Janis Bormanis

Value of assessment of pretest probability of deep-vein thrombosis in clinical management

BACKGROUND When ultrasonography is used to investigate deep-vein thrombosis, serial testing is recommended for those who test negative initially. Serial testing is inconvenient for patients and costly. We aimed to assess whether the calculation of pretest probability of deep-vein thrombosis, with a simple clinical model, could be used to improve the management of patients who present with suspected deep-vein thrombosis. METHODS Consecutive outpatients with suspected deep-vein thrombosis had their pretest probability calculated with a clinical model. They then underwent compression ultrasound imaging of proximal veins of the legs. Patients at low pretest probability underwent a single ultrasound test. A negative ultrasound excluded the diagnosis of deep-vein thrombosis whereas a positive ultrasound was confirmed by venography. Patients at moderate pretest probability with a positive ultrasound were treated for deep-vein thrombosis whereas patients with an initial negative ultrasound underwent a single follow-up ultrasound 1 week later. Patients at high pretest probability with a positive ultrasound were treated whereas those with negative ultrasound underwent venography. All patients were followed up for 3 months for thromboembolic complications. FINDINGS 95 (16.0%) of all 593 patients had deep-vein thrombosis; 3%, 17%, and 75% of the patients with low, moderate, and high pretest probability, respectively, had deep-vein thrombosis. Ten of 329 patients with low pretest probability had the diagnosis confirmed, nine at initial testing and one at follow-up. 32 of 193 patients with moderate pretest probability had deep-vein thrombosis, three diagnosed by the serial (1 week) test, and two during follow-up. 53 of 71 patients with high pretest probability had deep-vein thrombosis (49 by the initial ultrasound and four by venography). Only three (0.6%) of all 501 (95% CI 0.1-1.8) patients diagnosed as not having deep-vein thrombosis had events during the 3-month follow-up. Overall only 33 (5.6%) of 593 patients required venography and serial testing was limited to 166 (28%) of 593 patients. INTERPRETATION Management of patients with suspected deep-vein thrombosis based on clinical probability and ultrasound of the proximal deep veins is safe and feasible. Our strategy reduced the need for serial ultrasound testing and reduced the rate of false-negative or false-positive ultrasound studies.

Sensitivity and Specificity of a Rapid Whole-Blood Assay for D-Dimer in the Diagnosis of Pulmonary Embolism

