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Hemolytic Anemia Drugs Induced By Antihypertensive Agents: A Case Of Laboratory
Author: Aurelian Udristioiu
Publisher: Emergency County Hospital TARGU-JIU
4 pages
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Anemia most often is discovered through

laboratory tests, but the history and physical

examination can provide important clues about the

presence of hemolysis and its underlying cause [1].

Drug-dependent antibodies are those antibodies that

will only react in vitro in the presence of drug (eg,

bound to RBCs or added to the patient’s serum in test

systems to detect drug antibodies); these are antibodies

directed at epitopes on the drug and/or its metabolites,

or a combination of drug plus RBC membrane protein.

The mechanisms involved in the serological and clinical

findings are controversial.


A 58 year woman patient, since 8 years in

treatment with drugs for chronic cardiovascular disease,

was admitted to the county hospital, in department of

Cardiology in January month, because of clinical

symptoms of cardiovascular disease. The patient

complained dyspnea and fatigue and, occasionally, back

pain and the skin may appeared with easy jaundice. In a

resting tachycardia with a flow murmur was presented

and on image of ultrasound CT, the enlarged liver and

spleen reflected a hepatic steatosis and hypersplenism.

In history patient was noted that in medication

prescribed along of five years for Hypertension were

encompassed two drugs with a potential effect side of

hemolytic anemia, Trezen (Perindopril) and Chindin.

These drugs can cause serious side effects which

include; headache, dizziness and lightheadedness,

fatigue, dry, tickling cough, weakness, numbness or

tingling in the arms, legs or feet, nausea, taste

disturbances itching, rash or increased sweating and

hemolytic anemia after some years. After preclinical

investigations of screening, without a concluded

diagnosis, the currant doctor from cardiology

recommended the special analyses regarding the

discovery of signs and symptoms of anemia.

Laboratory blood , CBC, showed: HGB = 8.3

g/d L (n=12.6- 14 mg/dl); HTC = 24.8% (n= 37-47%);

RBC = 1.85 μL x 10³ (n = 3.8-5.8 μL x 10³), PLT = 166

μL x 10³ (n = 150-450 μL x 10³), WBC = 4.3 μL x 10³

(n= 4-10 μL x 10³) , Reticulocyte = 14 % (n = 0.5-

1.2%).. Erythrocyte indices with abnormal values

(MCV = 133.7 f L (n = 82-92 f L), MCH = 45 pg (n =

27-31 pg); MCHC= 36.6 g/dl (n = 32-36 g/dl).

Peripheral blood smear findings: on blood

smear in optic microscopy was registered, Band = 0,

Segmented = 55.2%, Eosinophile = 4.5%; Basophile =

0.5%, Lymphocyte = 36.6%, Monocyte = 3.2%, ESR =

55 mm/h.; Suspect flags on coulter HMX Analyser: No


Other laboratory tests relieved an increased

level LDH = 710 u/l (n = 313 – 618), glucose = 151

mg/dl (n = 75 – 110 mg/dl), urea = 50.5 mg/dl ( n = 17-

43 mg/dl), creatinine = 1.26 mg/dl, triglyceride = 575

mg/dl (20 – 150), iron = 139 ug/dl (N = 49 – 181),

serum ferritn = 15 ng/ ml, Total bilirubin = 2.4 mg/dl( n

= 0.20-1.30 mg/dl), Conjugate bilirubin = 0.6mg/dl (n =

0.0=0.30 mg.dl), Indirect bilirubin = 1.8 mg/dl (n =

0.0-1.10mg/dl), Delta Bilirubin = 0.6 ((n = 0.0-0.5

mg/dl), ALT= 33.6 U/L (n = 5-31 U/L), AST = 61.0

U/L, (N = 5-32 U/L). APTT (activate prothrombin

time), PT/PTT (prothrombin time/partial

thromboplastin time) with normal results.


Along with anemia, a characteristic laboratory

feature of hemolysis is reticulocytosis, the normal

Udristioiu et al.; Sch J Med Case Rep 2013; 1(1):8-11.

