Persistent Post-Splenectomy Thrombocytosis and Thrombo-embolism: A Consequence of Continuing Anaemia

splenectomy is usually followed by a mild, symptomless thrombocytosis which reaches a peak at about the end of the second week and gradually subsides within ₃ months (Evans, 1928; Doan, Curtis and Wiseman, 1935; Wollstein and Kreidel, 1936; Ek and Rayner, 1950; Welch and Dameshek, 1950; Sedgwick and Hume, 1960). Occasionally, however, post-splenectomy thrombocytosis persists (Rosenthal, 1925; Chesner, 1946; Mills and Lucia, 1949; Green, Conley, Ashburn and Peters, 1953; Merskey and Budtz-Olsen, 1953; Gelpi and Ende, 1958; Byrd and Cooper, 1961; Barry and Day, 1962; Hayes, Spurr, Hutaff and Sheets, 1963; Dacie, Grimes, Meisler, Steingold, Hemsted, Beaven and White, 1964; Grimes, Meisler and Dacie, 1964; Losowsky and Hall, 1965) and may be associated with thrombo-embolic complications (Rosenthal, 1925; Chesner, 1946; Mills and Lucia, 1949; Gelpi and Ende, 1958; Byrd and Cooper, 1961; Barry and Day, 1962; Hayes et al. , 1963). However, although per-sistent post-splenectomy thrombocytosis has thus been recognized for many years, the underlying cause is poorly understood and has seldom been discussed. A consideration of the mechanism of post-splenectomy thrombocytosis and its possible bearing on post-splenectomy thrombo-embolism forms the basis of this report.
The present findings, based on a study of patients with a variety of anaemias and haematologically normal controls, suggest that persistence of thrombosytosis after splenectomy can usually be predicted: this happens when anaemia continues after splenectomy in association with active haemopoiesis.     

When and how to use heparin prophylaxis and treatment.

Heparin is a naturally occurring anticoagulant drug that combines with anti-thrombin III to inhibit many steps of the coagulation pathway. Clinically, heparin is used in small doses to prevent venous thrombosis and pulmonary embolism; in large doses, it is the treatment of choice in acute venous thromboembolism. Heparin also is used to treat some acute arterial thromboembolic episodes. Heparin may be given by intermittent intravenous injection or continuous intravenous infusion, usually in doses of approximately 30,000 units per day. Hemorrhage, the main side effect of heparin, appears to be less frequent when therapeutic doses are given by continuous intravenous infusion rather than by intermittent intravenous injection.     

Acquisition, storage and release of iron by cultured human hepatoma cells.

BACKGROUND/AIMS: The recovery from iron overload is hampered by the limited number of pathways and therapeutic agents available for the augmentation of iron secretion/excretion. The present study was aimed to investigate the process of iron storage and release by cultured human hepatoma cells, the role of transferrin receptors and ferritin in this process as well as the effect of iron chelators. METHODS: We followed the acquisition, storage and release of iron by cultured cells HepG2 and Hep3B by biochemical means and electron microscopy. RESULTS: The uptake of iron from diferric transferrin (Trf) was extremely low, while iron as ferric-ammonium-citrate (FAC) was taken up readily, especially by Hep3B cells. Up to 80% of the iron taken up by hepatoma cells was released to the medium. The rate of spontaneous iron release depended on the extent of iron loading. ApoTrf and deferoxamine facilitated release after 1- and 7-day iron-exposure. Up to a third of the radio-iron released from the cells was associated with ferritin. The release of ferritin-iron was not enhanced by either deferoxamine or Trf. CONCLUSIONS: Ferritin-iron release appeared to be an important mechanism of iron discarding in cultured human hepatoma cells, independent of the activity of chelating agents.     

Stroke prevention in nonvalvular atrial fibrillation.

There has been considerable uncertainty about the best way to prevent stroke in patients with nonvalvular atrial fibrillation. Recent studies have suggested that low-dose warfarin therapy, in addition to producing fewer bleeding complications, may be as effective as higher-dose therapy in preventing thromboembolic events. Four large, prospective, randomized trials have examined the risks and benefits of warfarin therapy for stroke prophylaxis in patients with nonvalvular atrial fibrillation. All four studies showed a substantially reduced incidence of stroke and a low incidence of significant bleeding in patients treated with warfarin. One of these studies also showed that aspirin reduced the incidence of stroke. The benefits associated with long-term low-dose warfarin therapy appear to exceed the risks for serious bleeding in most patients with atrial fibrillation. Aspirin may be a viable therapeutic option for patients who are unable to take warfarin or for those in subgroups at a low risk for stroke.     

Further insights into digoxin-quinidine interaction: Lack of correlation between serum digoxin concentration and inotropic state of the heart

The digoxin-quinidine interaction was studied in nine healthy human subjects aged 26 to 31 years. A single oral dose (400 mg) of quinidine sulfate administered to subjects taking digoxin resulted in a mean (± standard error of the mean) increase within 1 to 6 hours in the serum digoxin concentration of 0.12 ± 0.01 ng/ml (p <0.0001), an increase of 21 percent. Continued quinidine administration for 24 hours resulted in a 59 percent increase in the mean serum digoxin concentration from 0.68 ± 0.04 to 1.04 ± 0.06 ng/ml (alpha = 0.05). At the same time, however, systolic time intervals demonstrated a lengthening of the mean left ventricular ejection time index from 406 ± 4 to 419 ± 2 ms (alpha = 0.05) and the mean Q?S₂ Index from 524 ± 6 to 532 ± 7 ms (difference not significant [NS]). When compared with the shortening of these intervals predicted from the digoxin dose-response curve if digoxin were the only variable, the lengthening actually observed for both intervals was highly significant. The negative inotropic effect of quinidine administration alone was assessed with systolic time intervals in four subjects. The left ventricular ejection time index lengthened from 419 ± 3 to 425 ± 6 ms (NS) and the Q?S₂ index from 541 ± 6 to 550 ± 7 ms (NS). Therefore, the lengthening of these intervals in subjects taking digitalis after the addition of quinidine represents more than just the negative inotropic effect of quinidine, and occurs despite the increase in serum digoxin concentration.The results of this study support the view that quinidine displaces digoxin from tissue-binding sites as a major mechanism of the interaction. Furthermore, it appears that quinidine may specifically displace digoxin from cardiac-binding sites. These results raise important questions concerning the recommendation to reduce the maintenance digoxin dose when concomitant quinidine therapy is initiated.     

