Marcelo Gomes

Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience.

We conducted a retrospective review to assess outcomes of therapy in patients with newly diagnosed Wegener granulomatosis (WG) using methotrexate (MTX) for mild to moderate disease and short-term treatment with cyclophosphamide (CYC) followed by MTX for severe disease. Patients with WG were included if their initial plan of therapy and subsequent care were directly supervised by the Cleveland Clinic Center for Vasculitis Care and Research. Severe disease (immediately life-threatening or involving critical organs) was initially treated with CYC and glucocorticoids. Mild to moderate disease was initially treated with MTX and glucocorticoids if serum creatinine was less than 2 mg/dL. Following initial improvement of severe disease, treatment was changed to MTX if serum creatinine was originally less than 2 mg/dL or had diminished to less than 2 mg/dL. Disease activity was determined at each visit and later converted to a Birmingham Vasculitis Activity Score, as modified for Wegener granulomatosis (BVAS/WG). Laboratory monitoring of disease and treatment toxicity was initially weekly and never less than monthly. Eighty-two (32%) of 253 patients with WG referred to the Center for Vasculitis Care and Research met eligibility criteria. Ineligible patients did not have new-onset disease or were not able to be followed principally in our center. Seventy percent of patients (57/82) initially had severe disease and received a short course of CYC for remission induction. In over half of these patients, illness was judged to be severe because of pulmonary hemorrhage; rapidly progressive glomerulonephritis, including need for dialysis; or neurologic abnormalities. All patients improved: remission was achieved in 50% (41/82) of patients within 6 months and in 72% (59/82) within 12 months. Sustained remission (BVAS/WG = 0 for at least 6 consecutive months) was ultimately achieved in 78% (64/82) of patients. Among the 75 (91%) patients who achieved remission of any duration, 45% relapsed within 1 year and 66% relapsed within 2 years following remission. Eighty-two percent of relapsed patients achieved subsequent remissions after additional treatment. About three-quarters of relapses were mild and promptly responded to treatment. Seventeen percent of patients developed serious infections. CYC-associated cystitis or bladder cancer did not occur in any patients. At least 1 form of permanent morbidity from WG alone was noted in 74.0% of patients. Three patients (3.7%) died over a median follow-up period of 4.5 years; no deaths were due to active disease. Although treatment was primarily directed toward achieving clinical improvement and not calculated to achieve marked lymphopenia, patients in whom treatment produced lymphocyte counts of ≤500/mm3, sustained over a median time of 4 (quartiles: 1, 8.5) months, were 3.8 times more likely to achieve a sustained remission (p = 0.015). Conversely, following remission, an absolute lymphocyte count of >1000/mm3 was associated with a hazard ratio for relapse of 3.0, although the latter difference was not statistically significant. In patients with WG, a strategy that limits or avoids CYC therapy produced a frequency of remission comparable to that achieved with conventional CYC protocols, excellent survival, and avoidance of long-term CYC toxicity. However, relapses were common and incremental permanent morbidity occurred in most patients. While not a goal of therapy, when treatment produced marked lymphopenia, prolonged remissions were more likely. Abbreviations: ALC = absolute lymphocyte count, BVAS/WG = Birmingham Vasculitis Activity Score for WG, CYC = cyclophosphamide, EUVAS = European Vasculitis Study Group, GCS = glucocorticoid, MTX = methotrexate, NIH = National Institutes of Health, WBC = white blood cell, WG = Wegener granulomatosis, WGET = WG-etanercept trial.

Risk Assessment for Thrombosis in Cancer

Patients with active malignancy are well-known to be at higher risk for venous thromboembolism (VTE). However, the risk of VTE varies considerably between patients and in the same patient over the natural history of their malignancy. Multiple clinical risk factors including primary site of cancer, use of systemic therapy including novel targeted agents, surgery, and hospitalization are known to increase the risk of VTE. Multiple candidate biomarkers including tissue factor, D-dimer, and soluble P-selectin have been identified. However, risk cannot be reliably predicted based on single risk factors or biomarkers. A risk assessment score has been validated in multiple populations and can identify patients at high risk for cancer-associated VTE. This review discusses the risk factors, predictive biomarkers, and new guidelines, which recommend risk assessment of VTE for all cancer patients. Potential applications of risk assessment, including targeted thromboprophylaxis, are also identified in this review.

