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Drugs of interest to pathologists

Drugs related to clinical pathology

Eculizumab


Authors: Him G. Kwee, M.D. and Nat Pernick, M.D. (see Reviewers/Authors page)
Revised: 19 January 2012, last major update December 2010
Copyright: (c) 2010-2012, PathologyOutlines.com, Inc.

General
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● Approved by US Food and Drug Administration for treatment of paroxysmal nocturnal hemoglobinuria (all cases) and in September 2011 for atypical hemolytic uremic syndrome refractory to plasma exchange therapy
● Eculizumab is a recombinant human monoclonal IgG2/4 kappa antibody against C5 (a terminal complement factor) produced by murine myeloma cell culture and given intravenously (Haematologica 2010;95:523, Blood 2009;113:6522)
● Eculizumab costs ~ $400,000 a year, considered the world's most expensive medicine
● Eculizumab increases the risk of meningococcal infections, so recommended to vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose, and monitor patients for early signs of meningococcal infections
● Only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS).
● Not currently indicated for treatment of typical (or Shiga-like toxin E.coli) HUS, but there are clinical trials investigating the efficacy of eculizumab for this condition (Alexion Pharmaceuticals)
● See also these PathologyOutlines.com links: CD55, CD59, Chronic myelogenous leukemia-LAP score

Trade name
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● Soliris®

Paroxysmal nocturnal hemoglobinuria (PNH)
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● PNH is a rare (affects 8000 Americans), potentially life-threatening blood disorder due to complement-induced intravascular hemolytic anemia; other symptoms include red urine (<50% of cases) and thrombosis (Wikipedia, Genes and Disease)
● Currently considered congenital, due to mutation of X chromosome PIGA gene, leading to inability to synthesize the glycosyl-phosphatidylinositol (GPI) anchor that binds CD55 and CD59 to cell membranes (eMedicine)
● May be primary (without) or secondary (with other bone marrow disorders, such as aplactic anemia)
● Treatment has traditionally been clinical support (transfusions for anemia, anticoagulation for thrombosis), bone marrow transplant for cure

Atypical hemolytic uremic syndrome
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● Approved by US Food and Drug Administration (23 Sept 2011) to treat atypical hemolytic uremic syndrome (aHUS)
● aHUS is due to uncontrolled complement activation resulting in complement-mediated thrombotic microangiopathy (TMA)
● aHUS has similar renal biopsy findings as HUS, but differs from HUS by:
(a) absence of diarrhea, present in 75% of HUS cases;
(b) in typical HUS, either Shiga-like exotoxins are present in stool (identified with Vero cell assay), serum antibodies against Shiga toxin are present (detect with ELISA), or lipopolysaccharides O157, O26, O103, O111 and O145 are present (detect with ELISA), but these tests are negative in aHUS (N Engl J Med 2009;361:1676)
(c) HUS may subside when the underlying cause is removed, but aHUS frequently relapses even after complete recovery, and usually causes death or permanent renal or neurologic impairment
● aHUS differs from TTP by:
(a) TTP has more protean systemic manifestations, but the manifestations of aHUS are usually limited to renal impairment
(b) 80 % of TTP patients have deficiency of ADAMTS13 activity not seen in aHUS.(ADAMTS13 is a protease that cleaves von Willebrand factor; its activity can be measured in serum or plasma by the collagen binding assay)

aHUS causes
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● Genetic, acquired (sporadic) or idiopathic
● Genetic: autosomal recessive or autosomal dominant manner with incomplete penetrance
● Genetic: due to mutation in one of six genes - CFH (encoding complement factor H), CD46 (encoding membrane cofactor protein), CFI (encoding complement factor I), CFB (encoding complement factor B), C3 (encoding the third component of complement C3), or THBD (encoding thrombomodulin, Pediatr Nephrol 2010;25:2431)
● Determine mutated gene by (a) measuring serum concentrations of CFH, CFI and CFB, (b) evaluating CD46 protein expression on peripheral blood leukocytes by flow cytometry, (c) sequence analysis of coding regions of these genes, (d) deletion / duplication analysis of CFH can detect the CFH/CFHR1 hybrid allele and the CFHR3/CFHR1 and CFHR1/CFHR4 deletions (Blood 2010;115:379)
● Note: 5-10% have serum anti-CFH IgG autoantibodies but normal plasma CFH levels; these patients may benefit from immunosuppressive therapy (J Am Soc Nephrol 2004;15:787)

aHUS triggering agents and treatment
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Streptococcus pneumoniae infection; do not treat with plasma infusion/exchange therapy; use washed red blood cells or platelets (Pediatr Nephrol 2008;23:1951)
● Drugs, including anti-cancer agents, immunosuppressive agents (including cyclosporine, tacrolimus, etc), anti- platelet agents (including clopidogrel), anti-inflammatory agents, oral contraceptives
● Cancer, especially gastric carcinoma
● Post-transplantation (kidneys or other organs)
● Preeclampsia or postpartum (within 3 months after delivery)
● Underlying medical conditions especially autoimmune diseases
● aHUS is considered idiopathic if no trigger (genetic or environmental) can be found

Diagrams
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Completement cascade

Laboratory
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PNH blood tests / results for diagnosis include:
● Tests for intravascular hemolysis - low hemoglobin, low haptoglobin, high lactate dehydrogenase (LDH), high bilirubin, high reticulocyte count
● Direct antiglobulin test (DAT, direct Coomb's test) is negative, as disorder is not caused by antibodies
● Screening test is sugar / sucrose lysis test; patient's RBCs are placed in low-ionic strength solution and observed for hemolysis
● Ham's acid hemolysis test is confirmatory test if sugar test is positive
● Other tests include flow cytometry for CD55 and CD59 on WBCs and RBCs (Indian J Pathol Microbiol 2010;53:699)
● Classified as Type 1: normal CD55 and CD59; Type II: reduced levels of CD55 and CD59; Type III: no CD55 or CD59; risk of hemolysis and thrombosis is related to the number of cells with no CD55 / CD59

End of Drugs > Drugs related to clinical pathology > Eculizumab


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