Objective testing is necessary to diagnose pulmonary embolism because clinical diagnosis alone is not accurate [1]. Diagnostic algorithms for patients with suspected pulmonary embolism usually involve ventilation-perfusion lung scanning as the initial test. If the scan is normal, pulmonary embolism is excluded; if it shows high probability, pulmonary embolism is diagnosed in most patients; and if it is nondiagnostic (also called non-high-probability, indeterminate, intermediate-probability, or low-probability), further testing is necessary [2-4]. In patients with nondiagnostic scans, who account for more than half of patients with suspected pulmonary embolism, the prevalence of pulmonary embolism is as high as 25%; thus, further investigation is necessary [2, 3]. Pulmonary angiography (the reference standard) or serial compression ultrasonography or impedance plethysmography over 14 days should be done in these patients to identify and treat those who develop proximal deep venous thrombosis [5]. However, these approaches are relatively costly, and pulmonary angiography is invasive. Accordingly, a simple test or combination of tests that could obviate the need to perform further tests in patients with nondiagnostic lung scans would be useful. Recently, high levels of d-dimer, a specific fibrin degradation product, were reported in studies of patients with deep venous thrombosis and pulmonary embolism [6-20]. The SimpliRED assay (Agen Biomedical, Ltd., Brisbane, Australia) is a whole-blood d-dimer assay that is suitable for bedside testing on both capillary and venipuncture samples and provides a result within 5 minutes, obviating the need to centrifuge blood and process plasma. Studies that we recently performed suggested that this assay reliably excludes deep venous thrombosis and pulmonary embolism when results are negative; these findings provided the impetus for the current study [17, 19, 20]. In addition, because our previous study of pulmonary embolism was relatively small [20], the results required confirmation in a larger study. To determine the sensitivity and specificity of the d-dimer assay in patients with suspected pulmonary embolism and to determine whether a negative d-dimer test result could be of value in excluding pulmonary embolism in patients with low pretest clinical probability, nondiagnostic lung scans, or both, we performed a cohort study of more than 1000 patients with suspected pulmonary embolism. Methods The study was performed from September 1993 to May 1996 and was approved by the institutional review boards of each participating hospital. Patients We included most patients from a recent management study that evaluated a standardized clinical model of pretest probability and developed a management strategy involving serial compression ultrasonography in most patients with nondiagnostic lung scans [21]. Thus, our sample comprised consecutive patients 18 years of age or older with clinically suspected acute pulmonary embolism who were referred to thromboembolism consultants at one of the participating tertiary-care hospitals: Chedoke-McMaster Hospitals and Hamilton Civic Hospitals, Hamilton, Ontario, Canada; Ottawa Civic Hospital, Ottawa, Ontario, Canada; and Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada. Patients were excluded from the study if they met any of the following criteria: 1) suspected upper-extremity deep venous thrombosis, 2) no symptoms within 48 hours of presentation, 3) treatment with anticoagulants for 72 hours or more, 4) life expectancy less than 3 months, 5) contraindication to contrast media, or 6) geographic inaccessibility. Informed consent was obtained from all patients in the study. Clinical Assessment Patients with clinically suspected pulmonary embolism were seen by a physician or nurse-practitioner (or both) on the health centers thromboembolism service. A history was taken and physical examination was done. Independent of diagnostic testing, all patients had clinical assessment of pretest probability, which was categorized as high, moderate, or low, as described elsewhere [21]. This evaluation involved assessment of 1) presenting symptoms and signs, 2) risk factors for venous thromboembolism, and 3) presence or absence of an alternative diagnosis at least as likely as pulmonary embolism. Objective Testing for Pulmonary Embolism The management approach used in the patient population is summarized in Figure 1. Ventilation-perfusion lung scanning was done in all patients within 24 hours of presentation by using a technique described elsewhere [22]. Scans were classified as normal (that is, the perfusion scan was normal), high probability (segmental or larger perfusion defects with normal ventilation) or nondiagnostic (perfusion defects not meeting criteria for a high-probability scan) [2]. All patients also had bilateral compression ultrasonography from the common femoral vein to the calf trifurcation within 24 hours of presentation, which was performed and interpreted according to a technique described elsewhere [23]. Figure 1. Diagnostic strategy. Patients with nondiagnostic lung scans, low or moderate pretest probability, and a normal initial compression ultrasonogram had repeated compression ultrasonography on days 3 to 5, 6 to 8, and 13 to 15. Anticoagulation was withheld provided that the results of compression ultrasonography remained normal. If the initial or serial ultrasonogram was abnormal, pulmonary embolism was diagnosed. Patients with nondiagnostic scans, high pretest probability, and normal initial compression ultrasonograms underwent venography; if the results of this test were normal, pulmonary angiography was done. If the perfusion lung scan was normal, compression ultrasonography was performed; if ultrasonography results were normal, no further testing was done and pulmonary embolism was considered excluded. If the results were abnormal, pulmonary embolism was diagnosed. Patients with a high-probability lung scan and a high or moderate pretest probability were considered to have pulmonary embolism regardless of compression ultrasonography results. Patients with a high-probability scan, low pretest probability, and normal initial compression ultrasonograms had venography; if venograms were normal, these patients also underwent pulmonary angiography. All patients who did not receive anticoagulants were followed-up for 3 months for the presence or absence of symptomatic venous thromboembolism by clinical evaluation. This consisted of a careful history to elicit symptoms of pulmonary embolism or deep venous thrombosis and appropriate investigation if such symptoms occurred. The final classification of patients as positive or negative for pulmonary embolism was based on a heterogeneous group of outcome measures. Patients were classified as positive if one or more of the following occurred: positive pulmonary angiogram; positive compression ultrasonogram (at any time) or positive contrast venogram; high-probability perfusion lung scan plus moderate or high pretest probability; or symptomatic, objectively confirmed venous thromboembolism during the 3-month follow-up. All other patients were classified as negative. Patients considered positive for pulmonary embolism received full-dose intravenous heparin or subcutaneous low-molecular-weight heparin followed by at least 3 months of oral anticoagulation. Patients who were considered negative for pulmonary embolism did not receive anticoagulant therapy. Measurement of D-Dimer Levels Blood was taken and processed by a research assistant for quantitation of d-dimer by the SimpliRED assay at the time of referral to the thromboembolism consultants. Results were categorized as normal or abnormal on the basis of the absence (normal) or presence (abnormal) of erythrocyte agglutination. This corresponds to the interpretation of d-dimer assay results used in our previous studies [17, 19, 20]. The method for the performance of the assay has been described comprehensively elsewhere [18]. The results of the d-dimer assay were not disclosed to caregivers and were obtained independently of the pretest probability assessment and results of other diagnostic tests. This assay has been shown to have excellent interobserver agreement ( = 0.95 [95% CI, 0.88 to 1.0]), between-assay agreement ( = 0.96 [CI, 0.90 to 1.0]), and reproducibility (97%) [24]. Statistical Analysis Negative predictive values, likelihood ratios, and posterior probabilities and their corresponding exact 95% CIs were calculated by using the binomial distribution [25]. Role of Industry Sponsor Agen Biomedical, Ltd., donated the d-dimer kits but had no role in the design or conduct of the study or the decision to submit this paper for publication. Results During the study, 1881 patients were screened for eligibility. Of these, 484 were excluded because of prolonged anticoagulant therapy (n = 158), expected survival less than 3 months (n = 89), geographic inaccessibility (n = 68), contraindication to contrast medium (n = 60), attending physician refusal (n = 57), pregnancy (n = 23), suspected upper-extremity deep venous thrombosis (n = 17), lack of acute symptoms within 72 hours (n = 7), or age younger than 18 years (n = 5). Of the 1397 eligible patients, 1250 (89%) agreed to enter the study. Of the consenting patients, 2 had inadequate lung scans, 58 could not undergo d-dimer assays because of assay unavailability, and 13 were lost to follow-up and could not be included. Therefore, 1177 patients (59% women; mean age, 53.4 years [range, 20 to 94 years]) were included in the final analysis. Of the 1177 patients, 197 (17%) were classified by the end of the study as positive for pulmonary embolism. None of the 980 patients classified as negative for pulmonary embolism after initial testing died of pulmonary embolism during follow-up. Overall, the d-dimer assay showed a sensitivity of 84.8%, a specificity of 68.4%, a likelihood r

