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.

Deep vein thrombosis in cancer: the scale of the problem and approaches to management.

Patients with cancer have long been recognised to be at high risk of venous thromboembolism (VTE), although the condition remains under diagnosed and under treated in these patients. As a consequence, the morbidity and mortality due to deep venous thrombosis and pulmonary embolism remains unacceptably high in this group. Furthermore, the management of VTE in the presence of malignancy is complex, due both to the effects of the cancer itself and its treatments. Conventional long-term management of VTE involves the use of vitamin K antagonists (VKAs), such as warfarin, to reduce the risk of recurrence. However, this approach is associated with a range of practical difficulties including the need for regular laboratory monitoring, the potential for drug interactions, in addition to the risk of treatment resistance and bleeding in patients with cancer. Recent research indicates that the use of low molecular weight heparin (LMWH) therapy instead of VKAs may be beneficial in these patients. In particular, evidence from a large clinical trial of the LMWH dalteparin indicates that this agent offers an effective alternative to VKAs in the long-term management of VTE, that is free from the practical problems associated with the use of VKAs and without increasing the risk of bleeding.

Fixed-dose low-molecular-weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study.

INTRODUCTION: Secondary prevention of venous thromboembolism (VTE) with vitamin K antagonists is often problematic in patients with cancer. We prospectively evaluated the effectiveness and safety of long-term subcutaneous dalteparin in a series of consecutive patients with symptomatic VTE and metastatic cancer. PATIENTS AND METHODS: The study included 203 patients, aged 36-96 years. The initial treatment consisted of a 7-day course of subcutaneous dalteparin according to body weight. Then, patients received a fixed dose of 10 000 IU dalteparin once daily for at least 3 months. In patients developing transient thrombocytopenia the dose was reduced to 5000 IU daily while the platelet count remained <50,000; and to 2500 IU daily while it remained <10 000. Patients undergoing any surgical intervention during the study were put on 5000 IU daily during the first 4 days, switching thereafter to 10,000 IU. Patients undergoing any other invasive procedure (i.e. biopsies, punctures) received a 5000 IU dose the same day, instead of 10 000 IU. RESULTS: Eleven patients (5.4%) developed major bleeding complications (6 fatal) during the 3-month study period, and 18 patients (8.9%) developed VTE recurrences (2 patients died). There were no higher complication rates in patients with either liver or brain metastases, nor during thrombocytopenia, surgery or invasive procedures. CONCLUSIONS: Fixed dose 10,000 IU subcutaneous dalteparin once daily for 3 months was not associated with more complications in patients with liver or brain metastases. The dose adjustment for patients with thrombocytopenia, surgery or invasive procedures was safe too.

A common ancestral mutation (C128X) occurring in 11 non-Jewish families from the UK with factor XI deficiency.

Factor XI (FXI) deficiency is a mild bleeding disorder that is particularly common in Ashkenazi Jews, but has been reported in all populations. In Jews, two FXI gene (F11) mutations (a stop codon in exon 5, E117X, type II, and a point mutation in exon 9, F283L, type III) are particularly common, but in other populations a variety of different mutations have been described. In the Basque region of France one mutation, C38R in exon 3, was found in eight of 12 families studied, haplotype analysis suggesting a founder effect. In the course of screening 78 unrelated individuals (including 15 Jewish and 12 Asian) we have found 10 Caucasian non-Jewish patients with the mutation C128X in exon 5. Individuals were investigated because of a personal or family history of bleeding, or finding a prolonged activated partial thromboplastin time. Individuals negative for the type II and type III mutations were screened by a combination of SSCP and heteroduplex analysis. The C128X mutation was found in 10 families (one previously described). Among three individuals with severe FXI deficiency, one was homozygous for the C128X mutation, and two were compound heterozygotes for the C128X and another mutation; other individuals were carriers of the C128X mutation. This is a nonsense mutation producing a truncated protein; individuals have FXI antigen levels concordant with FXI coagulant activity. Haplotype analysis of 11 families, including a further kindred previously reported from the USA, but which originally came from the UK (in which the index patient was homozygous for C128X), suggests a founder effect.

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.