Download MBBS (Bachelor of Medicine, Bachelor of Surgery) Final Year Medicine Notes Hematology
Letuda's
Hematology Notes
Version 1.0
Written, edited and compiled by
Prithwiraj Maiti
R.G.Kar Medical College
Email address: prithwiraj2009@yahoo.in
14.09.2014
Table of contents
Contents
Page no.
Disorders related to RBC
Anemia: Introduction
3
Iron deficiency anemia (IDA)
4
Vitamin B12/ Folate deficiency anemia
7
Hemolytic anemia (in general)
11
Hereditary spherocytosis (HS)
13
Paroxysmal nocturnal hemoglobinuria (PNH)
15
G6PD deficiency anemia
17
Sickle cell disease
19
Pernicious anemia
21
Thalassemia
21
Autoimmune hemolytic anemia (AIHA)
26
2
Microangiopathic hemolytic anemia (MAHA):
28
Thrombotic thrombocytopenic purpura (TTP)
Hemolytic uremic syndrome (HUS)
Sideroblastic anemia
31
Pancytopenia
33
Aplastic anemia
35
Anemia of chronic inflammation
37
Hematological malignancies
Acute leukemia (AML and ALL)
38
Acute promyelocytic leukemia
41
Chronic leukemia: CLL
42
Chronic leukemia: CML
45
Lymphoma
48
Myeloproliferative disorders: Myelofibrosis
51
Polycythemia rubra vera (PRV)
52
Essential thrombocytosis
54
Disorders related to platelets and coagulation pathway
Bleeding disorders: A general discussion
55
Basic concepts: Hematoma and purpura
56
Idiopathic thrombocytopenic purpura (ITP)
57
Thrombocytopenia
59
Hemophilia
60
von Wil ebrand's disease (vWD)
61
Coagulopathy due to chronic liver disease (CLD)
62
Coagulopathy due to vitamin K deficiency
63
Miscellaneous topics of hematopoietic system
Multiple myeloma
64
Myelodysplastic syndrome (MDS)
65
Disseminated intravascular coagulation (DIC)
66
Blood transfusion: types and complications
68
3
Anemia
Anemia
RBC synthesis
RBC desctruction
(Reticulocytosis)*
Iron deficiency anemia
Aplastic anemia
Hemolytic anemia
B12/ Folate deficiency
Bone marrow failure
Hypersplenism
anemia
Bone marrow
infiltration
*Reticulocytosis occurs due to:
Hyperfunctioning bone marrow
Iron replenishment in iron deficiency.
4
Iron deficiency anemia
Iron intake
Nutritional
deficiency
Coeliac
Iron
disease
absorption
Whipple
disease
Bleeding
varices
Peptic ulcer
disease
Etiology
Parasitosis
GI loss
IBD
Esophageal
Malignancy
Gastric
Angiodysplasia
Colonic
Iron loss
Hemorrhoids
Pregnancy
Menorrhagia
PPH
GU loss
Renal
UTI
Clinical features:
I
Features due to iron deficiency
D
Features due to underlying disease
A
Features due to anemia
5
Features due to iron deficiency:
1. Spoon shaped nail: Koilonychia
2. Glossitis, cheilitis
3. Pica: Abnormal craving due to non-iron rich food (appetite for substances largely
non-nutritive, such as ice, clay, chalk, soil, etc. sand).
Features due to underlying disease:
Any evidence of GI/ GU bleed must be looked for; however, bleeding may be
occult.
Features due to anemia:
A. Anemic look
B. Breathlessness
C. Cardiac palpitation
D. Dizziness
E. Exercise intolerance
F. Fatigue.
Investigations
1. Blood: Hb, TC, DC, CRP
Hb:
2. Peripheral film: Anisopoikilocytosis (variation in size and shape of RBC)
3. RBC indices: MCV:/Normal
4. Serum iron studies:
I.
Serum iron:
II.
Serum ferritin: (but may be falsely normal or due to any co-existing
inflammatory condition)
III.
Serum transferrin saturation:
IV.
Total iron binding capacity (TIBC):
5. Other relevant investigation(s) to look for underlying disease(s).
6. In suspected GI loss of iron:
I.
Fecal occult blood test (FOBT)
II.
Examination of stool for ovum, parasite, cyst (OPC)
III.
GI endoscopy:
Upper GI endoscopy
Colonoscopy
Capsule endoscopy.
6
Treatment
1. Treatment of anemia:
IV fluid resuscitation
Blood transfusion
Iron replacement therapy:
I.
Per oral:
FeSO4 /Fe-gluconate (Side effects: Black stool, constipation)
Usually continued for another 2-3 months after hematological
parameters normalize.
II.
IV iron therapy:
Indications:
Per oral iron intolerance
Non-compliance to oral therapy
Presence of malabsorption.
Dietary modifications:
I.
Green leafy vegetables
II.
Meat
III.
Vitamin C rich food (vitamin C increases iron absorption).
2. Treatment of the underlying cause.
Differential diagnosis of microcytic anemia
1. Iron deficiency anemia
2. Thalassemia
3. Anemia of chronic disease
4. Sideroblastic anemia
5. Lead poisoning.
7
Vitamin B12/ Folate deficiency anemia
Etiology of vitamin B12 deficiency
Intake
Absorption
Rare, seen in strict
Intrinsic factor
Terminal ileal disease
Competition for B12
vegetarians
Post gastrectomy
Crohn's disease
Bacterial overgrowth
Pernicious anemia
Coeliac disease
Fish tapeworm*
Ileal resection
[*Diphyllobothrium latum]
Note: It takes almost 3 years for vitamin B12 deficiency to develop after intake/
absorption is stopped.
8
Intake
Alcoholism
Intestinal
mucosal disease
Crohn's disease
Absorption
Ileal resection
Phenytoin
Etiology of folate
deficiency
Drugs
Sulfasalazine
Pregnancy
Demand
Chronic
hemolytic
anemia
Methotrexate
THFA reductase
inhibitors
Triamterene
Clinical features of vitamin B12 and folate deficiency anemia:
System
Hematological
CNS
Gastrointestinal
Anemia
Subacute combined
Damage to rapidly proliferating
Mechanism
degeneration (SACD) of
GI mucosal cells due to
spinal cord
impaired DNA synthesis
Anemic look
Degeneration of:
Diarrhea
Clinical
Breathlessness
Pyramidal tract
Abdominal pain
features
Cardiac palpitation Posterior column
Glossitis (Red beefy tongue).
Dizziness
Peripheral nerves
Exercise
Higher function
intolerance
abnormalities
Fatigue.
9
In folate deficiency, only hematological + GI manifestations are present.
Mechanism of clinical manifestations:
In B12/ folate deficiency, impaired DNA synthesis of hematological and other rapidly
proliferating cells occur, giving rise to the following manifestations:
1. RBC:
Cytoplasmic maturation continues normally, but nuclear maturation lags behind;
giving rise to nucleocytoplasmic asynchrony.
Same problems occurs in WBCs and platelets also.
2. GI mucosal cells damage
3. Neurological manifestations:
Vitamin B12 exists in body in 2 forms
Methyl cobalamin
Adenosyl cobalamin
Methyl malonyl CoA
Methionine
Propionyl CoA
Choline and phospholipid
Non-physiological fatty
(Essential for myelination)
acids (neurotoxic)
Demyelinating damage
Neurotoxic damage
Investigations
1. Blood: Hb, TC, DC, CRP, Platelet
Hb:
TC: Normal/
Platelet: Normal/
Pancytopenia: All the 3 series may be affected due to accelerated
destruction secondary to ineffective hematopoiesis.
2. Peripheral film:
RBC: Macrocytes
WBC: Hypersegmented neutrophils (4-6 lobes)
10
Platelets: Abnormally looking.
3. RBC indices:
MCV:
4. Bone marrow:
Erythroid hyperplasia + megaloblasts.
5. Estimation of serum vitamin B12/ folate level
6. Other relevant investigations to diagnose the underlying cause/ neurologic
complications.
Treatment
1. Vitamin supplementation:
a. Vitamin B12: IM
b. Folate: Oral.
- Often both of them are administered together as combined deficiency is
not uncommon.
- Always estimate levels of both vitamin B12 and folate in patients of
macrocytic anemia.
- If folate is supplemented alone in a patient with subclinical vitamin B12
deficiency, hematological picture improves satisfactorily but neurological
symptoms may aggravate.
