ANEMIA OF ACUTE AND CHRONIC BLOOD LOSS

MG Alfeche, MD
December 2, 2015, 8am-10am

BLOCK
18
MODULE
2
LECTURE
2

OUTLINE
I.

Overview of Acute and Chronic Blood Loss

II.
Acute Blood Loss
III.
Classification of Anemia
IV.
Hemolytic Anemia
A. Non-immune Hemolytic Anemia
1. Microangiopathic Hemolytic Anemia
a. Thrombotic Thrombocytopenic
Purpura
2. Macroangiopathic Hemolytic Anemia
a. March Hemoglobinuria
b. Traumatic Cardiac Hemolytic
Anemia
3. Hemolytic anemia resulting from a
chemical or physical agent
4. Hemolytic anemia resuting from
infectious agent
B. Immune Hemolytic Anemia
1. Autoimmune Hemolytic Anemia
a. Warm Reacting Antibodies
b. Cryopathic Hemolytic Anemia
c. Alloimmune Hemolytic Disease of
the Newborn
2. Drug-induced Hemolytic Anemia
V.
Chronic Blood Loss
1. Chronic GI bleeding
2. Abnormal Vaginal Bleeding
VI.
Hypoproliferative Anemia
1. Iron Deficiency Anemia
2. Anemia of Renal Disease
3. Anemia of Hypometabolic state

I.

Skipped topics
Paroxysmal Noctural Hemoglobinura
II.
Laboratory Tests

OVERVIEW
BLEEDING used to describe blood loss
- Blood loss inside the body (Internal)
- Blood loss outside the body (External)

INTERNAL BLEEDING blood leaks out through damage to a blood vessel or organ
EXTERNAL BLEEDING occurs either when blood exits:
Through a break in the skin
Through natural openings:
Mouth
Nose (Nose bleeding)
Vagina (menstruation)
Rectum (haemorrhoids, anal sex)

ACUTE BLOOD LOSS A condition in which a patient quickly loses a large volume of circulating
hemoglobin
CHRONIC BLOOD LOSS A condition wherein the blood loss develops slowly over time and symptoms
may be barely noticeable and gradually worsen

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 Normal: pinkish skin; fast capillary refill

Anemic: pale skin; slow capillary refill

CASE:
A 20 year-old college student was brought to the
emergency room due to a vehicular accident.

Pertinent P.E.:
Pale, unconscious, stretcher-borne
BP= 80/60 mmHg; CR = 127 bpm; RR = 12 cpm
Tachycardic
Shallow breathing, decreased breath sounds, left
lung field

Blood Pressure: Hypotension

Cardiac Rate: Tachycardic
Clinical Impression
o Blunt trauma in the lungs leading to Internal bleeding and blood loss making the
patient hypotensive
o First Aid:
Check for Airway, Breathing and Circulation
Start on IV fluids
Request for CBC, Chest Xray, ABG, Blood Typing for Blood transfusion
Indications for Blood Transfusion
o Acute Blood Loss secondary to trauma
OB-GYNE blood loss (massive)
o Chronic blood loss (Give Packed RBC)
Acute blood loss
has a direct impact on the integrity of the blood
volume and oxygen supply to tissues. Sudden,
severe haemorrhage can induce hypovolemic
shock, cardiovascular failure, and death. When
blood loss is more gradual, the hemoglobin level
can fall to a point where oxygen delivery to vital
organs
is
compromised
Chronic blood loss
will deplete iron stores and produce an iron
deficiency anemia. Therefore, diagnosis and
management
of
a
blood loss anemia must take into account the
reason behind the loss, the rate and amount of
blood loss, and the capacity of the patient to
compensate for both volume losses and anemia
Hematology on Clinical Practice 5th edition

ETIOLOGY OF ACUTE BLOOD LOSS

Obvious blood loss
Gastrointestinal tract or intra-abdominal
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Pulmonary
Intracranial
Trauma
Hemorrhage
Menstrual flow
Hemolysis increases erythrocyte destruction
Traumatic bleeding
Caused by injury
- Gunshot wounds
- Crushing injuries
- Puncture wounds - knife
Medical Conditions
Hemophilia
Intracranial
Intra-abdominal
Menorrhagia

*BLOOD LOSS CAUSES ANEMIA BY THE FOLLOWING MECHANISMS:

By the direct loss of red blood cells
If the blood loss is protracted

Decreased iron stores

Iron Deficiency Anemia

ACUTE BLOOD LOSS

Blood loss causes anemia in 2 mechanisms:
1. Post-Hemorrhagic Anemia
External
- Trauma
- Obstetric hemorrhage
Internal
- Gastrointestinal bleeding
- Ruptured spleen
- Ruptured ectopic pregnancy
- Subarachnoid hemorrhage
2. Hemolysis
*OTHER MANIFESTATIONS OF ACUTE BLOOD LOSS:
1. Chest discomfort
2. Arm or back discomfort
Hemarthrosis
3. Neck or jaw discomfort
Multiple myeloma which may represent as stiff neck
4. Trouble breathing, with or without chest discomfort
5. Feeling light-headed or breaking into a cold sweat
6. Feeling sick or discomfort in your stomach
If young woman you may consider gynecologic problems like ectopic pregnancy,
ovarian ruptured cyst

MILD BLOOD LOSS Enhanced oxygen delivery is achieved:

- Through changes in the O2-Hb dissociation curve mediated by a decreased pH or
increased CO2 (Bohr Effect)
- In acute blood loss,
Hypovolemia dominates
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Hematocrit and hemoglobin levels do not reflect the volume of blood lost

10-15% loss of total blood volume signs of vascular instability

o hypotension
o decreased organ perfusion
>30% acute blood loss failure to compensate with the usual mechanism of vascular
contraction and changes in regional blood flow
o patient remains in supine position
o postural hypotension
o tachycardia
>40% acute blood loss more than 2 liters (average sized adult)
o Hypovolemic Shock
- Confusion
- Dyspnea
- Diaphoresis
- Hypotension
- Tachycardia
o Immediate volume replacement!

