A single-centre study of haemostatic outcomes of joint replacement in von Willebrand disease and control patients and an analysis of the literature.

INTRODUCTION: Haemostatic assessments of patients with von Willebrand disease (VWD) who undergo total knee arthroplasty (TKA) and total hip arthroplasty (THA) have mainly relied on subjective parameters. AIMS: To compare objective haemostatic outcomes of TKA/THA in VWD patients and controls without bleeding disorders. METHODS: We retrospectively analysed haemostatic outcomes in VWD patients undergoing TKA/THA from 1993 to 2011 and compared them with two matched controls per operation. Using one-way analysis of variance, we tested the effect of VWD on bleeding risk after TKA and THA. RESULTS: Twelve VWD patients (6 type 1, 3 type 2M, 1 each of types 2A/2B/3) undergoing 19 operations (12 TKA, 7 THA) were matched to 38 controls. One (5%) of 19 operations in VWD patients and none of the control operations met clinical criteria for major bleeding. Baseline and postoperative day 1 haemoglobin levels, postoperative blood loss, transfused red blood cells (RBCs) and mean hospitalization days were not significantly different. More VWD patients than controls received RBC transfusions [12 (63%) vs. 12 (32%)]. Only 9 (47%) VWD patients vs. 38 (100%) controls received pharmacologic VTE prophylaxis. No postoperative symptomatic VTE occurred in either group. CONCLUSION: In this largest, single-institutional study, von Willebrand factor replacement based on daily levels resulted in low frequency of major bleeding in VWD patients after TKA/THA. RBC transfusion was more frequent compared with matched controls, but other objective measures of haemostasis were similar. Lack of sufficient details in published reports precluded comparison of haemostatic outcomes.

To circumcise or not to circumcise? Circumcision in patients with bleeding disorders.

SUMMARY: Circumcision is one of the most common procedures performed in male neonates, but few published reports have described circumcision in patients with bleeding disorders. The aim of this study was to analyse outcomes of circumcision among children evaluated at our institution to determine the extent of complications and to provide guidelines for circumcision management. We searched our patient database for records of children who were followed up at the Mayo Clinic Comprehensive Hemophilia Center from 2000 through 2007 and who had been circumcised. We retrospectively reviewed the medical records to document complications and determine management strategies in this patient population. Of 55 children and young adults identified (median [range] age, 15 years [11 months to 21 years]), 48 patients were circumcised. Indications for circumcision were parental request (n = 45) and medical recommendation (n = 3). Twelve of 21 patients with a known bleeding disorder at the time of circumcision received factor replacement before the procedure. Three of these 21 patients had bleeding complications. Of the other 27 patients, who were diagnosed later in life as having a bleeding disorder, 8 had bleeding complications. The overall incidence of bleeding after circumcision was 23% (11/48). The 23% overall incidence of bleeding complications in our patients with bleeding disorders is comparable to that reported for patients without a bleeding disorder (0.1-35%). Some of our patients had significant bleeding despite adequate factor replacement before and after the procedure. Parents and patients must be aware that bleeding risk is a possibility despite adequate factor replacement for hemostasis.

Central venous access devices for paediatric patients with haemophilia: a single-institution experience.

Use of a central venous access device (CVAD) can facilitate early introduction of home-based infusion of factor concentrate for long-term prophylaxis or immune tolerance therapy in children with bleeding disorders. The aim was to review outcomes associated with use of CVAD. Retrospective review of paediatric patients with bleeding disorders was observed at the Mayo Clinic Comprehensive Hemophilia Center. Thirty-seven CVAD were placed in 18 patients (haemophilia A [n = 15], type 3 von Willebrand disease [n = 2] and haemophilia B [n = 1]). Follow-up was for 45 952 CVAD days, and median time that CVAD remained in place was 1361 days per device. Factor VIII (FVIII) inhibitors were present in 4 of the 15 patients. Ten CVAD-related infections occurred (median, 672 days; range, 72-1941 days), of which six were in one patient with FVIII inhibitors. Overall infection rate was 0.22 (95% confidence interval [CI], 0.10-0.40) per 1000 CVAD days, with 0.11 infections in patients without FVIII inhibitors compared with a pooled incidence of 0.66 (95% CI, 0.44-0.97) reported in the literature. Indications for removal of 27 CVAD were blockage, change to peripheral venous access, catheter displacement, infection, leak in the port septum, short catheter and skin erosion. No clinically apparent thrombosis or sequelae of thrombosis were observed. Infection is the most common complication associated with CVAD use and is increased in patients who have inhibitors. The low rate of clinically apparent thrombosis reflects our practice of not screening for thrombosis. The low infection rate reflects our practice of using and reinforcing the aseptic technique.