Available Online: 9

response of the bone marrow to the peripheral loss of

red blood cells. In the absence of concomitant bone

marrow disease, a brisk reticulocytosis should be

observed within three to five days after a decline in

hemoglobin. In a minority of patients, the bone marrow

is able to chronically compensate, leading to a normal

and stable hemoglobin concentration. The anemia of

hemolysis usually is normocytic, although a marked

reticulocytosis can lead to an elevated measurement of

mean corpuscular volume, because the average mean

corpuscular volume of a reticulocyte is 150 f.

The more common extravascular hemolysis is

the removal and destruction of red blood cells with

membrane alterations by the macrophages of the spleen

and liver. Circulating blood is filtered continuously

through thin-walled splenic cords into the splenic

sinusoids with hipersplenism because of hemolytic

anemia which involved the following preclincal

features, after abnormal and accelerated destruction of

red cells.

Increased breakdown of hemoglobin, resulted

in: increased bilirubin level (mainly indirect-reacting)

with jaundice of urinary urobilinogen,

hemoglobinanemia, hemoglobinuria and

hemosiderinuria. The level of lactate dehydrogenase

(LDH) in the blood is elevated), haptoglobin levels was


Peripheral blood smear microscopy emphasis:

fragments of the red blood cells ("schistocytes"), some

red blood cells may appear smaller and rounder than

usual (spherocytesThe direct Coombs test was positive,

hemolysis being caused by an immune process. The

balance between red cell destruction and marrow

compensation determined the severity of anemia.

Hemosiderin in the urine indicated a chronic

intravascular hemolysis and also urobilinogen in the

urine was increased as a biological effect.

In the specialty lecture, the most acceptable

one involves drugs, like penicillin, that covalently bind

to proteins (eg, RBC membrane proteins); RBCs

become coated with drug in vivo and, a drug antibody

(usually IgG) attaches to the drug-coated RBCs that are

subsequently cleared by macrophages. The most

controversial is the so-called immune complex

mechanism, which has been revised to suggest that

most drugs are capable of binding to RBC membrane

proteins, but not covalently like penicillins [2].

The direct antiglobulin test (DAT), also known

as the direct Coombs' test, demonstrates the presence of

antibodies or complement on the surface of red blood

cells and is the hallmark of autoimmune hemolysis.The

patient's red blood cells are mixed with rabbit or mouse

antibodies against human IgG or C3. Agglutination of

the patient's antibody- or complement-coated red blood

cells by anti-IgG or anti-C3 serum constitutes a positive

test. Red blood cell agglutination with anti-IgG serum

reflects warm AIHA, while a positive anti-C3 DAT

occurs in cold AIHA (Figure 1).

Fig.1: Direct antiglobulin test, demonstrates the presence of autoanti-bodies (shown here) or complement on the

surface of the red blood cell

There are two types of drug-related antibodies.

Drug-independent antibodies are those antibodies that

can be detected in vitro without adding any drug; thus,

in vitro and in vivo characteristics are identical to cell

red blood cell (RBC) autoantibodies. The prototype

drug is methyldopa, which causes the production of

RBC autoantibodies in about 15% of the patients

receiving the drug, but only about 0.5% to 1% develop

an HA [3, 4].

The FDA reported on 85 cases of cefotetaninduced

HA from approval of cefotetan in 18% were

fatalities [5] Mean fall in hemoglobin (Hb) level was

6.7 g/dL, with mean final Hb of 5.2 g/dL.

Hydrocortisone antibodies have been detected in

individuals without HA (6). A recent finding should be

of interest to hematologists: the first case of a DIIHA

due to hydrocortisone has been described (7). This adds

another possible explanation for poor responses to

steroid therapy in some cases of AIHA where steroidinduced

DIIHA may be masked by the autoimmune

process (Table 1).

Udristioiu et al.; Sch J Med Case Rep 2013; 1(1):8-11.