The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin

The relative importance of antithrombin and anti-factor Xa activities of heparin fractions required to achieve optimal antithrombotic effects is unknown. To study this, we measured the effects of standard heparin, an octasaccharide heparin fraction (anti-factor Xa activity only), and dermatan sulfate (antithrombin activity only) on the prevention of thrombosis and related this to their anticoagulant effects in vivo in rabbits. Thrombosis was measured as the incorporation of 125I- fibrinogen into tissue thromboplastin-induced thrombi using a Wessler- type model. Ex vivo changes in thrombin clotting time (TCT) were used as an index of antithrombin activity, and a chromogenic anti-factor Xa assay was used to measure anti-factor Xa activity. In addition, the ability of the three sulfated polysaccharides to simultaneously inhibit the generation of thrombin activity and to enhance the inactivation of the factor Xa added to initiate thrombin generation in plasma was determined. Standard heparin, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 90%, prolonged the TCT by two seconds, and resulted in an anti-factor Xa level of 0.32 U/mL. The octasaccharide heparin fraction, in a dose of 10 anti-factor Xa U/kg, inhibited thrombus formation by 41%, had no effect on the TCT, and resulted in an anti-factor Xa level of 0.28 U/mL. Higher doses of the octasaccharide resulted in a further increase in the anti-factor Xa levels but had no further effect on thrombus formation. Dermatan sulfate, in a dose of 500 micrograms/kg, inhibited thrombus formation by 95%, but had no affect on the TCT. These results indicate that the antithrombotic effect achieved by inhibiting factor Xa is limited and that better antithrombotic effects are achieved by heparin or heparin- like substances capable of influencing the inactivation and/or the generation of thrombin.     

Von Willebrand's Syndrome Presenting as an Acquired Bleeding Disorder in Association With a Monoclonal Gammopathy

The clinical and laboratory findings of apatient with a bleeding disorder, laboratoryfeatures of von Willebrand's disease, and amonoclonal gammopathy are described.There was no evidence of von Willebrand'sdisease in his five children. Laboratory features of von Willebrand's disease in thepatient included a long bleeding time, lowfactor VIII level by one- and two-stageclotting assays and by immunoassay, decreased platelet glass adhesiveness usingnative and heparinized blood, and correction of platelet adhesiveness by additionof cryoprecipitate in vitro. Attempts to implicate the monoclonal IgG in the pathogenesis of the von Willebrand's syndromewere unsuccessful using the followingtests: immunoprecipitation with normalplasma, antibody activity identified bypassive cutaneous anaphylaxis, inhibitionof biological factor VIII activity, and binding to factor VIII. Despite these negativefindings, it is suggested that the clinicalpattern of this and previously describedcases of "acquired" von Willebrand's disease has an immunologic basis that maybe mediated by either humoral or cellularmechanisms.

Submitted on September 26, 1972 Revised on February 8, 1973 Accepted on February 9, 1973     

The emerging role of low-molecular-weight heparin in cardiovascular medicine

Although unfractionated heparin is widely used in the treatment of acute coronary syndromes, it has several pharmacokinetic, biophysical, and biological limitations. The practical advantages and success of low-molecular-weight heparin administered subcutaneously without laboratory monitoring for the treatment of venous thromboembolism have prompted a number of randomized studies investigating the efficacy and safety of these agents in patients with acute coronary syndromes. This article will review the limitations of unfractionated heparin and the mechanisms by which low-molecular-weight heparin overcomes these limitations, as well as the results of recent trials involving low-molecular-weight heparin in the management of patients with acute coronary syndromes.     

Dabigatran attenuates thrombin generation to a lesser extent than warfarin: could this explain their differential effects on intracranial hemorrhage and myocardial infarction?

Compared with warfarin, dabigatran is associated with less intracranial hemorrhage, but an increased risk of myocardial infarction. To explore these phenomena, we compared their effects on thrombin generation. Thrombin generation in plasma from 10 patients taking therapeutic doses of warfarin (mean INR 2.6) was compared with that in plasma containing 250 ng/mL dabigatran. Although lag times were similar when thrombin generation was induced by recalcification or with a range of tissue factor concentrations, there was a greater reduction in peak thrombin generation and endogenous thrombin potential in plasma from warfarin-treated patients than in dabigatran-containing plasma. Similar results were obtained when thrombin generation was determined in plasma samples from 18 warfarin or 36 dabigatran treated patients entered into the RE-LY trial. Warfarin suppresses thrombin generation more efficiently than dabigatran. Greater suppression of normal hemostatic mechanisms in the brain and pathological thrombosis at sites of atherosclerotic plaque disruption may explain the higher rate of intracranial bleeding and lower rate of myocardial infarction with warfarin compared with dabigatran.