A 2008 survey of American Association of Hip and Knee Surgeons membership explored current venous thromboembolism (VTE) protocols for lower-extremity total joint surgery. Fifty-three percent reported a change in VTE-related practices in the last 5 years. More than 70% reported that their primary hospital now mandates VTE prophylaxis. Although 74% of their primary hospitals recognized the American College of Chest Physicians guidelines, 68% of surgeons felt the American Academy of Orthopaedic Surgeons guidelines were more relevant to their practice. Respondents believe low molecular weight heparin to be the most efficacious but aspirin to be the easiest to use and has the lowest risks of bleeding and wound drainage. Warfarin was the most used in hospital prophylaxis, and 90% of respondents targeted an international normalized ratio of 1.6 to 2.5. Practice patterns continue to evolve, and there remains no consensus on specific treatment protocols or preferences.

Broadly speaking, C1 inhibitor plays important roles in the regulation of vascular permeability and in the suppression of inflammation. Vascular permeability control is exerted largely through inhibition of two of the proteases involved in the generation of bradykinin, factor XIIa and plasma kallikrein (the plasma kallikrein-kinin system). Anti-inflammatory functions, however, are exerted via several activities including inhibition of complement system proteases (C1r, C1s, MASP2) and the plasma kallikrein-kinin system proteases, in addition to interactions with a number of different proteins, cells and infectious agents. These more recently described, as yet incompletely characterized, activities serve several potential functions, including concentration of C1 inhibitor at sites of inflammation, inhibition of alternative complement pathway activation, inhibition of the biologic activities of gram negative endotoxin, enhancement of bacterial phagocytosis and killing, and suppression of the influx of leukocytes into a site of inflammation. C1 inhibitor has been shown to be therapeutically useful in a variety of animal models of inflammatory diseases, including gram negative bacterial sepsis and endotoxin shock, suppression of hyperacute transplant rejection, and treatment of a variety of ischemia-reperfusion injuries (heart, intestine, skeletal muscle, liver, brain). In humans, early data appear particularly promising in myocardial reperfusion injury. The mechanism (or mechanisms) of the effect of C1 inhibitor in these conditions is (are) not completely clear, but involve inhibition of complement and contact system activation, in addition to variable contributions from other C1 inhibitor activities that do not involve protease inhibition.

ABSTRACT: Hereditary angioedema is a serious medical condition caused by a deficiency of C1-inhibitor. The condition is the result of a defect in the gene controlling the synthesis of C1-inhibitor, which regulates the activity of a number of plasma cascade systems. Although the prevalence of hereditary angioedema is low - between 1:10,000 to 1:50,000 - the condition can result in considerable pain, debilitation, reduced quality of life, and even death in those afflicted. Hereditary angioedema presents clinically as cutaneous swelling of the extremities, face, genitals, and trunk, or painful swelling of the gastrointestinal mucosa. Angioedema of the upper airways is extremely serious and has resulted in death by asphyxiation. Subnormal levels of C1-inhibitor are associated with the inappropriate activation of a number of pathways - including, in particular, the complement and contact systems, and to some extent, the fibrinolysis and coagulation systems. Current findings indicate bradykinin, a product of contact system activation, as the primary mediator of angioedema in patients with C1-inhibitor deficiency. However, other systems may play a role in bradykininas rapid and excessive generation by depleting available levels of C1-inhibitor. There are currently no effective therapies in the United States to treat acute attacks of hereditary angioedema, and currently available agents used to treat hereditary angioedema prophylactically are suboptimal. Five new agents are, however, in Phase III development. Three of these agents replace C1-inhibitor, directly addressing the underlying cause of hereditary angioedema and re-establishing regulatory control of all pathways and proteases involved in its pathogenesis. These agents include a nano-filtered C1-inhibitor replacement therapy, a pasteurized C1-inhibitor, and a recombinant C1-inhibitor isolated from the milk of transgenic rabbits. All C1-inhibitors are being investigated for acute angioedema attacks; the nano-filtered C1-inhibitor is also being investigated for prophylaxis of attacks. The other two agents, a kallikrein inhibitor and a bradykinin receptor-2 antagonist, target contact system components that are mediators of vascular permeability. These mediators are formed by contact system activation as a result of C1-inhibitor consumption.

