro- and microvascular thrombosis in COVID-19. The pathophysiology of COVID-19 associated coagulopathy is an important determinant of appropriate treatment and monitoring of these complications. We highlight the importance of diagnosis and management of dysregulated coagulation in COVID-19 to improve outcomes in COVID-19 patients with thromboembolic complications.
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http://dx.doi.org/10.1097/SHK.0000000000001680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8122038PMC
June 2021

Anticoagulation in COVID-19: A Systematic Review, Meta-analysis, and Rapid Guidance From Mayo Clinic.

Mayo Clin Proc 2020 11 31;95(11):2467-2486. Epub 2020 Aug 31.

Evidence-based Practice Center and Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN. Electronic address:

A higher risk of thrombosis has been described as a prominent feature of coronavirus disease 2019 (COVID-19). This systematic review synthesizes current data on thrombosis risk, prognostic implications, and anticoagulation effects in COVID-19. We included 37 studies from 4070 unique citations. Meta-analysis was performed when feasible. Coagulopathy and thrombotic events were frequent among patients with COVID-19 and further increased in those with more severe forms of the disease. We also present guidance on the prevention and management of thrombosis from a multidisciplinary panel of specialists from Mayo Clinic. The current certainty of evidence is generally very low and continues to evolve.
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http://dx.doi.org/10.1016/j.mayocp.2020.08.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458092PMC
November 2020

Cerebral venous sinus thrombosis associated with spontaneous heparin-induced thrombocytopenia syndrome after total knee arthroplasty.

Platelets 2021 Oct 1;32(7):936-940. Epub 2020 Oct 1.

Department of Medicine, Mayo Clinic, Rochester, MN, USA.

Spontaneous heparin-induced thrombocytopenia (HIT) syndrome, characterized by clinical and serologic features of HIT despite the absence of proximate heparin exposure, can be triggered by total knee arthroplasty (TKA). A 56-year-old female receiving aspirin thromboprophylaxis post-TKA presented with aphasia and thrombocytopenia on post-operative day 11. Imaging studies revealed cerebral venous sinus thrombosis (CVST) and intravenous bivalirudin was initiated. Her serum tested strong-positive for IgG anti-PF4/polyanion complexes and serotonin-release assay in the presence and absence of heparin; strong-positive IgG-specific chemiluminescent immunoassay; and moderate-positive latex immunoturbidimetric assay. Two 65 g doses of IVIG were administered. With the improvement of her platelet count, she was transitioned from bivalirudin to warfarin. At one-year follow-up, she remained free of recurrent thrombosis and neurologically stable with a normal platelet count. Previous reports of post-TKA spontaneous HIT syndrome include venous/arterial thrombosis and adrenal hemorrhage, and this report of CVST expands the clinical spectrum of this rare complication of orthopedic surgery.
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http://dx.doi.org/10.1080/09537104.2020.1828574DOI Listing
October 2021

A prospective, blinded study of a PF4-dependent assay for HIT diagnosis.

Blood 2021 02;137(8):1082-1089

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.