11
Hemolytic anemia
Anemia characterized by accelerated destruction of RBCs.
Hereditary
spherocytosis
Hereditary
Membrane defect
eliptocytosis
PNH
G6PD deficiency
Intracorpuscular
Enzyme defect
Pyruvate kinase
deficiency
Quantitative
Thalassemia
Hemoglobinopathies
Sickle cell disease
Etiology
Qualitative
HbC disease
Autoimmune
HbE disease
hemolytic anemia
Immune mediated
Isoimmune
hemolytic anemia
Microangiopathic
hemolytic anemia
Extracorpuscular
Trauma
Prosthetic valve
Hypersplenism
Snake venom
Toxin induced
Malaria
Clinical features of hemolytic anemia:
1. Due to anemia:
Anemic look
Breathlessness
Cardiac palpitation
Dizziness
Exercise intolerance
12
Fatigue.
2. Due to excessive hemolysis:
Icterus
Splenomegaly (if spleen is the site of RBC destruction)
Calculus cholecystitis.
3. Due to extramedullary erythropoiesis:
Liver: Hepatomegaly
Spleen: Splenomegaly
Bones: Skeletal changes.
4. Due to underlying disease
5. Due to complication(s):
Iron overload
Iatrogenic complication (Ex.: blood borne infections).
Investigation
1. Evidence of anemia:
Blood: Hb, TC, DC, CRP
Hb:
2. Evidence of excessive hemolysis:
Unconjugated bilirubin:
LDH:
AST:
Urinary urobilinogen:
Fecal stercobilinogen:
3. Evidence of accelerated erythropoiesis:
Reticulocyte count:
Erythroid hyperplasia.
4. Investigations to confirm underlying disease
5. Investigations to detect complications:
Iron overload: Serum iron , serum ferritin .
Blood borne infections: Tests for HIV, HBV, HCV.
Treatment
1. Treatment of anemia
2. Treatment of iron overload
3. Treatment of underlying disease (specific treatment)
4. Treatment of complications.
13
Mention some differentiating parameters between extracorpuscular/ extravascular and
intracorpuscular/ intravascular hemolysis?
Parameter
Intravascular hemolysis
Extravascular hemolysis
Hemoglobin in urine
+
-
Hemosiderin in urine
+
-
Haptoglobin in blood
Now we will discuss the individual underlying diseases that cause hemolytic anemia.
Hereditary spherocytosis (HS)
Definition:
Congenital defect of RBC membrane protein resulting in accelerated destruction of RBCs
in the spleen.
Pathophysiology:
Abnormality of spectrin/ actin/ other membrane
proteins
RBCs loses its deformibility as these proteins
impart scaffolding effect
RBCs become spherical
They get trapped while passing through splenic
pulp
Accelerated hemolysis
Clinical features:
1. Due to anemia:
Anemic look
Breathlessness
Cardiac palpitation
Dizziness
14
Exercise intolerance
Fatigue.
2. Due to accelerated erythropoiesis:
Icterus
Splenomegaly
Calculus cholecystitis.
3. Anemia may worsen if bone marrow fails to compensate for accelerated
hemolysis. This problem particularly happens if there is associated folate
deficiency. This event is therefore known as "aplastic crisis".
Investigation
1. Blood: Hb, TC, DC, CRP
Hb:
2. Peripheral blood film: Spherocytosis ++ but it is not diagnostic of hereditary
spherocytosis as there are other causes of spherocytosis.
3. Reticulocyte count: (due to accelerated erythropoiesis)
Reticulocytopenia suggests impending aplastic crisis.
4. Evidence of excessive hemolysis:
Unconjugated bilirubin:
LDH:
AST:
Urinary urobilinogen:
Fecal stercobilinogen:
5. To confirm hereditary spherocytosis:
I.
Osmotic fragility test:
Spherocytes are vulnerable to get damaged by a hypotonic media.
II.
Coomb's test: -Ve
To rule out autoimmune hemolytic anemia where there is spherocytosis
and osmotic fragility as wel as HS.
Treatment
1. Uninterrupted folic acid supplementation to prevent aplastic crisis
2. Blood transfusion in case of significant anemia
3. Splenectomy in severe cases.
15
Paroxysmal Nocturnal Hemoglobinuria (PNH)
It is an acquired hematopoietic stem cell disorder characterized by excessive
complement mediated lysis of the cells.
Pathogenesis:
Acquired defect
of membrane
Cells become
Complete
proteins which
vulnerable to
mediated lysis of
Clinical
play an imprtant
complement
RBC, WBC and
manifestations
role in regulating
mediated
platelets
membrane attack
damage
complex
Clinical manifestations due to complement mediated lysis of RBCs:
1. Anemia and its clinical features
2.
Intravascular
Dark/ cola colored
Hemoglobinuria
hemolysis
urine*
*It particularly occurs in the early morning as CO2 retention during sleep acidifies
the blood which increases hemolysis.
Clinical manifestations due to complement mediated lysis of WBCs:
Increased risk of
More incidence of
Leukopenia
infection
sore throat
16
Clinical manifestations due to complement mediated lysis of platelets:
1.
Thrombocytopenia
Bleeding manifestations
2.
Complement
Hypercoagulable
Deep vein
mediated clumping
state
thrombosis (DVT)
Investigations
1. Blood: Hb, TC, DC, CRP, Platelet count
Hb:
TC:
DC:
Platelet count:
2. Evidence of hemolysis:
Unconjugated bilirubin:
LDH:
3. Evidence of intravascular hemolysis:
Urine Hb:
Urine hemosiderin:
Blood haptoglobin:
4. Confirmation of diagnosis of PNH:
Flow cytometry detects abnormal proteins:
CD55
CD59.
Treatment
1. Anemia: Blood transfusion
2. Prevention of venous thrombosis: Anticoagulants
3. Eculizumab: It is a humanized monoclonal antibody that is a terminal
complement inhibitor and the first therapy approved for treatment of PNH
4. Corticosteroid: For some unknown reasons.
17
G6PD Deficiency
Hemolytic anemia precipitated by oxidative stress in G6PD deficient individuals.
Pathogenesis:
G6PD deficiency
Glutathione (which plays a major role
in preventing oxidative damage of RBC)
Oxidative damage
induced hemolysis
These RBCs while
Denaturation of Hb
Intermittent
passing through
forming a precipitate
hemolysis
spleen gets trapped
within RBC
and destroyed
Heinz body
Clinical features:
Oxidative stress induced intermittent hemolysis causes:
Anemia
Icterus.
Often the oxidative stress is drug induced:
Primaquine
Nitrofurantoin
Sulfonamides.
Investigations
Investigations are abnormal during active hemolytic spells:
18
1. Hb:
2. Peripheral film:
a. Heinz body
b. Bite cells: Pitted RBCs looks like they have had a bite taken out of it (When a
macrophage in the spleen identifies a RBC with a Heinz body, it removes the
precipitate and a small piece of the membrane, leading to this characteristic
appearance).
3. Evidence of hemolysis:
a. Unconjugated bilirubin:
b. LDH:
4. Evidence of hemolysis:
Reticulocyte count:
5. Confirmation of diagnosis:
Estimation of G6PD: Ideally should be confirmed after couple of weeks of active
hemolytic spells as fresh crops of RBCs (young RBCs) present during hemolysis
may contain adequate amount of G6PD giving a false ?Ve result.
Treatment
Avoid offending drugs.
19
Sickle cell disease
Qualitative hemoglobinopathy characterized by abnormal shaped RBCs which are prone
to get destroyed and clumped.
Pathogenesis:
chain 6th position-glutamine is replaced by valine
Abnormal Hb molecules
Precipitates within RBCs
Structural abnormality of RBC
RBCs become elongated/ sickle shaped
Destruction by spleen
Clumping/ sickling
Hemolysis
Vaso-occlusive episodes
Clinical features:
1. Vaso-occlusive spells (particularly affecting veins):
Organ involved
Clinical features
Brain
Venous sinus occlusion
Lung
Pulmonary artery clot-> Acute chest syndrome
Bones
Ischemic necrosis (severe bony pain)
Osteomyelitis (Salmonella is the commonest organism)
Spleen
Splenic infarct causing acute LUQ pain
Repeated episodes leads to autosplenectomy
Penile blood clots Priapism (a painful condition where erect penis does not return to
its flaccid state in the absence of any stimulation)
20
2. Evidence of hemolysis:
a. Anemia
b. Icterus
c. Spleen: May be palpable in children, not palpable in adult due to
hyposplenism.