Günther Tulip Filter: Preliminary Clinical Experience with Retrieval

PURPOSE The Günther Tulip filter is a permanent filter that has a hook to permit retrieval. The authors report their preliminary clinical evaluation of the filter with regard to feasibility and safety of retrieval. MATERIALS AND METHODS Nine men and six women who ranged in age from 17 to 79 years (mean, 51 years) underwent treatment with use of the Günther Tulip filter. Patients judged to require caval interruption for < 14 days were selected to receive the filter and retrieval was planned for all patients. Indications for filter placement were: recent pulmonary embolism (PE) or proximal deep vein thrombosis (DVT) with a contraindication to anticoagulation (11 patients), massive PE treated with thrombolytic therapy (one patient), PE with heparin-induced thrombocytopenia (one patient), and prophylaxis after major trauma (two patients). Patients were followed for inferior vena cava (IVC) thrombosis, bleeding, and recurrent DVT or PE. RESULTS In all nine patients in whom it was attempted, the filter was successfully snared and retrieved via a jugular approach. The mean implantation period was 8.6 days (range, 5-13 days). Retrieval required 2.2-13 minutes (mean 5.3 minutes) of fluoroscopy. No caval injuries occurred as a result of retrieval. All retrieved filters had strands of organized thrombus on the filter struts. The patients were followed for 52-285 days (mean, 115 days) after retrieval. One patient developed a recurrent DVT 230 days after retrieval. No other patients developed a recurrent DVT and no patients developed IVC thrombosis, bleeding, or PE. Six filters were not retrieved: five because of an ongoing contraindication to anticoagulation and one because the patient died of causes unrelated to the filter. CONCLUSION This preliminary study confirms the feasibility and safety of retrieval of the Günther Tulip filter up to 13 days after implantation.

Preliminary Clinical Experience with the Gunther Temporary Inferior Vena Cava Filter

PURPOSE The authors describe their preliminary clinical experience with the Gunther temporary inferior vena cava (IVC) filter. PATIENTS AND METHODS Seven women and 10 men, mean age 52 years (range, 19-85 years), were treated with the temporary IVC filter. Indications for filter placement were pulmonary embolism (PE) in four patients and iliofemoral deep venous thrombosis in six. In these patients anticoagulation was contraindicated because of planned major surgery. Filters were placed in four patients following massive PE and in three for prophylaxis following cranial trauma. Four patients had underlying malignant disease. Filters were introduced through the right common femoral vein in 14 patients, the left common femoral vein in two, and the left internal jugular vein in one. RESULTS No patient developed recurrent PE with the filter in place. All filters were removed without complication 3-14 days (mean, 7 days) after placement. Two of the patients with underlying malignant disease required placement of a permanent filter. Two patients developed IVC thrombosis with the filter in place, and both developed recurrent PE after filter removal. Two patients developed insertion vein thrombosis. One patient developed a bleeding disorder that caused a massive hematoma at the insertion vein site, which may have contributed to her death. CONCLUSION The Gunther temporary filter can be used in selected patients; however, patients with underlying malignant disease may be more appropriately treated with a permanent filter. The temporary filter does not appear to reduce the rate of insertion vein and IVC thrombosis.

