Rajiv K. Pruthi

Chromosome anomalies detected by interphase fluorescence in situ hybridization: correlation with significant biological features of B-cell chronic lymphocytic leukaemia

Summary. Fluorescence in situ hybridization (FISH) was used to detect 6q–, 11q–, +12, 13q–, 17p– and translocations involving 14q32 in interphase nuclei from blood and/or bone marrow from 113 patients with B‐cell chronic lymphocytic leukaemia (B‐CLL). A total of 87 patients (77%) had a FISH anomaly: 13q– × 1 was most frequent (64%) followed by 13q– × 2 (28%), +12 (25%), 11q– (15%), 17p– (8%) and 6q– (0%). FISH results for blood and bone marrow cells in 38 patients were similar. Purified CD5+/CD19+ cells from blood were studied in eight patients and results indicate that in some patients not all B cells have FISH anomalies. We used a defined set of hierarchical FISH risk categories to compare FISH results by stable versus progressive disease, age, sex, Rai stage, CD38+ expression and IgVH mutational status. Significant differences in FISH risk distributions were associated with Rai stage, disease status and CD38+, but not by age, sex or IgVH mutational status. To look for baseline factors associated with high‐risk disease, multivariate analysis of age, sex, Rai stage, CD38+ and disease status versus FISH risk category was performed. Importantly, only CD38+ was significantly associated with high‐risk FISH categories (+12, 11q– and 17p–) after adjustment for the effects of other variables.

How to Interpret and Pursue an Abnormal Prothrombin Time, Activated Partial Thromboplastin Time, and Bleeding Time in Adults

The prothrombin time (PT) and activated partial thromboplastin time (APTT) are among the most commonly ordered coagulation tests. In 2005, more than 140,000 PT and more than 95,000 APTT tests were performed at Mayo Clinic. The most common indications for ordering these tests include anticoagulant monitoring, initial evaluation of hemorrhage, and, although not generally indicated, routine preoperative screening. In addition, the bleeding time (BT) test, which is infrequently performed, is still available in certain institutions. Abnormal results from these tests (prolonged PT, APTT, and BT), especially from tests conducted for initial evaluation of hemorrhage or for preoperative screening, may pose a diagnostic dilemma to the nonhematologist. We review the essential factors affecting test results; provide a practical approach to the evaluation of a prolonged PT, APTT, and BT; and offer suggestions on which reflexive tests are appropriate and when to consider a subspecialty consultation.

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.

Acquired von Willebrand Disease

Acquired von Willebrand disease (AvWD) is a relatively rare acquired bleeding disorder that usually occurs in elderly patients, in whom its recognition may be delayed. Patients usually present predominantly with mucocutaneous bleeding, with no previous history of bleeding abnormalities and no clinically meaningful family history. Various underlying diseases have been associated with AvWD, most commonly hematoproliferative disorders, including monoclonal gammopathies, lymphoproliferative disorders, and myeloproliferative disorders. The pathogenesis of AvWD remains incompletely understood but includes autoantibodies directed against the von Willebrand factor (vWF), leading to a more rapid clearance from the circulation or interference with its function, adsorption of vWF by tumor cells, and nonimmunologic mechanisms of destruction. Laboratory evaluation usually reveals a pattern of prolonged bleeding time and decreased levels of vWF antigen, ristocetin cofactor activity, and factor VIII coagulant activity consistent with a diagnosis of vWD. Acquired vWD is distinguished from the congenital form by age at presentation, absence of a personal and family history of bleeding disorders, and, often, presence of a hematoproliferative or autoimmune disorder. The severity of the bleeding varies considerably among patients. Therapeutic options include desmopressin and certain factor VIII concentrates that also contain vWF. Successful treatment of the associated illness can reverse the clinical and laboratory manifestations. Intravenous immunoglobulins have also shown some efficacy in the management of AvWD, especially cases associated with monoclonal gammopathies. Awareness of AvWD is essential for diagnosis and appropriate management.

The new oral anticoagulants in clinical practice.

Vitamin K antagonists were the only class of oral anticoagulants available to clinicians for decades. However, with the US Food and Drug Administration approval of new oral anticoagulants, such as dabigatran, rivaroxaban, and apixaban, clinicians now have a broader choice. Given the recent approval and availability of these medications, several questions arise while deciding which of them would be best suited for a particular patient. This article provides a concise review for clinicians entailing the main studies that evaluated the efficacy and safety of these drugs, their pharmacokinetic and pharmacodynamic properties, and a practical approach to their clinical use. For this review, we conducted searches of PubMed and MEDLINE for articles published between January 1, 2000, and January 30, 2013, using the following search terms: oral anticoagulants, dabigatran, apixaban, rivaroxaban, novel anticoagulants, bleeding complications, management of bleeding complications, pharmacodynamics, and pharmacokinetics. Studies published in English were selected for inclusion in this review, as were additional articles identified from bibliographies.

Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune-mediated severe ADAMTS13-deficiency: a report of four cases and a systematic review of the literature

Thrombotic thrombocytopenic purpura (TTP) is a potentially life‐threatening disorder that in significant proportion of cases is related to the development of autoantibodies to, and resulting severe deficiency of, the ADAMTS13 protease. However, ADAMTS13 deficiency does not account for all cases. Response to plasma exchange (PE) is seen in TTP with and without ADAMTS13 deficiency and is therefore indicated for all with a clinical diagnosis of TTP, although the pathogenesis of the latter group remains to be defined. Although the majority of cases respond to PE, a significant percent are refractory or experience relapse. Rituximab is being increasingly used off‐label in this setting, but many reports do not define the pathogenesis of TTP so treated. We here report our experience with, and systematically review the published experience to date, of rituximab in management of refractory and or relapsing TTP specifically related to immune‐mediated severe ADAMTS13‐deficiency. In total, 73 patients met defined study inclusion criteria. The majority (∼95%) achieved complete remission within weeks of the first application of rituximab. The reported relapse rate was low in this patient subgroup, which carry an anticipated relapse rate of up to 60%. However, caution in interpretation of this data is needed given the relatively short median duration of follow‐up of approximately 10 months. Rituximab was generally well tolerated, with few serious adverse events reported. However, three severe infectious complications were identified, including viral reactivation in keeping with black box warnings for this agent. Furthermore, reflecting the rarity of this disorder, only a relatively small number of patients have been treated and data with regards to long‐term follow‐up are largely based on individual case reports. Prospective studies are urgently needed to define the true efficacy and long‐term safety of rituximab.

Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in haemophilia patients with inhibitors undergoing major surgery - Results from an open-label, randomized, multicenter trial

Bolus infusion (BI) recombinant factor VIIa (rFVIIa) administration is safe and effective in the surgical management of haemophilia patients with inhibitors but has not been compared directly with continuous infusion (CI). We conducted an open-label, randomized, multicenter trial comparing the efficacy and safety of rFVIIa administered by BI or CI for the surgical management of haemophilia A or B patients with inhibitors to FVIII or FIX. Safety was compared with that of a control group of non-inhibitor patients receiving FVIII or FIX concentrates for major surgery. All inhibitor subjects received an initial bolus dose of 90 microg/kg rFVIIa and were then randomly assigned to BI (n = 12) or CI (n = 12). The BI group received 90 microg/kg rFVIIa every two hours (h) during surgery through day 5, then every four hours for days 6-10. The CI group received 50 microg/kg/h rFVIIa through day 5, then 25 mg/kg/h for days 6-10. The control group (n = 12) received FVIII or FIX per institutional protocols. Twenty-two major surgeries included orthopedic procedures on the knee (n = 13), hip (n = 3), and abdominal/pelvis procedures (n = 4). One patient with an autoimmune FVIII inhibitor randomized to the BI arm was excluded from efficacy analysis. Haemostatic efficacy of rFVIIa in each group was comparable: effective in 8/11 and 9/12 subjects in the BI and CI arms, respectively, and ineffective in three subjects in each arm. Serious adverse events were related to continued or increased bleeding. In conclusion, haemostatic efficacy and safety of BI and CI of rFVIIa are comparable for the surgical management of haemophilia subjects with inhibitors.

Systemic AL amyloidosis with acquired factor X deficiency: A study of perioperative bleeding risk and treatment outcomes in 60 patients

Systemic light‐chain (AL) amyloidosis may be associated with acquired factor X (FX) deficiency and optimal management of this coagulopathy is unknown. We reviewed our experience with 60 patients with isolated FX deficiency (≤50%) due to AL amyloidosis that underwent an invasive procedure between 1975 and 2007. They were classified as having severe (<10%; n = 6), moderate (10–25%; n = 15), or mild (26–50%; n = 39) FX deficiency. The patients underwent a total of 112 procedures, 19 (17%) of which were managed with periprocedural treatment with one or more hemostatic agents. There were complications in 14 (13%) procedures (bleeding = 12, thrombosis = 1, death = 1). Baseline FX level was not predictive of bleeding risk; the only association with postintervention bleeding was central venous catheter placement. However, bleeding complications were relatively infrequent, particularly in patients with mild or moderate FX deficiency undergoing nonvascular procedures. Activated recombinant factor VII might be considered in patients undergoing major surgical procedures, but further experience is needed. Optimal management of AL patients with FX deficiency undergoing invasive procedures remains to be determined. Am. J. Hematol., 2010.

Venous thromboembolism after hip fracture surgery in a patient with haemophilia B and factor V Arg506Gln (factor V Leiden).

We describe a patient with mild haemophilia B who developed symptomatic venous thromboembolism after hip arthroplasty for a traumatic fracture. A deep vein thrombosis developed in the operated leg while he was receiving a high‐purity factor IX concentrate. Subsequently, he was determined to be a heterozygous carrier for the factor V Arg506Gln (Leiden) mutation. This case illustrates the importance of providing thromboprophylaxis for all patients with haemophilia receiving coagulation factor replacement and who undergo surgical procedures known to be associated with a high risk of venous thromboembolism. In patients with haemophilia and a family history of venous thromboembolism, preoperative screening for the presence of the factor V Arg506Gln mutation and other thrombophilias may be useful.

Thromboembolism in Adults with Acute Lymphoblastic Leukemia During Induction with L-Asparaginase-containing Multi-agent Regimens: Incidence, Risk Factors, and Possible Role of Antithrombin

Thromboembolism (TE) is a known complication of L-asparaginase (ASP) therapy of acute lymphoblastic leukemia (ALL), possibly attributable to reduced synthesis of natural anticoagulants, in particular antithrombin (AT). This retrospective single institution study was performed to determine the TE incidence among adults undergoing induction with contemporary, ASP-containing regimens. Ten of 54 (18.5%) consecutive adults developed symptomatic, objectively confirmed TE, at a median of 5.5 days after the first ASP dose. These were notable for CNS and upper extremity localization, varied significantly according to ALL immunophenotype (precursor B: 11% vs. T cell: 33%), without apparent effect of schedule or total dose of ASP. Median baseline AT level was 94% and fell to a nadir of 47% (P < 0.0001) during ASP therapy. Prophylactic AT had been given to 17 during ASP therapy. None of these developed TE vs. 10/37 (27%) without replacement (P = 0.021). These observations merit further study to gain insight into disease and/or therapy-specific pathogenesis of TE in this population and call for the prospective evaluation of appropriate prophylactic interventions.