OBJECTIVE: To review the available evidence on the pathophysiologic mechanism of episodes of edema in hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed were searched using the following keywords: hereditary angioedema, C1 inhibitor, complement system, contact system, and bradykinin. STUDY SELECTION: Studies were selected based on their relevance to the pathophysiologic features of HAE. RESULTS: Early studies from the 1970s and 1980s disagreed as to whether the symptoms in HAE were mediated via complement or contact system activation. Studies have demonstrated that, in vitro, in C1 inhibitor (C1-INH)-deficient plasma, only contact system activation results in generation of a vascular permeability enhancing factor. Furthermore, individuals who express a variant C1-INH that is a normal inhibitor of contact system proteases but is deficient in the ability to inactivate complement system proteases do not develop angioedema. The blood of patients with HAE, during attacks, contains elevated levels of cleaved high-molecular-weight kininogen and bradykinin. Last, C1-INH-deficient mice develop increased vascular permeability that is mediated via contact system activation. CONCLUSIONS: Hereditary angioedema attacks are mediated by bradykinin generated via contact system activation. The specific factors that trigger attacks remain unclear.

BACKGROUND: It is commonly assumed that the aortic wall deforms uniformly and has uniform wall thickness about the circumference. The purpose of this study was to evaluate the aortic wall motion and thickness in the infrarenal aortic neck of patients with abdominal aortic aneurysms who were undergoing endovascular repair (EVAR) and to compare the dynamic measurements of intravascular ultrasonography with the static measurements of computed tomographic angiography (CTA). METHODS: A total of 25 patients were evaluated before surgery with CTA and three-dimensional reconstructions on a Vitrea workstation, followed by intraoperative assessment of the proximal aortic neck with intravascular ultrasonography (IVUS) before EVAR. Infrarenal aortic neck dimensions on CTA were obtained at 1-mm intervals, but for the purposes of this study all dimensions on CTA were obtained 1 cm below the lowest renal artery. IVUS analysis of the proximal aortic neck was obtained with a 10-second recorded data loop of aortic wall motion. A Digital Imaging and Communications in Medicine viewer was used to view the recorded loop of aortic movement, and each image was captured and then evaluated with a SCION PCI Frame Grabber to determine aortic dimensions and wall thickness. IVUS diameters (250 measurements of each aorta) were recorded through a full continuous cardiac cycle from the epicenter of the lumen (maintaining the left renal vein in its normal anatomic configuration) in an anteroposterior (AP) direction in the area of greatest wall movement and 90 degrees perpendicular to this direction (lateral movement). RESULTS: There was significant variation in infrarenal aortic wall movement about the circumference, with 1.7 +/- 0.6 mm (range, 0.6-2.7 mm) displacement in the AP direction and 0.9 +/- 0.5 mm (range, 0.3-1.5 mm) displacement in the lateral direction (P <.001). Aortic wall thickness was greater in the region of increased AP wall motion than in the area of lesser lateral wall motion (2.3 +/- 0.6 mm vs 1.2 +/- 0.3 mm; P <.001). There was no difference between the IVUS and CTA aortic neck measurements (25.5 vs 25.6 mm; not significant) during the midpoint of the cardiac cycle of IVUS. However, at peak systole, IVUS recorded a greater diameter than CTA (26.4 vs 25.6 mm; P <.001), and at end-diastole, IVUS recorded a smaller diameter than CTA (24.7 vs 25.6 mm; P =.01). CONCLUSIONS: The infrarenal neck of aortic aneurysms deforms anisotropically during the cardiac cycle. The greatest displacement is in the AP direction and corresponds with a significantly greater wall thickness in this area. The magnitude of cyclic change in aortic diameter can be as high as 11%. Further evaluation of proximal aortic neck wall motion after EVAR is warranted to determine the interaction of various stent designs and the aortic wall.