Tendency of sickling is aggravated by:
a. Dehydration
b. Hypoxia
c. Acidosis.
Investigation
1. Hb:
2. Peripheral blood film:
a. Howell Jolly bodies: Due to hyposplenism, nuclear remnant of RBCs seen
b. Sickle cells.
3. Evidence of accelerated hemolysis:
a. Unconjugated bilirubin:
b. LDH:
4. Evidence of accelerated erythropoiesis:
a. Reticulocyte count:
b. A normal reticulocyte count indicates an impending episode of aplastic crisis.
5. Confirmation of diagnosis:
Hb electrophoresis confirms the diagnosis: shows HbS.
Treatment
1. Treatment of vaso-occlusive spells:
Proper hydration
Oxygen in hypoxia
Treat infections by antibiotics
Analgesics to reduce pain
Exchange transfusion.
2. Definitive treatment:
Curative: Bone marrow/ stem cell transplantation
Hydroxyurea: Decreases tendency of sickling by increasing circulatory HbF
levels.
21
Pernicious anemia
Vitamin B12 deficiency anemia due to autoantibody mediated deficiency of intrinsic
factor.
Pathogenesis:
There is formation of autoantibodies against:
a. Gastric parietal cell: Causing decreased HCl secretion and atrophic gastritis
b. Intrinsic factor: Binds and neutralizes them.
Eventually, there is deficiency of intrinsic factor and impaired absorption of
vitamin B12.
Clinical features and Investigations
Same as vitamin B12 deficiency anemia.
Confirmation of diagnosis by:
Anti-parietal cell antibody
Anti-intrinsic factor antibody.
Treatment
Lifelong vitamin B12 supplementation (usually IM route is preferred).
Thalassemia
Quantitative type of hemoglobinopathy.
Quantitative defect in Hb synthesis leads to chronic hemolytic anemia.
Types
-thalassemia
-thalassemia
Reduced chain synthesis
Reduced -chain synthesis
22
1. -thalassemia:
If -chain deficiency is significant, -chain gets precipitated forming a tetramer
within the RBCs. These RBCs get destroyed by the spleen.
2. -thalassemia:
-chain synthesis goes on but proportion of 22 (HbA) gets reduced. Excess -
chain leads to 3 abnormalities:
a. Precipitation within RBCs: RBCs undergo hemolysis
b. Increased 22 (HbA2)
c. Increased 22 (HbF).
Clinical features of thalassemia:
1. Features due to anemia:
Anemic look
Breathlessness
Cardiac palpitation
Dizziness
Exercise intolerance
Fatigue.
2. Features of excess hemolysis:
a. Icterus
b. Splenomegaly.
3. Features of accelerated erythropoiesis:
a. Hepatomegaly
b. Splenomegaly
c. Frontal bossing
d. Prominent parietal eminence
e. Depressed bridge of nose.
4. Feature of iron overload:
Cardiomyopathy
5. Features due to iatrogenic complications:
Blood borne infections (HIV/ HBC/ HCV)
Investigations
1. Evidence of anemia:
a. Hb:
b. TC, DC, CRP: Normal
c. Peripheral blood smear: Microcytic anemia (microcytosis is out of proportion
to the degree of anemia)
23
d. MCV:
e. Iron studies:
Serum iron:
Serum ferritin:
2. Evidence of hemolysis:
Liver function test:
Unconjugated bilirubin:
LDH:
AST:
3. Evidence of accelerated erythropoiesis:
a. Reticulocyte count:
b. Bone marrow: Erythroid hyperplasia
c. Skull X Ray: Hair on end appearance.
4. Evidence of iron overload:
a. Serum iron/ serum ferritin:
b. Echocardiogram: To assess cardiac function
c. MRI heart.
5. Detection of iatrogenic complication:
Viral serology (for HIV/ HCV): +Ve.
6. Confirmation of diagnosis of thalassemia:
Hb electrophoresis.
Treatment
1. Supportive treatment:
Packed cell transfusion (the frequency of which depends upon severity of
symptoms and level of Hb in blood):
There are 2 types of regimens:
Supertransfusion: Target Hb > 12 gm %
Hypertransfusion: Target Hb > 8 gm%.
There are 2 types of transfusion:
Triple saline wash RBC (to make RBCs WBC depleted)
Neocyte transfusion.
2. Prevent and treat iron overload:
Continuous slow SC infusion of Desferrioxamine
To avoid iron rich vegetables
To avoid citrous fruits.
3. Treatment of complications:
24
Treat infections
Treat cardiomyopathy.
4. Definitive/ curative treatments:
Bone marrow transplantation
Splenectomy: As it is the main site of RBC destruction.
Differential diagnoses
1. Other causes of chronic hemolytic anemia:
a. Hereditary spherocytosis
b. Sickle cell anemia.
2. Other causes of microcytic anemia:
a. Iron deficiency anemia
b. Anemia of chronic inflammation
c. Sideroblastic anemia
d. Lead poisoning.
3. Other causes of prominent unconjugated hyperbilirubinemia:
a. Hemolytic diseases
b. Inherited liver diseases:
Defect in bilirubin transport: Gilbert syndrome
Defect in bilirubin conjugation: Crigler-Najjar syndrome
Defect in bilirubin delivery: Dubin-Johnson syndrome/ Rotor syndrome.
Extras (not needed for exam.)
1. RDW (Red cell distribution width):
It is a measure of variation of RBC size (anisocytosis).
Normal value: 11.5%-14.5%
Abnormality:
RDW
MCV
Interpretation
Iron deficiency anemia
N
Acute hemorrhage
B12/ Folate deficiency
N
Thalassemia/ other causes of chronic hemolytic anemia
2. Mentzer index:
= ()
(/)
25
MI > 13 is suggestive of iron deficiency anemia while a MI <13 is
suggestive of thalassemia.
It takes an extreme change in MCV and RBC count to significantly alter
this ratio, which has put the reliability of this index in question.
3. Types of thalassemia according to clinical scenario:
Minor
Intermediate
Major
Asymptomatic, with only
Symptomatic, clinical
Symptomatic, significant
abnormal hematological
impact of disease not
clinical impact
parameters
significant
Does not require blood
Requires occasional blood
Transfusion dependent
transfusion
transfusion
4. An insight into alteration of laboratory parameters in and thalassemia:
-thalassemia
Genes
Hematocrit
MCV
Comment
deleted
(Normal: 45-55%)
(Normal: 85-105)
1
Normal
Normal
Silent carrier
2
30-40%
60-75
-thalassemia trait
3
20-30%
60-70
Hemoglobin H disease
4
-
-
Hydrops fetalis
-thalassemia
Type
HbA
HbA2
HbF
(Normal: 95-96%)
(Normal: 1-3%)
(Normal: <1%)
Minor
85-95%
4-5%
1-5%
Intermediate
0-30%
1-10%
0-100%
Major
0-10%
4-10%
95-96%
26
Autoimmune hemolytic anemia (AIHA)
Hemolysis of autoantibody coated RBCs.
Causes/ types:
AIHA
IgG antibody coated RBCs
IgM antibody coated RBCs
These RBCs are destroyed at a relatively low temperature,
These RBCs are destroyed at a temperature of 37C, which
therefore often no hemolysis occurs in normal body
is almost equal to normal body temperature
temperature
So, these are called "Warm antibody"
So, these are called "Cold antibody"
Causes:
Seen in:
1. Idiopathic
Mycoplasma infection
2. Drugs (Penicillin/ cephalosporin)
3. Some patients of CLL
4. Some patients of ITP.
Clinical features:
1. In many persons, it is completely asymptomatic
2. In case of chronic hemolysis:
a. Anemia + symptoms due to anemia
b. Jaundice
c. Splenomegaly
d. Features due to the underlying disease.
Investigations
1. Evidence of anemia:
a. Hb:
b. Presence of Spherocytes.
27
2. Evidence of hemolysis:
a. Unconjugated bilirubin:
b. LDH:
3. Evidence of accelerated erythropoiesis:
a. Reticulocyte count:
b. Bone marrow: Erythroid hyperplasia
4. Coomb's test:
a. Direct: Usually +Ve (detects antibody coated RBCs)
b. Indirect: May/ may not be +Ve (detects free antibody in serum).