Absolute lymphocyte count recovery after induction chemotherapy predicts superior survival in acute myelogenous leukemia.

Absolute lymphocyte count (ALC) recovery postautologous stem cell transplantation is an independent predictor for survival in acute myelogenous leukemia (AML). The role of ALC recovery after induction chemotherapy (IC) in AML is unknown. We hypothesize that ALC recovery after IC has a direct impact on survival. We have now evaluated the impact of ALC recovery after IC on overall survival (OS) and leukemia-free survival (LFS) in 103 consecutive, newly diagnosed AML patients treated with standard IC and consolidation chemotherapy (CC) from 1998 to 2002. ALC recovery was studied at days 15 (ALC-15), 21 (ALC-21), 28 (ALC-28) after IC and before the first CC (ALC-CC). Superior OS and LFS at each time point were observed with an ALC-15, ALC-21, ALC-28, and ALC-CC > or = 500 cells/microl. Patients with an ALC > or = 500 cells/microl at all time points vs those who did not have superior OS and LFS (not reached vs 13 months, P<0.0001; and not reached vs 11 months, P<0.0001, respectively). Multivariate analysis demonstrated ALC > or = 500 cells/microl at all time points to be an independent prognostic factor for survival. Our data suggest a critical role of lymphocyte (immune) recovery on survival after IC in AML.

Optimal utilization of thrombophilia testing.

The global incidence of venous thromboembolism is high so laboratory testing for hereditary thrombophilia and selected acquired thrombophilia is common. Given the costs associated with testing and multiple pre-analytic and analytic variables affecting the assays, careful patient selection and timing of testing and diligent application to patient management are critical to providing high-value clinical care. Collaboration between the ordering providers and performing laboratories has the potential to achieve these goals. Herein, utility of thrombophilia testing, variables that affect the assays, and impact on patient management are reviewed. Where available, information on cost-effectiveness is discussed.

Do incident and recurrent venous thromboembolism risks truly differ between heterozygous and homozygous Factor V Leiden carriers? A retrospective cohort study.

INTRODUCTION: While Factor V Leiden (F5 rs6025 A allele) is a known venous thromboembolism (VTE) risk factor, VTE risk among heterozygous vs. homozygous carriers is uncertain. MATERIALS AND METHODS: In a retrospective cohort study of Mayo Clinic patients referred for genotyping between 1996 and 2013, we tested Factor V Leiden genotype as a risk factor for incident and recurrent VTE. RESULTS: Among heterozygous (n=268) and homozygous (n=111) carriers, the prevalence of VTE was 54% and 68%, respectively (p=0.016). While mean patient age at first VTE event (43.9 vs. 42.9years; p=0.70) did not differ significantly, median VTE-free survival was modestly shorter for homozygous carriers (56.8 vs 59.5 years; p=0.04). Sixty-nine (48%) and 31 (42%) heterozygous and homozygous carriers had ≥1 VTE recurrence (p=0.42). In a multivariable model, idiopathic incident VTE and a second thrombophilia were associated with increased and anticoagulation duration >6months with reduced hazards of VTE recurrence; Factor V Leiden genotype was not an independent predictor of recurrence. CONCLUSIONS: Aside from a higher VTE prevalence and modestly reduced VTE-free survival, VTE penetrance and phenotype severity did not differ significantly among homozygous vs. heterozygous carriers, suggesting that VTE prophylaxis and management should not differ by Factor V Leiden genotype.

Pernicious anemia revisited.

OBJECTIVE: We discuss the pathophysiologic mechanisms, clinical features, diagnosis, and treatment of pernicious anemia (PA). DESIGN: A review of the clinical applications of the diagnostic and therapeutic progress of PA is presented. MATERIAL AND METHODS: A patient with PA may have a wide range of initial complaints that affect various organ systems or may be entirely asymptomatic. Hematologic variables may be normal in patients with cobalamin (Cbl) deficiency. Because of the difficulties in diagnosing Cbl deficiency, alternatives to measuring Cbl have been sought. Determining the urinary methylmalonic acid level is a less invasive, more practical, and, possibly, more sensitive method. The Schilling test is performed for assessment of the absorption of orally ingested radiolabeled crystalline cyano-Cbl; results should be interpreted cautiously. RESULTS: Vitamin B12 therapy should be lifelong. It is customarily administered intramuscularly. Other routes of administration have been studied. CONCLUSION: PA is one of the most treatable hematologic disorders.

