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Immune Hemolytic Anemias (IHA)
Definition
Classification
Mechanism of hemolysis
Characteristics in clinical and laboratory
Diagnostic process
Definition of IHA
The shortened red cells life span is caused by the antigens existing on the surface of erythrocytes reacting with relative antibodies. This acquired hemolytic anemia is termed immune hemolytic anemia.
IHAClassification
1. According to the cause of Ab production
2. According to the nature of Ab
Autoimmunehemolytic anemia (AIHA)
Drug-induced immune hemolytic anemia (DIHA)
Allo-immune hemolytic anemia (ALIHA)
temperature
Warm Ab type(37 ℃ , IgG)
Cold Ab type (less than 37 ℃, IgM)
Mixed Ab type
I. Autoimmunehemolytic anemias (AIHAs)
Definition
AIHAs are a group of acquired hemolytic disorders that are the result of antibodies or complement binding to specific antigens on the RBC membrane, which leads to a shortened RBC life span and an increased RBC destruction.
1. IgG Warm Abs bind to RBCs at 37 but fail to aggl℃utinate the RBCs.
2. Cold agglutinins almost always are of IgM subtype and clump RBCs at cold tempratures. (CAS)
.3. Donath-Landsteiner(IgG) Abs bind to RBCs in the cold and activate the hemolytic complement cascade when the RBCs are warmed to 37 . (PCH)℃
Antierythrocyte antibodies can be divided into three general categories:
AIHA : Warm Antibody Type
overview:
•a group of diseases resulting from the binding of IgG to the RBC membrane.
• The IgG-bound RBCs either are trapped by macrophages as they pass through the spleen or may first have part of their membrane removed, then destroyed in the circulation.
• 70% of AIHAs.
Pathogenesis of hemolysis:
FcR
C3bR
macrophages37°C
IgG
Spleen sinus
spleenextravascular and/or intravascular
Idiopathic: females more than males?secondary causes:• Lymphoprolitive diseases (e.g., CLL , non-Hodgkin lymphoma )
• Connective tissue diseases(e.g., SLE)
•Immune deficiency disorders( e.g., AIDS)
•Drugs(e.g., penicillin, quinidine, methyldopa, cephalosporins)
Etiology:
1. jaundice, anemia(e.g., fatigue, shortness of breath, light-headedness) or asymptomatic
2 . PE: jaundice, splenomegaly, and some signs relate to underlying illness , such as fever, lymphadenopathy, skin rash,, hypertension, renal failure, petechiae or ecchymoses ( PC decrease)
Highly variable symptoms that are unrelated to temperature.
Evans syndrome is the combination of warm AIHA and idiopathic thrombocytopenia purpura.
Clinical Features
WBC? PC: N or low
Lab Findings
Blood : Hb, PCV , RBC( vary from normal to low) Ret , “3M” (MCV ?) and RDW fall
Morphology : polychromatic RBCs, macrocytosis, nucleated RBCs, or microspherocytes.
Bone marrow: hyperplasia figure
Serum bilirubin and urobilinogen(urine):elevated
DAT usually positive. ( confirm test)
•Blood smear may present macrocytes, spherocytes.
•Bone marrow reveals erythroid hyperplasia. Polychromatic and orthochromatic normoblasts increaes, M/E decreased, erythroid mitosis increased; mature RBC?
Coombs Test1. Direct Anti-immunoglobin Test ( DAT )
serum
Anti-immunoglobin
Poly-
Anti-IgG
Anti-complement
II. Cold AIHA
Cold Agglutinin Syndrome (CAS)
•a group of disorders caused by IgM auto-antibodies (usually against the I/i antigen)
• cold agglutinins bind to RBCs at cold temperatures (4 ℃ - 18 ℃).
overview
Hemolytic mechanism of CAS :
Extravascular
or Intravascular0 to 5 (4~18) ℃
agglutinate
cold agglutinins-IgM binding at low tempe
rature
anti-C3+
activate complement, and C3b fixation( at higher tempratures.)