C1 inhibitor (C1INH) protects mice from lethal Gram-negative bacterial LPS-induced endotoxin shock and blocks the binding of LPS to the murine macrophage cell line, RAW 264.7, via an interaction with lipid A. Using the cecal ligation and puncture (CLP) model for sepsis in mice, treatment with C1INH improved survival in comparison with untreated controls. The effect was not solely the result of inhibition of complement and contact system activation because reactive center-cleaved, inactive C1INH (iC1INH) also was effective. In vivo, C1INH and iC1INH both reduced the number of viable bacteria in the blood and peritoneal fluid and accelerated killing of bacteria by blood neutrophils and peritoneal macrophages. In vitro, C1INH bound to bacteria cultured from blood or peritoneal fluid of mice with CLP-induced sepsis, but had no direct effect on bacterial growth. However, both C1INH and iC1INH enhanced the bactericidal activity of blood neutrophils and peritoneal exudate leukocytes. C1INH-deficient mice (C1INH(-/-) mice) subjected to CLP had a higher mortality than did wild-type littermate mice. Survival of C1INH(-/-) mice was significantly increased with two doses of C1INH, one given immediately following CLP, and the second at 6 h post-CLP. C1INH may be important in protection from sepsis through enhancement of bacterial uptake by, and/or bactericidal capacity of, phagocytes. Treatment with C1INH may provide a useful additional therapeutic approach in some patients with peritonitis and/or sepsis.

OBJECTIVE: To evaluate percutaneous mechanical thrombectomy for deep venous thrombosis (DVT). DESIGN: A retrospective analysis. SETTING: Tertiary academic medical center. PATIENTS: Thirty patients with DVT who underwent percutaneous mechanical thrombectomy. INTERVENTIONS: Percutaneous mechanical thrombectomy of upper or lower extremity DVT. MAIN OUTCOME MEASURES: Thrombus removal, patency, and valvular function. Venography and intravascular ultrasonography assessed periprocedural lysis. Duplex ultrasonography assessed patency and valvular function before and after the procedure. RESULTS: Fourteen patients had iliofemoral, 6 had iliofemoropopliteal, 5 had femoropopliteal, and 5 had subclavian vein thromboses. Mean age was 50.9 years (range, 15-78 years); 10 patients (33%) had a documented hypercoagulable state. There was 100% technical success in crossing the DVT, with treatment performed in a single setting in 24 patients (80%). Mean +/- SD procedural time was 145 +/- 35 minutes; range, 55-210 minutes. Mean thrombolytic dose was 6.2 mg of tenecteplase with the Trellis-8 and 10 mg with the AngioJet. Adjunctive procedures were required in 28 patients (percutaneous transluminal angioplasty and stent placement in 17 and percutaneous transluminal angioplasty alone in 11). Recoverable inferior vena cava filters were placed in 21 patients and retrieved within 4 weeks. There were no clinically significant periprocedural pulmonary emboli; however, 5 patients (17%) had evidence of pulmonary embolism on computed tomographic angiography (all in patients without inferior vena cava filters). Venous patency was maintained in 27 patients (90%) and lower extremity valvular function was maintained in 22 (88%) of 25 treated lower limbs, with a mean follow-up of 6.2 months (range, 3-24 months). CONCLUSIONS: Percutaneous mechanical thrombectomy is effective in the treatment of acute DVT in the upper and lower extremity to restore venous patency. In the lower extremity, valvular function is maintained acutely. Continued surveillance and follow-up will be necessary to determine whether valvular function is maintained long-term.

