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Ariana Beck, M.D. PGY2

Ariana Beck, M.D. PGY2. Blood Bank Interesting Case Conference. Interesting Case #1 Patient AW. Interesting Case Conference: Pt AW. AW is a 23 year old woman with a history of sickle cell disease (hemoglobin S/ beta 0 thalassemia ).

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Ariana Beck, M.D. PGY2

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  1. Ariana Beck, M.D. PGY2 Blood Bank Interesting Case Conference

  2. Interesting Case #1 Patient AW

  3. Interesting Case Conference: Pt AW AW is a 23 year old woman with a history of sickle cell disease (hemoglobin S/ beta 0 thalassemia). She has a history of infrequent pain crises and is on Hydrea since 2007 for recurrent acute chest syndrome with a good response (last fetal hemoglobin in May of 2013 was 21.2%) She was recently admitted to VUMC with fever and pyelonephritis and went onto develop hospital acquired pneumonia. She also had persistent abdominal pain and was found to have a thickened gallbladder on imaging. An antibody screen performed on 9/19/2013 was negative During her hospitalization, she received a unit of RBCs on 9/19/2013 and a subsequent unit on 9/22/2013 (both were sickledex, K1 and E negative).

  4. Interesting Case Conference: Pt AW • After she was discharged, she followed up with general surgery for her thickened gallbladder and persistent abdominal pain • She underwent a laparoscopic cholecystectomy 10/30/2013 • A type and screen was ordered…

  5. Interesting Case Conference: Pt AW The antibody screen was performed on 10/17/2013 and was positive Follow up panels revealed the presence of anti Fya and anti Fyb antibodies A phenotype showed the patients red blood cells lack the Fya and Fyb antigens A DAT was negative for IgG

  6. Interesting Case Conference: Pt AW [1] • Enzyme treatment was done and enhanced the reactivity of the patients plasma to the test cells • Recall that Fya and Fyb reactivity should decrease with enzyme treatment… • Thus the patient has developed an anti-Fy3 alloantibody

  7. Interesting Case Conference: Duffy blood group [2] The duffy blood group system was named after a patient with hemophilia who developed a novel antibody after multiple transfusions Two codominant alleles, Fya and Fyb, are located on chromosome 1, and differ by 1 residue at location 42 Fy3 and Fy6 are high-prevalence antigens A negative red blood cell phenotype, Fya-b-, exists and these cells also lack the Fy3 and Fy6 antigens

  8. Interesting Case Conference: Fy3 [1,2,3] The Duffy antigen serves as a binding site for Plasmodium vivax and its absence may confer resistance to infection The FYa-b- phenotype occurs in ~ 1% of Caucasians and ~ 75% of Africans

  9. Interesting Case Conference: Fy3 [1,2] • Anti Fy3 antibodies can arise in individuals with the FYa-b- phenotype • The Anti-Fy3 antibody is clinically significant and reacts equally strongly with Fya+ and Fyb+ red blood cells • Associated with hemolytic transfusion reactions.

  10. Interesting Case Conference: Fy3 [1] • Individuals of African descent with the Fya-b- phenotype are usually Fyb homozygous and have a structurally normal Fyb gene with a mutation in the GATA-1 site to which erythroid specific transcription factors bind • Therefore the gene is not transcribed in red blood cells • It is, however, present in other tissues like the lungs, colon and spleen thus preventing immunization against the Fyb antigen • Therefore, Fya-b- patients that undergo multiple transfusions often develop antibodies only to Fya • Antibodies to Fyb and Fy3 are much rarer and form in those already sensitized to Fya

  11. Interesting Case Conference: Pt AW In the case of AW, we were able to determine her Fy3 antibody due to enzyme studies Fya, Fyb and Fy6 are located on the N-terminus and are sensitive to denaturation by proteolytic enzymes Fy3 is located on the last external loop of the duffy protein and is unaffected by protease treatment AW’s surgery went smoothly with an estimated blood loss of 5-25 mL (depending on the note) and no red blood cells were transfused

  12. Interesting Case #2 Patient KM

  13. Interesting Case Conference: Pt KM • KM is a 17 year old woman who presented to an outside hospital 7/9/2013 with a brief history of tachycardia, anemia, and thrombocytopenia of unknown etiology • The evening before she presented, she had an episode of left hand numbness and tingling which subsequently spread to her arm and left leg and resolved after 30 minutes • She then developed a headache • At that time a head CT was normal but a CBC showed anemia and thrombocytopenia • She was transferred to VUMC 7/10/2013

  14. Interesting Case Conference: Pt KM • DAT: negative • Blood smear: normal • Von Willebrand panel: WNL • Fibrinogen: WNL • Iron studies: WNL Labs ordered at VUMC at presentation: CBC:WBC: 7.4 Hgb: 7.9 PCV: 24 Plt-Ct: 32 RetiCt: 13.3 LDH: 306 Haptoglobin:<10 BMP: WNL Urinalysis: WNL TSH: 9.06 [0.3-5.0] ANA: negative

  15. Interesting Case Conference: Pt KM • She was discharged the next day with close heme/onc follow up • Her anemia was thought to due to a combination of heavy menses with possiblec component of hemolysis • Thrombocytopenia was thought to be due to autoimmune thrombocytopenia in the setting of untreated hypothyroidism. • She was seen by heme onc 7/18/2013 and 8/1/2013 • She continued to complain of paresthesias up to 4 times a week that were self resolving followed by headache • An MRI of the head done 8/6/2013 was normal • A bone marrow biopsy was ordered…