Heparin-induced thrombocytopenia (HIT) is a life-threatening, prothrombotic, antibody-mediated disorder. To maximize the likelihood of recovery, early and accurate diagnosis is critical. Widely available HIT assays, such as the platelet factor 4 (PF4) heparin enzyme-linked immunosorbent assay (ELISA) lack specificity, and the gold-standard carbon 14-labeled serotonin release assay (SRA) is of limited value for early patient management because it is available only through reference laboratories. Recent studies have demonstrated that pathogenic HIT antibodies selectively activate PF4-treated platelets and that a technically simpler assay, the PF4-dependent P-selectin expression assay (PEA), may provide an option for rapid and conclusive results. Based upon predefined criteria that combined 4Ts scores and HIT ELISA results, 409 consecutive adults suspected of having HIT were classified as disease positive, negative, or indeterminate. Patients deemed HIT indeterminate were considered disease negative in the primary analysis and disease positive in a sensitivity analysis. The ability of PEA and SRA to identify patients judged to have HIT was compared using receiver operating characteristic curve statistics. Using these predefined criteria, the diagnostic accuracy of PEA was high (area under the curve [AUC], 0.94; 95% confidence interval [CI], 0.87-1.0) and similar to that of SRA (AUC, 0.91; 95% CI, 0.82-1.0). In sensitivity analysis, the AUCs of PEA and SRA were also similar at 0.88 (95% CI, 0.78-0.98) and 0.86 (95% CI, 0.77-0.96), respectively. The PEA, a technically simple nonradioactive assay that uses ∼20-fold fewer platelets compared with the SRA, had high accuracy for diagnosing HIT. Widespread use of the PEA may facilitate timely and more effective management of patients with suspected HIT.
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http://dx.doi.org/10.1182/blood.2020008195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907721PMC
February 2021

Inference from longitudinal laboratory tests characterizes temporal evolution of COVID-19-associated coagulopathy (CAC).

Elife 2020 08 17;9. Epub 2020 Aug 17.

nference, inc, Cambridge, United States.

Temporal inference from laboratory testing results and triangulation with clinical outcomes extracted from unstructured electronic health record (EHR) provider notes is integral to advancing precision medicine. Here, we studied 246 SARS-CoV-2 PCR-positive (COVID) patients and propensity-matched 2460 SARS-CoV-2 PCR-negative (COVID) patients subjected to around 700,000 lab tests cumulatively across 194 assays. Compared to COVID patients at the time of diagnostic testing, COVID patients tended to have higher plasma fibrinogen levels and lower platelet counts. However, as the infection evolves, COVID patients distinctively show declining fibrinogen, increasing platelet counts, and lower white blood cell counts. Augmented curation of EHRs suggests that only a minority of COVID patients develop thromboembolism, and rarely, disseminated intravascular coagulopathy (DIC), with patients generally not displaying platelet reductions typical of consumptive coagulopathies. These temporal trends provide fine-grained resolution into COVID-19 associated coagulopathy (CAC) and set the stage for personalizing thromboprophylaxis.
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http://dx.doi.org/10.7554/eLife.59209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473767PMC
August 2020

Intravenous Bevacizumab in Hereditary Hemorrhagic Telangiectasia-Related Bleeding and High-Output Cardiac Failure: Significant Inter-Individual Variability in the Need for Maintenance Therapy.

Mayo Clin Proc 2020 08;95(8):1604-1612

Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To present our center's experience with a maintenance treatment algorithm for intravenous bevacizumab that allows for personalized therapy decisions.

Patients And Methods: We reviewed all patients treated with intravenous bevacizumab for hereditary hemorrhagic telangiectasia-related bleeding and/or high-output cardiac failure (HOCF) from January 1, 2013, to July 1, 2019, at the Mayo Clinic, Rochester, Minnesota. Data regarding subsequent bevacizumab dosing were abstracted.

Results: A total of 57 patients (n=40, 70.2% females) were identified with a median age of 65 (55 to 74; range, 37 to 89) years. High-cardiac output state was present in 21 patients (36.8%) and 10 (17.5%) were treated with intravenous bevacizumab primarily for HOCF. The median duration of follow-up after completion of the initial intravenous bevacizumab treatment was 25 (12.3 to 40.8; range, 0.1 to 65.4) months. A total of 20 (35.1%) patients with a median follow-up of 13.5 (range, 0 to 48.4) months required no maintenance dosing throughout the duration of follow-up. Among those who required subsequent maintenance doses, only a small fraction (8 patients; 14.0%) required regular maintenance doses every 4 to 8 weeks during follow-up whereas the majority of patients required intermittent "as-needed" doses at varying intervals.