C1 inhibitor therapy improves outcome in several animal models of inflammatory disease. These include sepsis and Gram negative endotoxin shock, vascular leak syndromes, hyperacute transplant rejection, and ischemia-reperfusion injury. Furthermore, some data suggest a beneficial effect in human inflammatory disease. In many inflammatory conditions, complement system activation plays a role in pathogenesis. The contact system also very likely is involved in mediation of damage in inflammatory disease. Therefore, the beneficial effect of C1 inhibitor has been assumed to result from inhibition of one or both of these systems. Over the past several years, several other potential anti-inflammatory effects of C1 inhibitor have been described. These effects do not appear to require protease inhibition and depend on non-covalent interactions with other proteins, cell surfaces or lipids. In the first, C1 inhibitor binds to a variety of extracellular matrix components including type IV collagen, laminin, entactin and fibrinogen. The biologic role of these reactions is unclear, but they may serve to concentrate C1 inhibitor at extravascular inflammatory sites. The second is a non-covalent interaction with C3b that results in inhibition of formation of the alternative pathway C3 convertase, a function analogous to that of factor H. The third is an interaction with E and P selectins on endothelial cells that is mediated by the Lewis(x) tetrasaccharides that are expressed on C1 inhibitor. These interactions result in suppression of leukocyte rolling and transmigration. The fourth interaction is the binding of C1 inhibitor to Gram negative bacterial endotoxin that results in suppression of endotoxin shock by interference with the interaction of endotoxin with its receptor complex on macrophages. Lastly, C1 inhibitor binds directly to Gram negative bacteria, which leads to suppression of the development of sepsis, as demonstrated in the cecal ligation and puncture model. These observations suggest that C1 inhibitor is a multi-faceted anti-inflammatory protein that exerts its effects through a variety of mechanisms including both protease inhibition and several different non-covalent interactions that are unrelated to protease inhibition.

BACKGROUND: Bipolar hip arthroplasty has been advocated by some as an alternative to total hip arthroplasty for the treatment of degenerative arthritis of the hip. We sought to assess the results of this procedure at our institution after a minimum duration of follow-up of ten years. METHODS: We retrospectively reviewed a consecutive series of 152 patients (173 hips) who underwent primary bipolar hemiarthroplasty for the treatment of symptomatic degenerative arthritis of the hip with a cementless femoral component between 1983 and 1987. Of the original cohort of 152 patients, ninety-two patients (104 hips) were available for clinical and radiographic review at a mean of 12.2 years postoperatively. At the time of the latest follow-up, self-administered Harris hip questionnaires were used to assess pain, mobility, activity level, and overall satisfaction with the procedure. Biplanar hip radiographs were made to evaluate bipolar shell migration, osteolysis, and femoral stem fixation. RESULTS: At the time of the latest follow-up, nineteen patients (nineteen hips) had undergone revision to total hip arthroplasty because of mechanical failure, and three patients (three hips) were awaiting revision because of symptomatic radiographic mechanical failure. Twelve acetabular revisions were performed or scheduled for the treatment of pelvic osteolysis or protrusio acetabuli secondary to component migration. Acetabular reconstruction required bone-grafting, an oversized shell, and/or a pelvic reconstruction ring. The overall rate of mechanical failure was 21.2%(twenty-two of 104 hips), with 91%(twenty) of the twenty-two failures involving the acetabular component. Reaming of the acetabulum at the time of the index arthroplasty was associated with a 6.4-fold greater risk of revision. The rate of implant survival, with revision because of mechanical failure as the end point, was 94.2% for femoral components and 80.8% for acetabular components at a mean of 12.2 years. Of the remaining sixty-nine patients (eighty-one hips) in whom the original prosthesis was retained, seventeeen patients (24.6%) rated the pain as moderate to severe. Nearly 30% of patients with an intact prosthesis required analgesics on a regular basis. Radiographs were available for fifty-eight hips (including all of the hips with moderate to severe pain) after a minimum duration of follow-up of ten years; twenty-eight of these fifty-eight hips had radiographic evidence of acetabular component migration. CONCLUSIONS: This bipolar cup, when used for hemiarthroplasty in patients with symptomatic arthritis of the hip, was associated with unacceptably high rates of pain, migration, osteolysis, and the need for revision to total hip arthroplasty, especially when the acetabulum had been reamed. To the extent that these findings can be generalized to similar implant designs with conventional polyethylene, we do not recommend bipolar hemiarthroplasty as the primary operative treatment for degenerative arthritis of the hip. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.