ACUTE HEMOLYSIS increased red cell destruction

Symptoms of moderate anemia:
- Fatigue
- Loss of stamina
- Breathlessness
- Tachycardia

What
-

are the signs of Acute Gastrointestinal Bleeding?

Hypotension (systolic BP < 90mmHg)
Tachycardia (>120 bpm)
Orthostatic changes in BP
Blood or coffee-ground-like material in NGT aspirate GI in origin
Hematemesis: vomiting of blood
Hematochezia: fresh blood from stool

THREE CLINICAL/PATHOPHYSIOLOGIC STAGES

OF ACUTE BLOOD LOSS
1. HYPOVOLEMIA
Loss of consciousness
Acute renal failure
-

Blood count will not show anemia since Hb level is not affected
Release of vasopressin and other peptide caused by baroreceptors and stretch receptors

Hypovolemia which poses a threat particularly to organs

that normally have a high blood supply, like the brain

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and the kidneys; therefore, loss of consciousness and

acute renal failure are major threats
Harrisons Book of Internal Medicine 19th edition

2. HEMODILUTION
- shift of fluid from the extravascular to the intravascular compartment
As an emergency response, baroreceptors and stretch
receptors will cause release of vasopressin and other
peptides, and the body will shift fluid from the
extravascular to the intravascular compartment,
producing HEMODILUTION thus hypovolemia gradually
converts to anemia
The degree of anemia will reflect the amount of blood
lost. If after 3 days the hemoglobin is, for example, 7
g/dL, it means that about half of the entire blood has
been lost.
Harrisons Book of Internal Medicine 19th edition

3. BONE MARROW RESPONSE

production of precursor cells wlll compensate for the loss
- if bleeding does not continue anemia will be corrected
- increase in reticulocyte count or presence of polychromatic cells and sometimes there
will be reactive thrombocytosis

Diagnosis of Acute Posthemorrhagic Anemia is usually

straightforward, although sometimes internal bleeding
episodes (traumatic injury), even when large, may not
be immediately obvious. Whenever an abrupt fall in
hemoglobin has taken place, whatever history is given
by the patient, APHA should be suspected.
Supplementary history may have to be obtained by
asking the appropriate questions, and appropriate
investigations (e.g., a sonogram or an endoscopy) may
have to be carried out.

TREATMENT
With respect to treatment, a two-pronged approach is
imperative
1. Blood lost needs to be replaced promptly
Unlike with many chronic anemias, when finding

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and correcting the cause of the anemia is the

first priority and blood transfusion may not be
even necessary because the body is adapted to
the anemia, with acute blood loss the reverse is
true because the body is not adapted to the
anemia, blood transfusion takes priority
2. While the emergency is being confronted, it is
imperative to stop the hemorrhage and to
eliminate its source
Blood loss during and immediately after surgery, which
can be substantial (e.g., up to 2 L in the case of a radical
prostatectomy). Of course with elective surgical
procedures, the patients own stored blood may be
available (through preoperative autologous blood
donation), and in any case, blood loss ought to have
been carefully monitored/measured. The fact that this
blood loss is iatrogenic dictates that ever more effort
should be invested in optimizing its management
Holy Grail of Emergency Medicine
for a long time has been the idea of a blood
substitute that would be universally available
suitable for all recipients, easy to store and to
transport, safe, and as effective as blood itself
2 main paths have been pursued:
1. Fluorocarbon synthetic chemicals that bond
oxygen reversibly
2. Artificially modified Hbs knowm as hemoglobinbased oxygen carriers
Although there are numerous anecdotal reports of the
use of both approaches in humans, and although HBOCs
have reached the stage of phase 23 clinical trials, no
blood substitute has yet become standard treatment
Harrisons Book of Internal Medicine 19th edition

CLASSIFICATION OF ANEMIA
I. ABSOLUTE ANEMIA (decreased red cell volume)
A. Decreased red cell production
1. Acquired
a. Pleuripotent stem cell failure
i. Aplastic Anemia
ii. Anemia of leukemia and of myelodysplastic syndromes
iii. Anemia associated with marrow infiltration
iv. Postchemotherapy
2. Hereditary
a. Pleuripotent stem-cell failure
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i. Fanconi anemia
ii. Schwachman syndrome
iii. Dyskeratosis congenital
b. Erythroid progenitor cell failure
c. Functional impairment of erythroid and other progenitors due to nutritional and
other causes
B. Increased Red Cell Destruction
1. Acquired
a. Mechanical
i.
Macroangiopathic (March hemoglobinuria, artificial heart valves)
ii.
Microangiopathic (DIC, TTP, Vasculitis)
iii.
Parasites and microorganisms (malaria, bartonellosis, C. welchii)
iv.
Chemical injury and complex chemicals
v.
Physical injury
b. Drug-mediated Hemolysis
c. Antibody-mediated
i.
Warm-type autoimmune hemolytic anemia
ii.
Cryopathic syndromes (cold agglutinin disease,
hemoglobinuria, cryoglobulinemia)
iii.
Transfusion reactions (immediate and delayed)
c. Hypersplenism
d. Red cell membrane disorders
i.
Spur cell hemolysis
ii.
Acquired acanthocytosis and acquired stomatocytosis

paroxysmal

cold

2. Hereditary
a) Hemoglobinopathies
b) Red cell membrane disorders
c) Red cell enzyme defects
d) Porphyrias
C. Blood loss and blood redistribution
Only way to replace blood loss is blood transfusion
1 unit of packed RBC will replace 1 g/dL of blood so you have to quantify the
volume of blood loss
If the patients Hgb is 7g/dL how many units of blood should be given to the
patient to maintain a Hgb of 10 g/dL
o Answer: 3 units
II. RELATIVE ANEMIA- increased plasma volume

