بیماری های کم خونی (آنمی) دانگاه علوم پزشکی دانشگاه واشنگتن 2009

Mon 10 Jan 2011

Anaemias
Szabolcs Modok
Symptoms of anaemia

• Fatigue
• Angina pectoris
• Dizziness
• Weakness
• Maldigestion
• Dyspnea
• Claudication
Grades of anaemia
Basic diagnostic tools
• Full blood count and indices (MCV)
• Blood smear (morphology and parasytes)
• Absulote reticulocyte count
• Serum iron, transferrin saturation, soluble transferrin receptor, serum ferritin
• Schilling test
• Bone marrow cytology, histology
• Coombs test
Low production
• Low absolute reticulocyte count
• Examples:
 iron deficiency
 folate/B12 deficiency
 anaemia of chronic disease
High destruction
• High absolute reticulocyte count
• Example:
 Autoimmune haemolytic anaemia 
Iron deficiency anaemia
• MCV < 70 fL
• Low Se Fe
• Low transferrin saturation
• Low serum ferritin

• 200 mg/day iron supplementation for at least 3 months to load iron stores
• Folate/B12 supplementation
Pathway of iron metabolism
Stages of iron deficiency
• storage Fe  , seFe normal, TIBC
• seFe  , TIBC  , transferrin sat. < 16%
    se. ferritin
• anaemia
• microcytosis  hypochromia
• iron deficiency in tissues
Iron-deficiency anemia
Symptoms/signs:
•  glossitis (above 40 y, diet) Plummer-
•  stomatitis angularis  Vinson
•  dysphagia    syndrome
• dry skin, koilonychia, fragile hair 
• fatigue
• pica (craving for dirt, paint, etc)
Most common causes
Children: growth requirement, diet
Aldolescence: ♀ rapid growth, menstr.
    ♂ rapid growth
Adults:  ♂ GI bleeding*
   ♀ menstr.
         pregnancy
      diet
  Absorption disturbances
   sprue, gastrectomy
* normal: 1 ml/day,  laboratory tests detect: >20 ml/day helminthiasis!

Diagnosis
Microcytic hypochrome
  SeFe    TIBC
  ferritin   < 12 µg/L
  transferrin sat.  < 16 %
  reticulocyte
  thrombocyte
Bone marrow:  Fe ø (Berlin blue staining)
        ↔ increased RBC prod.
Treatment: principles
1.) eliminate cause

2.) effective replacement

3.) follow response
Treatment: practice
Per os: 200 mg elemental iron for 3-6 months
  (ferrous sulfate/fumarate/gluconate)
IV: GI side effects or no compliance
Reticulocyte crisis: at two weeks
Hb rise: after 2-3 weeks
Vitamin-C
Folate

No improvement > underlying disease?


Treatment options in ACD
• Treatment of the underlying disease
• Red blood cell transfusions
• Erythropoetin

Pernicious anaemia
• Intrinsic factor deficiency (gastrectomia, dysbacteriaemia, short bowel syndrome)
• MCV > 110 fL

• 1000 μg B12, then 100 μg/month for life
B12 and folate deficiency
Changing „face” • B12 neurological signs only
    of disease  • folate = pregnancy  spina bifida
    (no anaemia    neural tube defect
    no macrocytosis)
        = homocysteine  endothel
    damage   thrombosis
   • preneoplastic syndroms
     cervix
     bronchial epithelium
     GI traktus

Atipical appearances
   • without macrocytosis
   changing of MCV!
  • pancytopenia
  • >5% neutrofils with
      hyperlobulated nucleus (=5)
  • neurological symptoms
   B12: 75-90%
    loss of position/vibratory
    sensation
    cognitive defects
   folate: depression
  • folate hides the hematological
   sings of B12 deficiency
Haemolytic Anaemias
• Corpuscular (sphero-, elliptocytosis)
• Non-corpuscular (IAHA, G6PD deficiency, others)
Haemolytic anaemias
Haemolysis = shortened RBC life span

Cr51 half-life  
28-32 days normal
< 18 d ays manifest
> 18 days „compensated”
Clinical and laboratory manifestations
• Signs of anaemia
• Jaundice (unconjugated (indirect) bilirubin , UBG , stool: stercobilin) gallstones
• Splenomegaly
• Serum haptoglobin  , LDH
• Peripheral blood (PB): fragmentocytes, spherocytes
• Reticulocytosis (RPI >/= 3)
• Bone marrow: hyper cellular, increased RBC production
• Special tests: Coombs, Hb electrophoresis, RBC enzyme assays, Cold agglutinins, Acid hemolysis, Sucrose lysis test

