Remission of paroxysmal atrial fibrillation with iron reduction in haemophilia A.

SUMMARY: Two male first cousins with mild haemophilia A had baseline factor VIII levels of 12-15% and experienced bleeding requiring coagulation factor infusion therapy with trauma and surgical procedures. Both the patients with haemophilia A also had electrocardiographically documented symptomatic paroxysmal atrial fibrillation (PAF) for several years that had become resistant to pharmacological suppression. Radiofrequency ablation was considered in both the cases but deferred considering refusal of consent by the patients to undergo the procedure. Remission of arrhythmias has been reported in patients with iron-overload syndromes. Body iron stores assessed by serum ferritin levels were elevated in both men but neither had the C282Y or H63D genes for haemochromatosis. Calibrated reduction of iron stores by serial phlebotomy, avoiding iron deficiency, was followed by remission of symptomatic PAF in both cases. Iron reduction may be an effective treatment for arrhythmias apart from the classic iron-overload syndromes and deserves further study particularly in patients with bleeding disorders who might be at risk for arrhythmias and other diseases of ageing.

Rectus sheath hematoma complicating low-molecular weight heparin therapy.

Rectus sheath hematoma (RSH) is an uncommon but serious bleeding complication of anticoagulant therapy that has received little attention in the literature. Two cases of RSH among recent admissions to an inpatient medicine service and four archival cases were reviewed. All six patients were on low-molecular weight heparin (LMWH) therapy. Five of the six patients had a creatinine clearance of 40 ml/min or less, and five also had cough. Two patients with the most serious outcome were aged 90 and 92 years. RSH complicating LMWH therapy appears to constitute a clinical syndrome consisting of sudden onset of abdominal pain in the setting of renal insufficiency, advanced age and abdominal straining (e.g. cough). Risk of RSH may be reduced in patients receiving LMWH by assessing renal function, monitoring heparin levels (e.g. when the creatinine clearance is 40 ml/min or less) and adjusting the dose accordingly; by avoidance of abdominal strain (e.g. by treating cough); and by attention to technique when the abdominal wall is used as the injection site. Patients of advanced age may be at particular risk for RSH.

The coagulation system as a target for experimental therapy of human gliomas.

The purpose of this paper is to review the rationale for the development of coagulation-reactive drugs for the experimental therapy of gliomas. Numerous reactants familiar to students of blood coagulation have been shown to contribute to neoplastic proliferation, invasion and metastasis. Recently, considerable progress has been made in demonstrating the ability of drugs capable of inhibiting these reactants to alter cancer progression. Biological features of gliomas within the realm of blood coagulation suggest that clinical trials of such drugs warrant consideration. This approach offers the prospect of a novel treatment for this devastating tumour type that does not share the toxicities of conventional cancer therapies.

The role of adenosine 5'-diphosphate receptor blockade in patients with cardiovascular disease.

Aspirin, which has been the mainstay of antiplatelet agent for many decades, affects a single pathway in the platelet activation process and provides incomplete protection against cardiovascular events. Aspirin also may blunt the hemodynamic effect of angiotensin-converting enzyme inhibitors. Dipyridamole may provide some additional benefit, but there is little evidence to suggest its superiority alone or in combination with aspirin compared to standard doses of aspirin. Oral platelet glycoprotein IIb/IIIa inhibitors, although initially promising, have had disappointing results in recent clinical studies. A new class of medications, the thienopyridines, blocks the activity of platelet adenosine 5'-diphosphate (ADP) receptors, thereby reducing platelet activation. This review discusses the pharmacology, clinical studies, and potential uses of these agents, which include ticlopidine and clopidogrel. ADP inhibitors, by blocking an alternate pathway of platelet activation, are slightly more effective than aspirin in reducing cardiovascular events.

Treatment of cancer with anticoagulants: rationale in the treatment of melanoma.

