Hypercoagulable state and thromboembolism following warfarin withdrawal in post-myocardial-infarction patients

Nine out of 47 (19%) patients on chronic anticoagulation withwarfarin, as secondary prophylaxis after myocardial infarction,initially treated with streptokinase, had thromboembolic complicationswithin 4 weeks after sudden (7/25) or gradual (2/22: NS) warfarinwithdrawal. The biochemical effects of warfar in withdrawal were repeatedlystudied in 20 of the patients during the first 14 days followingdrug cessation. During the first 4 days, the levels of coagulationfactors VII and IX increased more rapidly than proteins C andS. Thus, a gap was created between the factors provoking andinhibiting the coagulation process. Furthermore, plasma concentrationsof fibrinopeptide A (EPA) increased, reflecting activation ofthe coagulation system. These laboratory findings suggest that withdrawal of warfarin creates a transient hypercoagulable state, imposing a riskof thromboembolic events in patients given anticoagulant treatmentas secondary prophylaxis following myocardial infarction.     

Hypercoagulable state and thromboembolism following warfarin withdrawal in post-myocardial-infarction patients.

Nine out of 47 (19%) patients on chronic anticoagulation with warfarin, as secondary prophylaxis after myocardial infarction, initially treated with streptokinase, had thromboembolic complications within 4 weeks after sudden (7/25) or gradual (2/22:NS) warfarin withdrawal. The biochemical effects of warfarin withdrawal were repeatedly studied in 20 of the patients during the first 14 days following drug cessation. During the first 4 days, the levels of coagulation factors VII and IX increased more rapidly than proteins C and S. Thus, a gap was created between the factors provoking and inhibiting the coagulation process. Furthermore, plasma concentrations of fibrinopeptide A (FPA) increased, reflecting activation of the coagulation system. These laboratory findings suggest that withdrawal of warfarin creates a transient hypercoagulable state, imposing a risk of thromboembolic events in patients given anticoagulant treatment as secondary prophylaxis following myocardial infarction.     

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 significantly 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 age- and gender-specific 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 identification 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.     

Spontaneous remission in Cushing's disease

Four patients with proved Cushing's disease underwent spontaneous clinical and biochemical remission. They were part of an 11-patient group treated with methods that allowed spontaneous remission to be observed. Each patient was treated differently, one each with metyrapone tartrate, ketoconazole, bilateral adrenalectomy and adrenal autotransplantation, and no treatment. Spontaneous remission occurred 9 months to 5 years after diagnosis as evidenced by restoration of normal adrenal function occurring symptomatically in two patients and advent to hypoadrenalism with addisonian crisis in the two others. We conclude that spontaneous remission in Cushing's disease may not be a rare entity, although its actual incidence has yet to be established.     

Increased urinary albumin excretion in Cushing's syndrome: remission after correction of hypercortisolaemia

OBJECTIVES: Increased urinary albumin excretion (UAE) in diabetic and nondiabetic subjects is frequently associated with insulin resistance syndrome and central obesity. Cushing's syndrome is also characterized by central obesity and insulin resistance. This study was undertaken to see whether increased UAE is found in Cushing's syndrome. DESIGN: Cross-sectional study. PATIENTS: Thirteen consecutive patients with Cushing's syndrome. MEASUREMENTS: Patients collected three overnight urine samples for the measurement of UAE by radioimmunoassay. UAE was also measured in 479 nondiabetic subjects who comprised the control population for this study. In the patients who had initial microalbuminuria, UAE was remeasured 2 months after successful removal of pituitary or adrenal tumours. Kidney biopsy was performed in three patients during adrenalectomy. RESULTS: Eleven out of 13 patients (84.6%) had increased UAE (> 9.6 micrograms/min), and eight patients (61.5%) had microalbuminuria or overt proteinuria (> 20 micrograms/min). Kidney biopsy revealed apparently normal glomerular structures without evidence of diabetic nephropathy. After correction of hypercortisolaemia, UAE declined profoundly in all of the patients. CONCLUSIONS: More than 80% of patients with Cushing's syndrome had increased UAE. This was almost completely reversed after successful treatment of hypercortisolaemia. These results indicate that endogenous hypercortisolaemia increases UAE by a mechanism that is presently unknown.     

