Drug-induced immune hemolytic anemia: a case-study approach. Karen Quillen, M.D. Medical Director, Blood Bank Boston Medical Center

Size: px

Start display at page:

Download "Drug-induced immune hemolytic anemia: a case-study approach. Karen Quillen, M.D. Medical Director, Blood Bank Boston Medical Center"

Sophia Ray
7 years ago
Views:

1 Drug-induced immune hemolytic anemia: a case-study approach Karen Quillen, M.D. Medical Director, Blood Bank Boston Medical Center

2 Patient E.D. 61-year-old woman Presents to PCP with fatigue PMH: hypertension, alcohol and cig use Meds: BP med, occ Advil P/E: normal, guaiac neg

3 E.D. (continued) Hematocrit 26, normal WBC and PLT (normal CBC 6 mo. ago) Bilirubin 1.3, LDH 409 Retic count 12% A pos, Ab screen pos with both cells, DAT 4+ IgG, panel and eluate positive with entire panel

5 What is the diagnosis???

6 Drug-induced autoimmune hemolytic anemia Methyldopa Procainamide Fludarabine Cladribine Levodopa Alpha-interferon Mefenamic acid

7 Methyldopa Dr.Dameshek: Alpha-methyldopa red-cell antibody:cross-reaction or forbidden clones? NEJM 1967 Used to account for 70% of DIIHA Positive DAT in 15% of patients taking methyldopa, after 3-6 months. Dose-dependent: 36% of patients on 3 gm/day vs 11% of patients on 1 gm/d

8 Methyldopa AIHA Hemolytic anemia in 0.5% of patients on methyldopa Ab profile indistinguishable from WAIHA: serum and eluate react with normal RBCs in the absence of the drug Drug can induce positive ANA, RF, other autoantibodies

9 Methyldopa AIHA (cont) If drug stopped, hemolysis improves within 2 weeks but DAT can remain positive for up to 2 years At one week post drug: Hct 27 At 3 weeks post drug: Hct 30, LDH 309, retic count 7.6% At 2 months: Hct 44, retic count 0.9%.

10 Patient R.E. A 50- year- old man with a long history of paraplegia, chronic decubitus ulcer, and anemia of chronic disease presented to our hospital complaining of dizziness. Two weeks prior: group A streptococcus septicemia. Rx: surgical debridement of the sacral decubitus ulcer which had progressed to osteomyelitis. During this initial nine-day hospitalization, he had been transfused six units of blood. Current medications: insulin, fluoxetine, olanzapine, clonazepam, atenolol, vancomycin and piperacillin/tazobactam

11 R.E. (cont) Hct (%) WBC (/ul) PLT (/ul) BUN(mg/dl) Cr (mg/dl0 8 days ago 26 11, , Now 7 13, ,

12 R.E. (cont) Physical exam Pallor Mild hypotension No signs of bleeding No CHF PBS: anisocytosis, polychromasia, few spherocytes Retic count 10.2% Bilirubin 9.3/6.7 LDH 347 Haptoglobin <6

16 R.E. BB testing O pos, ABSC pos, anti-k DAT pos IgG and C3 Eluate negative Crossmatch comp w/ 6/6 K-neg units, 5 units transfused over next 3 days. Hct 7 to 23. Renal function normalized within 2 weeks. What next?

17 R.E. Further BB testing PBS- Zosyn- RBC RBC 37C PolyAG 37C PolyAG PtEluate ContEl PtPlas1: Micro+ PtPlas :20

18 drug drug-coated RBC anti-drug antibody Drug-Adsorption mechanism: high-dose penicillin RBC coated with drug and anti-drug Ab, extravasc hemolysis

19 Detection of antibodies to drugs by the immune complex method (Immunohematology Research Laboratory, ARC Southern California Region) Ficin-treated RBC 1-2 hr 37C Poly-AHG Check cells PtPlas + drug NA PtPlas + PBS PtPlas,C,drug NA PtPlas,C,PBS Comp + drug Comp + PBS

20 drug-antidrug immune complex anti-drug antibody Complement Sensitized RBC Immune complex mechanism: quinine, ceftriaxone RBC lysed intravasc

21 Drug-induced immune hemolytic anemia Mechanism Examples DAT Serum/ Eluate Drug adsorption Immune complex Auto- Immunity Non-immun adsorption Penicillin, cephalosp. Quinidine, 3 rd gen ceph Aldomet, interferon Cephalothin IgG, C3, albumin IgG (+/- C3) React w Rxcoated RBC C3 (+/- IgG) Serum w Rx react w rbc; eluate neg IgG React w rbc w/o Rx Low-titer anti-rx Ab in serum; eluate neg Clinical moderate severe moderate none

22 Case 2 conclusion Patient has new alloantibody plus DIIHA For a HCT 7, need to think quickly to stop offending drug, provide antigen-negative crossmatch compatible blood For a given drug, more than one mechanism may be operational Piperacillin/tazobactam commonly used in cystic fibrosis patient population

23 Patient K.C. An 11-year-old male with HIV infection presented with fever and a clinical picture consistent with pneumonia. Past medical history was significant for chronic thrombocytopenia for which he received anti-d immunoglobulin every 2-3 weeks, and multiple admissions for fever during which he received empiric treatment with ceftriaxone.