Treatment
1. None required in case of insignificant hemolysis
2. In case of significant hemolysis:
a. Prednisolone
b. Splenectomy.
3. Treatment of the underlying disease.
28
Microangiopathic hemolytic anemia (MAHA)
Accelerated intravascular hemolysis due to damaged microvasculature wall.
Ex.:
1. Thrombotic thrombocytopenic purpura (TTP)
2. Hemolytic uremic syndrome (HUS).
Thrombotic thrombocytopenic purpura (TTP)
Pathogenesis:
Triggering factor(s)
Increased activity of vWF (due to deficiency of vWF cleaving protease)
Platelet adhesion and aggregation
Microvascular thrombosis (composed of plalelet + fibrin)
Frictional damage of RBCs
Consumption of platelets
Ischemic organ damage
while passing through these
(used up in microvasculature
(Cerebral >> Renal)
vessels
thrombus formation)
Microangiopathy
Thrombocytopenia
Intravascular hemolysis
29
Clinical features:
T
Features due to thrombosis
CNS thrombosis:
Seizure
Confusion
Delirium
Encephalopathy
Fluctuating focal
neurological signs.
T
Features due to thrombocytopenia
Bleeding manifestations:
Purpura
Gum bleeding
Epistaxis
Internal bleeding:
Gastrointestinal,
Genitourinary,
Intracranial.
P
Pallor + Jaundice
Investigation
1. Blood:
Hb:
Peripheral film: Fragmented RBCs (Schistocytes)
TC: Normal
Platelet count:
2. Evidence of hemolysis:
Unconjugated bilirubin:
LDH:
3. Evidence of intravascular hemolysis:
Hemoglobinuria
Hemosiderinuria
Serum Haptoglobin: .
Treatment
Supportive (Plasmapheresis).
30
Hemolytic uremic syndrome (HUS)
Pathogenesis:
Triggering factors
(Bloody dysentery caused by Shigella/ E.coli O157)
Activity of platelet aggregating factors
Platelet adhesion and aggregation
Rest is same as TTP
(Only note that in HUS, the ischemic damage mainly
affects the kidneys)
Clinical features:
1. H/O bloody diarrhea is usually present
2. Features due to thrombotic damage to kidney:
Signs of volume
Acute kidney
overload ?
Oliguria/ anuria
injury
Uremic
encephalopathy
3. Features due to thrombocytopenia:
Bleeding manifestations:
Purpura, gum bleeding, epistaxis, internal bleeding (GI/ GU/ IC).
4. Pallor (mild) ? Jaundice (mild).
31
Investigations
1. Blood:
Hb:
Peripheral film: Fragmented RBCs (Schistocytes)
Platelet count:
2. Evidence of hemolysis:
Unconjugated bilirubin:
LDH:
3. Evidence of intravascular hemolysis:
Hemoglobinuria
Hemosiderinuria
Serum haptoglobin:
4. Renal function:
Urea Creatinine: (in case of uremic encephalopathy)
Serum K+:
5. Stool culture and sensitivity.
Treatment
Primarily supportive:
1. In case of acute kidney injury: Dialysis
2. In case of severe hemolysis: Plasmapheresis.
Sideroblastic anemia
Anemia resulting from defective haem synthesis/ metabolism.
Pathophysiology:
Defective haem synthesis ultimately leads to ineffective erythropoiesis; causing anemia.
Causes:
1. Idiopathic
2. Chronic alcohol use
3. Drug: Isoniazid
4. Chronic infection/ inflammation.
32
Clinical features:
1. Asymptomatic
2. Symptomatic due to anemia.
Investigations
1. Blood:
Hb:
WBC/ Platelet: Normal
2. Peripheral film:
Microcytic anemia
Dimorphic picture (Small + normal sized RBCs)
Reticulocyte: Absent
If caused by chronic alcohol use, there is macrocytic anemia.
3. Serum iron studies:
Picture of iron overload (due to defect in iron metabolism):
Serum iron:
Transferrin saturation:
Serum ferritin: May be
4. Evidence of hemolysis: Absent (to rule out hemolytic anemia)
Unconjugated bilirubin: Normal
Serum LDH: Normal
5. Bone marrow:
Shows ring sideroblast (iron gets deposited within abnormal nucleated RBCs
encircling the nucleus).
6. Stool for occult blood test
7. Endoscopy, if missed: colonoscopy.
Treatment
Supportive: Blood/ packed cell transfusion.
33
Pancytopenia
Reduction in all 3 series of blood cells.
Causes:
Aplastic anemia
Infiltrative disorders of bone
marrow (Leukemia)
Bone marrow disorders
B12/ Folate deficiency
Myelofibrosis
Causes of pancytopenia
Myelodysplasia
Hypersplenism
Non-marrow diseases/
peripheral causes
PNH
Clinical features of pancytopenia:
Patient may be completely asymptomatic
Features due to anemia:
Anemia
Breathlessness
Cardiac palpitations
Dizziness
Exercise intolerance
Fatigue.
Features due to thrombocytopenia:
Purpura
Gum bleeding
Epistaxis
Internal hemorrhage: GI/ GU/ IC.
Features due to neutropenia:
Increased risk of infections:
34
Fever
URTI/ LRTI (Sore throat)
Cellulitis/ abscess/ meningitis
Fungal infections.
Features due to the underlying disease.
Investigations
1. Blood:
a. Full blood count
b. Peripheral film: To look for abnormal/ immature cells
c. RBC indices: MCV (if , check for vitamin B12/ Folate deficiency anemia).
2. USG:
Liver and spleen size
3. Bone marrow:
a. Hypocellular: Indicates aplastic anemia
b. Fibrosis: Indicates myelofibrosis
c. Leukemic cells: Indicates infiltrative disorders of marrow (leukemia).
4. Special tests to confirm the diagnosis.
Treatment of pancytopenia
1. Supportive treatment:
a. Treatment of anemia:
Packed cell transfusion, when patient is symptomatic due to anemia.
b. Treatment of thrombocytopenia:
Platelet transfusion in case of significant bleeding.
c. Treatment of neutropenia:
Neutropenia is defined as an ANC < 1500/L:
Double barrier nursing
Febrile patient: IV 3rd generation cephalosporin/ Carbapenem ?
Fluconazole/ Itraconazole
Septic screen (to find the focus of infection)
Granulocyte- Colony Stimulating Factor (G-CSF): Filgrastim.
35
Aplastic anemia
Bone marrow hypocellularity leading to pancytopenia in the absence of marrow
infiltration and fibrosis.
Causes:
3I
Idiopathic: Autoantibody mediated
Iatrogenic:
Many drugs may potentially cause aplastic anemia:
Anticancer drugs
Antibiotics: Chloramphenicol/ Sulfonamide
NSAIDs: Phenylbutazone
Anti-rheumatic drugs: Gold, Sulfasalazine.
Infections:
HIV
HBV.
Clinical features:
1. Features of anemia
2. Features of thrombocytopenia
3. Features of neutropenia
4. Absence of hepatosplenomegaly.
Investigation
1. Blood:
a. Hb:
b. RBC count, WBC count, Platelet count:
c. RBC indices: MCV: Normal.
2. Serum vitamin B12 and folate level:
To rule out deficiency.
3. Unconjugated bilirubin and serum LDH:
To rule out hemolysis.
4. Viral serology (HIV, HBV):
To rule out infections.
36
5. USG abdomen:
To look for organomegaly.
6. Bone marrow examination:
Trephine biopsy detects hypocellular marrow.
Treatment
Pancytopenia
Treat any reversible
cause (Ex.: drugs etc.)
