PATHOLOGY

Pathology 167

Chapter 1
BLOOD GROUPS AND THEIR IMPORTANCE
V Manu 1
1. The ABO Blood Group system
5. SUB GROUPS OF ABO SYSTEM
Carl Landsteiner first described the existence of Many variants of A group antigen occur. They termed
serological differences individuals, allowing him to

MEDICINE AND ALLIED

them as Al, A2, A3, A4, Ax, Ao, Am etc; out of
classify people into one of the four groups depending these, except for Al and A2, all are extremely rare. A
on whether their contained either A or B antigen, or group people mainly belong to A1 (80%). Similarly,
both or neither. in the AB group 80% belongs to Al B and 20% to
2. Red Cell Antigens A2B subgroups. The importance of these subgroups
Blood groups represent systems of antigenic lies in the fact that antigen A2 is a very weak one and
as such it may not be detected in cell grouping. In
determinants found on the surface of the red cells.
such a case the person may be wrongly grouped as O
These are genetically inherited. The major systems
are ABO and Rh which are independent of each in place of A1 and B in place of A2B. Serum
other. ABO is on Chromosome 9 and Rh on grouping would clear the doubt in such a situation, by
Chromosome 1. showing the presence or absence of naturally
occurring antibodies.
Blood groups are identified by means of specific
antibodies present in serum either “naturally” or after 6. THE RH BLOOD GROUP SYSTEM
immunization with red cells or soluble blood group There is another antigen called the Rh factor, which
substances. can be either present (+) or absent ( – ). In Rh
3. Antigens of ABO system negative persons, there is absence of innate Anti Rh
antibodies and they usually develops after a
In the ABO blood group system, three genes are mismatched transfusion or post partum in a Rh
involve A,B and H; giving rise to three basic antigens negative mother if the baby was Rh positive. Such
viz. A, B and H. The H gene forms the base and A or mothers are given Anti D immunoglobulin to prevent
B gene only act when it is present. In the process of development of anti Rh antibodies.
antigen formation, the H gene acts on a precursor
7. IMPORTANCE OF BLOOD GROUP
forming a substance suitable for A or B gene to act.
The gene action leads to antigen formation, the gene The following conditions require determination of
forming ‘H’ antigen is common to all red cells in the ABO blood group:
ABO blood group system. (In very rare cases the H
a) Blood transfusion :
gene may not occur. In such a situation no suitable
substance is formed for A or B genes to act, resulting For safe blood transfusion, the recipients and donors
in non-formation of A, B and H antigens. Such a blood group must be the same. If an A group
phenotype of blood in ABO system is called recipient is transfused with B group of blood the
‘Bombay blood group’. ( first reported in 1952 by naturally occurring anti-B antibodies in his plasma
Bhende et al) will react with the transfused red cells causing
clumping and later lysis. At the same time the B
4. Antibodies in ABO system group donor’s plasma has anti-A antibodies which
In the ABO blood group system, A, B and H antigens will react with the recipient’s A cells. Thus they are
are present on the surface of red cells and in the mutually incompatible and such a transfusion may
plasma, corresponding antibodies occur naturally. lead to a serious transfusion reaction.AB group
BLOOD ANTIGEN ON ANTIBODY IN
blood has no naturally occurring antibodies and
GROUP RBC PLASMA therefore used to be called the “Universal Recipient”
A group A and H antigens anti - B antibody on the assumption that donor cells regardless of the
B group B and H antigen anti-A antibody blood groups, will not be acted upon in the
AB group A, B and H antigens no antibodies recipient’s plasma. However, if the donor’s plasma
O group only H antigen anti-A, anti-B has a high titre of anti A or anti B antibodies they
antibodies may react with recipient’s cells. Hence, the
Bombay NIL anti A, B and H “Universal Recipient” or universal donor for ‘O
phenotype antibodies group’ is to be discouraged .Similarly, Rh negative