HEMOLYTIC ANEMIA
-is anemia due to hemolysis, the abnormal breakdown of RBCs either in the blood vessels
(intravascular hemolysis) or elsewhere in the body (extravascular hemolysis).
-It has numerous possible causes, ranging from relatively harmless to life-threatening. The
general classification of hemolytic anemia is either acquired or inherited

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Red blood cell destruction can occur in the extravascular

or intravascular space
Extravascular Hemolysis
red
blood
cells
are
phagocytized
by
reticuloendothelial
cells,
the
membrane
structure is broken down, and the hemoglobin is
reduced to its essential components
Iron is recovered for transport by transferrin
back to the erythroid marrow. The porphyrin ring
is broken, and a molecule of carbon monoxide is
released.
The remaining portion of the porphyrin ring is
then transported as bilirubin to the liver for
conjugation and excretion in bile.
Intravascular hemolysis
red cell destruction, free hemoglobin binds
either to haptoglobin or hemopexin or is
converted to methemalbumin.
These proteins are cleared by the liver where the
heme is broken down to recover iron and
produce bilirubin
Hematology in Clinical Practice 5th edition

-Possible causes:
Infections (note: Direct Coombs test is sometimes positive in hemolytic anemia due to
infection)
Malaria
Babesiosis
Septicemia
Membrane disorders
Paroxysmal nocturnal hemoglobinuria (Rare acquired clonal disorder of red blood
cell surface proteins)
Liver disease
Drug-induced Hemolysis

Hereditary

Intracorpuscul
ar Defects
Hemoglobinopat
hies
Enzymopathies
Membranecytoskeletal

Extracorpuscul
ar Defects
Familial
hemolytic uremic
syndrome (HUS)

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Acquired

defects
Paroxysmal
Nocturnal
Hemoglobinuria
(PNH)

General Examination
Other physical findings

Hemoglobin
MCV, MCH
Reticulocytes
Bilirubin
LDH

Haptoglobin

Mechanical
destruction
(microangiopathi
c)
Toxic agents
Drugs
Infectious
Autoimmune

Jaundice, pallor
Spleen may be enlarged;
bossing of the skull in
severe congenital cases
From normal to severely
reduced
Usually increased
Increased
Increased
(mostly
unconjugated)
Increased (up to 10x
normal with intravascular
hemolysis)
Reduced to absent

NON-IMMUNE HEMOLYTIC ANEMIA

Red cell fragment syndrome/Mechanical Destruction of red cells

Microangiopathic hemolytic anemia
Macroangiopathic hemolytic anemia
Chemical agents
Infectious agents
Hypersplenism
Paroxysmal Nocturnal Hemoglobinuria

MICROANGIOPATHIC HEMOLYTIC ANEMIA

Intravascular hemolysis caused by fragmentation of normal red cells passing through
abnormal arterioles
- Deposition of platelets and fibrin the most common cause of microvascular lesions
- Chronic and iatrogenic
-

Microangiopathic hemolytic anemias (MAHAs)

are a group of potentially life-threatening
disorders characterized by RBC Fragmentation
and thrombocytopenia
The RBC fragmentation occurs intravascularly by
the mechanical shearing of RBC membranes as
the cells rapidly pass through turbulent areas of
small blood vessels that are partially blocked by
microthrombi damaged endothelium
Upon shearing, RBC membranes quickly reseal
with minimal escape of hemoglobin, but the
resulting fragments (called schistocytes) are
distorted and become rigid.
The spleen clears the rigid RBC fragments from
the circulation through the extravascular
hemolytic process

ETIOLOGY AND PATHOGENESIS:

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 Intravascular coagulation, with deposition of platelets and fibrin in small arterioles the
common antecedent
Red cells stick to fibrin and are fragmented by force of blood flow resulting in both
intravascular and extravascular hemolysis
UNDERLYING DISORDERS:
Invasive carcinoma
Complications of pregnancy: pre-eclampsia, eclampsia, abruptio placentae
Malignant hypertension
TTP, HUS
Drugs: antineoplastic agents, most often mitomycin, but also include bleomycin,
daunorubicin in combination with cytosine arabinoside, cisplatin (HUS may occur weeks or
months after discontinuing mitomycin therapy)
Posttransplation of kidney or liver
Post-allogeneic or autologous marrow transplantation
Generalized vascultis associated with immune disorders. Ex: SLE, polyarteritis nodosa,
Wegeners granulomatosis, scleroderma (Connective tissue disorders)
Localized
vascular
abnormalities:
cutaneous
cavernous
hemangiomas,
hemangioendothelioma of the liver
THROMBOTIC THROMBOCYTOPENIC PURPURA
- Characterized by the presence of thrombocytopenia, microangiopathic hemolytic
anemia, neurologic symptoms (headache, confusion, seizure, paresis, dysphagia), renal
involvement and fever
- Consistent with severe hemolysis, markedly increased s. LDH, increased indirect
bilirubin
- Microscopic hematuria and proteinuria also present

Urine of patients with TTP: tea colored due to increased indirect bilirubin
Tea colored urine can also be due to primary liver disease
If there is increased in conjugated bilirubin most likely it is caused by liver disease
There is different shades of jaudince
o Hemoytic: pale yellow
o Hepatic: dark or deep yellow

CLINICAL FEATURES:
Symptoms and signs are related to the primary process and to the organs affected by
the intravascular deposition of platelets and fibrin
Blood film: schistocytes, helmet cells, triangular cells, spherocytes; elevated reticulocyte
count
Increased concentrations of plasma hemoglobin, urine hemoglobin, and hemosiderin
s. LDH increased
Coagulation abnormalities due to consumption coagulopathy