Bivalirudin for the treatment of patients with confirmed or suspected heparin-induced thrombocytopenia

Heparin‐induced thrombocytopenia (HIT) is an adverse immune‐mediated response to unfractionated heparin and, less commonly, low molecular weight heparin. It is associated with a high thrombotic risk and the potential for limb and life‐threatening complications. Argatroban is the only approved and currently available anticoagulant for HIT treatment in the USA.

Patients with inferior vena caval filters should receive chronic thromboprophylaxis

A 32-year-old man with testicular carcinoma is diagnosed with an acute left leg deep venous thrombosis (DVT) during his fourth cycle of combination chemotherapy. Because of anticipated moderate to severe thrombocytopenia, anticoagulation is initially avoided and an inferior vena cava (IVC) filter is placed to prevent pulmonary embolism (PE). After completion of all chemotherapy he is deemed to be in remission and anticoagulation is begun. The optimal duration of anticoagulation in this patient is pondered.

Hypercoagulable state testing and malignancy screening following venous thromboembolic events

Mounting interest in hypercoagulability, increased availability of hypercoagulable state test ‘panels’ and enhanced ability to identify abnormalities in tested patients have prompted widespread testing. Testing for acquired and inherited hypercoagulable states uncovers an abnormality in over 50% of patients presenting with an initial venous thromboembolic event (VTE) but may have minimal actual impact on management in most of these patients. Such laboratory screening should be reserved for patients in whom the results of individual tests will signifi cantly impact the choice of anticoagulant agent, intensity of anticoagulant therapy, therapeutic monitoring, family screening, family planning, prognosis determination, and most of all duration of therapy. Testing ‘just to know’ is neither cost-effective nor clinically appropriate. The most important testing in patients following acute VTE may be ageand gender-specifi c cancer screening. Cancer screening following VTE seems most prudent in older individuals and in those with idiopathic VTE and no laboratory evidence for an inherited hypercoagulable state. Cancer screening should focus on identifi cation of treatable cancers and those where diagnosis in an early stage favorably impacts patient survival. Extensive searches for occult malignancy employing whole-body computed tomography and serum tumor markers may identify more cancers but without affecting patient outcome. We advocate that physicians should focus their attention more on VTE prophylaxis and proper treatment and less on costly and, at times, invasive testing of questionable value.

External validation of the HIT Expert Probability (HEP) score

The diagnosis of heparin-induced thrombocytopenia (HIT) can be challenging. The HIT Expert Probability (HEP) Score has recently been proposed to aid in the diagnosis of HIT. We sought to externally and prospectively validate the HEP score. We prospectively assessed pre-test probability of HIT for 51 consecutive patients referred to our Consultative Service for evaluation of possible HIT between August 1, 2012 and February 1, 2013. Two Vascular Medicine fellows independently applied the 4T and HEP scores for each patient. Two independent HIT expert adjudicators rendered a diagnosis of HIT likely or unlikely. The median (interquartile range) of 4T and HEP scores were 4.5 (3.0, 6.0) and 5 (3.0, 8.5), respectively. There were no significant differences between area under receiver-operating characteristic curves of 4T and HEP scores against the gold standard, confirmed HIT [defined as positive serotonin release assay and positive anti-PF4/heparin ELISA] (0.74 vs 0.73, p = 0.97). HEP score ≥ 2 was 100 % sensitive and 16 % specific for determining the presence of confirmed HIT while a 4T score > 3 was 93 % sensitive and 35 % specific. In conclusion, the HEP and 4T scores are excellent screening pre-test probability models for HIT, however, in this prospective validation study, test characteristics for the diagnosis of HIT based on confirmatory laboratory testing and expert opinion are similar. Given the complexity of the HEP scoring model compared to that of the 4T score, further validation of the HEP score is warranted prior to widespread clinical acceptance.

Transitioning Between Anticoagulants

There has been rapid growth in the development of anticoagulant drugs. Unfortunately, an “ideal” anticoagulant—one that is rapid-acting and fully reversible, does not require monitoring, and can be used in patients with end-stage renal disease and moderate-severe liver dysfunction—is not available to date. Currently, the differences in the pharmacokinetic and pharmacodynamic properties of each agent allow for a unique, individualized anticoagulation plan for different patients with different underlying indications for anticoagulation therapy. Because of the multiple options for both parenteral and oral anticoagulation available, transitioning between anticoagulants is becoming increasingly common both in the inpatient and outpatient settings. Given the absence of prospective randomized data comparing different strategies for transition between anticoagulants, suggested strategies are largely extrapolated from pharmacokinetic data, as well as from expert opinions. Despite limited data, better understanding on how to safely implement a transition from one anticoagulant drug to another is of utmost importance to minimize the risk of recurrent thromboembolic events and hemorrhagic complications during such periods of transition between different drugs.

