Citations

The propensity for both arterial and venous thrombotic disorders involves a genetic predetermination that operates In concert with environmental factors or triggers. Appropriate clinical assessment and therapeutic recommendations for patients with thrombosis requires a thorough knowledge of genetic variables that influence this propensity. This review focuses on the pathophysiology, natural history, and molecular biology of defined thrombophilic risk factors relevant to the care of patients with thrombotic disorders.

Spinal hematoma is a rare and potentially catastrophic complication of spinal or epidural anesthesia. The decision to perform spinal or epidural anesthesia or analgesia and the timing of catheter removal in a patient receiving antithrombotic therapy should be made on an individual basis, weighing the small, though definite risk of spinal hematoma with the benefits of regional anesthesia for a specific patient. Alternative anesthetic and analgesic techniques exist for patients considered an unacceptable risk. The patient's coagulation status should be optimized at the time the spinal or epidural needle or catheter is placed, and the level of anticoagulation must be carefully monitored during the period of epidural catheterization. Indwelling catheters should not be removed in the presence of therapeutic anticoagulation, as this appears to significantly increase the risk of spinal hematoma. Vigilance in monitoring is critical to allow early evaluation of neurologic dysfunction and prompt intervention.

Compared with adults, infants and children who undergo cardiopulmonary bypass for cardiac surgery present with a myriad of anticoagulation considerations. Inadequate anticoagulation during cardiopulmonary bypass may cause “subclinical” or “overt” thrombosis, while effective anticoagulation decreases excessive bleeding and transfusions. Current strategies for heparinization and its neutralization in pediatric patients undergoing congenital heart repair requiring cardiopulmonary bypass are examined. The coagulation system of the neonate and infant is immature and is further weakened by congenital heart disease. Changes in coagulation and fibrinolytic activity occur during cardiopulmonary bypass as a result of hemodilution and exposure of the blood to the extracorporeal circuit. Adequate anticoagulation is essential to minimize the thrombin generation that will result. The extent of excessive thrombin formation in pediatric patients undergoing cardiopulmonary bypass is better appreciated today than in the past, but no controlled study defines the optimal dose or technique for heparin dosing in these patients. Heparin concentration may even fall to 1.5 U/mL during cardiopulmonary bypass. However, the activated clotting time and heparin concentration correlate poorly. The ideal method to achieve adequate thrombin inhibition is unknown. Additionally, the dangers of excessive protamine are becoming more apparent. Heparin continues to be the most effective agent to achieve anticoagulation and protamine the most effective agent to neutralize it. A technique for heparin and protamine dosing with determination of heparin concentrations, may remove many variables associated with pediatric cardiac surgery that requires cardiopulmonary bypass and may provide clinicians with new therapies to achieve better anticoagulation for patients and consequently better outcomes.

Ongoing monitoring of heparin anticoagulation is an essential component of many cardiothoracic and vascular surgical procedures in order to prevent significant thrombotic and hemorrhagic complications. The classic test to assess high-dose (>1 unitlmL) heparin anticoagulation is the activated clotting time. Although simple to perform, the activated clotting time has many variations and can be affected by a number of nonanalytical and patient-related factors. Correlation with the heparin concentration may be poor. Alternatively, other test systems assess the individual patient's responsiveness to heparin in order to customize the heparin administration and subsequent protamine neutralization. The choice of test and system depends on the clinical application and the desired outcome. Regulatory and accreditation standards govern this type of testing; modern instrumentation can facilitate compliance with these standards. Understanding of the nature of the test and its performance under a variety of conditions is critical for proper interpretation.

We describe two examples of soft tissue perineurioma, a hard tumor, 1.7 cm in diameter, involving the dermis and superficial subcutaneous tissue of the left thumb, and the other a massive, lobulated lesion of the pelvis. Both occurred in 49-year-old men. Both were mobile and well demarcated but unencapsulated. Their cut surfaces were white and collagenous. Microscopically, each consisted of spindle-shaped or epithelioid tumor cells in a dense stroma of haphazardly oriented collagen bundles. Spindle-shaped cells were individually distributed, whereas epithelioid cells were often arranged in cords or clusters. Cytologic atypia was conspicuous in the massive tumor, but no mitotic activity was observed. Immunostains showed diffuse reactivity for vimentin, membrane pattern staining for epithelial membrane antigen and type IV collagen, as well as patchy CD34 reactivity. Stains for S-100 protein, Leu-7, smooth muscle actin, desmin, and cytokeratin were negative. Ultrastructural studies showed perineurial cell characteristics, including slender cytoplasmic processes, numerous pinocytotic vesicles, occasional tight junctions, and discontinuous surface basement membrane. Perineuriomas featuring marked stromal sclerosis often occur in the hands of young adults, as has recently been reported; the authors considered it a clinicopathologic variant. Herein we report two sclerotic perineuriomas, one a small tumor of the thumb and the other a centrally situated, massive pelvic tumor with sclerosis and degenerative cytologic atypia. We believe that exaggerated collagen deposition in perineuriomas, occasionally associated with degenerative nuclear changes, is not a manifestation of a unique, clinically relevant tumor variant but rather a manifestation of chronicity akin to that seen in “ancient schwannoma” and ‘atypical neurofibroma.’

