Search

Here we describe the case of an unfortunate 26 year old woman who developed a fatal combination of autoimmune hemolytic anemia (AIHA), hemophagocytic lymphohistiocytosis (HLH), and thrombotic thrombocytopenic purpura (TTP). Her initial clinical picture looked that of typical autoimmune hemolytic anemia but when she was refractory to standard therapy and her course progressed, alternative diagnoses were evaluated despite the lack of schistocytes on her peripheral smear. The case highlights consideration of TTP in severe hemolysis in absence of schistocytes and investigation of HLH in severe multiorgan dysfunction even after a primary diagnosis, in this case AIHA, has been made.

The development of inhibitor antibodies is a long-standing, well-documented complication of coagulation factor replacement therapy and is difficult to treat. Previous estimates of 5-15% of patients developing inhibitors may be low, since newer data suggest a wider range of occurrence. Factors that appear to affect inhibitor development include the severity of hemophilia, age, genetics, and, possibly, the type of replacement therapy administered. Recent studies raise the concern that recombinant factor therapies may be associated with more rapid development and higher levels of inhibitors in previously untreated patients. However, results of different studies are often difficult to compare owing to differences in methodology and populations studied. Further studies standardized in design and methods are clearly needed. Management of patients with inhibitors involves control of acute bleeding episodes and, over the long term, induction of immune tolerance for the coagulation replacement therapy. Many with low or moderate levels of inhibitors may be treated simply by administering higher doses of clotting factor. Other therapies appropriate for those with high levels of inhibitors include porcine F VIII and factor VIII "bypassing" agents, such as recombinant factor VIIa. Long-term immune tolerance has been achieved through the high-dose "Bonn" regimen and immunosuppressive regimens such as the "Malmö" method. Although management of inhibitor patients has improved, it still represents a major challenge. Further research is needed to identify which patients will develop inhibitors and tolerance, as well as to develop better methods to manage, reduce, or eliminate inhibitors from these patients.

A 53-yr-old man with a 33-yr history of Crohn's ileocolitis, complicated by arthritis and cologastric fistulization, was diagnosed with GI amyloidosis at the time of proctocolectomy. He had marked proteinuria (4.2 g/24 h) and moderate renal insufficiency (BUN of 35 mg/dl and serum creatinine of 2.5 mg/dl). During the operation, he had severe bleeding that required 11 U of blood. Postoperatively, desmopressin was administered, which resulted in a prompt cessation of bleeding. This case demonstrates the efficacy of desmopressin in reversing the bleeding diathesis in surgical patients with amyloidosis complicated by renal insufficiency.

AMG 531 is a novel thrombopoiesis-stimulating peptibody that increases platelet production by targeting the TPO receptor. The study described here is an ongoing, open-label extension assessing the safety and efficacy of long-term, weekly, subcutaneous administration of AMG 531 in ITP patients who have completed a previous AMG 531 study. Patients previously treated with AMG 531 receive the same starting dose as the final dose given in the previous study; placebo-treated patients begin the extension with a 1 μg/kg dose. Doses may be skipped, decreased, maintained, or increased based on platelet response. Patients who achieve a stable dose for at least 3 weeks (later amended to 4 weeks) may be allowed to self-administer the drug. A total of 104 patients have been enrolled; the longest AMG 531 treatment duration is 96 weeks. This planned interim analysis includes 36 patients (safety subset) whose previous study was a phase 2 trial. Data for patients previously enrolled in a phase 3 trial are still blinded. The 25 women and 11 men have a mean age of 50±13 (SD) years; 30 (83%) have had a splenectomy. Twelve patients entered the study using concurrent corticosteroids, which were tapered when the platelet count was >50x109/L. Adverse event (AE) profiles were similar for the intervals of weeks 1–24 vs 25–48 and beyond. The most frequent were headache (incidence of 2.0 per 100 weeks of subject exposure for weeks 1–24 vs 1.7 for weeks 25–48), upper respiratory infection (1.3 vs 0.8), and fatigue (0.9 vs 1.0). Four patients had serious treatment-related AEs: vaginal hemorrhage/anemia (withdrawn from treatment), diffuse reticulin formation in the bone marrow (withdrawn), bone pain (continues on treatment), and transverse sinus thrombosis with papilledema and temporary decrease in visual acuity (64-year-old patient with diabetes mellitus and a platelet count of 293x109/L at the time of the AE; this patient continues on treatment). No neutralizing antibodies have been detected to date. The efficacy subset consists of 27 patients who completed week 48 or beyond. Both the mean platelet count and the mean dose of AMG 531 have remained stable between weeks 24–48. The mean platelet count was 100x109/L ± 4.4 (SE) during weeks 1–24 and 131x109/L ± 5.3 (SE) during weeks 25–48. Eleven patients (41%) have had at least one platelet count >450x109/L, excluding counts associated with ITP rescue medication. Six of 12 patients were able to discontinue concurrent corticosteroids, and 2 had a >25% dose reduction. Individualized weekly doses of AMG 531 provide a therapeutic option for ITP. Most patients have been able to maintain a safe platelet count and to decrease or discontinue concurrent corticosteroid therapy.