24 K.C. (cont) During the current admission he was prescribed ceftriaxone again; minutes after the first dose he complained of severe back pain and promptly developed hypotension, disseminated intravascular coagulation and acute renal failure. Hematocrit dropped from 31% on admission to 19%. Multiple blood specimens were noted to be grossly hemolyzed. He died within 18 hours of this event from intracerebral hemorrhage. Blood cultures obtained prior to the institution of antibiotics and subsequent to the catastrophic event were negative.

25 K.C. BB testing O pos, ABSC neg DAT was positive for IgG only; an eluate showed anti-d (he had received intravenous anti-d immunoglobulin 20 days prior to admission).

26 Case study - massive hemolysis after ceftriaxone in SCD J Pediatr 1995; 126: month old male with SCD multiple admissions for acute chest, vasoocclusive crises, fever, sequestration admitted for fever and vomiting, blood cultures drawn, Hgb 7 gm/dl (Hct 20). 20 min after receiving ceftriaxone (not first dose), cardiorespiratory arrest - Hgb now 0.9 gm/dl (Hct 2)

27 Cephalosporin-induced drugdependent RBC antibodies 1987 (Salama) severe complementmediated intravascular hemolysis caused by cefotaxime DAT + C3d, eluate nonreactive with drugcoated or untreated RBCs, serum reactive with untreated RBCs in presence of drug. Our case negative for C3d delayed testing? immune complex theory of DIIHA

28 Ceftriaxone-induced hemolysis 20% of cephalosporin-induced IHA in series by Garratty (Transfusion 1999) all cases involved immune complex mechanism, severe intravascular hemolysis 7 reported cases in literature involving children with SCD, HIV, leukemia - high fatality rate Is it just because these patient populations more exposed to ceftriaxone?

29 Detection of antibodies to drugs by the immune complex method (Immunohematology Research Laboratory, ARC Southern California Region) Ficin-treated RBC 1-2 hr 37C Poly-AHG Check cells PtPlas + drug NA PtPlas + PBS PtPlas,C,drug NA PtPlas,C,PBS Comp + drug Comp + PBS

30 Screening study at BMC Screen pediatric patients in SCD and HIV clinics for presence of ceftriaxone- and cefotaxime-induced red cell antibodies, correlate with antibiotic history, DAT, evidence of hemolysis.

31 Detection of antibodies to drugs by the immune complex method (Immunohematology Research Laboratory, ARC Southern California Region) Ficin-treated RBC 1-2 hr 37C AHG Check cells Serum + drug Serum + PBS Serum,C,drug Serum,C,PBS Comp + drug Comp + PBS

32 Study findings 64 pediatric patients screened for RBC antibodies induced by ceftriaxone in serum 2 patients had hemolysis (fatal index case, one mild case) Correlation with antibiotic history imprecise

33 Results 0 100% 0 0 Control N=20 2/64 (3.1%) 54/64 (84%) 8/64 (12.5%) 2/60 (3%) 4.6 (3, 0-22) 88% Total N=64 2/45 (4%) 36/45 (80%) 7/45 (16%) 1/45 (2.2%) 3.9 (3, 0-20) 84% HIV N= /19 (95%) 1/19 (5.3%) 1/15 (6.7%) 6.2 (5, 0-22) 95% SCD N=19 Serology indet CTX-Ab neg CTX-Ab pos DAT pos (%) CTX exp

34 Case 3 conclusion Ceftriaxone-mediated DIIHA can present as catastrophic intravascular hemolysis especially in pediatric HIV/SCD. Confused/coexist with sepsis/dic, potentially even acute HTR. Presence of antibody alone not correlated with hemolysis. Other contributing factors to hemolysis?

35 Proposed unifying model of drug-induced antibodies When drugs (haptens) bind to RBC membranes, 3 types of antibodies could be made: 1. Ab to RBC membrane alone (autoantibody) - methyldopa 2. Antibody to drug alone ( hapten mech) 3. Antibody to drug and RBC membrane ( immune complex ) ceftriaxone Piperacillin/tazobactam can induce #2 alone or #2 and #3.

36 Summary DIIHA in 2007 Easily overlooked unless a careful medication history is obtained. Can be confused with AIHA, delayed hemolytic transfusion reaction, or even sepsis. Discontinue the medication while serologic studies are ongoing. Cephalosporins, new penicillins (or penicillin combinations such as Zosyn), even NSAIDs can be culprits.

Hemolysis. Intravascular vs. Extravascular. Classification. Warm vs. Cold Auto. Warm Auto. WAIHA Serologic Investigation

Hemolysis. Intravascular vs. Extravascular. Classification. Warm vs. Cold Auto. Warm Auto. WAIHA Serologic Investigation Positive Direct Antiglobulin Test and Autoimmune Hemolytic Anemias Jeffrey S. Jhang, M.D. Assistant Professor of Clinical Pathology College of Physicians and Surgeons of Columbia University Direct Antiglobulin