Deborah L. Ornstein

Prevalence of venous thromboembolism in patients with secondary polycythemia.

To investigate an association between secondary polycythemia and venous thromboembolism (VTE) risk, we performed a case–control study to compare the prevalence of VTE in participants with secondary polycythemia due to chronic obstructive pulmonary disease (COPD; N = 86) to that in age- and sex-matched controls with COPD without secondary polycythemia (N = 86). Although there was a significant difference in mean hematocrit between cases and controls (53.5% vs 43.6%, respectively; P < .005), we identified no difference in the number of total or idiopathic VTE events in the 2 groups. Patients with VTE, however, had a significantly higher body mass index than patients without VTE. Our findings suggest that secondary polycythemia alone may not be a significant risk factor for VTE but that VTE risk in this population may be related to known risk factors such as obesity. The role of phlebotomy for VTE risk reduction secondary polycythemia is therefore questionable.

Remission of paroxysmal atrial fibrillation with iron reduction in haemophilia A

Summary.u2002 Two male first cousins with mild haemophilia A had baseline factor VIII levels of 12–15% and experienced bleeding requiring coagulation factor infusion therapy with trauma and surgical procedures. Both the patients with haemophilia A also had electrocardiographically documented symptomatic paroxysmal atrial fibrillation (PAF) for several years that had become resistant to pharmacological suppression. Radiofrequency ablation was considered in both the cases but deferred considering refusal of consent by the patients to undergo the procedure. Remission of arrhythmias has been reported in patients with iron‐overload syndromes. Body iron stores assessed by serum ferritin levels were elevated in both men but neither had the C282Y or H63D genes for haemochromatosis. Calibrated reduction of iron stores by serial phlebotomy, avoiding iron deficiency, was followed by remission of symptomatic PAF in both cases. Iron reduction may be an effective treatment for arrhythmias apart from the classic iron‐overload syndromes and deserves further study particularly in patients with bleeding disorders who might be at risk for arrhythmias and other diseases of ageing.

Factor VIII/von Willebrand factor concentrate for treatment of life threatening epistaxis in Glanzmann’s thrombasthenia

1 Nichols W, Hultin M, James A et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel Report (USA). Haemophilia 2008; 14: 171–232. 2 Medical and Scientific Advisory Council of the National Hemophilia Foundation Recommendation # 185: MASAC Recommendation Regarding Women with Inherited Bleeding Disorders. Available at http://www.hemophilia.org/NHFWeb/MainPgs/ MainNHF.aspx?menuid=57&contentid=1192. Accessed May 29, 2009. 3 Acharya S, Dimichele D. Rare inherited disorders of fibrinogen. Haemophilia 2008; 14: 1151–8.

Bariatric surgery in haemophilia

ment with rituximab, probably given every 12 months given this patient’s antibody kinetics, might be of benefit as this has been reported in patients with relapsing immune thromobocytopenic purpura [3]. Unfortunately, we have not been able to procure the drug for this use. In addition to describing this unusual case and its successful treatment, it has been our intention to contribute to the global knowledge of disorders of haemostasis associated with the emergence of autoimmune antibodies. There is considerable experience in treating more common disorders, such autoimmune thrombocytopenia, with rituximab, yet haematologists face difficult decisions when treating less common diseases, such as immune thrombotic thrombocytopenic purpura or spontaneously acquired antibodies against factor VIII [4] or V (as in our case). It is unlikely there will ever be any high level evidence to recommend for or against the use of rituximab for these extremely rare conditions, however, disease registries can be very informative. We agree with a recent commentary by A. Cuker[5] regarding these difficult decisions, especially in light of potentially devastating relapses. We believe that, specifically, when facing life threatening recurrences of uncontrollable bleeding or thrombosis stemming from these rare disease entities, it is more than acceptable to inform our patients about our incomplete state of knowledge regarding comparative efficacy, the known potential risks and potential benefits, as reported by others, and to make a joint decision about incompletely evaluated therapies.

Detection of CALR Mutation in Clonal and Nonclonal Hematologic Diseases Using Fragment Analysis and Next-Generation Sequencing

OBJECTIVESnTo describe three methods used to screen for frameshift mutations in exon 9 of the CALR gene.nnnMETHODSnGenomic DNA from 47 patients was extracted from peripheral blood and bone marrow using the EZ1 DNA Blood Kit (Qiagen, Valencia, CA) and quantified by the Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen, San Diego, CA). After clinical history, cytogenetics, and molecular tests, patients were diagnosed with either clonal or nonclonal hematologic diseases. CALR screening was primarily performed using fragment analysis polymerase chain reaction, then next-generation sequencing and Sanger sequencing.nnnRESULTSnAmong the 18 patients diagnosed with clonal diseases, one had acute myeloid leukemia (positive for trisomy 8), and 17 had myeloproliferative neoplasms (MPNs), including chronic myeloid leukemia (CML), essential thrombocythemia (ET), primary myelofibrosis (PMF), and polycythemia vera (PV). Patients with CML were positive for the BCR-ABL1 fusion. Ten patients were positive for JAK2 (PMF, nu2009=u20091; ET, nu2009=u20092; PV, nu2009=u20097), and three were CALR positive (ET, nu2009=u20091; PMF, nu2009=u20092). Patients diagnosed with a nonclonal disease were negative for JAK2, BCR-ABL, and CALR mutations.nnnCONCLUSIONSnScreening for CALR mutations is essential in BCR-ABL-negative MPNs since it not only provides valuable diagnostic and prognostic information but also identifies potential treatment targets. Since this study describes the importance of screening for known and novel biomarkers, we described in detail three methods that could be easily integrated into a clinical laboratory.

