Vandita Johari

Myelodysplastic syndrome with isolated deletion of chromosome 20q: an indolent disease with minimal morphological dysplasia and frequent thrombocytopenic presentation

The present study analysed the clinicopathological features of nine myelodysplastic syndrome (MDS) patients in which del(20q) was the sole cytogenetic abnormality and a control group of 17 adult patients with idiopathic thrombocytopenic purpura (ITP). Seven of nine del(20q) patients were thrombocytopenic and six of nine were mildly anaemic at presentation. There was no significant morphological dysplasia identified in the del(20q) group as compared with the ITP group. These results indicate that MDS with del(20q) commonly presents with thrombocytopenia and has minimal morphological dysplasia. Cytogenetic analysis on adult patients undergoing bone marrow sampling for thrombocytopenia may help avoid misdiagnosis of MDS with del(20q) as ITP.

Brief Overview of the Coagulation Cascade

he increasing number of indications for anticoagulation, as well as an ncrease in the number of therapeutic anticoagulants being made availble, makes it imperative for the modern-day practitioner to understand urrently available coagulation testing and drug monitoring. Clinical esting includes a combination of clotting, immunologic, and chromoenic assays, which screen for disorders of coagulation, whether they be enetic in origin or acquired because of either disease or anticoagulant herapy. A brief review of the pathways of coagulation and clot lysis, and he factors regulating them, will help in the understanding of how nticoagulant drugs work and how they can be monitored or, if necessary, heir action reversed when toxicity is suspected.

Laboratory evaluation of clopidogrel responsiveness by platelet function and genetic methods

Clopidogrel is a widely used antiplatelet agent that irreversibly inhibits platelet P2Y12 ADP receptors after conversion to an active metabolite. There are a number of laboratory tests capable of detecting clopidogrel‐induced platelet inhibition and published literature correlates suboptimal clopidogrel response to adverse cardiovascular outcomes. Genetic polymorphisms are thought to affect conversion of the prodrug to the active metabolite, and the FDA has recently added a black‐box warning to clopidogrel to highlight the effects of these polymorphisms on drug bioavailability and to inform prescribers about the availability of genetic testing. For these reasons, there is growing interest in the use of laboratory tests to monitor patients treated with clopidogrel. This article summarizes the currently available laboratory testing, including platelet function tests and genotyping for CYP2C19 variants. Am. J. Hematol., 2011.

Primary Breast Lymphoma: Radiologic and Pathologic Findings

A 57-year-old woman presented with a mass behind her left nipple. Examination revealed a firm, immobile retroareolar mass without lymphadenopathy. Mammography showed an area of density in the subareolar region (Fig. 1) that ultrasonography characterized as a complex lesion (Fig. 2). Breast core biopsies revealed an infiltrating tumor composed of medium and large cells with entrapment of benign breast lobules and ducts (Fig. 3). The tumor cells were diffusely immunoreactive for CD20 (Fig. 4). Based on tumor morphologic features and immunophenotype, a diagnosis of non-Hodgkin’s lymphoma, diffuse large B-cell type (World Health Organization classification) was rendered. No other site of involvement was noted on subsequent examination. The patient received chemotherapy and involved-field radiation and remains free of disease. Primary breast lymphoma is a rare entity in the spectrum of malignant breast disease. There are at present no clear clinical or radiologic features that distinguish primary breast lymphoma from any other type of infiltrating breast carcinoma. The key in the evaluation of these cases remains adequate tissue biopsy for histopathologic evaluation and immunophenotyping. Primary breast lymphoma is not a surgical disease and can be treated successfully with combined chemotherapy and radiation therapy.

Development of electronic medical record charting for hospital-based transfusion and apheresis medicine services: Early adoption perspectives

Background: Electronic medical records (EMRs) provide universal access to health care information across multidisciplinary lines. In pathology departments, transfusion and apheresis medicine services (TAMS) involved in direct patient care activities produce data and documentation that typically do not enter the EMR. Taking advantage of our institution′s initiative for implementation of a paperless medical record, our TAMS division set out to develop an electronic charting (e-charting) strategy within the EMR. Methods: A focus group of our hospital′s transfusion committee consisting of transfusion medicine specialists, pathologists, residents, nurses, hemapheresis specialists, and information technologists was constituted and charged with the project. The group met periodically to implement e-charting TAMS workflow and produced electronic documents within the EMR (Cerner Millenium) for various service line functions. Results: The interdisciplinary working group developed and implemented electronic versions of various paper-based clinical documentation used by these services. All electronic notes collectively gather and reside within a unique Transfusion Medicine Folder tab in the EMR, available to staff with access to patient charts. E-charting eliminated illegible handwritten notes, resulted in more consistent clinical documentation among staff, and provided greater real-time review/access of hemotherapy practices. No major impediments to workflow or inefficiencies have been encountered. However, minor updates and corrections to documents as well as select work re-designs were required for optimal use of e-charting by these services. Conclusion: Documentation of pathology subspecialty activities such as TAMS can be successfully incorporated into the EMR. E-charting by staff enhances communication and helps promote standardized documentation of patient care within and across service lines. Well-constructed electronic documents in the EMR may also enhance data mining, quality improvement, and biovigilance monitoring activities.