Definitive treatment
Supportive treatment
(Idiopathic aplastic anemia)
Treat
Treat
Treat anemia
Age
thrombocytopenia
neutropenia
Platelet
Antibiotic,
Packed RBC
40 years
>40 years
transfusion
antifungal, G-CSF
for 7 days
HLA matched
siblings
Yes
No
Antithrombocyte
Antithrombocyt
HLA identical
globulin +
e globulin +
bone marrow
Cyclosporine for
Cyclosporine for
transplantation
12 months
12 months
(allogenic)
Response not
Repeat another
Upto 2 cycles
satisfactory
cycle
ATG + CSA
Matched
Bone marrow
unrelated donor
transplantation
37
Anemia of chronic inflammation
Causes:
1. Rheumatoid arthritis
2. Inflammatory bowel disease
3. Chronic kidney disease.
Pathogenesis:
It is a multifactorial disorder:
1. Iron depletion (due to increased activity of hepcidin which is an iron absorption
regulatory protein)
2. Decreased responsiveness of erythropoietin to its receptors
3. Decreased erythropoietin synthesis (particularly occurs in CKD).
Clinical features:
1. Mild to moderate anemia
2. Features of underlying disease.
Investigations
1. Blood:
Hb:
MCV: Normal/
2. Iron studies:
Serum iron: Normal/
Serum ferritin: Normal/
Differentiating among 3 common anemia from iron studies:
Parameters
IDA
Thalassemia
Chr. Inflam.
MCV
N/
Serum Fe
N/
Serum Ferritin
N/
Treatment
1. Treatment of the underlying disease
2. Packed cell transfusion (when anemia is symptomatic)
3. Iron supplementation
4. Regular erythropoietin supplementation (particularly in CKD).
38
Hematological
malignancy
Myeloid series
Lymphoid series
Myeloproliferative
AML
CML
ALL
CLL
Lymphoma
disorders
Acute leukemia
Malignant transformation of myeloid/ lymphoid cells characterized by overproduction as
well as defective maturation of cells.
Types:
2 types: ALL and AML.
Mechanisms of clinical manifestations:
Overproduction of cells in bone marrow
Hypermetabolic
Bone marrow
Organ infiltration
state
Hepatomegaly
Infiltration
Expansion
Uric acid
Splenomegaly
Lymphadenopathy
Gum hypertrophy
Bone marrow
Constitutional
Bony tenderness
Meningeal
Acute gout
failure
infiltration (ALL)
symptoms
Cytopenia
39
Clinical features:
Age group:
ALL: Pediatric age group (2-7 years)
AML: Middle aged/ elderly patients.
Symptoms:
Result from bone marrow infiltration/ failure:
1. Anemia:
Exercise intolerance
Fatigue
2. Bleeding manifestations
3. Infection:
Fever
URTI/ LRTI
Cellulitis/ abscess.
Signs:
1. Due to organ infiltration:
Hepatomegaly
Splenomegaly
Lymphadenopathy
Gum hypertrophy
Meningeal signs (particularly in ALL).
2. Due to marrow expansion:
Bone tenderness over sternum and pelvic region.
3. Due to hyperuricemia:
Acute gouty arthritis
Constitutional symptoms: Fever, sweating, weight loss etc.
Investigations
1. Blood:
Hb:
WBC count: Variable (/)
Platelet count:
2. Peripheral film: Blast cells
40
3. Bone marrow:
Plenty of blast cells (>20% blast cells in marrow confirms an ongoing acute
leukemic process):
Myeloblast
Lymphoblast.
4. Flow cytometry:
It detects cell surface markers which get expressed in leukemia:
ALL: CD10, CD19
AML: CD13, CD33.
5. Cytochemistry:
AML: Myeloperoxidase (MPO), Butyrate esterase
ALL: Detection of Philadelphia chromosome (some of the patients of ALL
will show this chromosome).
Diagnosis of complications:
1. Uric acid: (Due to hypermetabolic state)
2. Serum vitamin B12: (Due to levels of transcobalamin 3)
3. CSF: To look for meningeal infiltration (particularly in ALL)
4. Septic screen: To find the focus of infection:
Blood and urine: culture and sensitivity
Chest X Ray
C-reactive protein (CRP)
Throat swab: Gram stain and culture-sensitivity.
Treatment
1. Supportive treatment:
a. Treat anemia
b. Treat thrombocytopenia
c. Treat neutropenia
d. Treat hyperuricemia:
Allopurinol
Febuxostat.
2. Definitive treatment.
41
Definitive treatment of ALL
1. Chemotherapy:
a. Induction of remission:
Aggressive chemotherapy to destroy most of the leukemic cells.
Drugs used: Cytarabine + Doxo/ Dauno-rubicin.
b. Consolidation/ intensification of remission:
Destroy the rest of the leukemic cells.
Drug used: Daunorubicin.
c. Maintenance of remission.
2. Allogenic stem cell transplantation:
The decision depend on prognostic factors:
a. Response to chemotherapy
b. Comorbidities of the patient
c. Age of the patient.
Definitive treatment of AML
1. Chemotherapy:
a. Induction of remission (duration: 4 weeks):
Drugs used: Vincristine, Prednisone, L-asparaginase, Daunorubicin.
b. Consolidation/ intensification of remission (duration: 4 months):
Drugs used: Methotrexate, L-asparaginase, Cyclophosphamide, Cytarabine,
Etoposide.
c. Maintenance of remission (duration: >2 years):
Drugs used: Methotrexate, 6MP, Vincristine, Prednisone.
Note: If patient is BCR-Abl positive, a tyrosine kinase inhibitor (TKI) is added to
the above regimen.
2. Bone marrow transplantation (BMT):
Post-remission BMT may be indicated in certain patients depending on:
a. Response to chemotherapy,
b. Comorbidity,
c. Age of the patient.
3. Radiotherapy:
Post- remission prophylactic cranial radiotherapy may be given to treat any
meningeal infiltration.
Acute promyelocytic leukemia
1. Often patients present with DIC
42
2. Drug of choice in chemotherapy is Retinoic acid.
Chronic leukemia
CLL
Malignant transformation of lymphocytes typically characterized by mature
lymphocytosis (B lymphocytes).
Pathogenesis:
CLL
Silent indolent course
Functionally incompetent
Organ infiltration
Abnormal immune response
lymphocytes
Poor antibody response
Liver
AIHA
Risk of infection
Spleen
ITP
Bone marrow
Lymph node
Clinical features:
1. Often asymptomatic and diagnosed incidentally
2. Recurrent infection:
LRTI
URTI
Pneumonia
Recurrent viral infections
Recurrent cellulitis, abscess formation etc.
3. Features of organ infiltration:
Hepatomegaly
Splenomegaly
43
Lymphadenopathy (usually not generalized)
Features of lymph node enlargement may be present.
4. Features of anemia
5. Features of bleeding manifestations
6. Icterus.
Investigations
1. Blood:
Hb: Normal/ (in case of AIHA)
WBC count: (mild to moderate): predominantly lymphocytes
Peripheral smear: Small mature lymphocytes, presence of smear cells/
smudge cells
Platelet count:
2. Liver function test:
Low -globulin level: Hypogammaglobulinemia.
3. Evidence of autoimmune hemolytic anemia:
Unconjugated bilirubin:
Serum LDH:
Coomb's test: +Ve.
4. Serum uric acid: Normal/
5. Bone marrow: Lymphocytosis
6. CECT abdomen: To detect any organ infiltration
7. Flow cytometry:
It detects cell surface markers which get expressed in CLL (CD19, CD20, CD5,
CD23).
Treatment
There are 2 approaches in treatment of a CLL patient:
1. Wait and watch approach
2. Proceed to therapeutic intervention.
In the wait and watch approach, only supportive treatments are given:
Supportive treatment:
1. Anemia: Blood transfusion
2. Infection: Antibiotics, Prophylactic IgG
3. AIHA: Corticosteroid and Rituximab.
44
Therapeutic interventions:
Options are:
1. Chemotherapy:
Fludarabine
Cyclophosphamide
Rituximab.
2. Bone marrow transplantation:
In selected patients who have medically refractory CLL
3. Treatment of AIHA/ ITP:
Prednisone
Rituximab
Splenectomy.
Extras: Rai staging system of CLL
Staging
Description
Stage 0
Lymphocytosis
-
Stage 1
Lymphocytosis +
Lymphadenopathy
Stage 2
Lymphocytosis +
Organomegaly
Stage 3
Lymphocytosis +
Anemia
Stage 4
Lymphocytosis +
Significant thrombocytopenia
Indication for active treatment in CLL
1. Significant lymphadenopathy
2. Significant anemia/ thrombocytopenia.
Therefore, active treatment is required stage 2 and above.
Immunoglobulin therapy
Intermittently given, for treating hypogammaglobulinemia.
45
CML
It is a myeloproliferative disease characterized by relentless proliferation of cells of
myeloid series (but there is no defect of differentiation/ maturation process).
Pathogenesis:
1. The primary defect is reciprocal translocation between 2 arms of chromosome 22
and chromosome 9.