The blood coagulation mechanism regulates the growth and dissemination of malignancy by multiple mechanisms, and anticoagulant drugs have been shown to inhibit the progression of certain cancers. Although progress has been slow, there is ample information on the effects of anticoagulants in various tumors that suggests that the use of anticoagulants has considerable potential in the treatment of some cancers. For example, melanoma is one of a small number of human tumor types in which the tumor is associated with an intact coagulation pathway leading to thrombin generation and conversion of fibrinogen to fibrin in situ immediately adjacent to viable tumor cells. Observations in experimental models combined with the limited clinical trial data on this subject suggest that inhibition of tumor cell thrombin generation may improve outcomes in melanoma cases. Thus, we postulate that pharmacological interruption of the tumor cell-associated coagulation pathway at any one step or even at multiple levels might constitute effective therapy for this disease. Drugs that block the activity of tissue factor, factor Xa, or thrombin are available for clinical testing and, if effective, offer the prospect of a relatively nontoxic, novel treatment for this aggressive tumor.

Localization of blood coagulation factors in situ in pancreatic carcinoma.

Blood coagulation is activated commonly in pancreatic carcinoma but the role of the tumor cell in this activation is undefined. Immunohistochemical procedures were applied to fixed sections of 22 cases of resected adenocarcinoma of the pancreas to determine the presence of components of coagulation and fibrinolysis pathways in situ. Tumor cell bodies stained for tissue factor: prothrombin: and factors VII, VIIIc, IX, X, XII, and subunit "a" of factor XIII. Fibrinogen existed throughout the tumor stroma, and tumor cells were surrounded by fibrin. Staining for tissue factor pathway inhibitor, and plasminogen activators was minimal and inconsistent. Plasminogen activator inhibitors -1, -2, and -3 were present in the tumor stroma, and on tumor cells and vascular endothelium. Extravascular coagulation activation exists associated with pancreatic carcinoma cells in situ that is apparently unopposed by naturally occurring inhibitors or the plasminogen activator-plasmin system. We postulate that such local coagulation activation may regulate growth of this malignancy. These findings provide a rationale for testing agents that modulate the blood coagulation/fibrinolytic system (that inhibit tumor growth in other settings) in pancreatic carcinoma.

Cancer treatment with inhibitors of urokinase-type plasminogen activator and plasmin.

The urokinase-type plasminogen activator-plasmin system plays an important role in many normal physiological processes including clot lysis, wound healing, embryogenesis and tissue remodelling. It is also involved in the pathogenesis of human malignancy through its ability to mediate tumour cell growth, invasion and metastatic dissemination. Interfering with this system is an appealing approach for experimental therapy of malignancy for several reasons. This concept is supported by a wealth of preclinical data. Evidence exists suggesting a role for this system in several major human tumour types. Preliminary evidence suggests that agents which block this pathway are effective in therapeutic doses that are already defined and relatively non-toxic. This form of treatment is not likely to carry cross-resistance with other types of cancer therapy and should be applicable to both localised and advanced tumours. Since heterogeneity in responsiveness among various tumour types is expected, clinical effects in given tumours would provide a basis for interpreting mechanisms of tumour progression in vivo and for future development of drugs with improved efficacy. Inhibition of the urokinase-type plasminogen activator-plasmin system remains a promising, but largely untested, area of experimental cancer therapeutics.

Low-molecular-weight heparin and cancer.

Heparin is a familiar anticoagulant drug with properties that may impede tumor growth; it modifies properties of cells that contribute to malignant dissemination such as angiogenesis, growth factor and protease activity, immune function, proliferation, and gene expression. Heparin has antitumor effects in animal models of malignancy, and studies in human malignancy show improved cancer outcome with heparin treatment. Meta-analyses comparing unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) for treatment of deep-vein thrombosis have shown apparent substantial improvement in cancer outcome in the subset of patients with malignancy who were randomly assigned to receive LMWH. This experience, together with the favorable pharmacokinetic properties of LMWH, provides a rationale for prospective clinical trials of LMWH in patients with cancer. Such trials should provide (a) definitive data on possible antitumor effects of this treatment, (b) insight into possible heterogeneous responses to heparin treatment among different histological types and stages of malignancy, and (c) a setting for exploring mechanisms of antineoplastic effect in human malignancy.

Cancer, thrombosis, and anticoagulants.