  16. Interesting Case Conference: Pt KM The biopsy was done 8/6/2013 (signed out 8/7) and showed a normocellular marrow with trilineage hematopoiesis with a full range of maturation and megakaryocytic hyperplasia A blood smear was reviewed with the marrow examination and showed frequent fragmented RBCs and occasional microspherocytes. The pathology report stated that these findings, in the setting of anemia and thrombocytopenia raise a concern for a microangiopathic process, such as TTP…

  17. Interesting Case Conference: Pt KM • KM presented to the ED a second time with a headache on 8/7/2013 • She was discharged later that day • On 8/21/2013 heme/onc contacted the patient and requested that she come to the hospital • By this time, she had developed mental status changes and slurred speech • PT, PTT and fibrinogen at the time were normal • Platelet count: 37 • ADAMTS13activity was low at 5 and an inhibitor was identified • (a disintegrin and metalloprotease with thrombospondin type 1 repeats) • At that point, she was diagnosed with TTP

  18. Interesting Case Conference: Pt KM • Plasma exchange was done that evening after a line was placed • she received daily plasma exchanges until her platelet count recovered • 8/25/13 platelet count: 225 • Creatininewas always WNL • She was discharged 8/27/2013 with plasma exchange three times a week • She received rituximabx4 doses in hopes of remission • She currently scheduled to be exchanged 2 times in the next 2 weeks • Her ADAMTS13 activity is monitored

  19. Interesting Case Conference: TTP • TTP is classically associated with the pentad of symptoms • Microangiopathic hemolytic anemia • Non-immune mediated (DAT -) • >1% schistocytes on peripheral blood smear • Abnormal hemolysis labs • Thrombocytopenia • Acute renal insufficiency • Mild proteinuria is common • Neurologic abnormalities • usually fluctuating and most commonly headache and confusion • Imaging is usually normal • Fever- rare and more likely in sepsis/ DIC [4]

  20. Interesting Case Conference: TTP • It is rare for all symptoms in the pentad to be present • Currently, only thrombocytopenia and MAHA without another clinically apparent etiology must be present for suspected diagnosis and the initiation of treatment • First line therapy is plasma exchange (category I, recommendation grade 1A) • This has decreased overall mortality to ~10-20% • TTP is a clinical diagnosis but lab tests can be helpful • Thrombocytopenia • Normal PT/ INR, PTT and fibrinogen • Negative DAT • Abnormal hemolysis labs • Reduced ADAMTS13 activity <10% • Therapy should not be delayed waiting for results • Draw prior to the initiation of exchange • Useful in management decisions • An inhibitor may be present and is an acquired autoantibody [4,5]

  21. Interesting Case Conference: TTP-HUS • Etiology of TTP in patient KM: ADAMTS13 reduction due to an inhibitor • Von Willebrand factor (VWf)is synthesized in endothelial cells and is present in multimers in plasma • Unusually large multimers are degraded by ADAMTS13 into normal sized multimers • In the absence of ADAMTS13 activity, large multimers accumulate attach to activated platelets causing aggregation • This leads to platelet thrombi • 80% of inhibitors are IgG [4]

  22. Interesting Case Conference: TTP • The role of rituximab (chimericmurine/human monoclonal antibody directed against CD20 ) • 10-20% of patients become refractory to TPE or have early relapsed disease • In these patients, rituximab has been shown to be effective in cases with and without ADAMTS13 inhibitors • It has been postulated that B-cell depletion reduces excess cytokine production which maintains levels of von Willebrand factor multimers in normal limits • The use of rituxumab also decreases ADAMTS13 inhibitors (sometimes to the point that they can no longer be detected) and has been shown to normalize ADAMTS13 levels • Should be given after the pheresis procedure [5]

  23. Interesting Case Conference References [1] Olteanu H, Gerber D, Partridge K, Sarode R. Acute hemolytic transfusion reaction secondary to anti-Fy3. Immunohematology. 2005;21(2):48-52. [2] Went R, Wright J, Webster R, Stamps R. Anti-Fy3 in sickle cell disease: a difficult transfusion problem. Br J Haematol. 2009 Feb;144(4):621-2. [3] Howes RE, Patil AP, Piel FB, Nyangiri OA, Kabaria CW, Gething PW, Zimmerman PA, Barnadas C, Beall CM, Gebremedhin A, Ménard D, Williams TN, Weatherall DJ, Hay SI. The global distribution of the Duffy blood group. Nat Commun. 2011;2:266. [4] Caramazza D, Quintini G, Abbene I, Malato A, Saccullo G, Coco LL, Di Trapani R, Palazzolo R, Barone R, Mazzola G, Rizzo S, Ragonese P, Aridon P, Abbadessa V, Siragusa S. Relapsing or refractory idiopathic thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: the role of rituximab. Transfusion, 50: 2753–2760. [5] Schwartz J, Winters JL, Padmanabhan A, Balogun RA Linenberger ML, Szczepiorkowski ZM, Williams ME, WU y, Shaz BH. Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Sixth Special Issue. J ClinAper. 2013 Jul;28(3):145-284.

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