1. Cold-induced acrocyanosis (Raynaud’s phenomenon) :
blue color of the skin at fingertips, toes, nose, and ear lobes) due to vascular sludding arising from agglutination.
2. cold-associated hemoglobinuria
Specific clinical features of CAS
4. Symptoms worse in cold weather and higher IgM titer and activity)
3. Secondary to upper respiratory tract infection
--anemia: Hb
--Hemolysis: ret, bilirubin, LDH,
--blood smear: RBC agglutination
Lab Findings:
--bone marrow
--DAT +: for C3 only. (screening)--The Cold agglutinin test (confirm)
Coombs TestDirect Anti-immunoglobin Test ( DAT )
serum
Anti-immunoglobin
Poly-
Anti –C3 +
Patient serum cold agglutinin IgM
autoerythrocytes
or O type RBC
or the same type RBC
4 to 30 ℃ ℃
37 ℃
Cold agglutinin test
【 Result 】 Normal: titer<1:40, CAS: titer>1:64
• IgG autoantibodies are specific for the P antigen.
• D-L Ab: mono- or polyclonal; IgG;
III. Paroxysmal cold hemoglobinuria (PCH)
syphilis
• paroxysms of fever, back pain, leg pain,
abdominal cramps; rigors (after exposure to cold temp.) hemoglobinuria
• hemolysis: intravascular , less than 20 ℃• children often , secondary to viral disorder
1. Hb, PCV (severity of anemia)
2. Ret low in episode; elevated in recovery phase.
3. Blood smear: anisocytosis, poikilocytosis, polychromatophilia, spherocytes, nucleated RBCs.
4. FHb , Hp ; hemoglobinuria, methemoglobin (urin)
5 DAT negative usually, or C3 + only, IAT+
6 Donath-Landstainer Test : D-L Ab +
Lab findings:
Indirect Anti-immunoglobin Test ( IAT )
T<20 ℃
Sample of patient
Anti-IgG , IgM or / and C
Cold Warm Hemolysis Test
(Donath-Landstainer Test)
【 Principle 】
At lower temperature(<20 ), D-L antibody ma℃y attach to the surface of the patient’s red cell. When temperature up to 37 , the red cells with D-L antib℃odies lysis rapidly with the help of activated complements.
【 Result 】 Negative: no lysis in normal people.
37 ℃
<20℃
Diagnostic process of IHA
jaundice, hemoglobinuria
Splenomegaly, fever, chilly
PLC
Coombs test
cold agglutinin test cold warm hemolysis test
CAS PCH
DAT+
titer>1:64
Anti-C3
Anemia and type of anemia
Hemolytic anemia and its type
IHAunderlying diseases and specific featrues?
Warm type of AIHA
Evan syndrome
Hb, RBC, PCV; 3M, RDW
Fatigue, weakness
Retmorphology serum and urine
Anti-C3, ITA+
Questions :
1. Summarize the features of blood and bone marrow smear in IHA?
2. How do you know the patient may have IHA?
Case
A female, 45 years old
Complaintof “having been fatigue, weakness for about 6 months. Sometimes had black urine.”
PE: moderate splenomegaly and slightly enlarged liver.
Lab: Hg 80g/l, Hct 0.30 , RBC 2.5X1012 , RDW 16.7
What do you know from these information?
Blood smear
Marrow cellularity (×100)
Marrow smear (×1000)
No.5 is the result of Coombs test of the patient
DAT(anti IgG+anti C3)
1 2 3 4 5
Discussing questions:
1. What is your primitive impression of the patient?
Describe your evidence?
2. What clinical information do you need to support your diagnosis?
3. Which further tests do you need to complete the diagnosis?
4. Why the patient had black urine.
MYELOPATHIC ANEMIAS
These anemias are due to the bone marrow infiltration or replacement by abnormal tissues such as malignant metastases, myelosclerosis, leukemia and myeloma.
