Angelina Carvalho

Platelet Function in Hyperlipoproteinemia

Abstract Platelet function was studied in 17 patients with Type II hyperlipoproteinemia. As compared with 26 normal subjects, platelets from patients with the Type II syndrome aggregated in response to 1/25 the mean concentration of epinephrine, one third the concentration of collagen, and one third the concentration of ADP. Total nucleotide release was increased from four to six fold with all aggregating agents. However, release of platelet factors 3 and 4, platelet adhesiveness and clot retraction were all normal in patients with Type II hyperlipoproteinemia. In contrast, platelets from 11 patients with Type IV hyperlipoproteinemia showed normal sensitivity to ADP and collagen, normal nucleotide release and normal release of 14C serotonin. The data suggest that heightened platelet function is associated with the thrombotic complications and accelerated atherogenesis of Type II hyperlipoproteinemia. (N Engl J Med 290:434–438, 1974)

Altered Factor VIII in Acute Respiratory Failure

Acute respiratory failure is characterized by pulmonary vascular injury and increased endothelial permeability. Since endothelial cells synthesize or release factor VIII, we studied factor VIII:antigen, factor VIII:von Willebrands factor, and factor VIII:coagulant activity in 100 patients with acute respiratory failure, in 29 critically ill patients without evidence of lung disease, and in 60 normal subjects. As a group, patients with respiratory failure had factor VIII:antigen levels that were five times normal, whereas their factor VIII:coagulant and von Willebrands activities were normal or above normal. However, there was a remarkable disproportion between the levels of factor VIII:antigen and those of factor VIII:coagulant and von Willebrands factor. In the other ill patients and in the normal group, these levels were in close proportion. In patients with respiratory failure, both slowly and rapidly migrating components of factor VIII:antigen had abnormal electrophoretic patterns; in moderate and severe cases, there was a marked increase in the fast component. Patients who recovered from acute respiratory failure had electrophoretic patterns that returned toward normal. Factor VIII:antigen may be a sensitive circulating indicator of pulmonary endothelial injury and repair.

Platelet autoantibody in a case of infectious mononucleosis presenting as thrombocytopenic purpura

Abstract In this unusual case acute thrombocytopenic purpura was the sole clinical manifestation of infectious mononucleosis. An antiplatelet antibody was demonstrated in the serum by two newly described technics: release of radioactive serotonin from platelets and inhibition of platelet aggregation following exposure of platelets to serum containing antiplatelet activity. The antiplatelet activity was completely inactivated by adsorption to washed platelets and was located in the immunoglobulin G (IgG) gamma globulin fraction of serum. The patients serum also reacted against her own platelets indicating that the antiplatelet factor behaved as a true autoantibody.

Hereditary antithrombin III deficiency: Effect of antithrombin III deficiency on platelet function

Antithrombin III (AT III) is the main physiologic inhibitor of thrombin, and activated factors X and IX as well. Normal levels of AT III appear to be necessary to maintain blood fluidity and to prevent thrombosis. Four families with AT III deficiency and recurrent venous thromboembolism have been reported on. We present an additional family with AT III deficiency and a high incidence of thromboembolism. AT III levels were determined by both a functional and an immunologic assay. Results of platelet function tests, not previously reported in persons with AT III deficiency, were found to be normal. Following gel filtration, the platelets were very sensitive to thrombin. Thrombin-induced platelet aggregation appears to be dependent on a balance between the amount of thrombin and AT III present.

Bleeding in Uremia — A Clinical Challenge

IN this issue of the Journal, Mannucci et al. report that infusions of a synthetic derivative of antidiuretic hormone — l-deamino-8-D-arginine vasopressin (DDAVP) — shorten the prolonged bleeding t...

Activation of hageman factor in the nephrotic syndrome

Abstract The patient described had the nephrotic syndrome associated with decreased levels of plasma coagulation factors XI (35 per cent) and XII (15 per cent). The patient also had a decrease in concentration of prekallikrein and kallikrein inhibitor, suggesting that the kallikrein system was activated. Addition of purified factor XII did not correct this defect. The fibrinolytic system was activated as indicated by an increase in fibrinogen split products. Thus, it seems that three Hageman-dependent proteolytic pathways (coagulation, fibrinolysis and kallikrein) were activated in this patient with the nephrotic syndrome. Another possible cause of decreased factors XI and XII is urinary loss of these proteins. The urine did contain apparent activities of factors XI and XII. The finding of factor VIII in the urine in higher concentrations than XI or XII, however, as well as the inability to adsorb the activity with Celite®, suggested that the activity was due to a nonspecific urinary procoagulant. This hypothesis was confirmed by removal of the activity via adsorbtion of the urine with barium citrate.