 168 Textbook of Family Medicine
blood is given to Rh-negative patients, and Rh
positive blood or Rh negative blood may be given to
Rh positive patients. All transfusions must be
grouped and cross matched.
1 b) Organ Transplantation
For the successful transplantation of any organ and
for the graft to ‘take’ the donor must be of the same
ABO blood group as the recipient to avoid rejection
of the transplant.
MEDICINE AND ALLIED
c) Haemolytic disease of the Newborn -
To rule out or establish any blood incompatibility
between the husband and wife and between the
mother and the foetus as the cause of the haemolytic
disease of the newbom. ABO blood grouping is
done as a routine procedure during the antenatal
period.
d) Clinical Medicine
Persons belonging to certain blood groups are
known to be more prone to certain diseases. For
example A group people are more susceptible to
develop gallstones, cirrhosis of the liver, salivary
gland tumours, carcinoma of the stomach, pancreas,
ovaries and pemicious anaemia. Similarly O group
non-secretors are more prone to develop duodenal
ulcer. It is thought that some genetic factors may be
involved in conferring either resistance or
susceptibility to disease, in relation with blood group
genes.
e) Forensic Medicine
Determination of blood groups is useful in
identification of suspects and victims from
bloodstains and also in settling cases of disputed
paternity.
f) Anthropological and Genetic Research
ABO blood groups play an important role in studies
in various racial and ethnic groups for
anthropological and genetic research.
g) Malignant Diseases
In these conditions there may be phenotypic changes
like loss or suppression of A, in leukemia or
acquisition of B like antigen .The prognosis of
certain cancers like those of the urinary bladder is
said to vary with the degree of expression of red cell
antigens in the malignant cells.
8. METHODS OF ABO BLOOD GROUPING
a) Principle:
The antigens on red cells are determined by using
highly potent anti-A and anti-B sera available
commercially. If the corresponding antigen is
present on the red cells, agglutination will occur
when cells in saline suspension are treated with anti
A/B sera. At the same time, the serum is also tested
to detect the presence of naturally occurring
antibodies by using known A, B and O cells.
Agglutination of the cells denotes the presence of
corresponding antibodies. The tests can be carried
out on porcelain tiles or in test tubes.
b) The tube technique has the following advantages:
(a) The test can be hastened by centrifugation.
(b) It detects weak reactions and thereby, weak
antigens
(c) Drying of the contents is eliminated.
(d) Weak tests can be confirmed by microscopy.
c) Possible causes of discrepancies between results of
cell and serum grouping
i. Patient recently transfused with ABO
incompatible blood
ii. Patient suffering from hypogammaglobinemia
iii. Puerperal mother’s sample mixed with blood of
an ABO incompatible foetus
iv. Subgroups of A or B
v. Cold antibodies
vi. Warm antibodies
vii. Poly agglutinable red cells
viii. Cancers and especially lymphomas/ leukemias.
ix. Patient sampling , labeling errors and clerical
errors
COMPATIBILITY TESTS
1. Compatibility tests are carried out on the donor’s
and the recipients’ blood to provide suitable blood
for transfusion to a patient. This is also called
Matching Test.
2. The stepwise tests necessary for a safe transfusion
are:
(a) Accurate ABO and Rh typing of both the donor
and recipient.
(b) Screening tests of the sera of both the patient
and donor for detection of any irregular
antibodies (This is possible in a pre-planned
case or in those cases showing incompatibility
in cross-matching tests).
(c) Cross matching tests.
The above tests comprise the compatibility tests. In
routine practice ABO grouping and Rh typing and
cross- matching tests are done.
3. Cross Matching Tests.
lt must be remembered that even by accurate
grouping of donor and recipient of ABO and Rh
antigens it is not necessarily true that they are fully
compatible for transfusion. There are other blood