Secondary anemia
Pathogenesis of myelopathic anemia:
--bone marrow damage
--hemorrhage
--hemolysis
Clinical Features
--severe anemia
--bleeding problems may occur
--splenomegaly and hepatomegaly is common
--symptoms referable to underlying disease
Lab Findings
Blood
--varying degrees of anemia (most normocytic; slightly macrocytic)
--distinct anisocytosis and poikilocytosis
--leukoerythroblastic anemia:--reticulocytosis and polychromatophilia--The WBC count may be variable--The platelet count is often low, giant, bizarre shaped with abnormal function.
What is leukoerythroblastic anemia?
The patients suffering from anemias with nucleated RBCs and immature granulocytes in the peripheral blood.
disruption of marrow sinusoids
hematopoiesis in extramedullary sitesWhy?
.Bone marrow
--The marrow aspiration may fail or show metastatic cells and so on.
--The marrow biopsy is necessary to establish the diagnosis.
Other tests:
--x-ray
--NAP
--CD
ANEMIA
贫血的病因及发病机制分类
贫 血红细胞生成减少 红细胞破坏过多 红细胞丢
失增加 骨髓造血功能障碍
造血物质缺乏或利用障碍
铁缺乏和铁利用障碍
维生素 B12或叶酸缺乏
红细胞 内在缺陷 外在异常
干细胞增殖分化障碍
骨髓被异常组织侵害
骨髓造血功能低下
免疫因素
非免疫因素
急性失血性贫血
慢性失血性贫血
微血管病性溶血性贫血
化学、物理、生物因素致溶血
脾功能亢进
各种原因致免疫性 溶血性贫血
巨幼细胞贫血等
缺铁性贫血
铁粒幼细胞性贫血等
再障,纯红再障等
骨髓增生异常综合征等
膜异常 酶异常 Hb异常
珠蛋白生成障碍性贫血
异常血红蛋白病
不稳定血红蛋白病
葡萄糖6磷酸脱氢酶缺乏症
丙酮酸激酶缺乏症等
遗传性球形红细胞增多症
遗传性椭圆红细胞增多症等
阵发性睡眠性血红蛋白尿症
肾病、肝病、感染性疾病、
内分泌疾病等
白血病、骨髓瘤、癌转移、
骨髓纤维化等
Anemia: weakness,fatigue, listlessness,palpitation, pallor jaundice, splenomegaly
MCV increase normal decrease
MCH MA IDA,SA,Thala
MCHC infection
decrease ret increase acute loss blood hypopoiesis HA (Coomb’s)
decrease PL normal IHA
infection extracellular defect intra-
WBC chronic renal disease osmotic fragility
decrease increase increase normal decrease
AA,MF AM HS,HE, G-6PD, PK Thala
PNH (ham’s) abnormalHb
Diagnostic steps of HA:
history,infection, underlying diseases,drugs,pallor,weakness
dark urine, jaundice,hepatosplenomegaly
blood film
spherocytes, autoagglutination, red cell fragments
ret increased immune assay
cold agglutinin test Coomb’s test
positive
CAS AIHA negative cold warm
hemolysis test
transfusion reaction infection, congenital syphilis
Normocytic normochromic anemia
history, underlying diseases, pallor,weakness
blood film
decrease/ increase ret increase
morphologic features acute blood loss HA
normal abnormal
secondary hypoplasia abnormal proliferation
anemia infiltration in marrow
Infection AA MDS leukemia
renal disease MF
liver disease metastatic cancer
endocrinic disease
Microcytic hypochromic anemia:
history, underlying diseases, anemia,MCV,MCH
Blood film
SI
increased normal/ increased decreased
Iron stain Hb eletrophoresis SF
HbA2,F
increased normal/ increased decreased
SA Thalasemia anemia of chronic IDA
HbC,S, D,E disorders
etc.
Differentiation of macrocytic anemias:MCV, MCH
history, anemia ,underlying diseases,
drugs,nutrition,neurologic signs, hepatosplenomegly
blood film
increased Ret normal / decreased
marrow morphology
acute blood loss HA non-MA MA
erythroblastic anemia abnormal proliferation
Alchohol poisoning MDS Folate deficiency
Liver disease VitB12 deficiency
Pernicious anemia
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