Conclusion: There is significant inter-individual variability in the need for maintenance intravenous bevacizumab when patients are followed using a predefined bevacizumab maintenance dosing treatment algorithm. The use of "as-needed" maintenance bevacizumab appears to be an effective strategy for management of hereditary hemorrhagic telangiectasia-related bleeding and HOCF.
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http://dx.doi.org/10.1016/j.mayocp.2020.03.001DOI Listing
August 2020

Leukocytosis and Tobacco Use: An Observational Study of Asymptomatic Leukocytosis.

Am J Med 2021 01 16;134(1):e31-e35. Epub 2020 Jul 16.

Division of Hematology.

Purpose: This study aimed to characterize the white blood cell differential of tobacco smoking-induced leukocytosis and describe the longitudinal impact of smoking cessation on this peripheral blood abnormality.

Methods: Medical records of patients undergoing evaluation by hematologists for persistent leukocytosis were reviewed. Patients in whom leukocytosis was determined to be secondary to tobacco use after exclusion of other causes were identified. Demographic and laboratory data were collected at time of diagnosis. Patients were longitudinally followed and information regarding smoking cessation and follow-up white blood cell values were recorded.

Results: Forty patients were determined to have smoking-induced leukocytosis. The median age was 49.5 years (range: 28-75 years), 24 patients were female, and the mean body mass index (BMI) was 31.5 kg/m. The mean white blood cell count was 13.3 × 10/L (range: 9.8-20.9 × 10/L); 39 patients had absolute neutrophilia (98%), 21 had lymphocytosis (53%), 20 had monocytosis (50%), and 19 had basophilia (48%). During follow-up, 11 patients either quit (n = 9) or reduced (n = 2) tobacco use. Reduction in tobacco smoking led to a significant decrease in mean white blood cell count (13.2 × 10/L vs 11.1 × 10/L, P = 0.02). The median time to decrease in white blood cell count following reduction in tobacco use was 8 weeks (range: 2-49 weeks).

Conclusions: Tobacco-induced leukocytosis was characterized by a mild elevation in total white blood cell count and was most commonly associated with neutrophilia, lymphocytosis, monocytosis, and basophilia. Cessation of smoking led to improvement in leukocytosis. Tobacco history should be elicited from all patients presenting with leukocytosis to limit unnecessary diagnostic testing, and counseling regarding smoking cessation should be offered.
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http://dx.doi.org/10.1016/j.amjmed.2020.06.014DOI Listing
January 2021

A study of dedicated haemophilia carrier clinics in the United States: Prevalence, services offered and barriers to development.

Haemophilia 2020 Sep 14;26(5):e253-e255. Epub 2020 Jun 14.

Division of Hematology, Department of Internal Medicine, Comprehensive Hemophilia Center, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1111/hae.14071DOI Listing
September 2020

Clinical outcomes of adults with hemophagocytic lymphohistiocytosis treated with the HLH-04 protocol: a retrospective analysis.

Leuk Lymphoma 2020 07 11;61(7):1592-1600. Epub 2020 Mar 11.

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathologic immune activation in children that is increasingly being recognized in adults. Efficacy data for the HLH-04 protocol in adults is lacking. This study retrospectively analyzed 31 adult patients, median age 46 years, who received HLH-04 from 1/1/2004 to 5/1/2018. HLH etiology included malignancy ( = 9), autoimmune ( = 8), infection ( = 8), and idiopathic ( = 6). Eighteen patients were evaluable for response at week 4 with 7 having no response, 11 reaching partial response, and 0 reaching complete response (CR). Six patients eventually achieved CR at a median 195 days. The 1-year overall survival (OS) was 35% and median OS was 3.2 months. Univariate analysis showed shorter survival for hemoglobin <9 g/dL (HR 4.29,  = 0.003), platelets <100 × 10/L (HR 4.06,  = 0.027), ANC <1 × 10/L (HR 5.24,  = 0.001), and total bilirubin >1.2 mg/dL (HR 3.30,  = 0.022). Outcomes of adults treated with HLH-04 remain dismal and newer treatment modalities are needed.
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http://dx.doi.org/10.1080/10428194.2020.1737684DOI Listing
July 2020

Hemostatic prophylaxis and colonoscopy outcomes for patients with bleeding disorders: A retrospective cohort study and review of the literature.