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TREATMENT:
o Management of the primary process
o Supportive: red cell transfusions (to maintain adequate level of Hb) and platelet
transfusions (for bleeding due to thrombocytopenia)
MACROANGIOPATHIC HEMOLYTIC ANEMIA
-

MARCH HEMOGLOBINURIA
Acute and self-inflicted
Mild anemia occurs in individuals involved in sustained, strenous physical activity

PATHOGENESIS:
Hemoglobinuria may occur from trauma sustained by intravascular red cells in the feet
of long distance runners or in the hands of karate practitioners or in persons playing the
conga drums
Gastrointestinal bleeding occurs in 20% of long distance runners (usually not enough to
cause anemia)
CLINICAL FEATURES:
Concentration of Hb and Hct are at lower limits of normal
RBCs tend to be macrocytic
Increased reticulocyte count
Hemoglobinuria may be noted for 6 to 12 hours in runners after a race
THERAPY:
o Reassure the patient
o Add cushioned insoles to the shoes
o Sports anemia: no treatment
Anemia also occurs in ASTRONAUTS
- Caused by a decrease in plasma volume, followed by a decrease in erythropoietin
levels, and the rate of red cell production. When the plasma volume is restored after
reentry an anemia is evident
TRAUMATIC CARDIAC HEMOLYTIC ANEMIA
-

Complications of prosthetic heart valves that lead to turbulence and high shear stresses
within a space enclosed by a foreign surface resulting in red cell fragmentation and
hemolysis
Cardiac valve disorders, especially severe aortic or subaortic stenosis, may also cause
hemolysis

CLINICAL FEATURES:
Hemolytic anemia is usually mild and compensated but may be severe
Presence of thrombogenicity of non-endothelialized surfaces, which promote platelet
thrombosis and embolization
Blood film: schistocytes, helmet cells, triangular cells, and spherocytes present. Small
hypochromic cells may be present
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Increased reticulocyte count, increased s. LDH, increased plasma Hb, urine hemosiderin
present
Stigmata of iron deficiency: including a high unsaturated iron-binding capacity and a low
serum ferritin
Decreased platelet count may indicate platelet thrombi on valve surfaces

THERAPY:
o Replace urinary iron loss with FeSO4
o For severe anemia replacement of prosthesis
o Blood transfusion
o Recombinant EPO treatment for severe anemia ineligible for reoperation

HEMOLYTIC ANEMIA RESULTING FROM A

CHEMICAL OR PHYSICAL AGENT
Certain drugs can induce hemolysis in individuals with abnormalities of erythrocytic
enzymes, like G6PD deficiency or with an unstable Hb
Common chemicals:
ARSENIC HYDRIDE
Inhalation of arsenic gas can lead to severe anemia, hemoglobinuria, and jaundice

LEAD
Lead poisoning in CHILDREN: due to ingestion of lead paint flakes or chewing leadpainted objects
Lead poisoning in ADULTS: due to industrial exposure
Intoxication leads to anemia inhibition of heme synthesis modest decrease in
red cell life span
Inhibits pyrimidine 5-nucleotidase responsible for the basophilic stippling
Ringed sideroblasts are frequently found in the marrow

COPPER
May be induced by high levels of copper in patients hemodialyzed with fluid
contaminated by copper tubing
Caused by inhibition of several erythrocyte enzymes

WATER
Administered intravenously, inhaled in near-drowning, or gaining access to the
circulation during irrigation procedures can cause hemolysis

OXYGEN
HA has developed in patients receiving hyperbaric oxygenation and in astronauts
exposed to 100% oxygen

INSECT AND ARACHNOID VENOMS

Severe hemolysis may occur in patients following bites by bees, wasps, spiders,
scorpions
Snake bites only RARELY cause hemolysis

HEAT
Extensive burns may develop severe HA result of direct damage to the red cells
by heat

DRUGS AND CHEMICALS THAT HAVE BEEN

SIGNIFICANT HEMOLYTIC ANEMIA
CHEMICALS
Aniline

REPORTED TO CAUSE CLINICALLY

DRUGS
Amyl nitrate
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Apiol
Dichloroprop (herbicide)
Formaldehyde
Hydroxyllamines
Lysol
Mineral spirits
Nitrobenzene
Resorcin

Mephenesin
Methylene blue
Omeprazole
Pentachlorophenol
Phenazopyridine
Salicylazosulfapyridine

HEMOLYTIC ANEMIA RESULTING FROM

INFECTIOUS AGENTS
MECHANISMS
Hemolysis may be caused by:
Direct invasion by infecting organism (Malaria)
Elaboration of hemolytic toxins (C. perfringens)
Development of autoantibodies against red blood cells antigens (Mycoplasma pneumoniae)
ETIOLOGIC AGENTS:
Aspergillus
Babesia microti and Babesia divergens
Bartonella bacilliformis
Campylobacter jejuni
Clostridium welchii
Coxsackie virus
Cytomegalovirus
Diplococcus pneumoniae
Epstein-Barr virus
Escherichia coli
Haemophilus influenza
Hepatitis A
Hepatitis B
Herpes simplex virus
HIV
Influenza A
Leishmania donovani
Leptospira ballum and/or butembo
Malaria worlds most common cause of hemolytic anemia
Mumps virus
M. tuberculosis
M. pneumoniae
Neisseria intracellularis
Parvovirus B19
Plasmodium falciparum

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IMMUNE HEMOLYTIC ANEMIA

Immune Hemolytic Anemias
These can arise through at least two distinct
mechanisms
1. There is a true autoantibody directed against
a red cell antigen, i.e., a molecule present on the
surface of red cells.
2. When an antibody directed against a certain
molecule (e.g., adrug) reacts with that molecule,
red cells may get caught in the reaction,
whereby they are damaged or destroyed
Harrisons Book of Internal Medicine 19th edition