Available Online: 10

Table 1: Selected Drugs that Cause Immune-Mediated Hemolysis

Mechanism Drug absorption


Immune complex Autoantibody

DAT Site of




Positive anti-IgG


Penicillin, Ampicillin,

Methicillin, Carbenicillin

Cephalothin (Keflin)*

Cephaloridine (Loridine)*

Positive anti-C3


Quinidine, Phenacetin ,

Hydrochlorothiazide , Rifampin (Rifadin) ,

Sulfonamides, Isoniazid, Quinine, Insulin,

Tetracycline, Melphalan (Alkeran),

Acetaminophen, Hydralazine (Apresoline),

Probenecid, Chlorpromazine (Thorazine),

Streptomycin, Fluorouracil (Adrucil),

Sulindac (Clinoril)

Positive anti-IgG




Mefenamic acid

(Ponstel), L-dopa,


Ibuprofen, Diclofenac,

(Voltaren) Interferon

In our case of this study, in drug prospects of

Trezen and chinidin, as side effect is written

hypersensitivity reactions: rash and thrombocytopenia,

rare pancytopenia and agranulocytosis. Occasionally

there have been reports of photosensitivity and lupus

erythematosus-like syndrome.

Differntial diagnosis was made with Glucose-

6-phosphate dehydrogenase deficiency with can lead to

hemolysis in the presence of oxidative stress.

Hereditary spherocytosis which is characterized by

spherocytes, a family history, and a negative direct

antiglobulin test. Sickle cell anemia and thalassemia

which are hemoglobinopathies characterized by chronic

hemolysis. When and iron deficiency is severe the

anemia is hypochromic and microcytic but in milder

degrees of iron deficiency the anemia is normocytic

(Figure 2).

Fig. 2: Algorithm for the evaluation of hemolytic anemia

(CBC = complete blood count; LDH = lactate dehydrogenase; DAT = direct antiglobulin test; G6PD = glucose-6-

phosphate dehydrogenase; PT/PTT = prothrombin time/partial thromboplastin time; TTP = thrombotic thrombocytopenic

purpura; HUS = hemolytic uremic syndrome; DIC = disseminated intravascular coagulation)

Udristioiu et al.; Sch J Med Case Rep 2013; 1(1):8-11.

In the megaloblastic anemia, the anemia is

normocytic and is not associated with leucopenia,

thrombocytemia in peripheral blood. Macrocytes and

ovalocytes can be also presented on blood film,

differently, Hemolitic Anemia where appear

Poikilocitosis and Heintz body in erithrocytes (Figure


Fig. 3: Poikilocitosis and Heintz body in Eritrocytes

(Hemolitic Anemia)

Deficiency of vitamin B12 or folic acid also

leads to the production of giant metamielocytes and

multi-segmented macropolicites. The abnormalities in

the granulocytic series do not disappear as promptly as

then megaloblasts after specific therapy and their

present may be helpful in diagnosis. To microscopic

examination of slide from bone morrow, can occurred

the hyperplasic series of erythrocytes ~ 45%, deficiency

of erythropoiesis, poly-cromathopil and acidophil

erythroblasts with megaloblastic character, large

metamielocytes and giant band forms


The combined membrane plus drug can create

an immunogen; the antibodies formed can be IgM or

IgG and often activate complement, leading to acute

intravascular lysis and sometimes renal failure; fatalities

are more common in this group. It is still unknown why

and how some drugs induce RBC autoantibodies,

sometimes causing AIHA.


1. Dhalival G, Cornett AP, Tiernely ML;

Hemolytic Anemia. Am Fam Physician, 2004;

69(11): 2599-2607.

2. Garratty G; Drug-induced immune hemolytic

anemia. ASH Education Book, Volume 1,

2009: 73-79.

3. Petz LD, Garratty G; Immune Hemolytic

Anemias. 2nd edition, Philadelphia: Churchill

Livingstone, 2004:261- 317.

4. Garratty G, Arndt P, Prince HE, Shulman IA;

The effect of methyldopa and procainamide on

suppressor cell activity in relation to red cell

autoantibody production. Br J Haematol.,

1993; 84(2): 310–315.

