Stroke secondary to thrombotic microangiopathy

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a hematological disease resulting from the ADAMTS 13 plasmatic protein deficit. It can be congenital or sporadic, and is usually autoimmune. Pathological platelet adhesion occurs, leading to microthrombi in capillary and arterial circulation, microangiopathic anemia and ischemia. The clinical picture includes thrombocytopenia, renal dysfunction, fluctuating neurological symptoms, microangiopathic hemolytic anemia, and fever. Methods: Case report of a 51-year-old male hypertensive patient, diagnosed with idiopathic thrombocytopenic purpura (ITP) 10 years ago and submitted to splenectomy 5 years ago, who developed acute cholecystitis. He underwent urgent colecistectomy, and on the fourth postoperative day presented sudden space and time disorientation, transcortical motor aphasia and right faciobrachial paresis, with ipsilateral Babinski and Hoffman signs. Results: Brain CT showed left frontoparietal hypodensity. During hospitalization, there was worsening of renal function, increased LDH, and thrombocytopenia. Hematoscopy identified signs of intravascular hemolysis (erythrocyte fragmentation, reticulocytosis, helmet erythrocytes). Direct Coombs was negative. There was no history of heparin use. TTP was diagnosed, and fresh frozen plasma and prednisone 1mg/kg were prescribed. There was resolution of thrombotic microangiopathy, with subsequent increase of platelet levels, decreased LDH and improved hematoscopy. Conclusions: This case illustrates a rare cause of stroke and an unusual association of two hematological conditions: ITP and TTP. The treatment of TTP consists of replacement of deficient ADAMTS13 protein through plasmapheresis or fresh frozen plasma. The use of immunosuppressants is also associated, initially with glucocorticoids, followed by rituximab or splenectomy in order to prevent recurrences.

Standardization of Schistocyte Identification and Quantitation for the Diagnosis of Thrombotic Microangiopathic Anemia at University of Cincinnati Medical Center

Background: Thrombotic microangiopathic anemia (TMA) is a hematological emergency that requires prompt review of a peripheral blood smear for the presence of schistocytes. Within our institution, we had concern for lack of consistency in identifying schistocytes, lack of consistency in reporting methods, possible variation in schistocyte quantitation due to microscope differences, and the threshold for which our laboratory had been reporting increased schistocytes. The objective of our quality improvement project was to implement published practice standards for morphological identification, quantitation, and reporting of schistocytes across different groups at the University of Cincinnati Medical Center (UCMC). Methods: The International Council for Standardization in Haematology (ICSH) recommendations for the identification, diagnostic value, and quantitation of schistocytes (Zini et. al. International Journal of Laboratory Hematology 2012) were reviewed prior to designing this project. We next conducted a survey of groups that were reviewing peripheral blood smears for schistocytes on a routine basis: medical technologists (n=9), pathology residents (n=10) and hematology-oncology fellows (n=13). The survey included questions about schistocytes, including desire for standardization and normal reference values, desire for pathologist instruction, and reporting patterns. One question included 8 images of various red cell morphologies, and participants were asked to select ones they would classify as schistocytes. The microscopes were compared for objective and field diameter measurements. Six (6) peripheral blood smears with previously reported schistocytes were re-reviewed. Schistocytes were identified per ICSH guidelines and counted as a percentage (%) of 1000 total red blood cells using a Miller optical disc and also as an average number per field for a total of 10 high power fields. The results were plotted on a linear X-Y axis graph (Fig 1) and compared to the ICSH guidelines (Fig 2) and the policy for reporting schistocytes in our laboratory. Results: Survey results showed that the majority of each group desired standardization, normal reference values, and pathologist instruction. For reporting of schistocytes, residents answered present/absent (50%) or average per high power field (HPF) (50%), whereas 92% of fellows answered average per HPF. No participants reported a percentage of 1000 red blood cells, the current ICSH recommendation. For the morphological identification, 50% of residents, 62% of fellows and 67% of technologists correctly identified keratocytes as schistocytes. Fifteen (15%) of fellows misidentified bite cells as schistocytes, whereas one fellow (8%) and one technologist (11%) misidentified acanthocytes as schistocytes. Only 70% of technologists correctly identified helmet cells as schistocytes, whereas all residents and fellows chose them correctly. Almost all participants failed to recognize microspherocytes as schistocytes. The microscopes all showed the same objective and field diameter measurements. The schistocyte percentage plotted versus the number of schistocytes per HPF showed a 0.99% correlation co-efficient (R=0.99%) (Fig 1). The results were compared to the ICSH threshold of 1%, above which the ICSH reports is a robust morphologic indicator for the diagnosis of TMA (Fig 2), and to the current reporting policy at UCMC. Two (2) schistocytes per HPF correlated with 1% schistocytes on the linear plot. At UCMC, policy had been to report 2-8 schistocytes per HPF as present and >8 per HPF as increased. These findings indicated that the threshold for reporting increased schistocytes should be lowered from >8 per HPF to >2 per HPF. The above data were reviewed with each survey group. A process was also initiated to change the laboratory schistocyte reporting policy. Conclusion: All survey groups needed and desired education on schistocyte identification and reporting per ICSH guidelines. All microscopes showed the same measurements and were therefore expected to produce the same quantitation results. Schistocyte percentage correlated with the number of schistocytes per HPF. By implementing the ICSH guidelines, we aimed to decrease inter-observer bias and to standardize the quantitation and reporting of schistocytes at UCMC, thereby assisting in timely and accurate diagnosis of thrombotic microangiopathic anemia. Disclosures No relevant conflicts of interest to declare.