• Haemolytic crisis
 acut illness chills, fever
    pain in abdomen
    jaundice
    hemoglobinuria

• Aplastic crisis parvo B19

• Megaloblastic crisis B12/folate def.
Classification of hemolytic an.
A. extrinsic RBC defects    B. intrinsic RBC defects
  acquired      inherited

1 – immunhaemolytic an.  1 – alteration of membrane
2 – microangiopathic    2 – hereditary enzyme
  hemolytic an.    deficiencies
3 – toxic    3 – hemoglobin abnorm.
       (defective synthesis)
      4 – PNH (parox. nocturnal
       hemoglobinuria)


Alteration of Red Cell Membrane
• Hereditary spherocytosis (chronic familiar icterus dominant trait
  Diagnosis: spheroidal RBCs, microspherocytes
     +
    hemoytic anaemia
  Treatment: splenecomy
• Hereditary elliptocytosis (ovalocytosis)
     rare autosomal dominant
   Hemolysis in 15 % of cases
• Stomatocytosis
  congenital: hemolytic anaemia
  acquired: alcoholism, liver disease


Disorders of Red Cell Metabolism
Hereditary enzyme deficiencies
• G6PD-deficiency x-linked disorder 400 M people
  - drug-sensitive variety (drugs, fava beans,
   acute viral and bacterial inf.)
  - chr.hemolytic anaemia
  Dg.: screening tests  „bite cells”
• Pyruvat kinase deficiency autosomal recessive
  chr. hemolytic anaemia

Treatment - supportive
   - prevention (avoiding drugs and chemicals)
   - splenectomy
Defective Hemoglobin Synthesis
haemoglobinopathies
normal adult Hb HbA(2 2)  HbA2(2 2)   HbF(2 2)
          98 %         2 %        <2 %

• A) defective globin-chain production – thalassemia

• B) abnormal hemoglobins - hemoglobinopathies
 
A. Thalassemias
•  thalassemia two paris of structural genes
    tha 2 „silent carrier” (deletion of one allele)
    tha 1 deletion of two genes
  Hb-H disease 3 alleles are missing (4)
  Hydrops fetalis – Hb Barts (4) die in utero

•  thalassemia one pair of gene
 

Clinical Classification
• Tha major severe anemia Hb<60 g/l, requires treatment

• Tha intermedia Hb>70 g/l, does not require therapy but complications occur

• Tha minor (trait)
Thalassemia Major
• Hydrops fetalis (Hb Bart) – die in utero
• Severe  tha (Cooley’s anemia)

Symptoms and signs: - at 3-6 months jaundice, severe
               anaemia, hepatosplenomegaly
       - bones (extramedullary tumors)
       - thrombosis, leg ulcers
       - infections
       - hemosiderosis – heart failure
     (cause of death in 70%)
       - blood smear characteristic
Thalassemia intermedia
- anaemia and jaundice mild
- hepatosplenomegalia
- hemosiderosis (ferritin)
- require no transfusion except the case of complication
  Hb-H (4) hemolytic crises by infection
  fever, drugs
Thalassemia minor
- not a disease
- no treatment except counseling
- monitoring during pregnancy (drop of Hb)

Diagnosis: -  tha trait: difficult – normal Hbs
    MCV<75fl, PCV>30%, normal Hbs   tha trait
    MCV 75fl, PCV<30% iron deficiency

         -  tha trait: MCV<75fl, HbA2  (5%)
Treatment
• transfusion
• intensive iron chelation therapy
 - deferoxamine continuous infusion (pump.or balloon infuser)
  (retinal and auditory disturbances, growth failure)
 - deferiprone per os (agranulocytosis 1-3%, arthropathy,
  zink deficiency)
• reactivation of fetal globin  genes
   recruitment into proliferation of erythroid progenitors with
   HbF synthesis
   - EPO – not effective
   - cytostatics (hydroxyurea) – case reports
   HbS disease:  HbF,  painful crisis
• BMT – radical treatment – complete recovery
• gene therapy - experimental
B.) Abnormal Hemoglobins
HbS (2 2/6 glut  val) Sickle cell disease in blacks
      (2nd most common)
HbE (2 2/26 glut  lys) disease 
  Southeast Asia (3rd most common)
  Alone mild hypochromic an., targeting prominent

• Hb-S Sickle cell disease
 Deoxy HbS polymeraises  > occlusion in microvascular     circulation   ischemia and/or infarction
 Membran damage and fragility of RBC hemolysis
Occlusive effects dominate the clinical picture in most patients.
Hemolysis is usually brisk, but not life threatening.