Haemophilia 2020 Mar 6;26(2):257-268. Epub 2020 Mar 6.

Comprehensive Hemophilia Center, Division of Hematology, Mayo Clinic, Rochester, Minnesota, United States.

Introduction: Hemostatic prophylaxis (HP) is recommended for patients with bleeding disorders (PWBD) before invasive procedures. However, evidence-based guidelines are needed to determine optimal HP strategies.

Aim: To determine outcomes of HP for PWBD undergoing colonoscopy.

Methods: We undertook a retrospective cohort study of HP and outcomes of colonoscopy procedures performed between 9 November 1993 and 13 February 2018 for PWBD who received care in the Mayo Clinic Comprehensive Hemophilia Treatment Center.

Results: During the study period, 73 PWBD (58 with milder phenotypes: haemophilia, von Willebrand disease [subtypes 1 and 2; II, VII and XI deficiency]) underwent 141 procedures. Preprocedural HP was given to 61%, and interventions were performed in 47%. Of the 39% without preprocedural HP, postprocedural HP was given for 11%. One major (0.7%; 6 days postprocedure despite HP) and 10 minor (7%) bleeding complications occurred, which tended to be in patients with severe disease and/or after excision of larger polyps. There was no significant difference in the rate of bleeding complications with or without preprocedural HP (8.1% vs 5.5%, respectively; P = .74, Fisher's exact test).

Conclusion: The low bleeding rates in our cohort suggest that preprocedure HP may be withheld for patients with mild bleeding disorders who undergo colonoscopy with a low likelihood of requiring an intervention or who require only low-risk intervention. This strategy may be best used in experienced centres, provided optimal local hemostasis measures are undertaken and postprocedural HP is rapidly available if high-risk intervention is required. Further studies are needed to determine optimal evidence-based HP strategies for PWBD undergoing colonoscopy.
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http://dx.doi.org/10.1111/hae.13954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154734PMC
March 2020

Laboratory testing in hemophilia: Impact of factor and non-factor replacement therapy on coagulation assays.

J Thromb Haemost 2020 06 23;18(6):1242-1255. Epub 2020 Apr 23.

Hämostaseologie, Campus Innenstadt, Klinikum der Universität München, München, Germany.

The advent of extended half-life (EHL) recombinant clotting factors and innovative non-factor replacement therapeutics, such as emicizumab, offers several advantages over existing products for the prophylactic treatment of people living with hemophilia (PwH). These include low annual bleeding rates with less frequent dosing, higher trough plasma concentrations, and a more convenient route of administration. However, increasing use of these therapies poses challenges to clinicians and coagulation laboratories due to the lack of standardized assays for monitoring of hemostatic parameters, and the potential for misinterpretation of test results, which may jeopardize patient safety. Definitive diagnosis of hemophilia and treatment monitoring is reliant on demonstrating factor VIII (FVIII; hemophilia A) or factor IX (FIX; hemophilia B) deficiency using a functional coagulation assay. The most frequently used assays are based on activated partial thromboplastin time, using a one-stage or two-stage process. While one-stage and chromogenic assays have performed well with human-derived FVIII and FIX and full-length recombinant products, EHL recombinant factors are heterogeneous in structure and mode of action and therefore show wide variation in activity levels between different one-stage assays, and between one-stage and chromogenic assays. In the context of the recommended stepwise approach for laboratory diagnosis of hemophilia, we examine the diagnostic challenges associated with the use of EHL factors and novel non-factor therapeutics and consider the optimal diagnostic approach in PwH who are receiving these treatments. Ultimately, accurate diagnostic solutions are a prerequisite for personalized therapy to minimize treatment burden and improve quality of life in PwH.
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http://dx.doi.org/10.1111/jth.14784DOI Listing
June 2020

Evidence for the Misfolding of the A1 Domain within Multimeric von Willebrand Factor in Type 2 von Willebrand Disease.