5. Viraghavan R, Chakravarty AG, Soreth J;

Cefotetan-induced haemolytic anaemia. A

review of 85 cases. Adv Drug React Toxicol

Rev., 2002; 21(1-2):101–107.

6. Umlas J, Turner LA; Antibodies to

hydrocortisone in reagent red cells causing

positive antibody screening tests. Transfusion,

1993; 33(8): 686–688.

7. Martinengo M, Ardenghi DF, Triopdi G, Reali

G; The first case of drug-induced immune

hemolytic anemia due to hydrocoTransfusion, 2008; 48(9): 1925-1929.

About the publisher:

- My Book written in Clinical Laboratory Medicine, “ Hematological and Metabolical Aspects from Laboratory Medicine” , confirm the aria of my interest in discovery of carcinogenesis mechanisms, especially in onco-haematology field, Leukemia.


Also, my new e-Book: e-BOOK: Hematological and Metabolical Aspects of Laboratory Medicine (Hematological and Metabolical Aspects from Laboratory Medicine) ( Second Edition ) [Large Print] [Paperback].

Publisher: Aurelian Udristioiu, 2 edition (September 9, 2013) Full Color on White paper, 122 pages. ISBN-13: 978-1492186816 (CreateSpace-Assigned) ISBN-10: 1492186813, BISAC: Medical / Laboratory Medicine, USA. Sold by   

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1. Udristioiu A. The Assessment of Uncertainty in Measurement of Cholesterol; A Model of Calculation. Biophysical Journal; Volume 96, Issue 3, Supplement 1, February 2009; Page 504a.

2. Udristioiu A, Florescu Cristina, Popescu Manuela Andrei. “High Concentration of anaerobic ATP implicated in aborted apoptosis from CLL”. LabMedicine, American Journal of Clinical Pathology-ASCP, Manuscript 09-08-LM-S-SCI-0122R1, Published in 04-05/2010.

3. Aurelian Udristioiu. First Hematological Signal of Latent Anemia to Aging Population. Nature Publishing Group. Advance Search 0.1038 npre 2009.3285.1. Creative Common Attribution 3.0 License, accepted for the work online posted.

4. Udristioiu A, Cojocaru M, Florescu C. Screening Tests for Latent Anemia in Hospitalized Adults Over 65.   LabMedicine, American Journal of Clinical Pathology-ASCP, Manuscript  09-11-LM-S-SCI-0156.R1,  Published  in 07-05/2010.USA American Journal of Clinical Pathology p-ISSN: 0002-9173 ICV 38.53 LabMedicine ; Ascp Press) , Impact Factor ISI, IF = 2.853 , 18 Index Copernicus Journals Master List 2006.


1 University of Medicine and Pharmacy “Carol Davila, Faculty of Pharmacy, Department of Microbiology, Traian Vuia 6, Sect. 2, 020956,Bucharest, Romania. 6“Stefan S. Nicolau” Virology Institute, Bucharest, Romania. FARMACIA 2010; (57); 3: 420-427 IMPACT FACTOR ISI THOMSON 0.144 .

6. Moleular Biological  Tchiniques  user for identification  of Candida SPP. MANUELA-ANDA RADU-POPESCU1*, SILVIA DUMITRIU2, SIMONA ENACHE-SOARE3,  AURELIAN UDRISTOIU4. 1 University of Medicine and Pharmacy “Carol Davila, Faculty of Pharmacy. FARMACIA 2010; (58); 4: 422-429

7. Udristioiu A. Role of Mg2+ ion as cofactor ATP in assurance of energetic environment cells( Abstract). Magnesium Research 2011; 24 (1): 22-6.

8. -Aurelian Udristioiu, Radu G. Iliescu, Cristina Popescu. Variability of bilirubin values in serum samples with high triglycerides; interference or congenital liver syndromes. J Biosci Tech Volume 2, Issue 4 (JULY 2011).