Rapid progress has been made recently in our understanding of the pathogenesis of coagulation activation in malignancy and mechanisms by which the coagulation mechanism may control malignant growth. Idiopathic thromboembolic disease may be the sentinel presentation in patients subsequently diagnosed with malignancy. Thrombosis complicating the course of malignancy may be notoriously difficult to treat, but the introduction of the low-molecular-weight heparins has greatly improved management and may obviate the need for invasive approaches, such as the use of inferior vena cava filters, in many cases. Tantalizing clues from clinical trials of anticoagulant therapy in cancer have suggested that components of coagulation pathways may support tumor growth. Many of these can be intercepted using drugs that are well known and non-toxic. The importance of performing high-quality controlled clinical trials that build on past studies and on data from basic research cannot be overemphasized.

Association of age, sex, and race with body iron stores in adults: analysis of NHANES III data.

BACKGROUND: This study examined age-, sex-, and race- related increases in body iron stores that have been implicated in disease and the relative utility of the serum ferritin versus the percentage of transferrin saturation for population-based estimation of iron status. METHODS AND RESULTS: Serum ferritin levels were examined by age, sex, and race, and values were compared with the percent transferrin saturation in 20,040 individuals >17 years of age from the third National Health and Nutrition Examination Survey (NHANES III) database. Body iron stores reflected by serum ferritin levels rose in the late teens in men and after menopause in women. This rise was more rapid and maximum ferritin levels were greater for blacks than whites and Hispanics of comparable age and sex. The distribution of values for the serum ferritin differed from the percent transferrin saturation. CONCLUSIONS: Different patterns of iron accumulation exist according to age, sex, and race. Serum ferritin levels reflect graded, population-based differences in body iron stores, but the percentage of transferrin saturation does not. The hypothesis that iron accumulation may contribute to higher morbidity and mortality rates can be tested in clinical trials of calibrated reduction of body iron stores in defined disease settings.

The iron (Fe) and atherosclerosis study (FeAST): a pilot study of reduction of body iron stores in atherosclerotic peripheral vascular disease.

BACKGROUND: Levels of body iron stores, represented by the serum ferritin concentration, rise with age after adolescence in men and menopause in women. This rise has been implicated mechanistically and epidemiologically in the pathogenesis of atherosclerosis through iron-induced oxygen free radical-mediated lipid oxidation. However, the precise contribution of iron stores to atherosclerosis and its complications are unknown because prospective randomized trials designed to test effects of reduction of iron stores on clinical outcomes in this disease have not been performed. METHODS AND RESULTS: In preparation for a prospective randomized trial, a randomized pilot study was conducted to evaluate the feasibility, safety, and methodologic accuracy of calibrated reduction in iron stores by phlebotomy in a cohort of patients with advanced peripheral vascular disease. Phlebotomy resulted in a significant reduction in serum ferritin concentration to near targeted levels. Thus the formula for calculating the volume of blood to be removed to achieve a predetermined decrement in serum ferritin concentration was accurate and phlebotomy was not associated with any adverse laboratory or clinical effects. CONCLUSIONS: Reduction of body iron stores to a predetermined level is feasible and can be achieved in a timely manner with excellent patient compliance. Prospective randomized trials of calibrated reduction of body iron stores may be undertaken to define their pathophysiologic significance in atherosclerosis and other diseases in which excessive iron-induced oxidative stress has been implicated.

Role of stored iron in atherosclerosis.

Myocardial infarction remains the No. 1 killer of American men and women, with a death rate of 225,000 per year, and stroke, the third leading cause of death in the United States, afflicts about 600,000 per year. The combined financial burden of these diseases is approximately $134 billion per year. Therefore, interventions that reduce mortality and suffering will have a significant impact on the health care system. This article summarizes research conducted during the last 2 decades that addresses the idea that stored iron plays a role in the pathogenesis of atherosclerosis and that iron reduction through phlebotomy may play a role in the treatment or prevention of atherosclerosis. Body iron stores rise after adolescence in men and menopause in women. This rise has been linked to the pathogenesis of atherosclerosis through iron-induced oxidation of low-density lipids and foam cell formation. However, the available evidence on the iron hypothesis remains circumstantial. Reduction of body iron stores in the setting of a controlled, prospective intervention trial is necessary to determine whether the amount of stored iron is related to clinically meaningful vascular disease. Such a study is feasible because reduction in iron stores can be achieved safely and predictably without induction of iron deficiency by graded phlebotomy. The Iron and Atherosclerosis Study (FeAST), a Veteran's Administration Cooperative Study, is under way to test this concept.