Plasma catecholamine concentration and platelet aggregation were studied in 22 patients with uncomplicated primary hypertension and 13 age-matched normotensive, healthy subjects at rest and in some during isometric handgrip exercise. The effect of norepinephrine (NE) infusion upon platelet aggregation was also examined. Plasma catecholamine concentration was slightly higher in the hypertensive than the normotensive group, but the difference was not significant. However, platelet aggregation to ADP was significantly greater in the hypertensive than the normotensive subjects. Exercise increased significantly both catecholamines and aggregation in both groups. Platelet aggregation was correlated with age (r = 0.62, P less than 0.01) and plasma NE (r = -0.34, P less than 0.05 for the total group of subjects). The infusion of NE increased significantly plasma NE and platelet aggregation and there was an inverse correlation between NE increase and threshold decrease (r = -0.69, P less than 0.05). Thus, plasma catecholamines and important determinants of platelet aggregation. However, in our study, uncomplicated primary hypertension was not associated with abnormal plasma catecholamine concentration. It is likely that the observed abnormal platelet aggregability to ADP represents a secondary phenomenon, possibly related to more advanced atherosclerotic vascular changes in hypertensive than normotensive subjects.

The platelet lipid peroxidation technique was used to determine platelet survival time in 10 patients with uncomplicated essential hypertension and 10 age-matched normotensive and healthy subjects. Mean platelet survival time was 7.3 ± 0.65 days in the hypertensive group and 9.6 ± 0.82 days in the normotensive group ( P However, shortened survival time was observed in four hypertensive and in two normotensive subjects. It is possible that the significant decrease in survival time found in the hypertensive group might reflect more advanced atherosclerotic vascular changes than in the normotensive group. Posture change affects lipid peroxides, probably via the catecholamines.

The effects of propranolol on blood pressure, plasma catecholamine concentration and platelet aggregation were examined in 16 patients with uncomplicated primary hypertension. The patients were studied at rest, during isometric handgrip stress and 48 hours after sudden discontinuation of propranolol therapy. Plasma catecholamine concentration and platelet aggregation studies were also carried out in 11 age-matched normotensive and healthy subjects at rest. Plasma catecholamine concentration and platelet aggregation were greater in the hypertensive than in the normotensive subjects, but the difference reached statistical significance for aggregation only. Exercise significantly increased catecholamines and platelet aggregability. The administration of propranolol (240 mg/day) produced a significant decrease in systolic and diastolic blood pressure and in aggregation (the percent of light transmission at 1 μM adenosine diphosphate, at rest) and a significant increase in catecholamine concentration. However, propranolol did not prevent the changes in all these variables with exercise. The abrupt discontinuation of propranolol was not associated with any subjective or objective untoward cardiovascular effect or abnormal changes in plasma catecholamines. However, in some patients the platelet aggregation studies demonstrated a hyperaggregable state, which may be due to a state of supersensitivity of platelets to circulating catecholamines.

This study demonstrates that Ca2+ regulates thrombosthenin ATPase activity, likening the control of platelet contraction to that of cardiac and skeletal muscle. Thrombosthenin, the platelet contractile protein, was isolated by repeated low ionic strength and isoelectric precipitation. Thrombosthenin superprecipitation and ATPase activity were measured in 10−4 M CaCl2 (high ionized Ca2+) and 0.25 mM ethylene glycol bis-(β-aminoethyl ether)-N,N′-tetraacetic acid (EGTA) (low ionized Ca2+). In both high and low Ca2+, superprecipitation, measured as an increase in turbidity, ocurred shortly after addition of ATP. ATP hydrolysis by thrombosthenin, which proceeded linearly for several hours, was greater in high Ca2+ (approx. 2.3 nmoles·mg−1·min−1) than in low Ca2+ (approx. 1.8 nmoles·mg−1·min−1). This difference, when analyzed by the Student's t-test for paired samples was highly significant (P