The different faces of myelodysplasia in peripheral blood granulocytes.

A 75 year-old woman presented with fevers, night sweats and weight loss four months after completing a course of adjuvant chemotherapy for ovarian cancer. A CBC showed normocytic anemia (hemoglobin 56 g/L), thrombocytopenia (34 3 10/L) and leukocytosis (16.6 3 10/L) with a granulocyte left-shift and 11% blasts. The peripheral blood findings seen in this patient illustrate the different manifestations of myelodysplasia in the granulocytes: cells with ring nuclei (Figure 1, panels A and B), christened “donut cells”; cells with abnormal cytoplasmic granules (pseudo Chediak-Higashi granules; panel C), and bi-lobed nuclei (pseudo Pelger-Huet cells; panel D and panel E, arrow). Platelets were large and agranular (panel D, arrow) which are also part of the underlying dysplasia. Nucleated RBCs were also present in the peripheral blood suggesting trilineage dysplasia (panel F). The bone marrow was hypercellular with trilineage dysplasia and 22% myeloblasts with a complex karyotype (including del-5q and del-7). [1] She was treated with four cycles of decitabine, resulting in resolution of fevers, eradication of bone marrow blasts, and restoration of normal hematopoiesis.[2] Evidence for a salutary effect of the hypomethylating agent in this patient was seen also by restoration of normal peripheral blood cells morphology (panels G–I). This case illustrates several unique morphological changes in dysplastic granulocytes on a peripheral blood smear in one patient with secondary acute myeloid leukemia.

Hematuria in a Former Smoker

A 75-year-old woman presented with painless, massive hematuria. She was a former smoker but had no history of a bleeding disorder. Laboratory studies revealed a hemoglobin level of 6.7 g/dL [reference interval (RI) 11.2–15.7], prothrombin time (PT)2 of 47.9 s (RI 12.5–15.5), activated partial thromboplastin time (aPTT) of >160 s (RI 25–35), and a thrombin time of …

Küttner Tumor: IgG4-Related Disease of the Submandibular Gland

Küttner tumor/chronic sclerosing sialadenitis is a fibroinflammatory process that characteristically involves the submandibular gland of patients with IgG4-related disease. Histologic examination is often important to make the diagnosis because of its nonspecific clinical and radiologic findings. Microscopically, Küttner tumor should be distinguished from other entities such as extranodal marginal zone lymphoma, Sjögren’s syndrome, and lymphoepithelial sialadenitis. The lesion is histologically well-demarcated with lobular architecture, extensive fibrosis, marked lymphoplasmacytic inflammation, formation of lymphoid follicles, acinar atrophy, and obliterative phlebitis, without the presence of lymphoepithelial lesions. The IgG4-to-IgG positive plasma cell ratio of >40xa0% is also an important feature to support the diagnosis of Küttner tumor. Moreover, flow cytometry is helpful to exclude a lymphoproliferative process. Clinicians and pathologists should consider the diagnosis of Küttner tumor in patients with elevated serum IgG4 level. Timely and accurate diagnosis is important for appropriate management.

Thromboprophylaxis and Outcomes for Total Joint Arthroplasty in Congenital Bleeding Disorders: A Single-Center Experience.

Total joint arthroplasty (TJA) improves the quality of life for patients with end-stage osteoarthritis but is associated with an increased risk of venous thromboembolism (VTE), thus pharmacologic thromboprophylaxis is recommended for most patients. Patients with congenital bleeding disorders may develop severe arthropathies due to repeated hemarthroses and derive similar benefit from TJA as the general population. No guidelines for pharmacologic thromboprophylaxis in this population exist, however, as the risks and benefits are not well defined. We undertook the current study to assess the safety and efficacy of pharmacologic VTE prophylaxis in patients with congenital bleeding disorders undergoing TJA. We retrospectively reviewed the medical records of patients with bleeding disorders who underwent TJA at our academic institution between 1987 and 2012. We identified 28 patients who underwent 38 TJA procedures. Low-molecular-weight heparin (LMWH) was administered in 29 procedures (76%) and was discontinued early in 3 procedures (2 patients) due to nonjoint bleeding. No symptomatic VTE was identified, and no joint or deep wound infections were seen. Twenty-two patients accounting for 31 procedures were contacted to discuss their experience with TJA. All reported decreased pain, and 97% reported improved function after the surgery. Impressively, 97% stated that they would choose to have the surgery again. These results confirm the benefit of TJA in patients with congenital bleeding disorders and end-stage arthropathies and suggest that LMWH thromboprophylaxis is safe. No patient in our cohort developed symptomatic VTE, whether or not thromboprophylaxis was administered, thus necessity of thromboprophylaxis remains an unanswered question.