J Mol Biol 2020 01 17;432(2):305-323. Epub 2019 Oct 17.

Division of Hematology, Departments of Internal Medicine and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, 55905, USA. Electronic address:

Von Willebrand factor (VWF), an exceptionally large multimeric plasma glycoprotein, functions to initiate coagulation by agglutinating platelets in the blood stream to sites of vascular injury. This primary hemostatic function is perturbed in type 2 dysfunctional subtypes of von Willebrand disease (VWD) by mutations that alter the structure and function of the platelet GPIbα adhesive VWF A1 domains. The resulting amino acid substitutions cause local disorder and misfold the native structure of the isolated platelet GPIbα-adhesive A1 domain of VWF in both gain-of-function (type 2B) and loss-of-function (type 2M) phenotypes. These structural effects have not been explicitly observed in A1 domains of VWF multimers native to blood plasma. New mass spectrometry strategies are applied to resolve the structural effects of 2B and 2M mutations in VWF to verify the presence of A1 domain structural disorder in multimeric VWF harboring type 2 VWD mutations. Limited trypsinolysis mass spectrometry (LTMS) and hydrogen-deuterium exchange mass spectrometry (HXMS) are applied to wild-type and VWD variants of the single A1, A2, and A3 domains, an A1A2A3 tridomain fragment of VWF, plasmin-cleaved dimers of VWF, multimeric recombinant VWF, and normal VWF plasma concentrates. Comparatively, these methods show that mutations known to misfold the isolated A1 domain increase the rate of trypsinolysis and the extent of hydrogen-deuterium exchange in local secondary structures of A1 within multimeric VWF. VWD mutation effects are localized to the A1 domain without appreciably affecting the structure and dynamics of other VWF domains. The intrinsic dynamics of A1 observed in recombinant fragments of VWF are conserved in plasma-derived VWF. These studies reveal that structural disorder does occur in VWD variants of the A1 domain within multimeric VWF and provides strong support for VWF misfolding as a result of some, but not all, type 2 VWD variants.
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http://dx.doi.org/10.1016/j.jmb.2019.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028320PMC
January 2020

Etiologies of Extreme Thrombocytosis: A Contemporary Series.

Mayo Clin Proc 2019 08;94(8):1542-1550

Division of Hematology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To describe the multifactorial etiologies of extreme thrombocytosis (EXT) in different care settings and the frequency of finding an occult malignancy.

Patients And Methods: We conducted a retrospective chart review at Mayo Clinic from January 1, 2011, through December 31, 2016. Adult patients who had at least 2 readings of platelet counts greater than 1000×10/L within 30 days of each other were included. We determined the causes of EXT on the basis of preset definitions of precipitating factors and identified the dominant causes on the basis of the trend of platelet counts.

Results: A total of 44,490 patients had thrombocytosis, and 305 patients (0.7%) had EXT. In 242 patients (79.3%), EXT was multifactorial. Surgical complications (54.1%) and hematologic malignancies (27.9%) were the 2 most dominant causes. Thirty-eight patients (12.5%) had new diagnoses of malignancies, mostly myeloproliferative neoplasms. In inpatients, surgical complications (71.9%), concurrent/previous splenectomy (50.5%), and infections (44.9%) were the most common causes, whereas hematologic malignancies (56.9%), iron deficiency (36.7%), and previous splenectomy (28.4%) were the most common causes in outpatients. Hematologic malignancy was 3.4 times more likely to be the cause of EXT in outpatients than in inpatients (56.9% vs 16.8%), and a new diagnosis of hematologic malignancy was 1.9 times more likely to be made in outpatients (15.6% vs 8.2%). Eighty-four percent of patients had resolution of EXT within 30 days. One patient died during the period of EXT. Nonsurgical patients with hematologic malignancies had the most prolonged period of EXT.