Ancrod: A practical alternative to heparin

To rapidly start systemic anticoagulation there are few alternatives to heparin; those that may be used are often less effective and are impractical substitutes for various reasons. We report the cases of seven patients in whom anticoagulant therapy was begun with ancrod instead of heparin for one or more of the following reasons: (1) failure to achieve systemic anticoagulation in response to heparin (e.g., antithrombin III deficiency), (2) heparin-associated complications (e.g., thrombocytopenia, thrombosis, or both), and (3) combined anticoagulation and improved blood rheology considered to be potentially more beneficial than anticoagulation alone (e.g., massive thrombosis). In the cases reported, ancrod permitted systemic anticoagulation equal to that of heparin; this was achieved without bleeding complications. In contrast to streptokinase or urokinase, ancrod does not degrade preformed, fully cross-linked thrombin fibrin; consequently hemorrhagic complications are uncommon. Ancrod appears to be an appropriate alternative to heparin and may be preferable to it in certain circumstances.

Prothrombin complex concentrate for the urgent reversal of warfarin. Assessment of a standard dosing protocol

BACKGROUND Octaplex®, a six factor prothrombin complex concentrate (PCC), has recently been approved for use in Canada. The optimal dose of Octaplex has yet to be established and our study was designed to monitor the efficacy of a low standard dose. STUDY DESIGN AND METHODS Patients on warfarin treatment in need of urgent reversal for bleeding, invasive procedures or surgery were given a standard dose of 40 ml (1000 IU FIX, 14 IU/kg). We conducted a retrospective chart review of 231 patients. RESULTS Patients given concurrent frozen plasma (FP) for reversal were eliminated from the study. Overall, 150 patients were reviewed and divided into three groups: (1) non-CNS bleeders, (2) CNS bleeders, and (3) non-bleeders. Correction of INR to 1.5 or less was achieved to the same extent in each group. Patients with active bleeding had the least successful bleeding cessation and patients with intracranial bleeding had the most dismal outcome compared to non-intracranial bleeders. CONCLUSIONS Our data suggests that Octaplex, when given as a low standard dose is effective at INR reversal with 76% of our patients correcting to an INR of 1.5 or less. It appears that this dose is sufficient for non-bleeding patients. Bleeding patients may benefit most from a dose increase to achieve more complete reversal and patients with intracranial bleeding should achieve more complete reversal within 2h of presentation.

Leukemic reticuloendotheliosis: Polyclonal surface immunoglobulin on “hairy” cells

The cytochemistry, surface markers and functional properties of purified mononuclear cells obtained from the peripheral blood and spleen of a patient with leukemic reticuloendotheliosis were studied. Nonspecific esterase activity, a monocyte marker, was demonstrable in 83% of the peripheral blood mono‐nuclear cells and 84% of the splenic mononuclear cells. Rosetting techniques failed to detect T or B lymphocyte surface markers on the majority of the cells. Direct immunofluorescence revealed capped, noncytophilic surface immuno‐globulin on the cells with all immunoglobulin classes being detectable. Since noncapping conditions had been used during immunofluorescence staining, the observed caps were attributed to in vivo binding of autoantibodies to the “hairy” cells. This conclusion was supported by the demonstration of susceptibility of the “hairy” cells to lysis mediated by normal allogeneic lymphocytes. It is postulated that the “hairy” cells in this patient are leukemic monocytes which bear autoantibodies directed against leukemia associated antigens.

Trilineage myelodysplasia and hemophagocytosis associated with systemic lupus erythematosus