groups and therefore incompatibility may arise due
to various other antigens/antibodies. So cross-
matching should always be done.
There are two types of cross-matching tests : Major
& Minor.
a) Major Matching
In this, donors’ red cells are tested against recipients
serum (DC + RS). Since in transfusion, the fate of
donor’s cells and their functional efficiency are of
prime importance for a safe and successful
transfusion, major matching must be done. This test
shows whether donor cells are acceptable to the
recipient or not.
This test further act as a check on routine ABO
grouping and helps also to detect any antibodies in
the recipient’s serum-natural or immune .Major
matching is the most important test in compatibility
determination.
b) Minor matching
ln this donors’ sera are tested with recipients’ cells
(DS+RC) to find out if donors’ sera contain any
antibody deleterious to recipients cells. Some people
feel that the minor matching test is unnecessary
because donor’s serum gets diluted in recipient’s
circulation and therefore the effect is negligible.
However few donor serums may contain a high titer
or potent antibody hence minor crossmatch is also
always advised.
c) The antibodies of all blood group systems are not
natural. They may be of immune types - either
complete or incomplete. Naturally occurring
antibodies are detected in saline at 37°C; where as
incomplete immune antibodies are detected in
albumin medium at 37°C and by enzyme treatment
of cells and AG Tests.
Therefore the following methods are adopted for
Cross matching tests
i. Tests of cells and sera in saline at room
temperature
ii. At 37°C in a water bath, in albumin at 37°C
iii. Indirect AntiGlobulin tests.
Pathology 169
3. Certain points to remember in Cross-matching
tests in special cases
a. In patients who had or require repeated
transfusion:
The temptation to obtain a large sample of serum 1
from a patient and to use it for cross matching for
transfusions on successive days should be avoided.
It should be remembered that each transfusion may
evoke antibody formation and therefore subsequent
MEDICINE AND ALLIED
transfusions may lead to. It is therefore a wise
practice to take blood frequently for cross matching
test and after every 24 hours. A good routine should
be –
i. Screen Pre-transfusion serum and all subsequent
serum samples with a pool of red cells
containing common red cell antigens.
ii. A direct AGT should be done on the pre-
transfusion red cell and on all subsequent
samples obtained from the patient. ,
iii. For Cross matching sera should be fresh.
b. Compatibility tests in new born infants
As a rule Donor red cells should be cross matched
against infants serum, but if there is difficulty in
obtaining infant’s serum or if infant has a Direct
AGT positive red cells, mother’s serum should be
used. Infant’s red cells should also be tested by
Direct AGT and when required serum should be
screened for irregular antibodies.
c. Compatibility tests in major Cardio-Pulmonary
Surgery
Here a large number of donors are required and all
donors/donor units of blood are to be matched
against the recipient’s blood. All donor sera should
be screened for immune antibodies against pooled O
group cells.
 170 Textbook of Family Medicine
Chapter 2
1 BLOOD TRANSFUSION REACTION
V Manu
1. Acute Reactions (occurs within 24 hrs of
MEDICINE AND ALLIED
transfusion, usually in minutes)
a) Acute Hemolytic Reactions
b) Sepsis/Bacterial Contamination
c) Transfusion-Related Acute Lung
Injury (TRALI)
d) Allergic (Severe) Anaphylactic or
Anaphylactoid Reactions
e) Transfusion-Associated Circulatory
Overload (TACO)
f) Febrile Nonhemolytic Reactions
g) Allergic (Mild) Reactions
2. Delayed Reactions ( occurs after 24 hrs,
usually after days)
a) Graft-vs-Host Disease (GVHD)
b) Delayed Hemolytic Reactions
c) Post transfusion Purpura (PTP)
3a) Acute haemolytic reactions
A major haemolytic reaction is almost always due to
the infusion of ABO incompatible blood.
These reactions are almost always due to clerical
error or to failure of adequate checking of patient
identification prior to transfusion.
Acute haemolytic reactions are generally
accompanied by an acute deterioration in the
patient’s condition, major feelings of apprehension,
rigors, chest pain, loin pain, abdominal pain,
dyspnoea, shock, hypotension, oliguria and at times
haemoglobinuria.
Table 1: Immediate action required
i. Stop transfusion
ii. Check patient identification
iii. Take down the blood pack and blood administration
set
iv. Replace with fresh administration set and keep line
open with saline
v. Report to medical officer or DMO
vi. Maintain airway
vii. Catheterise and measure hourly urine volume
viii. Notify duty staff in Blood Bank
ix. Follow reaction investigation protocol
x. Return blood bag to the Blood Bank.
xi. If further blood transfusion is required discuss with
duty medical officer & Blood Bank Officer
b) Febrile non-haemolytic transfusion reactions
Fever and rigors or shivering during transfusion may
suggest an acute haemolytic reaction but may also
result from leukocyte antibodies. However, when
this type of reaction is suspected:
i. Check blood group of unit is compatible with
patient
ii. Slow the transfusion and observe the patient
iii. Give antipyretic (e.g. paracetamol)
iv. Give antihistaminic and Hydrocortisone if
required
c) Allergic reactions
i. Most allergic reactions consist of urticaria and
itch occurring within minutes of starting the
transfusion and usually settle with an
antihistamine (e.g. chlorpheniramine 10-20mg
iv or Phenargan 25 mg iv/im).
ii. These reactions are more likely in multiple
transfused patients and result from infusion of
plasma proteins or allergens to which the patient
has preformed antibodies.
iii. The transfusion may be continued slowly if
there is no progression of symptoms after 30
minutes.
d) Severe anaphylaxis
This is a rare complication and occurs most
commonly with the administration of fresh
frozen plasma. The transfusion should be
stopped and supportive and anti-anaphylactic
measures applied.
e) Sepsis/bacterial contamination
Sepsis is the result of transfusion of bacterially
contaminated blood components. The bacteria
usually originate from the blood donor,
processing stage or storage. Components
especially platelets are more likely to be
contaminated.
f) Transfusion-Related Acute Lung Injury
(TRALI)
Defined as Acute respiratory distress or failure
(non-circulatory) during or within 6 hours after
transfusion; often dramatic onset. TRALI most
commonly results from the infusion of donor
antibodies directed against recipient HLA class
I or II antigens or neutrophil antigens.
g) Transfusion-Associated Circulatory Overload
(TACO)
 Pathology 171

