Recent advances in haemostasis and thrombosis.

PURPOSE: To review recent advances in hemostasis and thrombosis. METHODS: A review of recent studies that have changed our understanding of hemostasis and thrombosis. RESULTS: The cascade model of coagulation divided coagulation into extrinsic and intrinsic pathways. Factor VIIa/tissue factor complex of the extrinsic system is the major initiating event of hemostasis in vivo. The intrinsic pathway (the contact system) does not play a physiologic role in hemostasis. The cascade model has been replaced with a cell-based model with three overlapping phases: initiation, amplification, and propagation. Although Factors XI and XII of the intrinsic system are not involved in hemostasis, they may have a key role in abnormal hemostasis or thrombosis. The pathways of coagulation and inflammation are intertwined at numerous points. The procoagulant factors, VIIa, Xa, and thrombin can activate members of the protease-activated receptor family, which play an important role in coagulation, inflammation, and vascular hemostasis. Factor V plays a crucial role in both the procoagulant and anticoagulant systems. CONCLUSION: New insights into hemostasis provide greater understanding of the causes of both venous and arterial thrombosis.

Choroidal metastasis from submandibular salivary gland adenoid cystic carcinoma.

A case of choroidal metastasis from an adenoid cystic carcinoma ofsubmandibular salivary gland is described. A 50-year-old woman with loss of vision in her left eye for 1 week was evaluated clinically, radiologically, and pathologically. A fundus image of the left eye showed an amelanotic, plateau-shaped choroidal mass measuring 17 x 12 X 4 mm with overlying exudative retinal detachment. A choroidal biopsy was consistent with metastatic adenoid cystic carcinoma from her submandibular salivary gland treated 5 years previously. She was treated with external beam radiotherapy but developed liver and lung metastases 3 months later and died within 1 month. All of the metastases demonstrated a basaloid histologic variant of adenoid cystic carcinoma that is known for its aggressive potential. Salivary gland carcinoma rarely metastasizes to the choroid; however, evaluation of patients with this carcinoma should include ophthalmic examination.

Biomarkers of cardiovascular disease as risk factors for age-related macular degeneration.

PURPOSE: To measure and contrast 2 biomarkers of cardiovascular disease, C-reactive protein (CRP) and plasma homocysteine, in individuals with age-related macular degeneration (AMD) and control individuals without AMD. DESIGN: Case-control study. PARTICIPANTS: Seventy-nine affected individuals and 77 unaffected individuals from the AMD Genetic Study Group returned to obtain CRP and homocysteine levels. METHODS: Both affected and unaffected individuals underwent testing for CRP and homocysteine. A detailed cardiovascular history was taken. MAIN OUTCOME MEASURES: Mean CRP and homocysteine levels in affected and unaffected individuals. RESULTS: Mean CRP levels for affected and unaffected individuals were 3.42 and 2.30 mg/l, respectively (P = 0.03). Mean homocysteine levels for affected and unaffected individuals were 11.72 and 8.88 micromol/l, respectively (P<0.0001). In logistic regression models, older age, higher CRP, and higher homocysteine were risk factors for AMD. There were no significant differences between cases and controls in terms of gender, diabetes, hypertension, use of statin drugs, and smoking. The control group was significantly younger and had a lower rate of vitamin usage than the affected group. CONCLUSIONS: Elevated CRP and homocysteine levels are associated with AMD and implicate the role of chronic inflammation and atherosclerosis.

Choroidal and skin metastases from papillary thyroid cancer: case and a review of the literature.

A patient with widely metastatic papillary thyroid cancer who had been previously treated with (131)I and external beam radiation presented with purple nodular lesions on his face and scalp. On biopsy, the nodules were papillary carcinoma with cells that stained for thyroglobulin. Subsequently he developed decreased left eye visual acuity, and fundoscopy revealed lesions typical of choroidal metastases. Dermal and choroidal metastases of papillary thyroid carcinoma are both rare. However, the significance of these clinical manifestations may be overlooked and ignored unless the diagnosis is considered. New skin nodules or visual acuity decline in a patient with papillary thyroid cancer may represent manifestations of distant metastatic disease and should prompt thorough evaluation with dermatological examination and fundoscopy. Choroidal and skin metastases have almost always occurred in patients with advanced disease, but initial presentation with these lesions is possible, and in such instances a thorough search for additional sites of metastatic disease is recommended. Occasionally such metastases may respond to (131)I therapy or external beam radiation.

Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease.

Age-related macular degeneration (AMD) is a complex multifactorial disease that affects the central region of the retina. AMD is clinically heterogeneous, leading to geographic atrophy (GA) and/or choroidal neovascularization (CNV) at advanced stages. Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. We have performed a high-resolution (5-cM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria and also by dividing the affected individuals according to GA or CNV phenotype. Our results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236-240 cM in the Marshfield genetic map), 5p (40-50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. Our results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.

Tetrathiomolybdate as an antiangiogenesis therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration.

PURPOSE: Since previous studies have shown that angiogenesis requires copper, this study assessed the efficacy and safety of oral tetrathiomolybdate, an antiangiogenesis drug that binds copper, in subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration. METHODS: This phase I trial involved 10 patients with age-related active subfoveal CNV. After patient consent was obtained and initial laboratory tests were performed, patients were given a loading dose of tetrathiomolybdate, followed by a maintenance dose to maintain serum ceruloplasmin (Cp) levels at 5 to 15 mg/dL. Serum Cp levels are a surrogate marker of copper status. Patient follow-up consisted of a detailed protocol that included best corrected visual acuity, measurement of extent of CNV (both classic and occult) on fluorescein angiograms, and laboratory tests to ensure that anemia did not develop. The study was approved by the institutional review board of the University of Michigan Medical Center and by the Food and Drug Administration. RESULTS: Follow-up of the 10 patients ranged from 4 to 12 months. The targeted serum Cp level was achieved in 8 of the 10 patients. Initially, patients showed stabilization of CNV, but with continued follow-up, all patients showed progression of CNV and loss of visual acuity. Initial mean visual acuity was 20/60; final mean visual acuity was 20/131. At completion of the study, 2 patients showed about a 25% increase in CNV, 1 patient a 60% increase, 1 patient a 100% increase, and 6 patients a 700% to 1,600% increase in CNV. CONCLUSION: At the dosages used in this study, tetrathiomolybdate was ineffective in preventing the progression of CNV secondary to age-related macular degeneration.