Microangiopathic Anemia of Acute Brucellosis – is it a True TTP?

Thrombotic thrombocytopenic purpura (TTP) is a severe disease, potentially fatal, if not diagnosed and treated promptly. TTP is clinically characterized by the pentad of thrombocytopenia, Coombs-negative hemolytic anemia, fever, renal abnormalities and neurological disturbances. Advances in recent years have delineated the molecular mechanisms of acquired and hereditary TTP.Many infectious organisms have been reported to be associated with TTP, especially mycoplasma, but only 6 cases of Brucella infection associated with thrombotic microangiopathy were reported.We describe a young woman who presented clinically with TTP following acute infection with both Brucella melitensis and Brucella abortus. The patient completely recovered after an aggressive therapy with plasmapharesis, high-dose corticosteroids and appropriate antimicrobial therapy.Since measurement of ADMTS13 activity and neutralizing antibodies is now available, and in none of the reported cases of brucellosis with thrombotic microangiopathy (including the present report) were tested, we recommend this work-up in future cases for better understanding of this rare association.

Autoantibodies in haemolytic uraemic syndrome (HUS)

SummaryHaemolytic uraemic syndrome (HUS) is a severe disease with renal failure, microangiopathic anemia and thrombocytopenia. Several mechanisms leading to HUS have been identified, like infections with enterohaemorrhagic Escherichia coli, as well as genetic mutations of complement genes, which result in defective complement control on the surface of host cells. The complement system forms the first defense line of innate immunity and mediates the attack against foreign microorganisms. Defective regulation of this cascade results in attack of self cells and in autoimmune disease. Apparently, the alternative pathway convertase C3bBb is central for the pathophysiology of HUS as gene mutations of the components (C3 and Factor B) or of regulators (Factor H, Factor I and MCP/CD46) are observed in the genetic form of HUS. Recently, a novel mechanism leading to atypical HUS (aHUS) was identified, in form of autoantibodies that bind the complement inhibitor Factor H. Here we summarize the current concept of HUS and focus in particular on the novel subgroup of aHUS patients with IgG autoantibodies to Factor H which develop on the genetic background of CFHR1/CFHR3 deficiency, and which define a new subform termed DEAP-HUS (deficient for CFHR proteins and Factor H autoantibody positive).