TACO is a life-threatening condition due to
rapid increases in blood volume in patients with
compromised cardiac or pulmonary function
and/or in patients with chronic anemia and
expanded plasma volumes.
h) Post transfusion Purpura (PTP)
Thrombocytopenia occurs in a patient who has
made an antibody against a foreign platelet
antigen as a result of pregnancy or a previous
transfusion. Through a mechanism not clearly
(iii) Inform MOI/c or DMO and blood bank at
the earliest.
(iv) Make entry in case sheet & reaction form.
(v) Check & confirm patient identity, label and
date of expiry on bag & compatibility
report, if error noted inform blood bank
1
immediately to prevent further errors.
(vi) Blood bag along with the administration set
should be dispatched to blood bank at the
earliest (keep in fridge if dispatch is

MEDICINE AND ALLIED

elucidated, likely auto-immune, the patient’s delayed).
own antigen-negative platelets are also
(b) SAMPLE COLLECTION –
destroyed.
(i) Post transfusion venous blood sample is to
i) Pseudo reaction
be collected from a vein away from the one
This is not an actual reaction but slowing of in, which the transfusion is being given
flow and stasis commonly seen when (preferably from the other arm).
transfusing packed cells. Avoid cold
(ii) Ensure that there is no hemolysis while
blood/components, improper transfusion sets
drawing blood. Send relevant samples as
and filters and select a good vein with good
per protocols. Once transfusion reaction has
flow dynamics. Avoid panic and do not discard
occurred do not discard blood bag/s and
the blood or stop transfusion superfluously. If in
infusion sets under any condition. In case of
doubt consult senior staff or DMO.
any delay keep in fridge
4. Investigation Of Transfusion Reaction
(a) CHECK LIST
(c) TESTS (PROTOCOL)
(i) STOP TRANSFUSION IMMEDIATELY.
Urine (Pathology Lab)
(ii) RESUSTICATE PATIENT-
 Naked eye examination for evidence of
 Oxygen (100%) hemolysis.
 Inj Hydrocortisone 100 mg iv stat  Urine RE&ME for microscopic hematuria.
(repeat if indicated)
 Test for Hemosiderinuria.
 Inj Phenargan 25 mg im stat
 Life line with 0.9% saline(Using
venflow/wide bore needle)

(i) BLOOD (1ST SAMPLE IMMEDIATELY)

5 ml blood in 2ml blood in 2ml blood in Slide for Blood for culture
sterile bottle EDTA bottle EDTA bottle PBS in sterile bottle

BloodBank Haematology For evidence Aerobic/ Anaerobic

Lab of hemolysis

a)-Complete ABO Rh - Hb & PCV Microbiology Lab

Grouping with pre/ - Platelet count - Test of blood &
Post transfusion - Plasma Hb - Test of Administration
Sample & donor bag set for sterility
b)- DAT on patient and
donors blood
c)- Titre of Anti A &
Anti B if ‘O’ group
Blood is being
Transfused
 172 Textbook of Family Medicine

Do not discard blood bag/s and infusion sets under

any condition. If in doubt contact blood bank and
moi/c and confirm from oi/c blood bank disposal
instructions.
1
(ii) SECOND POST TRANSFUSION SAMPLE (24 hrs later)

BLOOD
MEDICINE AND ALLIED

Haematology Biochemistry 5ml in Citrate

2ml in EDTA bottle - Serum Bilurubin (1:9 Ratio)
- Hb - Serum Urea/Creatinine for
- Platelet count - Serum LDH levels Coagulation Profile
- PCV (If available) (If DIC or ongoing intravascular
hemolysis is suspected)
URINE ( Pathology Lab)
Second Sample (24 hrs later)
- RE
- ME
- Hemosiderinuria

(iii) THIRD POST TRANSFUSION SAMPLE (10th DAY AFTER REACTION)

BLOOD

2 ml blood in 2 ml blood in
sterile bottle to EDTA to
Blood Bank Haematology Lab
- DAT - Hb
- PCV
- Platelet count
 Pathology 173

Chapter 3
OVERVIEW OF ANEMIA
Vibha Dutta
1
Anaemia is not a disease but sign of disease. It occurs in The process of investigation of anaemia begins with
all age groups. Increasingly recognized as a cause of careful history taking and skillful clinical examination.