Conclusion: Extreme thrombocytosis is a multifactorial hematologic condition, and its etiology differs substantially between inpatients and outpatients. Occult hematologic malignancies are uncommon in EXT when other major causes are present.
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http://dx.doi.org/10.1016/j.mayocp.2019.01.041DOI Listing
August 2019

Favorable pharmacokinetics in hemophilia B for nonacog beta pegol versus recombinant factor IX-Fc fusion protein: A randomized trial.

Res Pract Thromb Haemost 2019 Apr 23;3(2):268-276. Epub 2019 Mar 23.

Department for Internal Medicine Vascular Medicine and Haemostaseology Vivantes Klinikum Berlin Germany.

Background And Objective: Nonacog beta pegol (N9-GP) and recombinant factor IX-Fc fusion protein (rFIXFc) are extended half-life rFIX compounds. We report the first single-dose pharmacokinetic trial of N9-GP and rFIXFc.

Patients/methods: Paradigm 7 was a multicenter, open-label, randomized, crossover trial in previously treated (>150 exposure days) adults with congenital hemophilia B (FIX activity ≤2%). Patients received single intravenous injections (50 IU/kg) of N9-GP and rFIXFc with at least 21 days between doses. Plasma FIX activity, predose, and at serial time points up to 240 hours postdose, was measured using validated one-stage clotting assays (SynthAFax for N9-GP; Actin FSL for rFIXFc) and a chromogenic assay (ROX factor IX) with normal human plasma as calibrator. The primary endpoint was area under the FIX activity-time curve from 0 to infinity, dose-normalized to 50 IU/kg (AUC).

Results: Fifteen patients received study treatment. Based on FIX activity results from the one-stage clotting assays, estimated AUC was significantly greater for N9-GP than rFIXFc (ratio: 4.39; <0.0001, based on a two-sided test on 5% significance level). In addition, N9-GP had a longer terminal half-life, two times higher incremental recovery at 30 minutes and maximum FIX activity (dose-normalized to 50 IU/kg) and six times higher FIX activity at 168 hours than rFIXFc. These findings were largely comparable with the chromogenic assay data and are consistent with published data for each compound.

Conclusions: In this comparison, N9-GP demonstrated favorable pharmacokinetic characteristics versus rFIXFc, helping clinicians to understand differences between N9-GP and rFIXFc.

Registration: This trial is registered with clinicaltrials.gov (NCT03075670) and the European Clinical Trials Database (EudraCT: 2016-001149-25).
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http://dx.doi.org/10.1002/rth2.12192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462750PMC
April 2019

The Epidemiology of Antiphospholipid Syndrome: A Population-Based Study.

Arthritis Rheumatol 2019 09 1;71(9):1545-1552. Epub 2019 Aug 1.

Mayo Clinic, Rochester, Minnesota.

Objective: To estimate the annual incidence and prevalence of and frequency of mortality associated with antiphospholipid syndrome (APS).

Methods: An inception cohort of patients with incident APS in 2000-2015 from a geographically well-defined population was identified based on comprehensive individual medical records review. All cases met the 2006 Sydney criteria for APS (primary definition) or had a diagnosis of APS confirmed by physician consensus (secondary definition). Levels of lupus anticoagulant, IgM and IgG anticardiolipin antibodies, and anti-β2-glycoprotein I antibodies were tested in a centralized laboratory. Incidence rates were age- and sex-adjusted to the 2010 US white population. Prevalence estimates were obtained from the incidence rates, assuming that there was no increased mortality associated with APS and that migration in or out of the area was independent of disease status.