9. Aurelian Udristioiu¹*,Radu G. Iliescu², Lucian Udristioiu¹ and Manole Cojocaru. A new approach of abnormal apoptosis as a cause of autoimmunity and malignancy. Biotechnology and Molecular Biology Review Vol. 6(8), pp. 166-171, November 2011 . Available online at <>

10. Aurelian Udristioiu, Cristina Popescu, Manole Cojocaru, Sorina Comisel, Valentina Uscatescu. Relation between LDH and Mg as Factors of Interest in the Monitoring and Prognoses of Cancer. Journal of Bioanalysis & Biomedicine. Ref.:  Ms. No. JBABM-11-48R1 accepted on Jan 27, 2012

11. UDRISTIOIU A. Florescu C, Popescu C, Cojocaru M "Significance of Neutrophil Alkaline Phosphatase versus Isoenzymes ALP in Acute or Chronic Diseases,"accepted for publication in LabMedicine, LabMedicine Manuscript 11-03-LM-U-MR-0052.R2/11/12/2011.

12. Aurelian Udristioiu¹, Radu Iliescu ², Manole Cojocaru³. Errors in Counting Platelets in Hemodialysis Patients by Use of Optical Microscopy. Review of Applied Physics (RAP) Volume 2 Issue 1, March 2013; p: 17-22

13. Aurelian Udristioiu¹, Radu Iliescu ², Manole Cojocaru³. Energetic Levels of Metabolic Pathways in Malignant B and T Cells Mini-Review. Advances in Chemical Science Volume 2 Issue 4, December 2013; 2; 90-95

14. Aurelian Udristioiu¹, Manole Cojocaru² Hemolytic Anemia Drugs Induced by Antihypertensive Agents: A case of Laboratory. 13 Scholars Journal of Medical Case Reports ISSN 2347- 6559. Sch J Med Case Rep 2013; 1(1):8-11

15. Aurelian Udristioiu1*, Radu G. Iliescu2, Manole Cojoraru Molecular mechanisms of bone reconstruction in new dental implant technology. Integrated Journal of British. Volume 1 2014 Issue 1(5-6), pg: 1-7; IJBRITISH.


1.Aurelian Udristioiu. Cicloergometrul si Sanatatea. Ed. Medicala 1990, Bucuresti. ISBN: 973-39-01105-9; Formatul 16/10 x 100; Nr pagini: 78.

2.Aurelian Udristioiu. “Bioenergetica Celulara si Maligna” Ed. Academica Brancusi 2002, Targu Jiu, Bun de tipar, Bucuresti, Tipografia Everest 2001; ISBN 973 85342-6-7; Formatul 16/14 x 100; Nr. Pagini: 307.

3. Aurelian Udristioiu, Manole Cojocaru, Radu Iliescu., Hematological and Metabolic Aspects from Laboratory Medicine" (ISBN 978-3-8473-0775-4). LAP LAMBERT Academic Publishing GmbH & Co. KG Heinrich-Böcking-Str. 6-8 , 66121, Saarbrücken, Germany, 2012.

4. Book title: Renal Diseases / Book 2 (ISBN 979-953-307-704-7). Chapter title: Variability of Biological Parameters in Blood Samples between Two Consecutive Schedules of Hemodyalsis

Authors: Aurelian Udristioiu, Manole Cojocaru, Victor Dumitrascu, Daliborca Cristina Vlad, Alexandra Dana Maria Panait and Radu Iliescu, Publishing Group 2011., Volume 2, Issue 4 (JULY 2011)

5. e-BOOK: Hematological and Metabolical Aspects of Laboratory Medicine (Hematological and Metabolical Aspects from Laboratory Medicine) ( Second Edition ) [Large Print] [Paperback].


Publisher: Aurelian Udristioiu, 2 edition (September 9, 2013) Full Color on White paper, 122 pages. ISBN-13: 978-1492186816 (CreateSpace-Assigned) ISBN-10: 1492186813, BISAC: Medical / Laboratory Medicine, USA. Sold by  

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