Anticardiolipin antibodies: detection by radioimmunoassay and association with thrombosis in systemic lupus erythematosus

Background Patients who have a first episode of venous thromboembolism in the absence of known risk factors for thrombosis (idiopathic thrombosis) are often treated with anticoagulant therapy for three months. Such patients may benefit from longer treatment, however, because they appear to have an increased risk of recurrence after anticoagulant therapy is stopped. Methods In this double-blind study, we randomly assigned patients who had completed 3 months of anticoagulant therapy for a first episode of idiopathic venous thromboembolism to continue receiving warfarin, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0, or to receive placebo for a further 24 months. Our goal was to determine the effects of extended anticoagulant therapy on rates of recurrent symptomatic venous thromboembolism and bleeding. Results A prespecified interim analysis of efficacy led to the early termination of the trial after 162 patients had been enrolled and followed for an average of 10 months....

https://www.nejm.org/doi/pdf/10.1056/NEJM199903253401201

A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.

Background Factor XI, a component of the intrinsic pathway of coagulation, contributes to the generation of thrombin, which is involved in both the formation of fibrin and protection against fibrinolysis. A deficiency of factor XI is associated with bleeding, but a role of high factor XI levels in thrombosis has not been investigated. Methods We determined factor XI antigen levels in the patients enrolled in the Leiden Thrombophilia Study, a large population-based, case–control study (with a total of 474 patients and 474 controls) designed to estimate the contributions of genetic and acquired factors to the risk of deep venous thrombosis. Odds ratios were calculated as a measure of relative risk. Results The age- and sex-adjusted odds ratio for deep venous thrombosis in subjects who had factor XI levels above the 90th percentile, as compared with those who had factor XI levels at or below that value, was 2.2 (95 percent confidence interval, 1.5 to 3.2). There was a dose–response relation between the facto...

https://www.nejm.org/doi/pdf/10.1056/NEJM200003093421004

High levels of coagulation factor XI as a risk factor for venous thrombosis.

This review examines the evidence that platelets play a major role in localizing and controlling the burst of thrombin generation leading to fibrin clot formation. From the first functional description of platelets, it has been recognized that platelets supply factors that support the activation of prothrombin. Studies have demonstrated that on activation, the amount of one specific lipid, phosphatidylserine, is significantly increased on the outer leaflet of platelet membranes. When it was found that phosphatidylserine containing lipid extracts could be substituted for platelets in clotting assays, this suggested the possibility that changes in platelet lipid composition were necessary and sufficient to account for platelet surface thrombin generation. Because a growing body of data suggest that platelet-binding proteins provide much of the specificity for platelet thrombin generation, we review in this report data suggesting that changes in lipid composition are necessary but not sufficient to account for platelet surface regulation of thrombin generation. Also, we review data suggesting that platelets from different individuals differ in their capacity to generate thrombin, whereas platelets from a single subject support thrombin generation in a reproducible manner. Individual differences in platelet thrombin generation might be accounted for by differences in platelet-binding proteins.

Platelets and Thrombin Generation

Haemophilia A is a classic X-linked disease which affects 1 in 5-10,000 males in all populations and is caused by defects in coagulation factor VIII. Roughly 60% of patients have severe disease with factor VIII activity < 1% of normal; they have frequent spontaneous bleeding into joints, soft tissues, muscles and internal organs. These patients usually require regular injections of plasma-derived or recombinant human factor VIII. Because this is expensive and can potentially lead to life-threatening complications, other forms of therapy, including gene therapy, have been proposed. Natural canine models of factor VIII and factor IX deficiency have been available for many years, and gene therapy attempts on these dogs have met with partial success. However, a small animal model of the disease is desirable for studies of factor VIII function and gene therapy. Using gene targeting, we have made a mouse with severe factor VIII deficiency.

Targeted disruption of the mouse factor VIII gene produces a model of haemophilia A

The partial thromboplastin time (PPT) test consists of recalcifying plasma in the presence of a lipid reagent that supplies optimal platelet thromboplastic factor-like activity. Thus, the test measures the overall adequacy of the intrinsic plasma-clotting factors. It has proven particularly valuable in the recognition of hemophilia and the hemophilioid states, i.e., deficiencies of antihemophilic globulin (AHG, Factor VIII), of plasma thromboplastin component (PTC, Factor IX), of plasma thromboplastin antecedent (PTA), and of Hageman factor (HF). Despite its simplicity, the PTT is not widely used in clinical laboratories. Instead, when faced with the task of screening patients for possible plasma thromboplastic factor deficiencies, most laboratories either rely upon insensitive or erratic technics, such as clotting times or prothrombin consumption tests, or resort to the complicated thromboplastin generation test. This neglect of the partial thromboplastin time technic has stemmed partly from the lack of a commercially available partial thromboplastin and partly from a failure to obtain short clotting times consistently with normal plasma in some laboratories. Waaler has demonstrated that long times with normal plasma may be caused by inadequate contact activation of the test plasma when

Robert R. Proctor

Papers

The Partial Thromboplastin Time with Kaolin: A Simple Screening Test for First Stage Plasma Clotting Factor Deficiencies

The mode of inheritance of PTA deficiency: evidence for the existence of major PTA deficiency and minor PTA deficiency.