2. The portion of chromosome 9 which gets translocated is called Abl (Abelson
murine leukemia viral oncogene).
3. The point on chromosome 22 where the translocated portion of chromosome 9
gets attached to, is called Bcr (Breakpoint cluster region).
4. The fusion gene is called Abl-Bcr, which exhibits abnormally high tyrosine kinase
activity, which plays a central role in the pathogenesis of CML.
5. The abnormal chromosome is called Philadelphia chromosome, which can be
detected by cytological studies.
6. The abnormal gene (Abl-Bcr fusion gene) can be quantified using molecular
studies.
46
Mechanism of clinical manifestations:
Overproduction of myeloid cells
Organ
Hypermetabolic
Bone marrow
Leukostasis
infiltration
state
LIver, spleen,
Constitutional
Expansion
Infiltration
Hyperuricemia
skin
symptoms
Failure
Clinical features:
Symptoms
1. Constitutional symptoms:
Fever
Night sweat
Weight loss.
2. Bone marrow failure:
Anemia (early manifestation)
Thrombocytopenia (bleeding manifestations)
Neutropenia (at late stage).
Signs
1. Due to organ infiltration: Hepatosplenomegaly
2. Due to marrow expansion: Sternal tenderness
3. Due to leukostasis:
a. Pulmonary vascular occlusion: Acute chest pain
b. Cutaneous vascular occlusion: Vasculitic rash
c. Occlusion of CNS vessels: Temporary focal neurological signs.
47
Investigation
1. Blood:
Hb:
WBC count:
Platelet count: Normal/ (due to marrow failure).
2. Peripheral film:
Abundant mature WBCs (Promyelocyte/ Metamyelocyte)
Myeloblast: Usually very few (Significant number of blast cell is seen in
blast crisis phase, i.e. transformation of CML into acute leukemia)
Basophilia: Indicates an impending episode of blast crisis.
3. Bone marrow:
Myeloid hyperplasia
Blast cells: Usually <5% (When it is 10-20%, signifies blast crisis)
Note that: Blast cel s of CML usual y don't contain Auer rod.
4. Special tests:
a. Cytogenetic study:
Detection of Philadelphia chromosome confirms the diagnosis.
b. Molecular study:
Quantification of Bcr-Abl gene.
Treatment
1. Supportive treatment:
a. Treatment of anemia
b. Treatment of thrombocytopenia
c. Treatment of neutropenia
d. Treatment of hyperuricemia.
2. Definitive treatment:
a. Chemotherapy:
Drug of choice is tyrosine kinase inhibitor:
1st generation: Imatinib
2nd generation: Nilotinib, Dasatinib.
In case of accelerated stage/ blast crisis, more aggressive
chemotherapy is given.
Response to chemotherapy can be assessed by:
Response
Description
Hematological
Normalisation of hematological parameters and
response
significant reduction of spleen size by 3 months
48
Cytogenetic
Philadelphia chromosome becomes undetectable
response
by 6 months (latest: by 12 months)
Molecular
Significant reduction in quantity of Bcr-Abl gene.
response
b. Bone marrow transplantation:
In case of medically unresponsive/ poorly responsive patients.
Lymphoma
Malignant transformation of lymphocytes.
Classification:
Lymphoma
Hodgkin's lymphoma
Non-Hodgkin's lymphoma
Type
Types
Nodular
Mixed
Lymphocyte
Lymphocyte
Precursor T
Precursor B
Mature T cell
Mature B cell
sclerosis
cellularity
predominant
depleted
cell
cell
Mechanism of clinical manifestations:
1. Enlargement of lymphoid follicle-------- Lymphadenopathy
Lymph nodes commonly involved:
a. Above diaphragm:
Cervical
Axillary
Epitrochlear
Mediastinal.
b. Below diaphragm:
Para-aortic
Inguinal.
2. Extranodal spread:
a. Liver
b. Spleen
49
c. Bone marrow (advanced stage); resulting in marrow infiltration/ failure.
Clinical features:
1. Constitutional symptoms:
Fever
Sweating
Weight loss
2. Features of lymphadenopathy:
Palpable lymph nodes: Firm, non-tender, discrete
Mediastinal lymphadenopathy: May result in SVC obstruction/ Superior
mediastinal syndrome
- For some unknown reasons, Hodgkin's lymphadenopathy becomes
painful after alcohol ingestion.
3. Features due to Extranodal spread:
Hepato/spleno-megaly
Pleural effusion/ ascites
Bone marrow failure at late stage (showing features of anemia,
thrombocytopenia, neutropenia).
4. Pal Ebstein's fever:
In Hodgkin's lymphoma, there is period of high fever followed by prolonged
afebrile period after which fever recurs.
5. Acute gouty arthritis.
Investigations
1. Blood:
Hb, TC, DC, Platelet count: Normal (cytopenia is a late manifestation)
2. Liver function test:
Often normal (but may be non-specifically deranged)
3. Serum uric acid estimation
4. CXR
5. CECT of chest, abdomen and pelvis (to look for lymphadenopathy)
6. Confirmation of diagnosis of lymphoma:
FNAB
Excisional biopsy.
7. Bone marrow (to look for bone marrow infiltration).
50
Treatment
Hodgkin's lymphoma
Staging (Ann Arbor classification):
Stage
Description
1
Single lymph node region on one side of diaphragm
2
2 lymph node region on one side of diaphragm
3
Involvement of lymph node region on both sides of diaphragm
4
Extranodal spread
A
No constitutional symptoms
B
Constitutional symptoms present
(fever, night sweat, 10% unintentional weight loss)
Management according to stage
o Stage 1 and 2: Chemotherapy + Local field radiotherapy
o Stage 3 and 4/ any stage B (symptomatic): High dose chemotherapy
o Chemotherapeutic drugs used:
Doxo/ Dauno-rubicin
Bleomycin
Vinblastine
Dacarbazine.
Non-Hodgkin's lymphoma
Chemotherapy (CDPRV):
C. Cyclophosphamide
D. Doxorubicin
P: Prednisolone
51
R: Rituximab
V: Vincristine.
Myeloproliferative disorders
Characterized by overproduction of any hematopoietic cell series in an isolated manner/
simultaneously.
Causes:
1. Polycythemia rubra vera
2. Essential thrombocytosis
3. CML
4. Myelofibrosis.
Myelofibrosis
Characterized by marrow fibrosis and exuberant extramedullary hematopoiesis.
Clinical features:
1. Asymptomatic
2. Due to marrow fibrosis:
a. Marrow failure, leading to features of pancytopenia
b. Features due to anemia (earliest manifestation)
c. Features due to thrombocytopenia (bleeding manifestations)
d. Features due to neutropenia (recurrent infections).
3. Due to extramedullary hematopoiesis:
a. Significant splenomegaly (causing LUQ discomfort and sensation of fullness) ?
hepatomegaly
b. Usually occurs in elderly population.
Investigations
1. Blood:
Hb: (earliest and often the only abnormality on presentation)
WBC, platelet count: May be
Peripheral film:
Poikilocytosis
Teardrop cells
Bizarre looking platelets
52
Leuko-erythroblastic picture.
2. Bone marrow:
Marrow aspirate shows reticulin (fibrosis).
Treatment
1. Supportive treatment:
Treatment of anemia, thrombocytopenia and neutropenia.
2. Definitive treatment:
a. Medical:
Lenalidomide
Pomalidomide.
b. Bone marrow transplantation.
Polycythemia rubra vera (PRV)
Hyperproliferation of all 3 series of blood cells.
Pathogenesis:
JAK2 mutation plays a central role in PRV.
Clinical features:
1. Often asymptomatic
2. Features due to RBC count and associated hyper-viscosity state:
a. Headache
b. Dizziness
c. Plethoric appearance.
3. Features due to WBC count:
Basophilia: Pruritus typically after having a shower (due to increased
histamine release)
4. Features due to thrombocytosis:
53
DVT in absence
Occurs in unusual
Prothrombotic
Venous
of any
Thrombocytosis
sites: Portal vein,
state
thrombosis
favorable
hepatic vein
factors
5. Although not common, bleeding manifestations may occur due to functional
defect of the platelets.
6. Often splenomegaly is present.
Investigations
1. Blood:
Hb: (often markedly high and usually the earliest manifestation)
RBC count:
RBC mass:
PCV: Abnormal y
Platelet count: .