Pharmacology of Anticoagulants

Antithrombotic drugs are used for the prevention and treatment of thrombosis. Targeting the various components of thrombosis, these agents include (1) antiplatelet agents; (2) anticoagulants; and (3) fibrinolytic agents. This review focuses on anticoagulants. The older classification of anticoagulants into oral and parenteral agents is giving way to one based on their biochemistry. Even so, most oral anticoagulants, notably warfarin, are vitamin K antagonists (VKAs) and thrombin inhibitors make up most parenteral agents. Thrombin inhibitors may be classified as indirect, such as unfractionated heparin (UFH), low molecular weight heparin (LMWH), and the synthetic heparin derivative fondaparinux and idraparinux, or direct inhibitors of thrombin activity, such as argatroban, lepirudin, and bivalirudin. Among the newer agents, all administered orally, are factor Xa inhibitors rivaroxaban and apixaban and the IIa (thrombin) inhibitor dabigatran. Conventionally used anticoagulants warfarin and UFH have been limited by a narrow therapeutic index, the need for laboratory monitoring, and, in the case of warfarin, numerous drug and dietary interactions. Some of the newer anticoagulants circumvent these disadvantages and may dramatically change the way we manage patients who require anticoagulation. This review summarizes the pharmacology of conventional and newer anticoagulants. Vitamin K Antagonists (VKAs) Oral anticoagulant warfarin inhibits the biosynthesis of vitamin K‐dependent procoagulant factors II, VII, IX, and X, reducing the coagulant potential of the blood. The antithrombotic effect of warfarin depends on the reduction in the functional levels of factor X and prothrombin that have half-lives of 36 and 50 hours, respectively. Because the long half-lives of some of these factors, full antithrombotic effect of VKA is

ADAMTS13 activity and inhibitor

Thrombotic thrombocytopenic purpura (TTP) is often associated with acquired or congenital deficiency of the von Willebrand factor‐cleaving metalloprotease, ADMATS13 (Lammle B et al., J Thromb Haemost 2005;3:1663‐1675; Schneppenheim et al., Blood 2003;101:1845‐1850). Although undetectable levels of enzyme activity (<10%) are diagnostic of inherited or acquired TTP in the correct clinical setting (absence is specific), not all patients diagnosed with TTP have severe protease deficiency, and it is therefore not recommended as an initial test for diagnosis (Copelovitch and Kaplan, Pediatr Nephrol, in press). Many prospective and retrospective studies have demonstrated that patients with severe protease deficiency have a higher likelihood of relapse, making it helpful as an indicator of recurrence. The short‐term prognostic usefulness of ADAMTS13 testing during acute TTP warrants further investigation because of limited prospective studies (Ferrari S et al., Blood 2007;109:2815‐2822; Peyvandi et al., Haematologica 2008;93:232‐239). Am. J. Hematol., 2008.

Issues Surrounding Age-Adjusted d-Dimer Cutoffs That Practicing Physicians Need to Know When Evaluating Patients With Suspected Pulmonary Embolism