Intravascular coagulation in hyperlipidemia

Abstract Activation of the coagulation system was evaluated in 30 patients with familial hyperlipoproteinemia (types II and IV), by measurement of high molecular weight fibrin(ogen) derivatives (HMWFD). These HMWFD can be separated from fibrinogen and its derivatives X, D, and E by gel filtration of plasma on 4% agarose columns. Type II patients had a higher plasma concentration of HMWFD (31.6% of total plasma fibrinogen-like material) than type IV patients (19.8%) or normal subjects (3.2%). The HMWFD were shown to consist at least in part of crosslinked fibrin by polyacrylamide gel electrophoresis. Serum fibrin(ogen) degradation products (FDP) were assayed by staphylococcal clumping test and tanned red cell hemagglutination inhibition immunoassay and were found to be normal in type II and type IV patients. Our data show that type II patients have increased circulating HMWFD, while type IV patients have lesser increases in these soluble fibrin complexes.

Neutralization of low molecular weight heparin by polybrene prevents thromboxane release and severe pulmonary hypertension in awake sheep.

Protamine reversal of heparin anticoagulation in patients is occasionally associated with life-threatening acute pulmonary hypertension. In a sheep model, we evaluated the effect on this adverse cardiopulmonary reaction of modifying the type of heparin (low molecular weight heparin compared with unfractionated heparin) and the type of heparin antagonist (polybrene compared with protamine). Protamine reversal of low molecular weight heparin (LMWH) and polybrene reversal of unfractionated heparin induced more than a 10-fold increase of plasma thromboxane B2 levels, a threefold increase of pulmonary vascular resistance and pulmonary artery pressure, and a 25% decrease of PaO2. A similar adverse reaction followed protamine reversal of conventional unfractionated heparin. However, with polybrene (1 mg/kg) reversal of LMWH (1 mg/kg), we measured neither pulmonary hypertension (pulmonary artery pressure was 22.6 +/- 3.6 mm Hg at 1 minute after polybrene reversal of LMWH compared with 47.9 +/- 4.2 mm Hg after protamine reversal of unfractionated heparin, p less than 0.005 groups differ), hypoxemia (PaO2 was unchanged 2 minutes after polybrene compared with a decrease of 26 mm Hg 2 minutes after protamine, p less than 0.05), nor acute release of thromboxane into arterial plasma (thromboxane B2 was 0.2 +/- 0.1 at 1 minute after polybrene compared with 3.7 +/- 1.7 ng/ml at 1 minute after protamine, p less than 0.005). The hemodynamic effects and mediator release were also benign after neutralization of larger doses of LMWH (3 mg/kg) by polybrene (3 mg/kg). The increases of activated clotting time and activated partial thromboplastin time due to both types of heparin were completely reversed with polybrene. Anti-Xa activity increased to more than 3 IU/ml 4 minutes after LMWH anticoagulation (p less than 0.01) but was only partially neutralized by polybrene. Various polyanion-polycation complexes that are formed when heparin anticoagulation is reversed induce thromboxane release and acute pulmonary vasoconstriction in awake sheep. Reversal of LMWH anticoagulation with polybrene does not elicit this adverse reaction.

Plasma heparin neutralizing activity in coronary artery disease.

Platelets contain heparin neutralizing activity that is released into plasma after platelet aggregation. Increased amounts of plasma heparin neutralizing activity were found in patients with acute myocardial infarction, unstable angina pectoris and stable arteriographically confirmed coronary artery disease. Plasma heparin neutralizing activity levels provide additional evidence for a role of platelet aggregation in coronary artery disease.

The Pathogenetic Significance of Intravascular Coagulation in Experimental Acute Renal Failure

Serum and urine fibrin(ogen) degradation products (FDP), FDP clearances, and serum urea nitrogen (SUN) concentrations of rats challenged with glycerol-induced myohemoglobinuria were measured serially over a period of 4 days. The results obtained in animals that developed acute renal failure (ARF) were compared with those obtained in rats made refractory to renal failure by long-term salt loading or recent recovery from prior renal failure. Only the rats susceptible to ARF experienced a major rise in serum FDP concentration. Urine FDP excretion rose most markedly in the same rats but, being elevated in all groups. showed the utilization of fibrinogen whether serum FDP values increased or not. The results obtained might reflect differences in the degree of intravascular coagulation which are pathogenetically important. It is possible, however, that increased serum FDP concentrations found exclusively in rats with ARF are the results rather than the cause of impaired filtration, and that reduced tubular absorption may at least partly account for the high urinary FDP excretion observed in this model of experimental acute renal failure.