AUTOIMMUNE HEMOLYTIC ANEMIA

CLASSIFICATION:
I. On basis of serologic characteristics of involved autoimmune process:
A. Warm-autoAb type: AutoAb maximally active at body temperature, 37C
B. Cold-autoantibody type: AutoAb active at
temperature below 37C
C. Mixed cold and warm auto-Abs
II. On basis of presence or absence of underlying or significantly associated disorder
A. Primary or idiopathic AHA
B. Secondary AHA
1. Associated with lymphoproliferative
disorders
(NHL,
Hodgkins lymphoma)
2. Associated with the rheumatic disorders
3. Assocd with certain infections
4. Assocd with certain nonlymphoid
neoplasms (ex. Ovarian
tumors)
5. Assocd with certain chronic
inflammatory diseases
(ex. Ulcerative
Colitis)
6. Assocd with ingestion of certain drugs (methyldopa)
HEMOLYTIC ANEMIA RESULTING FROM WARM-REACTING ANTIBODIES
-

Caused by an autoantibody directed against a red cell antigen

In autoimmune hemolytic anemia (AHA), shortened red blood cell survival result of host
antibodies that react with autologous RBC
Most of the phagocytosis mediated red cell destruction takes place in the spleen and liver
extravascular hemolysis
AHA may be classified by the nature of the antibody:
Warm-reacting Abs have optimal activity at 37C
Cold-reacting Abs show affinity at lower temperatures
Warm antibody AHA most common type
AHA occurs in all age groups, but the incidence rises with age
May be also classified by whether an underlying disease is present (secondary) or not
(primary or idiopathic)

Primary AHA the autoantibody often is specific for a single RBC membrane protein
suggesting that an abberant immune response has occurred to an autoantigen or a similar
immunogen

Page 14 of 27

Antibody-coated RBCs are trapped by macrophages primarily in the spleen, where they
are ingested and destroyed or partially phagocytosed and a spherocyte with similar
surface area is released.
Macrophages have cell surface receptors for the Fc portion of IgG and fragments of C3
and C4b.
Direct RBC lysis by complement is unusual in warm antibody AHA, probably as a result
of interference with complement activity by several mechanisms

Secondary AHA - autoantibody most likely develops from an immunoregulatory defect

Symptoms are usually slow in onset, but rapidly developing anemia can occur
P.E. may be normal if the anemia is mild
Splenomegaly is common but not always observed
Blood film: polychromasia (indicating reticulocytosis) and spherocytosis
With severe cases, nucleated RBCs, RBC fragments, and occasionally,
erythrophagocytosis by monocytes may be seen
Mild neutrophilia and normal platelet count occur
Evans syndrome rare condition in which both immune-mediated RBC and platelet
destruction occur
BMA: erythroid hyperplasia
Unconjugated hyperbilirubinemia often present
Diagnosis of AHA: requires demonstration of immunoglobulin and/or complement bound
to the RBC
Usually achieved by the direct antiglobulin test (DAT)
THERAPY FOR HA - WARM-REACTING ABS:
o Generally, anemia develops slowly so that RBC transfusion is not required
o Glucocorticoids quickly slow or stop hemolysis in 2/3 of patients
o 25% will achieve a complete remission
o Splenectomy removes the main site of RBC destruction

CRYOPATHIC HEMOLYTIC ANEMIA

-

Caused by autoantibodies that bind red cells best at temperatures below 37C, usually
below 31C
Mediated through two major types of cold antibody: cold agglutinins and DonathLandsteiner antibodies
The complement system plays a major role in red cell destruction

COLD AGGLUTININ-MEDIATED AUTOIMMUNE HEMOLYTIC ANEMIA

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 Cold agglutinins are IgM autoantibodies that agglutinate red cells optimally between 0C
and 5C
DONATH-LANDSTEINER ANTIBODIES
Usually associated with an acute viral syndrome in children common
Complement fixation occurs at higher temperatures
-

This is classified as either

o Primary: chronic cold agglutin disease
o Secondary: generally as a result of mycoplasma or infectious mononucleosis
Peak incidence: primary/chronic syndrome is in persons older than 50 years old
This disorder characteristically has monoclonal IgM cold agglutins and may be considered a
monoclonal gammopathy
Cold agglutinins bind red cells in the superficial vessels impeding capillary blood flow
acrocyanosis
Direct lysis results from propagation of the full complement sequence
Commonly, fragments C3b and C4b are deposited on the red cell surface, providing a
stimulus for phagocytosis

*Reaction at temperatures usually below 30C they occur in peripheral circulation

and in cold weather

Occur in 10-20% of cases of AHA

Splenomegaly may occasionally be seen in the idiopathic form
Anemia is usually mild to moderate
PBS: autoagglutination, polychromasia, spherocytosis
Therapy: keeping the patient warm
o High dose steroids-for severely ill patient

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ALLOIMMUNE HEMOLYTIC DISEASE OF THE

