Histidine-rich protein II (HRPII) is an abundant protein released into the bloodstream by Plasmodium falciparum, the parasite that causes the most severe form of human malaria. Here, we report that HRPII binds tightly and selectively to coagulation-active glycosaminoglycans (dermatan sulfate, heparan sulfate, and heparin) and inhibits antithrombin (AT). In purified systems, recombinant HRPII neutralized the heparin-catalyzed inhibition of factor Xa and thrombin by AT in a Zn 2؉ -dependent manner. The observed 50% inhibitory concentration (IC 50 ) for the HRPII neutralization of AT activity is approximately 30nM for factor Xa inhibition and 90nM for thrombin inhibition. Zn 2؉ was required for these reactions with a distribution coefficient (K d ) of approximately 7M. Substituting Zn 2؉ with Cu 2؉ , but not with Ca 2؉ , Mg 2؉ , or Fe 2؉ , maintained the HRPII effect. HRPII attenuated the prolongation in plasma clotting time induced by heparin, suggesting that HRPII inhibits AT activity by preventing its stimulation by heparin. In the microvasculature, where erythrocytes infected with P falciparum are sequestered, high levels of released HRPII may bind cellular glycosaminoglycans, prevent their interaction with AT, and thereby contribute to the procoagulant state associated with P falciparum infection. (Blood. 2011;117(23): 6347-6354) IntroductionMalaria is an ancient parasitic disease that continues to take an enormous toll on persons and communities, as well as on global economies. In humans, the disease is caused by 5 protozoan parasites of the genus Plasmodium, including P ovale, P malariae, P vivax, P knowlesi, and P falciparum. Current infection rates are estimated at 250 million annually, with approximately 1 million of those cases resulting in fatalities. 1,2 P falciparum infection is the most dreaded, accounting for almost all malaria deaths. Morbidity and mortality from P falciparum malaria result from serious complications that arise during the course of the infection, including severe anemia, neurologic impairment, acute renal failure, and coagulopathy. Coagulation disturbances may contribute to the inflammation and organ failure associated with severe disease. 3,4 Patients with P falciparum infections have prolonged prothrombin time and activated partial thromboplastin time (aPTT), 5,6 reduced levels of clotting factors, including antithrombin (AT), 7,8 and elevated levels of fibrin degradation products. 9,10 Although uncommon, frank disseminated intravascular coagulation is observed in severe cases. 5,9,11 Activation of the intrinsic coagulation cascade and induction of tissue factor expression have been proposed, [12][13][14] but the precise mechanisms leading to hemostatic alterations in P falciparum infection remain poorly understood. Whether secreted parasite products are involved has not been established. Products released by intraerythrocytic parasites include a pair of proteins with unusually high histidine content: histidine-rich protein II (HRPII) and HRPIII. 15 Of these 2 homologous proteins...

BACKGROUND: Practice patterns regarding on‐site assessment of the adequacy of image‐guided fine‐needle aspiration biopsies (FNABs) vary among laboratories, but in many laboratories primary responsibility rests with the cytotechnologists. On‐site evaluation provides feedback on the need for additional passes and facilitates triaging of the specimen for time‐sensitive ancillary studies. Prior studies have suggested that cytotechnologists can assess the initially obtained specimens correctly, but they are few in number and limited by small size. The purpose of this study was to assess the frequency with which our cytotechnologists were able to correctly assess specimens as adequate using a large‐scale database that included a wide range of image‐guided FNABs. METHODS: The frequency that on‐site adequacy assessments of 5241 image‐guided FNABs were correct was determined by correlating the cytotechnologists' assessments of adequacy with the final cytologic interpretation. An adequacy assessment was considered correct if the FNAB was ultimately reported as satisfactory and unequivocally benign or malignant. An adequate reading on a case that was ultimately reported as unsatisfactory, atypical, or suspicious was deemed “incorrect.” The effect of imaging modality was also analyzed. RESULTS: Of 5241 FNABs, 2784 (53%) were interpreted as adequate on site. Of these, 2637 (95%) were correctly considered adequate. Of the common biopsy sites sampled, the adequacy assessments for liver FNABs demonstrated the highest frequency for being correctly considered adequate (97%) and those for kidney FNABs showed the lowest (90%). Imaging modality had no effect on accuracy. CONCLUSIONS: Cytotechnologists are almost always correct when assessing initial FNAB samples as adequate. Cancer (Cancer Cytopathol) 2012;. © 2011 American Cancer Society.