Marked trilineage myelodysplasia and hemophagocytosis was noted in the marrow of a 28-year old male of Filipino decent. Six days prior he had been admitted to the hospital for work-up of renal failure, proteinuria, hematuria, and pancytopenia. Past medical history was noteworthy for a 2-year history of a psoriatic like skin rash. The patient also had an emergency room visit for chest pain 1 week prior. He was diagnosed with likely pericarditis and discharged with indomethacin. At admission the patient’s initial laboratory investigation was significant for a creatinine of 270 lmol/L (normal 62–106), potassium of 5.9 mmol/L (normal 3.5–5.1), hemoglobin 104 g/L (normal 130–170), mean corpuscular volume (MCV) of 79.7 fL (normal 80–100), reticulocytopenia of 19.3 3 10/L (normal 25–100), neutrophil count of 2.0 3 10/L (normal 2–7.5), and a platelet count of 105 3 10/L (normal Image 1. Top two rows, left and middle: Evidence of dysplastic erythropoiesis: karyorrhexis (A), cytoplasmic nuclear dysynchrony predominantly in the late normoblasts (B), multinucleation (A,C), and nuclear blebbing (D). 31000 on oil. Top two rows, right: Micromegakaryocyte. 31000 on oil (above). Hemophagocytosis. 31000 on oil (below). Bottom two rows: Normocellular bone marrow with a few strikingly pyknotic megakaryocytes at 3200 and 3400, respectively (A,B), abnormal clustering of megakaryocytes at 3200 (C), mild gelatinous transformation occupying 10% of the core biopsy at3200 (D).

Disseminated histoplasmosis diagnosed by peripheral blood film in a patient with chronic lymphocytic leukaemia.

A 72-year-old Caucasian female had been diagnosed with chronic lymphocytic leukaemia (CLL) 4 years earlier and received the most recent dose of oral chlorambucil 1 month before presentation. She was admitted to a local hospital for treatment of febrile neutropenia with a blood culture positive for Klebsiella pneumoniae. Ten days later, she was transferred to a tertiary care hospital intensive care unit (ICU) for further diagnosis and treatment. She had fever, fluctuating loss of consciousness and clinical manifestations consistent with septic shock. Laboratory investigations showed a pancytopenia with a normocytic anaemia, haemoglobin concentration 93 g/l, thrombocytopenia (platelet count <10 9 10/l) and severe neutropenia (neutrophil count below detectable limits). Lactate dehydrogenase (LDH) was significantly elevated at 2134 iu/l (reference 100–205 iu/l). Chest radiography showed moderate to severe pulmonary oedema with bibasal atelectasis. A computerized tomography scan of the abdomen and pelvis demonstrated hepatosplenomegaly and lymphadenopathy consistent with the known diagnosis of CLL, and multiple small hypodense lesions in the spleen suggestive of lymphomatous deposits or splenic abscesses (left). The patient was treated with piperacillin-tazobactam, vancomycin, fluconazole and filgrastim. Microscopic evaluation of a peripheral blood film revealed rare neutrophils, a relative but not absolute lymphocytosis, smear cells and lymphocytes with clumped chromatin, compatible with CLL. A giant reactive monocyte with multiple intracellular yeast-like organisms was discovered at the feather-edge of the film. These organisms were about 2–4 lm in diameter and were eccentric within a typical clear pseudocapsule, findings diagnostic of Histoplasma capsulatum (right). Careful scrutiny of the whole film demonstrated a neutrophil with one organism inside the cytoplasm, which had the same morphological features. Only 10 neutrophils and/or monocytes were observed in the film, and of these, 3 (30%) contained 1–9 intracellular organisms per cell. Following the diagnosis of disseminated histoplasmosis, liposomal amphotericin was added to the treatment regimen. Additional histoplasmosis-specific workup was implemented, including fungal culture from both blood and tracheal aspirate and serological tests. Next day, the patient displayed evidence of respiratory failure and required urgent intubation. She deteriorated quickly and died 3 d after admission to ICU. Fungal culture from both blood and tracheal aspirate isolated Histoplasma capsulatum, confirming that patient had disseminated histoplasmosis. Disseminated histoplasmosis is a progressive haematogenous extra-pulmonary infection. It may occur in patients during the acute infection before cellular immunity develops or by reactivation in immunocompromised patients. In our patient, the clinical presentation of histoplasmosis, including lymphadenopathy and hepatosplenomegaly, was somewhat masked by the underlying CLL and febrile neutropenia that could be attributed to Klebsiella pneumoniae infection. But several clues existed for the diagnosis of histoplasmosis besides the peripheral blood film examination. One clue was the multiple hypodense areas in the spleen, which may have represented histoplasma abscesses. This case emphasizes the importance of microscopic examination of peripheral blood films. Zhaodong Xu, Greg German, Peter Jessamine, Janis Bormanis, Antonio Giulivi and Ruth Padmore Division of Hematopathology, Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, and Division of Medical Microbiology, Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, Canada. E-mail: zxu@toh.on.ca images in haematology

Current perceptions of Canadian autologous blood donors

Background and Objectives  We determined the perceptions and motivations of autologous donors to establish their regard for this process and the new blood system established in 1999 in Canada.