NEWBORN
Definition:
- A disease in which there is fetal to maternal transfer of red cells that results in
immunization of the mother
- Transplacental transfer of maternal anti-red cell antibodies to the fetus shortens the life
span of fetal or newborn red cells
- Manifestations: anemia, jaundice, and hepatosplenomegaly
- In severe cases: anasarca and kernicterus
Etiology and Pathophysiology
Transplacental passage of fetal cells occurs in 76% of pregnancies
If there is blood group incompatibility between mother and fetus, the chance of
maternal immunization increases with the volume of any transplacental haemorrhage
Larger volume transplacental hemorrhages are more likely to occur at delivery or during
invasive obstetric procedures
The risk of sensitization increases with each trimester of pregnancy and is greatest
(65%) at delivery
Prior blood transfusion or abortions also can immunize the mother
Without prophylaxis, immunization occurs in 7-8% of those at risk with an Rh-positive,
ABO-compatible fetus, and 2% of these with ABO-incompatible fetus
Ant-D IgG readily crosses the placenta and leads to a positive antiglobulin test and
hemolysis of the infant
In ABO haemolytic disease: themother is usually type O and the fetus is Type A or B
Anti-A and Anti-B ordinarily cause mild and rarely severe hemolysis
Clinical Features
With severe hemolysis, profound anemia leads to hydrops fetalis (anasarca caused by
cardiac failure), and most such features die in utero
With milder cases: hemolysis persists until incompatible RBCs or the offending IgG is
cleared (Half-life of IgG: 3 weeks)
Most affected infants are not jaundiced at birth due to transplacental transport of
bilirubin
Generally with mild disease, the bilirubin peaks at day 4 or 5 postpartum and declines
slowlt thereafter
Increased serum bilirubin-> kernicterus (due to deposition of unconjugated bilirubin in
the basal ganglia and cerebellum
If Rh-negative: should be tested again at 28 weeks gestation before Rh immunoglobulin
is given

Page 17 of 27

CASE
J.T., a 24-year old employee sought consult at the
E.R. due to dizziness with tea-colored urine

(+) fever, (+) headache, (+) pallor

What laboratory tests are you going to request?

Follow the flowchart

DRUG-INDUCED IMMUNE HEMOLYTIC ANEMIA

- Drugs produce a positive direct antiglobulin test and accelerated red cell destruction
Three mechanisms of drug-related immunologic injury to red cells are recognized:
1. Hapten/drug adsorption involving drug-dependent antibodies
2. Ternary complex formation involving drug-dependent antibodies
3. Induction of autoantibodies that react with red cells in the absence of the inciting drug
-

In patients receiving high-dose penicillin red cells have a substantial coating of the
drug
In a small proportion of patients, an antipenicillin Ab (usually IgG) develops and binds to
the penicillin on the red cell
The direct antiglobulin test positive hemolytic anemia: occurs after 7 to 10 days
of treatment
Ceases a few days to 2 weeks once the drug is stopped

MECHANISMS:
1. DRUG ADSORPTION MECHANISM
Penicillins, Cephalosporins, and Streptomycins
Mechanism:
- First, the drug is nonspecifically adsorbed to the patients red cell
- Second, the drug must be able to elicit an antibody response

The patient produces an IgG antibody to a drug. When

the drug is taken by the patient, the drug binds strongly
to the patients RBCs. The IgG drug antibody binds to the
drug attached to the RBCs, usually without complement

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activation.
Because the offending antibody is IgG and is strongly
attached to the RBCs via the drug, hemolysis is
extravascular by splenic macrophages, which remove
the antibody- and drug-coated RBCs from the circulation

2. TERNARY COMPLEX MECHANISM

Drug-Antibody Target-Cell Complex
- The mechanism of red cell injury is not clearly defined
- Appears to be mediated by a cooperative interaction to generate a ternary complex
involving the drug or drug-metabolite, a drug-binding membrane site on the
target cell, and antibody, with consequent activation of complement
- The Ab attaches to a neoantigen consisting of loosely bound drug and red cell Ag;
binding of drug to the target cell is weak until stabilized by the attachment of the Ab to
both drug and cell membrane
- Direct antiglobulin test is usually positive with complement reagents
In ternary drug-induced hemolysis, IgG antibodies bind
drug-epitope combination sites, called neoantigens. The
drug-epitope-antibody complex on the membrane
activates complement to trigger acute intravascular
hemolysis, often with thrombocytopenia.
The drugs most often implicated are quinidine,
phenacetin, and stibophen. Hemolysis occurs after short
periods of administration or upon readministration. The
DAT detects only complement. In the indirect
antiglobulin test using reagent RBC, the serum is
reactive in the presence of the drug.

Immune Complex Mechanism: Innocent Bystander

Clonidine and Phenacetin

Some drugs can cause an immune hemolytic anemia

even though they do not bind to RBCs. These drugs,
bound to plasma proteins, stimulate the formation of
complement-fixing antibodies that activate the classical
complement pathway. Generated C3b binds to the RBC,
which leads to intravascular hemolysis of these
innocent bystanders.

3.

AUTOANTIBODY MECHANISM
Mechanism by which the drug can induce formation of an autoantibody is unknown
Positive direct antiglobulin test: 8-36% of those taking alpha-methyldopa
Positive test develops 3-6 months after the start of therapy
Less than 1% of those taking alpha-methyldopa develop hemolytic anemia
Abs in the serum or eluted from RBCs react optimally at 37C with autologous or
homologous RBCs in the absence of drug
As in Autoimmune HA, these Abs frequently react with the Rh complex
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Destruction of RBCs occurs chiefly by splenic sequestration of IgG-coated RBCs

A drug induces the patient to produce IgG warm-reactive

autoantibodies against RBC selfantigens. These
autoantibodies react at 37 C, and the laboratory
findings are indistinguishable from those in WAIHA.
Hemolysis is extravascular and is mediated by
macrophages
predominantly in the spleen.