Unexpected finding in a femoral head specimen after elective total hip arthroplasty.

To the Editor: Mastocytosis is a myeloproliferative neoplasm with cutaneous and/or systemic manifestations. The disease occurs in all age groups, with the cutaneous version more common in children and systemic mastocytosis (SM) generally occurring later in life. The initial presentation of SM ranges from no or mild nonspecific constitutional symptoms to end organ dysfunction or pain associated with the site(s) of disease. We describe a case of unexpected systemic mastocytosis diagnosed on routine pathology evaluation of a femoral head from a total hip arthroplasty (THA) procedure. Our experience highlights the importance of vigilance when evaluating apparently routine specimens submitted for suspected bone and joint pathology. A 49 year-old otherwise healthy woman presented with bilateral hip pain, worse on the right than on the left side. A magnetic resonance imaging scan showed multifocal cartilage loss on both sides of the right hip joint and tears of the anterior and superior labrum. The pain only partially improved with conservative measures and eventually caused severe limitation in her normal daily activities. Later imaging studies showed dysplasia and small osteophytes on both femoral head surfaces. Intra-articular corticosteroid injections provided short-term relief, and she ultimately opted for bilateral THA performed as sequential procedures. A pre-operative complete blood count was unremarkable, with normal absolute values for all white blood cell lineages. The femoral heads were submitted to surgical pathology and showed mild osteoarthritis grossly. Histologic review confirmed mild osteoarthritis but also showed an abnormal bone marrow leading to subspecialty consultation with hematopathology and further diagnostic evaluation. Grossly the right femoral head showed eburnation, osteophytes and subchondral sclerosis on the cut surface, consistent with osteoarthritis. Microscopically, the bone marrow was hypercellular and showed polyclonal Band Tcell lymphoid aggregates with admixed eosinophils and histiocytes. Large collections of atypical mast cells with spindled and round morphology (Fig. 1a and insert) were closely associated to the lymphohistiocytic aggregates. In addition, atypical, faintly granular, mast cells were dispersed singly in an interstitial pattern throughout the marrow space. Immunohistochemistry was performed on formalin-fixed paraffin embedded tissue using the Leica BOND system (Newcastle, UK) with antibodies directed against the following antigens: CD1a, CD2, CD3, CD15, CD20, CD30, CD117 (C-KIT), PAX-5 (Leica, premade antibodies diluted by the manufacturer), mast cell tryptase (1:200, Dako, Carpinteria, CA, USA), CD45 (premade antibodies diluted by the manufacturer, Biogenex, Freemont, CA, USA). Standard immunohistochemical protocols were followed with negative and positive controls run concurrently. The abnormal mast cells expressed CD117 (C-KIT), tryptase and CD25 (Fig. 1b–d) but lacked CD2 and CD30 (not shown). Additionally, the atypical cells were negative for CD20, CD3, CD15, PAX-5 and CD1a. Stains for acid-fast bacilli and fungi were negative. The surgical specimen from the subsequent left THA showed similar histologic features, consistent with a mast cell neoplasm. Follow up laboratory testing performed later on the peripheral blood revealed an elevated serum tryptase level (26.8 ng/mL; normal <11.5 ng/mL) and the presence of the KIT activating mutation, Asp816Val. Our institutional policy for handling femoral head specimens submitted with a clinical diagnosis of osteoarthritis (OA) calls for gross examination of multiple cross sections and review of the clinical history. Histologic evaluation is reserved for any specimen with additional clinical questions, gross osteonecrosis or fracture, abnormal lesions not included in the spectrum of OA, or specimens lacking typical gross findings of OA. Though a neoplastic disease was unexpected in this patient, the orthopedic surgeon suspected a pathologic process in addition to osteoarthritis, thus prompting histologic evaluation of the resected femoral heads. SM is a neoplastic disorder in which mast cells proliferate in one or more extracutaneous organs and is subdivided into aggressive (ASM) and indolent (ISM) forms. Though many SM patients show skin manifestations, the aggressive form usually lacks skin involvement. Conversely, organomegaly, organ dysfunction and skeletal involvement with osteolytic lesions or pathologic fractures are associated with ASM but not with the indolent form. Symptoms associated with SM may be due to local effects of organ and tissue infiltration and/or systemic effects of potent mast cell mediators. The World Health Organization (WHO) has published criteria for diagnosis of the various forms of SM. The patient we describe met all of the WHO criteria for SM (dense mast cell infiltrates with abnormal morphology and immunophenotype, activating KIT mutation, elevated serum tryptase level). Subsequent clinical and radiographic evaluation identified no skin lesions, organ dysfunction or skeletal pathology, thus her mast cell disorder was classified as isolated bone marrow Disclosure: The authors have no relevant disclosures. Pathology International 2014; 64: 585–587 doi:10.1111/pin.12210 bs_bs_banner