Heparin-induced thrombocytopenia (HIT)

Heparin-induced thrombocytopenia, or HIT, occurs in some patients who have been taking the anticoagulant (blood thinner) heparin. Less commonly, drugs related to heparin called low-molecular-weight heparins (LMWHs) can cause HIT. Heparin and LMWH are used to treat clotting disorders, to prevent blood clots in certain heart conditions, and to prevent blood clots in patients who have undergone surgery or are hospitalized. Thrombocytopenia is the medical term for low platelets, which are blood cell fragments that help with clotting the blood in response to injury. A normal platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. The platelet count is low if it is less than 150,000. Platelets are measured on a routine blood test called a ‘CBC’ or complete blood count. Antibodies are blood proteins the body makes against substances it recognizes as foreign to help eliminate them. For example, people who catch the flu make antibodies that help fight the flu virus. In a similar way, vaccines trigger the body to make antibodies against infectious diseases like hepatitis or measles. Sometimes, though, the body makes antibodies to medications or, in the case of autoimmune diseases like rheumatoid arthritis and lupus, to parts of the body. HIT occurs when heparin or LMWH cause an immune reaction that creates antibodies that attach to platelets and heparin at the same time, causing platelets to stick together and be abnormally active, despite their low level in the bloodstream. When this occurs, the affected person is at high risk for developing blood clots in any blood vessel in the body.

Venous Thromboembolism After Adult Lung Transplantation: A Frequent Event Associated with Lower Survival

Background The incidence of venous thromboembolism (VTE) after lung transplantation (LTX) varies significantly across studies. Two studies have suggested that these thrombotic events are associated with a lower posttransplant survival. Herein, we sought to determine the incidence, predictors, and impact of VTE on survival after LTX at a quaternary referral center. Methods This was a large cohort study of LTX recipients. Key outcome parameters were time to VTE after transplant and survival. Deep vein thrombosis (DVT) diagnosis required a positive ultrasound. Pulmonary embolism diagnosis required either a positive chest computed tomography angiogram or a high-probability ventilation/perfusion scan. Results The overall incidence of VTE among 701 LTX recipients was 43.8%, of which 97.7% were DVT episodes, of which 71.3% were in the upper extremities. Predictors of VTE were prior history of DVT (hazard ratio [HR], 2.82; 95% confidence interval [CI], 1.49-5.37), days in intensive care (HR, 1.01; 95% CI, 1.01-1.02), and the use of extracorporeal membrane oxygenation (HR, 2.22; 95% CI, 1.43-3.45). Importantly, VTE predicted a lower posttransplant survival (HR, 1.70; 95% CI, 1.28-2.26), when occurring within or after the first 30 days. The location of the DVT, either upper extremity or below the knee, also predicted a poor survival. Conclusions VTE was frequent in LTX recipients and predicted a poor survival even when located in the upper extremities or below the knee. These data suggest that aggressive VTE screening/treatment protocols be implemented in post-LTX population.

Pulmonary Thromboendarterectomy in the Setting of a Mediastinal Venous Malformation with a Congenitally Absent Left Subclavian Vein

Venous malformations have static venous lakes that predispose to spontaneous venous thrombosis within the malformation due to its low-flow static state. Thrombi of varying sizes can then embolize continually into the pulmonary arterial circulation, and occlude and narrow elastic pulmonary arteries causing chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary thromboendarterectomy (PTE) is potentially curative in CTEPH, but has not been previously reported in the setting of mediastinal and chest wall venous malformations. We report the case of a 21-year-old female with such a large malformation treated successfully with PTE. The patient underwent complete endovascular reconstruction of her subclavian vein system from the axillary vein to the innominate vein stump with covered stent grafts to exclude the malformations from causing recurrent pulmonary emboli. This was followed by embolization of the malformation to allow for the surgical approach. The series of events in this case serves as a novel approach in managing such rare patients.