Methyldopa-Induced (Autoimmune) Mechanism

Methyldopa and related drugs (Aldomet, L-dopa): treatment of hypertension

An induced inhibition of T-suppressor allowing

uninhibited autoantibody production by B cells. Despite
drug withdrawal, antibodies may remain for months

A: The antibody attaches only to the drug, which is

tightly bound to the red blood cell (RBC) membrane
(penicillin type)
B: The antibody attaches to a neoantigen created by
components of both the drug and the RBC membrane
(quinidine/stibophen type)
C: The antibody attaches mainly to the membrane, not
requiring the presence of the drug (-methyldopa type)

CHRONIC BLOOD LOSS

CHRONIC GASTROINTESTINAL BLEEDING
Bleeding is slow, may continue for a long time, or stop in a short period of time
Hemorrhoids (Internal, External)
Inflammation (Esophagitis, Varices)
Ulcers (Gastric, Duodenal)
Malignancy (Colonic, Rectal)
Gastritis
- Signs and symptoms are less obvious
Fatigue/easy fatigability/loss of energy
Weakness
-

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Dizziness or lightheadedness
Pallor/pale skin
Shortness of breathing, esp. on exertion
Difficulty concentrating
Palpitations
Chest pain
Cold hands and feet
Headache
Investigate:
CBC (RBC indices, morphology)
Reticulocyte count
Fecalysis with fecal occult blood
Iron studies
Treatment:
Control the bleeding
Medications
Surgical intervention
-

ABNORMAL VAGINAL BLEEDING

Adenomyosis
Cervical cancer
Cervical polyps
Endometrial cancers, hyperplasia
PID

Chronic blood loss leading to iron deficiency is usually

caused
by gastrointestinal blood loss. However, some
patients may present with a defect in iron absorption,
secondary to small-bowel disease, such as non-tropical
sprue or extensive Crohn disease.
Patients who have had a Billroth II operation with
vagotomy for
ulcer disease can also exhibit food iron malabsorption. In
developing countries, hookworm infestation is a frequent
cause of
chronic blood loss leading to severe iron deficiency. Less
frequently, patients can present with a blood loss
anemia secondary
to hemoglobinuria (paroxysmal nocrurnal
hemoglobinuria, see
Chapter 9), pulmonary hemosiderosis, or self-induced
blood loss.

HYPOPROLIFERATIVE ANEMIA
Most common anemias
Anemias associated with normocytic, normochromic RBCs and an inappropriately low
reticulocyte response (reticulocyte index: <2.0 to 2.5)
Includes:
Early Iron Deficiency (before hypochromic microcytic red cells develop)
Acute and Chronic Inflammation (including malignancies)
Abnormal erythropoietin response to anemia (Anemia due to renal disease,
Inflammation, Cancer, Hypometabolic states)
Chronic blood loss can lead to Iron Deficiency Anemia

IRON DEFICIENCY ANEMIA

Most common chronic maladies in humans
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Developmental stages of Iron Deficiency:

IRON DEPLETION Storage iron decreased or absent
IRON DEFICIENCY storage iron decreased or absent with low serum iron
concentration and transferrin saturation
IRON DEFICIENCY ANEMIA storage iron decreased or absent, low serum iron
concentration and transferrin saturation, and low hemoglobin level and reduced
hematocrit

STAGES OF IRON DEFICIENCY

A. NEGATIVE IRON BALANCE
- Demands for (or losses of) iron exceed the bodys ability to absorb iron from the diet
- Causes:
Blood loss (greater than 10-20 ml RBCs/day)
Pregnancy (demands for RBC production by the fetus outstrip the mothers ability to
provide iron)
Rapid growth spurts in the adolescent
Decreased dietary iron intake
-

Iron deficit is remedied by mobilization of iron from RE storage sites

Menorrhagia most common cause of iron defiency in women

Gastrointestinal bleeding most common cause of iron deficiency in men and
postmenopausal
900 mg the average iron loss from transfer to fetus and blood in placenta
Lack of iron interferes with heme synthesis

CLINICAL FEATURES:
General symptoms of anemia
Signs depend upon the severity and chronicity of anemia
Irritability and headache occur frequently
Paresthesias and burning of the tongue may occur

Koilonychia

Cheilitis
TREATMENT:
o IRON REPLACEMENT
Response to treatment varies depending upon the erythropoietin stimulus and the
rate of absorption
Rise in reticulocyte count: within 4 to 7 days
Oral or IV/IM
o RED CELL TRANSFUSION
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 For symptomatic elderly patients with severe iron deficiency anemia and
cardiovascular instability
Reserved for those with symptoms of anemia, cardiovascular instability, and
continued and excessive blood loss from whatever source, and those who require
immediate intervention
-

ANEMIA OF RENAL DISEASE

Chronic renal failure is usually seen with moderate to severe hypoproliferative anemia
Normocytic, normochromic RBCs
Decreased reticulocytes
Due to inadequate amounts of erythropoietin and reduction in red cell survival
Normal serum iron, TIBC, and ferritin levels

ANEMIA IN HYPOMETABOLIC STATES

Protein malnutrition causes mild to moderate hypoproliferative anemia
Release of erythropoietin from the kidney is sensitive to the need for O2
Endocrine deficiency states: related to the effects of androgen and estrogen
Treatment: Transfusions and EPO

This topic was skipped by doc:

PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
DEFINITION
- An acquired hematopoietic stem cell disorder characterized by a deficiency of
phosphatidylinositol-anchored proteins on the surface of hematopoietic cells
- This leads to complement-mediated intravascular hemolysis
- The only haemolytic anemia caused by an intrinsic defect of the red cell that is acquired
EPIDEMIOLOGY
- Same frequency in men and women
- Prevalence is 1 to 5 per million
- No evidence of inherited susceptibility
- Median survival: 8-10 years
- May evolve into aplastic anemia and PNH may manifest itself in patients who previously
had aplastic anemia
- 1-2 % -> Acute Myelogenous Leukemia
DIAGNOSIS
The classic abnormality is increased sensitivity to complement-mediated lysis of
erythrocytes, detected by different tests
- Acid hemolysis test
- Sucrose hemolysis test
- CD-59 negative (Product of PIG-A gene)
The disorder is a consequence of somatic mutations which cause an error in synthesis of
the glycosylphosphatidylinositol (GPI) anchor
Deficiencies in several GPI-anchored membrane proteins, such as decay accelerating
factor, CD 59, CD 58, CD 16, CD 14 have been identified
PIG-A gene (phosphatidylinositol glycan class A: X-linked gene which is required for an
early step in GPI biosynthesis
CLINICAL FEATURES
Nocturnal hemoglobinuria is uncommon
Hemoglobinuria occurs irregularly in most patients, precipitated by a variety of events:
infection, surgery, or contrast dye injection
Patients have chronic haemolytic anemia, which may be severe
Modest splenomegaly in some patients
Pancytopenia is often present
Iron deficiency as a consequence of iron loss in the urine
Bleeding may occur secondary to thrombocytopenia
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Thrombosis is prominent feature