Intraabdominal myositis ossificans (IMO) is a rare benign disorder characterized by reactive bone formation in intraabdominal soft tissue that should be distinguished from a malignant condition. We retrospectively searched our patient records and report 9 new cases of IMO. The lesions occurred in 7 men and 2 women with a mean age of 50 years (range, 24-76 years), 5 of whom had previous abdominal surgery. Histologically, all the cases were similar, consisting of a reactive mesenchymal process in adipose tissue. Mitosis was observed, but with no atypical forms, and the lesions lacked malignant cytologic features. IMO is an uncommon benign lesion that develops relatively rapidly. The pathogenesis is related to intraabdominal surgical procedures, but the exact mechanism remains to be determined.

Studies of the immunohistochemical profiles and clinical course of desmoplastic melanoma have produced conflicting results. We identified 28 cases of desmoplastic melanoma after a search of our files for spindle cell neoplasms of the head and neck from 1960 through 1995. The 17 male (61%) and 11 female (39%) patients averaged 65 years of age. The cheek was the most common location (12 cases, 43%). The average length of follow-up was 5 years. Overall 5-year survival rate was 46%. Melan A and tyrosinase positivity (P = 0.0195), smooth muscle actin positivity (P = 0.0328), tumor size (P = 0.0297), and tumor thickness (P = 0.0419) were significantly associated with local progression-free survival. No histologic or immunohistochemical marker was associated with overall or metastasis-free survival.

Abstract The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.

ABSTRACT Obesity is one of the major health problems of our times. Elucidating the signaling mechanisms by which high‐fat caloric diet induces obesity is critical for the understanding of this condition and for the development of therapeutic strategies for its treatment. Here, we demonstrate a novel role for protein CD38 as a regulator of body weight during a high‐fat diet. CD38 is a ubiquitous enzyme that catalyzes the synthesis of second messengers and has been implicated in the regulation of a wide variety of signaling pathways. We report that CD38‐deficient mice are pro‐tected against high‐fat diet‐induced obesity owing to enhanced energy expenditure. In fact, calorimetric studies indicate that CD38‐deficient animals have a higher metabolic rate compared to control mice. Analysis of the mechanism revealed that this resistance to diet‐induced obesity is mediated at least in part via a NAD‐dependent activation of SIRT‐PGC1α axis, a well‐established cascade, involved in the regulation of mito‐chondrial biogenesis and energy homeostasis. Thus, together these results identify a novel pathway regulating body weight and clearly show that CD38 is a nearly obligatory component of the cellular cascade that led to diet‐induced obesity.—Barbosa, M. T. P., Soares, S. M., Novak, C. M., Sinclair, D., Levine, J. A., Aksoy, P., Chini, E. N. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet‐induced obesity. FASEB J. 21, 3629–3639 (2007)

Attenuation of endothelial-dependent coronary vasodilation has been reported in idiopathic dilated cardiomyopathy and anatomically normal coronaries; however, data are insufficient for understanding the incidence and extent of this finding. The response of conductance and resistance coronary arteries to endothelial stimulation with acetylcholine was examined in 25 patients. Coronary blood flow had a variable response to acetylcholine and suggested coronary endothelial dysfunction in approximately half of the patients. Abnormal endothelial dysfunction involved the large conductance epicardial coronary arteries and the small resistance vessels. Abnormal endothelial response of coronary blood flow to acetylcholine could not be predicted by demographic and hemodynamic data. Conclusions: Coronary artery endothelial function is heterogeneous in patients with idiopathic dilated cardiomyopathy. Endothelial dysfunction is present in approximately half of the cases and involves both resistance as well as conductance coronary blood vessels. Furthermore, coronary endothelial function cannot be predicted by demographic and hemo-dynamic parameters or left ventricular ejection fraction.