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. A recent best-practice advice paper from the Clinical Guidelines Committee of the American College of Physicians (ACP) provides an algorithmic approach that uses an initial clinical pretesting risk assessment (such as Wells or Geneva scores and Pulmonary Embolism Rule-out Criteria [PERC]), d-dimer testing for intermediate- and low-risk patients with positive PERC scores, and evaluation by imaging studies for high-risk patients and patients with positive d-dimer results (1). The authors recommend age-adjusted d-dimer (AADD) cutoffs based on several recently published studies (2), which demonstrated that the use of AADD cutoffs for patients older than 50 years (defined as AADD cutoff = age10 ng/mL) improved specificity for diagnosing pulmonary embolism while maintaining at least 97% sensitivity. Supplement. Original Version (PDF) We agree in principle with the approach of AADD cutoffs. However, from a laboratory perspective, widespread implementation of these cutoffs in clinical practice poses substantial concerns, including a lack of standardized d-dimer unit reporting, limitations of d-dimer testing in clinical studies, and a lack of defined strategies for clinical laboratories to adopt AADD cutoffs. Here, we elaborate on these difficulties to ensure that our clinical colleagues understand the issues surrounding d-dimer testing, but we also offer immediate and long-term strategies. The College of American Pathologists (CAP) and Clinical Laboratory and Standards Institute (CLSI) require d-dimer results to be reported with both a unit type and a unit of magnitude (3, 4). The d-dimer unit type includes either fibrinogen equivalent units (FEUs) or d-dimer units (DDUs). The FEU is a mass equivalent of the d-dimer fragments of the fibrinogen molecule from which it is derived, and the mass equivalent of the DDU is approximately half that of the FEU (5) (for example, 250 ng/mL DDU= 500 ng/mL FEU). The commonly reported d-dimer units of magnitude are milligrams per liter, micrograms per liter, micrograms per milliliter, and nanograms per milliliter. Such an array of d-dimer result formats is confusing and may result in clinical error. Based on recent CAP proficiency testing data, a small proportion but a substantial number of laboratories are reporting the incorrect d-dimer units (6). As currently written, the ACP best-practice advice does not include a unit type (that is, FEU or DDU) for the AADD cutoffs when evaluating low- and intermediate-risk patients for a possible pulmonary embolism, and the failure to report the unit type may result in misinterpretation of the d-dimer. For instance, if a cutoff of 500 ng/mL FEU were assumed for an assay calibrated in nanograms per milliliter of DDU, a d-dimer measurement of 400 ng/mL DDU (equivalent to ~800 ng /mL FEU) would be misinterpreted as a value below the cutoff for excluding pulmonary embolism. Physicians also should be mindful of the limitations of the AADD clinical studies. Differences in monoclonal antibodies used in manufactured d-dimer assays contribute to a lack of agreement among d-dimer test results (6, 7), causing differences in venous thromboembolism (VTE) exclusion cutoffs for the d-dimer kits approved or cleared by the U.S. Food and Drug Administration (FDA) (8). Most AADD clinical studies used only a few commercially available d-dimer kits. For instance, only 5 commercial, high-sensitivity, quantitative d-dimer assays (Table) were used in the most frequently quoted studyADJUST-PE (Age-Adjusted d-Dimer Cutoff Levels to Rule Out Pulmonary Embolism) (9)representing only a small portion of the commercially available assays used in U.S. clinical laboratories (8). The laboratory data from these clinical studies were insufficient to determine whether the assays performed equally or whether any assay had sufficient statistical power to avoid potential error. This concern was exemplified in an 86-year-old patient who had pulmonary embolism but a range of d-dimer values (590 to 1170 ng/mL FEU) measured by 5 commercial d-dimer assays (10). Furthermore, the numbers of patients older than 75 years or from a minority ethnic group were relatively limited among the studies (9). The d-dimer units in many studies (that is, DDU vs. FEU) were not clearly specified, and different units of magnitude were used (9). The lack of understanding of d-dimer units and assay performance in these investigations causes confusion among physicians and puts patient safety at risk. Table. d-Dimer Assays Used in Clinical Studies of AADD Cutoffs for Pulmonary Embolism Exclusion* The CLSI (guideline H59-A) and FDA requirements provide a detailed discussion of the performance characteristics that must be considered when using a d-dimer assay to exclude VTE, either pulmonary embolism or deep venous thrombosis (4). These requirements for a VTE cutoff are very strict, and any modification to the FDA-approved or -cleared cutoff value, as in the AADD cutoff recommendation, requires a laboratory or assay manufacturer to carry out the appropriate investigation. In light of the current regulatory environment, defined strategies for implementing the AADD cutoffs are not available, and if a laboratory adopts or reports AADD cutoffs on an FDA-approved or -cleared d-dimer assay, it must demonstrate assay-specific evidence of clinical performance characteristics. If literature is not available to support AADD cutoffs for a specific assay, the laboratory must perform a validation that exceeds the resources of most institutions. On the basis of our earlier discussion, we propose a short-term recommendation and a long-term strategy to help address these issues. First, we recommend clarification of the d-dimer unit type (that is, FEU or DDU) of the AADD cutoffs proposed by the ACP best-practice advice. As for the short-term strategy, for clinical laboratories interested in implementing d-dimer AADD cutoffs, we recommend that they consider only specific d-dimer assays adequately evaluated in clinical studies based on the CLSI guidelines (4). The most widely studied d-dimer assays for AADD cutoffs are listed in the Table. Each kit was examined in several studies, which combined had a total of more than 300 low- and intermediate-risk patients and provided substantial evidence that these assays have a negative predictive value of 98% or greater if the AADD cutoffs are used. Clinical laboratories should communicate with physicians regarding d-dimer assay performance, units of magnitude and type, and specific literature supporting the validity of AADD cutoffs for their d-dimer assay. As for quantitative d-dimer kits without substantial data, their validity and safety in the context of AADD cutoff implementation are uncertain. The long-term strategy is to harmonize d-dimer assays and reporting by improving assay performance and unifying reporting units. The ACP, CAP, and International Society on Thrombosis and Haemostasis should collectively advocate that the FDA and manufacturers select a uniform unit type and magnitude for reporting d-dimer. Additional d-dimer assay comparison studies in patients with pulmonary embolism are necessary to provide clinical validation data and support AADD cutoff implementation for more commercial d-dimer kits. Finally, the current vendors of d-dimer assays are urged to perform clinical validation studies and obtain FDA clearance for AADD for their existing d-dimer kits. This approach will significantly facilitate widespread implementation of AADD cutoffs in clinical practice. In conclusion, the current state of d-dimer testing and reporting is far from standardized and creates significant challenges in safely implementing AADD cutoffs. Although several d-dimer assays have data to support AADD cutoffs to exclude pulmonary embolism, assays that have not been sufficiently investigated should not be used with AADD cutoffs. Collaboration among professional organizations, regulatory bodies, and manufacturers may be necessary to improve the overall safety of AADD testing to exclude pulmonary embolism.