Clinical features   Treatment
- vasoocclusive crisis   hydration, analgesics
 „painfull crises”    (O2, aticoagulation?)
 „hand-foot sydrome”
 leg and ankle ulcers
- acute splenic sequestration  excange transf.(splenectomy)
- acute chest syndrome  oxygenation!!!
- CNS and retinal effects  exchange transfusion
- hemolytic component
 aplastic crises   transfusion (htk:18-20%)
  parvovirus B-19
- infections (Pneumococcus sepsis)
 moderately immunocompromised  Iron chelation, hydorxiurea, BMT
Paroxysmal Nocturnal Hemoglobinuria (PNH)
Acquired hemolytic disorder
  somatic mutation of PIG-A gene, X-chromosome

  GPI-anchor missing CD59 (MIRL), CD55 (DAF)
RBCs unusual sensitivity to complement

Clinical picture anaemia/hemolysis, dark urine
    thrombosis
    WBC  , platelet
Diagnosis   HAM test
          sucrose hemolysis test (more sensitive, less specific
          GAPA

Course of the disease - PNH-AA syndrome
       PNH  AA
       AA treated with ALG 30% PNH
     - PNH  AML 1 %
     - spontaneous recovery 10 %
      (double clones together)

Treatment - BMT
   - supportive: transfusion (free of complement)
     anticoagulation
     steroid, immunsuppression
Immunhaemolytic anaemias
Immunhemolytic anaemias
• Isoimmun hemolytic anaemia transfusion    hemolytic reaction
• Autoimmun hemolytic anaemia AIHA

• Warm antibody hemolytic an.
  IgG, ♀, age>50y (anti Rh)
  hall mark: pozitive Coombs test (antiglobulin test)
forms:- idiopathic AIHA
  - drug-related AIHA (m-dopa)
  - secondary: autoimmun disease (SLE etc)
     lymphoma
     cancer

treatment aim of therapy
  1. reduction in the production of Ab
  2. reduction in the amount of available Ab
  3. diminution of RBC destruction

1.) prednisone 1mg/kg/day (60mg/day), recuction (20mg/day)
 cytostatics azathioprine  150mg/day
   cyclophosphamide 100mg/day
 cyclosporin A
2.) plasmapheresis
3.) splenectomy
 iv IgG high doses, not so effective as in ITP
Transfusion selected RBC concentrate (fenotyping!)
  small amount and slowly (complement free)

•  Cold atibody disease
 IgM anti I or i

Froms - idiopathic Cold-Ab dis.
  - secondary – viral infections Mycoplasma
      Mononucleosis inf.
      Hepatitis
  - malignant lymphomas
Treatment: warm environment, anything else ineffective
  plasmapheresis preparing pt for surgery
  chemotherapy in the case of lymphoma
Transfusion warm up the blood!
Iron overload
Body iron is increased
• HLA – linked hereditary hemochromatosis A
• Transfusional hemosiderosis B
• African hemosiderosis (dietary iron overload)

A.) HLA-linked hereditary hemochromatosis
 dysregulation of iron metabolism
 HFE gene mutation in Caucasian population 1:300
Cause: HFE gene (chromosome 6 near to-HLA-A locus)
 mutation: C282Y (H63D, S65C)

  loss of control of iron uptake

Symptoms: early sings:
 • middle – age
 • rule of three A’s: - asthenia
    - arthralgia
    (2nd and 3rd metacarpophalangeal     joints – „spain ful handshake”)
    - transaminase (GOT, GPT  )
 • skin and nail as in iron deficiency

 classical clinical picture:
  hyperpigmentation (bronze)
  hepatomegaly
  diabetes mellitus
  cardiomyopathy

Diagnosis:
Early signs + transferrin saturation  + ferritin  = genteic test transferrin saturation > 45% (♀ 50%, ♂ 60%)
Ferritin   (hepatitis, inflammation)
Liver biopsy (hepatic iron index)

Treatment: • venasections (1 U of blood per Week)
   efficacy: asthenia – good
     arthropathy – no
     cirrhosis/hetocell.cc.risk. - no
  • diet:  alcohol, tea

C282Y homozygous can be treated only in case of symptoms.

B.) Transfusional hemosiderosis
 liver disease is the most common manifestation
 diabetes mellitus (risk  if falmily history poz.)
 cardiomyopathy

Rate of acculmulation
 1 U of blood 200-250 mg Fe
 Signs if iron-stores 15-20 g
 cardiac iron deposition 20-25 g (100 U blood)
Dangerous deposition in a fully transfusion dependent
patient in 1-2 years.

Treatment: C282Y
  SeFe, TVK, ferritin  deferoxamine
  liver biopsy


Posted in time 7:29 PM by MA2 Fix link