Results: Among this cohort in 2000-2015, 33 cases of incident APS, as defined by the Sydney criteria, were identified (mean age of patients 54.2 years; 55% female, 97% white). The annual incidence of APS in adults ages ≥18 years was 2.1 (95% confidence interval [95% CI] 1.4-2.8) per 100,000 population. Incidence rates were similar in both sexes. The estimated prevalence of APS was 50 (95% CI 42-58) per 100,000 population, and was similar in both sexes. Six patients (18%) had a concurrent diagnosis of systemic lupus erythematosus. The most frequent clinical manifestation was deep vein thrombosis. The overall frequency of mortality among patients with APS was not significantly different from that in the general population (standardized mortality ratio 1.61, 95% CI 0.74-3.05).

Conclusion: APS occurred in ~2 persons per 100,000 population per year. The estimated prevalence was 50 per 100,000 population. Overall mortality was not notably different from that observed in the general population.
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http://dx.doi.org/10.1002/art.40901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717037PMC
September 2019

The Mayo Clinic Experience With Psychogenic Purpura (Gardner-Diamond Syndrome).

Am J Med Sci 2019 05 7;357(5):411-420. Epub 2019 Feb 7.

Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota; Division of Hematopathology and Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background: The objective of this study was to describe presentation, natural history, management and long-term outcomes of patients with psychogenic purpura (PP), also known as Gardner-Diamond Syndrome.

Methods: In this retrospective study, records of patients with a diagnosis of PP seen at Mayo Clinic, Rochester from 1976 to 2016 were reviewed. Available literature regarding PP was also comparatively reviewed.

Results: Seventy-six patients with a diagnosis of PP were identified and 54/76 (71%) experienced a prodromal sensation. The Condensed MCMDM-1 bleeding score, excluding cutaneous manifestations, was <3 in 91% of patients. Laboratory tests of primary and secondary hemostasis were normal. Fifty-four percent of patients had an underlying psychiatric diagnosis. Management approaches included psychological counseling and psychiatry evaluation in 44 patients. Pharmacologic treatment for 30 patients included psychotropic agents, antihistamines, hormonal medications and anti-inflammatory agents. At a median follow-up of 5years (range 1-34),13/28 (46.4%) experienced recurrent ecchymoses and 6 continued to seek hematology follow-up at Mayo Clinic, Rochester. Our data was similar to the aggregate data from case reports in the literature.

Conclusions: For patients with unexplained recurrent ecchymosis a diagnosis of PP should be considered. Diagnosis is one of exclusion and initial evaluation should include documenting a bleeding score and obtaining laboratory tests assessing primary and secondary hemostasis. The relatively low bleeding scores together with laboratory assessments support that PP is primarily a dermal rather than a systemic bleeding diathesis. In our cohort, addressing psychological stressors was the most effective treatment; however pharmacologic therapy can be used for refractory disease.
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http://dx.doi.org/10.1016/j.amjms.2019.02.002DOI Listing
May 2019

Patterns and utility of vitamin B12 and folate testing in patients with isolated thrombocytopenia.

Ann Hematol 2019 Aug 15;98(8):1993-1994. Epub 2019 Mar 15.

Division of Hematology, Department of Medicine, Mayo Clinic, 200 1st St. SW, Rochester, MN, 55905, USA.

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http://dx.doi.org/10.1007/s00277-019-03666-2DOI Listing
August 2019

Heat inactivation of extended half-life factor VIII concentrates.

Haemophilia 2019 03 12;25(2):e130-e131. Epub 2019 Feb 12.

Special Coagulation Laboratory, Division of Hematopathology, Department of Laboratory Medicine, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1111/hae.13700DOI Listing
March 2019

Factor V Deficiency with a Thrombotic Clinical Phenotype.

Semin Thromb Hemost 2019 Feb 10;45(1):108-112. Epub 2019 Jan 10.

Division of Hematology, Department of Internal Medicine, Mayo Clinic Rochester, Rochester, Minnesota.

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http://dx.doi.org/10.1055/s-0038-1677041DOI Listing
February 2019
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