The biochemical basis of cobalamin deficiency.

OBJECTIVE: In this report, our goal was to summarize the current knowledge of the biochemical basis for the impaired DNA synthesis and neuropathy associated with vitamin B12 deficiency. MATERIAL AND METHODS: We reviewed the pertinent literature and our clinical experience with cobalamin deficiency. RESULTS: Studies have established that the megaloblastic hematopoiesis associated with vitamin B12 and folate deficiency is secondary to impaired DNA synthesis. Two mechanisms of impairment of DNA synthesis have been proposed: the "methylfolate trap hypothesis" and the "formate starvation hypothesis." One possibility is that both hypotheses may be contributory--that is, incoming dietary folate may be inaccessible for polyglutamation in accordance with the methylfolate trap hypothesis, whereas the formate starvation hypothesis may explain the failure to use already polyglutamated forms of folate. CONCLUSION: Although the pathophysiologic mechanisms of vitamin B12 and folate deficiency are not completely understood, nutritional anemias offer suitable models for the study of the biochemical basis of disease.

Human babesiosis.

OBJECTIVE: To describe a case of human babesiosis and review the literature on the disease. MATERIAL AND METHODS: We describe a 62-year-old man with babesiosis, outline his clinical course and response to therapy, and discuss the use of the polymerase chain reaction for the diagnosis and monitoring of the infection. RESULTS: The onset of the disease was insidious, with fatigue, fever, weight loss, intermittently discolored urine, and anemia. Computed tomography of the abdomen revealed a small, shrunken spleen with an irregular border. With treatment, the symptoms gradually resolved. Although peripheral blood smears were negative soon after therapy, Babesia microti DNA was detected by polymerase chain reaction 53 days after initial examination. CONCLUSION: The development of improved methods for diagnosis, including indirect immunofluorescent antibody assays and the polymerase chain reaction, provides more sensitive detection of the parasitemia associated with babesiosis. Use of these methods may help to delineate the complete clinical spectrum of this infection and its geographic distribution in the United States.

Fluorescent in situ hybridization studies of lymphocytes and neutrophils in chronic granulocytic leukemia.

Using immunomagnetic cell separation and fluorescent in situ hybridization (FISH), we studied nine patients who had chronic granulocytic leukemia (CGL) for the proportion of interphase nuclei with Mbcr/abl fusion in a direct preparation of the bone marrow and also in the mononuclear cell (MNC), neutrophil, and B- and T-cell fractions of the peripheral blood. In five untreated patients, conventional cytogenetics revealed 97% to 100% Philadelphia chromosome (Ph)+ metaphases. In three of these five patients, FISH studies on bone marrow direct preparations and peripheral blood MNCs indicated that an Mbcr/abl fusion occurred in 62% to 69% of the cells. We observed 69% to 88% of nuclei with Mbcr/abl fusion within the neutrophil fractions. In contrast, the values were 12% to 39% within the T-cell fractions in the four patients we studied. B-cell fractions were studied in three patients, and only one had an abnormal value (58%). In the four patients receiving alpha-interferon therapy, the degree of conventional cytogenetic remission correlated best with the degree of FISH remission observed in the peripheral blood neutrophil fraction. Our results are in agreement with earlier studies in that both B and T lymphocytes may be involved with the clonal process in CGL. The FISH-based detection of Mbcr/abl fusion in the peripheral blood neutrophil compartment provided the best estimate for the proportion of Ph metaphases determined by conventional cytogenetics.

Sensitivity and specificity of denaturing high-pressure liquid chromatography for unknown protein C gene mutations.

Screening methods for unknown DNA sequence variations are laborious, expensive, and relatively insensitive. To evaluate the sensitivity and specificity of denaturing high-pressure liquid chromatography (DHPLC) screening for unknown protein C gene (PROC) mutations, we studied 31 PROC-deficient patients. Eleven amplimers containing 4 kb of the PROC gene and spanning all exons, splice junctions, and the putative promoter and 3'-untranslated regions were amplified by PCR for each patient. Each amplimer (n = 341) was sequenced with a fluorescence-based method, and screened by DHPLC. Sequencing identified 10 unique mutations and three polymorphisms. Combining all mutations and polymorphisms, 227 amplimers were homozygous wildtype, and 63 and 51 were heterozygous and homozygous mutant, respectively. DHPLC screening correctly identified all amplimers (100% sensitivity and specificity). DHPLC is a rapid, automated, sensitive and specific screening method for unknown mutations within the PROC gene, and may be a useful screening method for unknown mutations within other genes.