- Venous thrombosis occur frequently
- Arterial thrombosis also occur
- Budd-Chiari syndrome or portal vein thrombosis
- Pulmonary hypertension may develop secondary to thrombosis in the pulmonary
microvascular
Pregnancy in PNH patients may be associated with abortion and venous
thromboembolism
Renal manifestations include
- Hyposthenuria- excretion of urine of low specific gravity
- Abnormal tubular function
- Acute and chronic renal failure
Neurologic manifestations
- Headache
- Cerebral venous thrombosis uncommon

Clinical Symptoms of PNH: A Triad of Clinical Features

1. Acquired corpuscular haemolytic anemia
- Chronic hemolysis or acute hemolysis crises
- Hemosiderinuria, Iron deficiency
2. Thrombophilia
- Atypical thrombosis: Budd-Chiari syndrome, portal vein thrombosis, mesenterial
thrombosis, cerebral thrombosis
3. Bone marrow failure
- Thrombocytopenia and/or leukopenia
- Aplastic anemia
LABORATORY FEATURES
Anemia is the most consistent finding
- Mild to severe; usually normo-macrocytic
- Neutropenia and/or thrombocytopenia
- Unconjugated bilirubin mildly or moderately elevated
- LDH markedly elevated
- Haptoglobin usually undetectable
Marrow exam
- Erythroid hyperplasia
Urine findings
- Hb sometimes present
- Hemosiderinuria
TREATMENT
o Transfusions for anemia: washed pRBCs
o Oral iron therapy for IDA
o Steroid hormones
o Anticoagulants
o Marrow transplantation is curative
o Eculizumab a humanized monoclonal antibody that binds to the human C5
complement protein
o Administered weekly, 600mg IV, for the first 4 weeks then 900mg on week 5 then
900mg every 14 days thereafter

LABORATORY TESTS
Routine Laboratory Tests
Complete Blood Count
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the test documents anemia, leukocyte counts, and differential counts

Platelet count: exclude an underlying infection or hematologic malignancy. The platelet
count is within the reference range in most haemolytic anemias
Thrombocytopenia can occur in SLE, CLL, and Microangipathic haemolytic anemia.
Thrombocytopenia associated with a positive direct Coombs test result is known as
EVAN SYNDROME

Red blood cell Indices

Decreased MCV and MCH:
- Microcytic hypochromic anemia: chronic intravascular hemolysis (PNH)
High MCV: macrocytic anemia
- Usually due to megaloblastic anemias but can occur in liver disease. A high
number of reticulocytes also may cause a high MCH
A high MCH and MCHC: spherocytosis
Increased RDW study
- Measure of anisocytosis which is likely in haemolytic anemia
LABORATORY TESTS FOR HEMOLYSIS
Serum Haptoglobin <6 mg/dL
Most sensitive test for RBC destruction
A glycoprotein synthesized mainly in the liver
Sequesters free Hb released from hemolyzed RBCS-> transported by macrophages to
the liver-> heme broken down to bilirubin
Lactate dehydrogenase
Increased (LD >22)
LD occurs in the cytoplasm of all cells
Increased in all haemolytic anemias
Indirect bilirubin
Unconjugated bilirubin is a criterion for hemolysis, but is not specific because an
elevated bilirubin is also may indicate Gilbert Disease
With hemolysis, the level of indirect bilirubin usually is less than 4 mg/dL
Higher levels of indirect bilirubin indicate compromised hepatic function or cholelithiasis
and hemolysis
Changes in the LDH and Serum Haptoglobin levels are the most sensitive general tests
because the indirect bilirubin is not always increased

Coombs test

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Direct and indirect antiglobulin (Coombs) tests

(a) The direct antiglobulin test (DAT) is performed by
incubating the patients washed red blood cells (RBCs)
with a reagent that contains antibodies to IgG, C3
complement or both (nonspecific reagent). Agglutination
of the RBCs indicates that there is either IgG or C3,
respectively, bound to the RBC membrane
(b) The indirect antiglobulin test is performed by
incubating a normal donors washed RBCs with the
patients serum in the presence of a reagent that
contains antibodies to IgG, C3 or both. Agglutination of
the RBCs indicates the presence of an antibody, or
complement, directed toward an RBC cell surface
antigen in the patients serum

Specific studies diagnosed by history, PE, peripheral smear and other lab findings
DAT result

is usually positive in autoimmune haemolytic anemia, but it may be occasionally

negative in this disorder
Urine free Hb test
reveals hemoglobinuria, which occurs with intravascular hemolysis when the amount of
free Hb exceed the available haptoglobin. Urine may be dark due to hemoglobinuria, but
myoglobinuria porphyria, and other conditions can also cause dark urine
Urine hemosiderin
may suggest intravascular hemolysis. Hemosiderin is detected in spun urinary sediment
as an iron stain in sloughed renal epithelial cells
RBC survival chromoim-51 survival

is rarely used but it can definitely demonstrate a shortened RBC survival (hemolysis).
This test is ordered when the clinical history and laboratory studies cannot establish a
diagnosis of hemolysis

Cold agglutin titer

A high titer of anti-I antibody may be found in mycoplasmal infections and a high titer
of anti-I antibody may be found in hemolysis associated with infectious mononucleosis.
An anti-P cold agglutin may be seen in Paroxysmal Cold Hemoglobinuria
LALUMA = LAMPREA = LUCES = MOLINA

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