Long-term impaired quality of life in Cushing's syndrome despite initial improvement after surgical remission

CONTEXT: Cushing's syndrome (CS) is associated with symptoms that may impair health-related quality of life (HRQL). METHODS: We used the short-form 36 survey to evaluate HRQL in 23 patients with Cushing's disease before and after transsphenoidal surgery (age, 42.7 +/- 12.0 yr; 19 women and four men) and in a cross-section of 343 CS patients (age, 48.2 +/- 14.1 yr; 265 women and 78 men) in remission for up to 25.8 yr after surgery (adrenal, 5%; ectopic, 6%). The z-scores were calculated for short-form 36 domains, and physical (PCS) and mental (MCS) summary scores were compared with those of age- and sex-matched controls (n = 6742). RESULTS: Active Cushing's disease was associated with low PCS and MCS scores (P < 0.05). Despite residual postoperative impairment, primarily of physical domains, all HRQL parameters improved after treatment with transsphenoidal surgery (3.2 +/- 1.5 yr; P < 0.05). In the cross-section in remission at follow-up, there was a small, but significant (P < 0.05), impairment of both PCS and MCS. A longitudinal postoperative analysis confirmed stable, but impaired, HRQL over time. Logistic regression demonstrated that previous pituitary radiation and current glucocorticoid use had little effect on HRQL outcomes. CONCLUSION: CS is associated with impaired HRQL, which partially resolves after treatment. At longer-term follow-up, however, there is residual impairment of HRQL. Determination of modifiable factors that contribute to impaired HRQL may help reduce the physical and psychosocial burden of this disease.     

Hypercoagulable state in five thalassemia intermedia patients.

Fifty-three patients of thalassemia intermedia and 40 controls were studied for clinical evidence of thrombosis and laboratory evidence of hypercoagulable state. Thrombotic episodes were detected in 5 (9.4%) patients. Two of these 5 patients with thrombosis were splenectomized. Laboratory evaluation showed presence of thrombocytosis in 8 (15%), 5 of these were splenectomized. Platelet hyperaggregation was detected in 12 (22.2%) patients. Although rate of aggregation was slow in 7 (13.2%) patients, degree of aggregation was normal in these 7 patients and platelet hypoaggregation was not detected in any patient. Level of coagulation inhibitors protein C and protein S, and antithrombin III were decreased in 31 (58.4%) patients. There was no correlation between low level of protein C and protein S with hepatic dysfunction and iron overload. Antithrombin III level was decreased only in 8 (15%) patients. There was a statistically significant association between the lower level of this inhibitor and hepatic dysfunction. In conclusion, this study provides evidence for the existence of a chronic hypercoagulable state in patients with beta thalassemia intermedia, and suggests that expression of a procoagulant surface by thalassemia intermedia red blood cells may be the major underlying factor giving rise to platelet and coagulation inhibitor abnormalities in these patients. These alterations are not related to iron overload or hepatic dysfunction.     

Cushing's syndrome

The clinical characteristics and current concepts of pathophysiology of Cushing's syndrome have been reviewed. The specific type of pituitary or ectopic ACTH-dependent and ACTH-independent Cushing's syndrome and the underlying pathology can be determined biochemically and with the aid of anatomic localization procedures. Several approaches are available for treating pituitary ACTH-dependent Cushing's syndrome, but transsphenoidal pituitary microsurgery is the ideal type, with remission of the disease being observed in 80 to 90% of cases. When successful, pituitary microsurgery is followed by preservation of normal pituitary function and restoration of normal hypothalamic-pituitary-adrenal function within 6 to 12 months postoperatively. Medical therapy of Cushing's disease includes drugs that inhibit CRH-ACTH secretion, such as cyproheptadine and bromocriptine, and agents that inhibit cortisol synthesis, such as aminoglutethimide, metyrapone, ketoconazole, and mitotane, or that block the action of cortisol at the glucocorticoid receptor level, such as RU-485. With the exception of mitotane, which has adrenalytic effects, the action of the other pharmacologic agents is promptly reversed when treatment is discontinued. Thus, drug therapy is effective only as temporary treatment for Cushing's syndrome when surgical approaches are contraindicated or when attempts are made to improve the patient's clinical and metabolic status in preparation for surgery. Mitotane is effective in extending survival of patients with adrenal carcinoma, particularly when it is administered early as adjuvant therapy or when it is combined with repeated debulking resection of recurrent tumor. The toxicity associated with mitotane administration limits the use of larger and probably more effective doses in these patients. The synthesis of more specific cytochrome P-450 enzyme inhibitors and of mitotane analogues with more limited toxicity may ultimately provide more effective tools in the pharmacologic management of Cushing's syndrome.     

Cushing's syndrome

Cushing's syndrome results from lengthy and inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. The syndrome remains a challenge to diagnose and manage. Here, we review the current understanding of pathogenesis, clinical features, diagnostic, and differential diagnostic approaches. We provide diagnostic algorithms and recommendations for management.     

Cushing's syndrome

During the past 30 years, there have been advances in understanding of the pathogenesis of Cushing's syndrome and in differential diagnosis of its various forms. Improved diagnostic tests and procedures have increased the ability to recognise even mild hypercortisolism and have provided the means to obtain an accurate diagnosis. Despite these advances, the occurrence of unusual clinical presentations and laboratory shortcomings may produce diagnostic problems and challenge clinical intuition. This article reviews recent pathogenic views, new tests, and new diagnostic problems in the evaluation of Cushing's syndrome. Atypical clinical presentations of hypercortisolism and some laboratory shortcomings that may confuse the diagnosis of Cushing's syndrome are also reported.