2. Diagnosis is confirmed by detecting the presence of JAK2 mutation.
Treatment
1. Regular phlebotomy
2. Medical treatment:
a. Hydroxyurea
b. Prophylactic aspirin.
Extras: Differentiating PRV from secondary polycythemia
Points
PRV
Secondary polycythemia
Hypoxia in patient
Patients are non-hypoxic
Often patients are chronically
hypoxic (COPD/ ILD/ Congenital
heart disease etc.); non-hypoxic
causes are uncommon (EPO
secreting tumor/ RCC/ Cerebellar
hemangioblastoma etc.)
Blood cells
RBC WBC Platelet
RBC
54
EPO
JAK2 mutation
+Ve
-Ve
Essential thrombocytosis
Myeloproliferative disorder characterized by abnormal proliferation of platelets only.
Clinical features:
1. Often asymptomatic
2. Prothrombotic state, leading to unprovoked DVT at unusual site
3. Erythromelalgia: Reddish discoloration of skin due to vascular stasis in cutaneous
vessels.
Investigations
1. Blood:
RBC/ WBC/ Hb: Normal
Platelet count: Abnormal y
2. Bone marrow:
Megakaryocytes are found plenty in number.
55
A general discussion on bleeding disorders
Introduction:
Spontaneous bleeding/ abnormal bleeding following minor trauma.
Etiology of bleeding disorders:
Defective hemostasis
Local
Platelet aggregation/
Coagulation cascade
vasoconstriction
adhesion
activation
Age related
Defective platelet
Thrombocytopenia
Coagulopathy
damage/ weakness
function
Scurvy (Deficiency of
vWD
Congenital
Acquired
vitamin C and defective
collagen tissue formation)
Antiplatelet drugs
Hemophilia
DIC
Cushing syndrome
Chronic liver disease
Vasculitis
Vitamin K deficiency
Clinical features:
Purpura
Superficial
Gum bleeding
Epistaxis
Bleeding
manifestations
Gastrointestinal
Deep
Genitourinary
Intracranial
56
Investigations
1. Clotting profile:
Platelet count
BT: Mainly assess the integrity of blood vessels, platelet aggregation and
activation status
CT: Roughly assess the integrity of coagulation cascade pathway
PT, INR: Assess the function of extrinsic pathway
aPTT: Assess the function of intrinsic pathway
Thrombin time.
2. Special tests to diagnose the underlying disease.
Treatment of bleeding disorders
1. Treatment of bleeding manifestations:
Antifibrinolytic:
o Tranexamic acid
o Aminocaproic acid
Platelet transfusion
Fresh frozen plasma.
2. Treatment of the underlying disease.
Basic concepts
Hematoma
Collection of blood underneath the skin.
Types:
Hematoma
Petechiae
Purpura
Echymosis
Bleeding into the skin
Cutaneous bleeding spot
Cutaneous bleeding spt >1 cm
(pinpoint bleeding spot)
>3 mm but <1 cm
Size <3 mm
Bruise
57
Purpura
Reddish discoloration of skin due to bleeding underneath the skin.
Causes:
1. Purpura + Thrombocytopenia:
a. Part of pancytopenia
b. Isolated thrombocytopenia.
2. Purpura (without thrombocytopenia):
a. Vessel wall related disorder:
I.
Age related
II.
Vasculitis
III.
Scurvy
b. Defective platelet function:
von Wil ebrand's disease (vWD)
c. Coagulopathy.
Clinical manifestations:
1. Due to thrombocytopenia: Spontaneous bleeding
2. Purpura: Reddish, non-blanching spots; palpable (vasculitis)/ non-palpable (non-
inflammatory cause)
3. Features of the underlying disease.
Investigations:
1. Clotting profile
2. Investigations to detect the underlying disease.
Idiopathic thrombocytopenic purpura (ITP)
Disease characterized by immune autoantibody mediated thrombocytopenia.
Types:
ITP is of 2 types:
Acute ITP: Usually occurs in newborns/ children
Chronic ITP: Usually occurs in adults.
58
Pathophysiology:
Antibody formation
Antibody
Entrapment
Platelet
Viral infection
against platelets
coated
by spleen
destruction
(Gp 1b-9/ Gp 2b-3a)
platelets
Clinical features:
1. Often asymptomatic
2. Bleeding manifestations: Superficial/ deep
3. Splenomegaly is characteristically absent (in acute ITP, mild splenomegaly may
be present).
Investigations
1. Platelet count:
2. Hb, WBC count: Normal
3. Clotting profile: Usual y normal (BT may be )
4. Antiplatelet antibody may be detected.
Treatment
1. Supportive treatment:
Often not required in acute ITP
If significant bleeding present:
Platelet transfusion
IV IgG therapy.
2. Specific treatment:
Long term prednisolone (as ITP is an immune mediated disease)
Rituximab
Newer drugs (Thrombopoietic receptor agonist):
These are used when patients don't response to other treatments:
Eltrombopag
Romiplostim.
59
Splenectomy (in case of splenomegaly and also because spleen is the site
of antibody production against platelets)
Difference between acute and chronic ITP
Acute ITP
Chronic ITP
Newborns/ infants
Adults
Preceded by an episode of viral infection
Afebrile
Splenomegaly (mild) may present
Usually absent
Often self-limiting
Often needs treatment
Thrombocytopenia
Reduction in the number of platelets <1.5 lakhs/L (normal level: 1.5-4.5 lakhs/ L).
Etiology:
Thrombocytopenia
As part of
Selective
pancytopenia
thrombocytopenia
Bone marrow
Immune mediated
Iatrigenic
Infection
disorders
(ITP)
Non-bone marrow
Heparin induced
Dengue
disorders
(HIT)
Aspirin
HIV
Clopedogrel
60
Clinical features:
1. Due to thrombocytopenia:
a. Asymptomatic
b. Symptomatic: Spontaneous bleeding manifestations
Note: Risk of spontaneous bleeding increases significantly when platelet count
goes <20000/ L. A count <10000/ L is cal ed "critical thrombocytopenia".
2. Features due to underlying disease.
Investigation
1. Platelet count:
2. Hb, WBC count: Normal/
3. Coagulation profile:
a. BT:
b. Other parameters (CT/ PT/ INR/ aPTT) are often normal
4. Investigation(s) to confirm the underlying disease.
Treatment
1. Supportive treatment:
Platelet transfusion
Indication:
a. Significant bleeding
b. Before any invasive transfusion.
2. Definitive treatment:
Treatment of the underlying disease.
Hemophilia
It is a congenital coagulopathy due to deficiency of factor VIII.
Types:
A. Hemophilia A: Deficiency of factor VIII
B. Hemophilia B: Deficiency of factor IX
C. Hemophilia C: Deficiency of factor XI.
Clinical features:
Spontaneous bleeding:
61
1. Superficial: Purpura, gum bleeding, epistaxis
2. Deep: Hemarthrosis: May lead to painful swollen joints. Recurrent hemarthrosis
in the same joint may lead to joint damage; resulting in restriction of movement.
Investigation
Clotting profile:
BT: Normal
CT:
PT, INR: Normal
aPTT: (defect in the intrinsic pathway)
Note: If aPTT fails to normalize even after mixing patient's serum with a
normal serum, then circulating antibody against factor VIII is suspected.
Estimation of factor VIII level/ activity.
Treatment
1. Minor bleeding:
Desmopressin (stimulates release of any stored factor VIII)
Antifibrinolytic agents (prevent degradation of fibrin):
o Tranexamic acid
o Aminocaproic acid.
2. Major bleeding:
Fresh frozen plasma/ factor VIII concentrate.
von Wil ebrand's disease (vWD)
It is a bleeding disorder due to congenital deficiency of von Willebrand factor (vWF)
which plays an important role in:
1. Platelet aggregation and adhesion
2. Transportation of factor VIII.
Clinical features:
Bleeding manifestations:
1. Prolonged bleeding even after minor injury
Ex.: After dental extraction/ from wound site/ suture site, the bleeding refuses to
stop.
2. Spontaneous bleeding: Superficial/ deep.
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Investigations
1. Platelet count: Normal
2. BT:
3. CT: Normal
4. PT, INR, aPTT: Normal.
Note: In severe forms of vWD, aPTT may get prolonged due to reduced functional
activity of factor VIII.
