Key Points• Immunization against protamine/heparin complexes was frequently observed in patients undergoing cardiac surgery.• Platelet-activating antiprotamine-heparin antibodies are a potential risk factor for early postoperative thrombosis and thrombocytopenia.Protamine, which is routinely used after cardiac surgery to reverse the anticoagulant effects of heparin, is known to be immunogenic. Observing patients with an otherwise unexplained rapid decrease in platelet count directly after protamine administration, we determined the incidence and clinical relevance of protamine-reactive antibodies in patients undergoing cardiac-surgery. In vitro, these antibodies activated washed platelets in a FcgRIIa-dependent fashion. Using a nonobese diabetic/severe combined immunodeficiency mouse model, those antibodies induced thrombocytopenia only when protamine and heparin were present but not with protamine alone. Of 591 patients undergoing cardiopulmonary bypass surgery, 57 (9.6%) tested positive for anti-protamine-heparin antibodies at baseline and 154 (26.6%) tested positive at day 10. Diabetes was identified as a risk factor for the development of anti-protamine-heparin antibodies. In the majority of the patients, these antibodies were transient and titers decreased substantially after 4 months (P < .001). Seven patients had platelet-activating, anti-protamine-heparin antibodies at baseline and showed a greater and more prolonged decline in platelet counts compared with antibody-negative patients (P 5 .003). In addition, 2 of those patients experienced early arterial thromboembolic complications vs 9 of 584 control patients (multivariate analysis: odds ratio, 21.58; 95% confidence interval, 2.90-160.89; P 5 .003). Platelet-activating antiprotamine-heparin antibodies show several similarities with anti-platelet factor 4-heparin antibodies and are a potential risk factor for early postoperative thrombosis. (Blood. 2013;121(15):2821-2827
Summary Heparin‐induced thrombocytopenia (HIT) is an adverse drug reaction and prothrombotic disorder caused by immunization against platelet factor 4 (PF4) after complex formation with heparin or other polyanions. After antibody binding to PF4/heparin complexes, HIT antibodies are capable of intravascular platelet activation by cross‐linking Fc gamma receptor IIa (FcγRIIa) on the platelet surface leading to a platelet count decrease and/or thrombosis. In contrast to most other immune‐mediated disorders, the currently available laboratory tests for anti‐PF4/heparin antibodies show a high sensitivity also for clinically irrelevant antibodies. This makes the diagnosis of HIT challenging and bears the risk to substantially overdiagnose HIT. The strength of the antigen assays for HIT is in ruling out HIT when the test is negative. Functional assays have a higher specificity for clinically relevant antibodies, but they are restricted to specialized laboratories. Currently, a Bayesian approach combining the clinical likelihood estimation for HIT with laboratory tests is the most appropriate approach to diagnose HIT. In this review, we give an overview on currently available diagnostic procedures and discuss their limitations.
A, H€ user N. Anti-platelet factor 4/heparin antibodies in patients with impaired graft function after liver transplantation. J Thromb Haemost 2014; 12: 871-8.Summary. Background: Heparin, the standard perioperative anticoagulant for the prevention of graft vessel thrombosis in patients undergoing liver transplantation (LT), binds to the chemokine platelet factor 4 (PF4). Antibodies that are formed against the resulting PF4/heparin complexes can induce heparin-induced thrombocytopenia. LT is a clinical situation that allows the study of T-cell dependency of immune responses because T-cell function is largely suppressed pharmacologically in these patients to prevent graft rejection. Objectives: To investigate the immune response against PF4/heparin complexes in patients undergoing LT. Patients and Methods: In this prospective cohort study, 38 consecutive patients undergoing LT were systematically screened for anti-PF4/ heparin antibodies (enzyme immunoassay and heparininduced platelet aggregation assay), platelet count, liver function, and engraftment. Results: At baseline, 5 (13%) of 38 patients tested positive for anti-PF4/heparin IgG (non-platelet-activating) antibodies. By day 20, an additional 5 (15%) of 33 patients seroconverted for immunoglobulin G (two platelet-activating) antibodies. No patient developed clinical heparin-induced thrombocytopenia. Two of six patients with graft function failure had anti-PF4/heparin IgG antibodies at the time of graft function failure. Graft liver biopsy samples from these patients showed thrombotic occlusions of the microcirculation. Conclusions: Anti-PF4/heparin IgG antibodies are generated despite strong pharmacologic suppression of T cells, indicating that T cells likely have a limited role in the immune response to PF4/heparin complexes in humans.
Germany finds itself among the most iodine deficient countries of Europe. Voluntary use of iodized salt constitutes the only goiter prophylaxis. In the last few years, measures such as the opening up of European internal markets, abolition of lac pertaining to the alimentary iodine consumption. Random samples of urine collected from 5932 persons without thyroid ailment, distributed over 32 regions of Germany, were measured for iodine excretion. The median value of iodine excretion was 72.4 micrograms I/g creatinine. Children under 10 years (76.9) and persons over 70 years (80.7) showed a slightly higher iodine elimination than those between 11-70 years (71.9). No differences between the former East Germany and West Germany as well as North, South and middle regions of unified Germany were observed. 55% of the study population presented with iodine values between 50 and 100 micrograms, 19% with lower than 50 micrograms. Only 9% showed sufficient iodine state. The results expose the inadequacy of the voluntary measures to tackle the problem of alimentary iodine deficiency.
Improved legislation (1989, 1993), as well as education of the public, are likely to improve the iodine supply for the German population. Children and adolescents will be the first to profit. We investigated thyroid size and urinary iodine excretion in a total of 2906 students aged 10 to 18 in Mecklenburg-West-Pomerania in 1993, 1995, and 1997. The median urinary iodine excretion rose from 73 microg/g creatinine in 1993 to 133 microg/g in 1997. The prevalence of goiter, according to the reference range of Gutekunst, dropped from 33% to 10% over the same interval, and the median thyroid size declined from 11 ml to 6 ml. While only 6% of the test subjects excreted more than 150 microg iodine per g creatinine in 1993, this figure rose to 33% in 1997. The improved alimentary iodine supply is due to the increased use of iodine enriched salt by the food industry, food factories and in common food supply services.
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