5. Confirmation of diagnosis by detecting vWF level/ activity.
Treatment
1. Minor bleeding:
a. Desmopressin
b. Antifibrinolytic agents:
Tranexamic acid
Aminocaproic acid.
Coagulopathy due to chronic liver disease (CLD)
Etiology:
Decreased synthesis of clotting factors in chronic liver disease.
Clinical features:
1. Asymptomatic
2. Symptomatic: Bleeding manifestations: may be superficial/ deep.
Investigations
1. Platelet count: May be
2. BT: Normal/
3. CT:
4. PT, INR, aPTT:
Note: Usually PT and INR get prolonged before prolongation of aPTT as factor VII
has got a very short half-life.
5. Liver function test.
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Treatment
Treatment of coagulopathy due to CLD
Treatment of
Significant bleeding/ before
underlying liver
Vitamin K
invasive procedures
disease
Although doesn't have any role
Fresh frozen plasma
except in cholestatic liver
disease, is often used
Coagulopathy due to vitamin K deficiency
Cause:
Lack of carboxylation of vitamin K dependent factors (factor II, VII, IX, X).
Causes of vitamin K deficiency:
1. Decreased intake
2. Malabsorption
3. Cholestatic liver disease.
Clinical manifestations:
1. Asymptomatic
2. Symptomatic: Bleeding manifestations.
Investigations
Clotting profile:
BT: Normal
CT: Normal
PT, INR, aPTT:
Note: Often PT and INR only are prolonged as factor VII is the key factor of
extrinsic pathway.
Treatment
1. Vitamin K: Oral/IM
2. Treatment of the underlying disease.
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Miscellaneous topics
Multiple myeloma
Malignant transformation of those hematopoietic stem cells which eventually leads to
plasma cells.
Pathogenesis + Clinical features:
Plasma cell infiltration
Bone marrow
Bone
Normal Ig
Ig light chain
Hyperviscosity
failure (late
involvement
state
stage)
Recurrent
Headache,
Pancytopenia
Osteoclastic
Renal tubular
infections
dizziness, visual
and its
activity
damage
(Bacterial/ viral)
manifestations
manifestations
Bone pain
affecting long
Manifestations
Vertebral
Acute kidney
bones and
of Ca++
collapse
injury (AKI)
vertebrae
Compressive
Chronic kidney
myelopathy
disease (CKD)
Investigations
1. Blood:
CBC: Anemia (normochromic normocytic)
WBC and platelet count: Normal (may decrease in late stage due to bone
marrow infiltration and failure)
ESR: (due to rouleaux formation from hyperviscosity state)
2. Urea creatinine:
3. Globulin level:
4. Serum Ca++: when ALP level is typically normal.
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5. Serum protein electrophoresis:
Monoclonal spike (may be IgG/ IgA/ light chain)
6. Urine:
Proteinuria (Bence Jones protein: Ig light chain)
7. Urine electrophoresis:
Monoclonal spike
8. X-Ray:
Areas of osteolysis: `punched out lesions'.
Treatment
1. Supportive treatment:
a. Emergency treatment of hypercalcemia (IV fluid)
b. Treatment of CKD
c. Treatment of vertebral pain by radiotherapy.
2. Definitive treatment:
a. Chemotherapy: [Bortezomib + Dexamethasone + Lenalidomide]
b. Bisphosphonate
c. Bone marrow transplantation (in selected patients).
Myelodysplastic syndrome
It is a hematopoietic stem cell disorder characterized by combination of pancytopenia,
morphological abnormalities of blood cells and hypercellular marrow.
Clinical features:
1. Due to pancytopenia:
Features of anemia
Features of thrombocytopenia
Features of neutropenia.
2. Due to compensatory extramedullary hematopoiesis:
Splenomegaly ? Hepatomegaly.
Investigations
1. Blood:
Hb:
WBC count:
Platelet count:
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2. Peripheral film:
Regarding RBC: Reticulocyte count typically abnormally low (sometimes
absent) despite anemia
WBC: Hyposegmented neutrophils, typically bilobed nucleus, also called
"Pelger Huet abnormality".
Platelet: Very small (dwarf) megakaryocytes.
3. Bone marrow:
Hypercel ular marrow showing "Ring sideroblast".
Treatment
1. Supportive treatment:
a. Anemia:
RBC transfusion
Erythropoietin
Lenalidomide.
b. Neutropenia:
Treatment of infections
G-CSF.
c. Thrombocytopenia:
Platelet transfusion
Thrombocyte receptor agonist.
2. Definitive treatment:
a. Myelosuppressive agent:
Azacytidine.
b. Bone marrow transplantation.
Disseminated intravascular coagulation (DIC)
It is a thrombohemorrhagic disease characterized by spontaneous bleeding as well as
microvasculature thrombosis.
Triggering factors:
D. Severe tissue damage (Ex: Burn, head injury)
I. Infection (Septicemia)
C. Cancer (Acute promyelocytic leukemia)
O. Obstetric causes (Ex: IUFD/ Abruptio placentae).
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Pathogenesis:
Triggering factors
Release of tissue factors
Abnormal activation of coagulation pathway
Pro-thrombotic state
Widespread microvasculature thrombosis
(thrombus rich in platelet and fibrin)
Consumption of
Consumption of
Frictional damage
Ischemic damage
coagulation
platelets
to RBCs
factors
All these ultimately leads to consumptive coagulopathy.
Clinical features:
1. Features of the underlying disease
2. Patients with intravascular hemolysis are often asymptomatic
3. Ischemic injury to kidney: Acute kidney injury (AKI)
4. Due to consumptive coagulopathy:
Spontaneous bleeding, starts with superficial bleeding.
Ex: Oozing of blood from venipuncture surgical site.
Gum bleeding, epistaxis etc. may occur.
Investigations
1. Platelet: Mild
2. Hb, WBC: Variable (depending upon the underlying disease)
3. Peripheral film: Fragmented RBCs (Schistocytes)
4. Clotting profile: PT, INR, aPTT:
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5. D-Dimer test: Fibrin degradation product (FDP):
6. Serum fibrinogen: .
Treatment
1. Treatment of the underlying disease
2. Supportive:
Treat bleeding manifestations by Fresh frozen plasma
Low dose heparin.
Blood transfusion
Type of blood products:
Blood product
Indications
Packed cell/ packed RBC
Symptomatic anemia
(1 unit RBC increases Hb level by 1 gm% and hematocrit by 4%)
Platelet
Thrombocytopenia with significant bleeding/ before any invasive
procedure
Fresh frozen plasma
Coagulopathic bleeding
Complications of blood transfusion:
1. Immediate (within minutes to hours):
a. Hypersensitivity reaction:
Cause: Presence of antigen in donor plasma
Clinical feature: Urticaria (itch), rash, chill and rigor; lid swelling,
bronchospasm, hypotension in severe cases
Treatment:
Immediately stop the transfusion
Anti-allergic: IV Diphenhydramine
In severe cases: IV hydrocortisone/ IV adrenaline.
2. Early (within hours to days):
a. Hemolytic transfusion reaction:
Acute hemolytic episode precipitated by mismatch blood transfusion.
It is of 2 types:
I.
Early:
Within hours of transfusion
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Major hemolysis
Cause: ABO incompatibility.
II.
Late:
Occurs 4-5 days after transfusion
Minor hemolysis
Cause: Antigenic discrepancy (minor blood group
antigens), autoantibodies form in the intervening 4-5
days following transfusion before hemolysis starts.
Clinical features:
Major hemolysis
o Acute back pain
o General uneasiness
o Cardiovascular collapse
o Acute kidney injury
o DIC.
Minor hemolysis
o Mild jaundice
o Mild anemia.
Treatment:
Immediately stop transfusion
Send/ resend the bag of blood and patient's blood sample for
grouping and cross-matching.
Aggressive rehydration to prevent AKI.
b. Leukoagglutinin reaction:
Cause: Due to antigens on WBC of the donor blood to which the
recipient had already been sensitized during previous transfusion.
Clinical features:
Fever with chill and rigor occurs usually 10-12 hours after transfusion.
Treatment:
Immediately stop the transfusion
IV Diphenhydramine/ IV Hydrocortisone.
c. Transfusion related acute lung injury (TRALI):
ARDS precipitated by massive transfusion.
3. Late (within weeks to months):
Blood borne infections:
a. HIV
b. HBV
c. HCV.
This post was last modified on 01 September 2021