MEDICINE AND ALLIED

morbidity and mortality in critically ill patients. Today These processes are aimed at identifying possible clues
there is an ongoing hidden world wide epidemic of toward aetiology and estimate the severity of anaemia.
anaemia. One needs to understand the underlying cause The under mentioned history and points in clinical
of anaemia so that the treatment of anemia along with its examination shall be useful in fulfilling these objectives.
underlying cause – improves health care outcomes. Drugs: particularly NSAIDS, antiretroviral,
DEFINITION: Reduction below normal limits of total anticonvulsants
circulating red cell mass i.e. when haemoglobin level is
Past illnesses: particularly GI surgery, previous GI
below the lower extreme of normal range for age and sex
diagnosis/evaluations, malignancy, thyroid disease
of the individual. Misdiagnosis occurs when there is
failure to refer to normal range for age and sex of the Exposure to toxins: lead, benzene
individual. Family history: sickle cell anemia, hereditary
Normal Range: spherocytosis, thalassemia
Changes in menstrual pattern: menorrhagia, amenorrhea
Male Hb : 13.0-18.0 g/dl
Duration/speed of onset of symptoms: suggests whether
PCV (HCT) : 0.40-0.54 acute blood loss or chronic cause like nutritional
deficiency is cause.
Female Hb : 11.5- 16.5 g/dl
Fatigue, maelena, headache, anorexia, syncope, sleep
PCV : 0.37-0.47
disturbance, vertigo,decreased libido, tinnitus,
The values of Hb vary in infants & children., at birth - palpitations, dizziness, nausea, change in bowel
16.5 g/dl, 06 weeks-11g/dl, 01yr of age -12 and in habits,smooth, beefy tongue, cold sensitivity and
childhood-12 g/dL. At puberty- Adult value of respective exertional dyspnea occur in most patients.
sex occurs. The WHO defines anemia as Hb <13 g/dL in Clinical examination:
men and <12 g/dL in premenopausal, nonpregnant Pallor: What is the cause of this pallor?
women.
Constitutional
Clinical features are weakness, lassitude, easy
fatiguability, pallor, dyspnoea on exertion and Uremic
palpitations as main symptoms. Occasional patient may Anaemia
present with angina. The process of investigation of a
suspected case of anaemia involves following four steps: Tachycardia: in response to hypoxia of tissues
1. Initial work up to establish anaemia and identify Systolic ejection murmur: due to hyperdyanamic
clue to its severity and possible aetiology. circulation
2. Morphological sub typing of anaemia into Initial laboratory examination
a. Microcytic hypochromic anaemia Hb
b. Normocytic Normochromic anaemia RBC count
c. Macrocytic anaemia Hematocrit
3. Identifying the aetiology of anaemia e.g. iron Indices - MCV, MCH, MCHC
deficiency anaemia, haemolytic anaemia etc. PBS
4. Establishing the underlying disease Reticulocyte count
 174 Textbook of Family Medicine
Morphological sub typing of anaemia
Anaemia are morphologically divided into
Microcytic hypochromic anaemia
1 Normocytic Normochromic anaemia
Macrocytic anaemia
MCV and MCHC are the red cell indices used for this
categorization. In laboratories equipped with blood cell
counter former is preferred. Value below 80fl and above
MEDICINE AND ALLIED
100fl is considered to indicate microcytosis and
macrocytosis respectively. Hypochromasia virtually
always accompanies microcytosis. MCHC can be used
for separating hypochromic from normochromic anemia
and is useful for laboratories not equipped with a blood
cell counter as this can be more accurately assessed than
MCV.
This classification based on RBC indices is further
reaffirmed by peripheral blood examination. Size of
RBC smaller than a small lymphocyte is considered to
indicate microcytosis and increase in central pallor of
RBC greater than 1/3rd indicates hypochromasia.
This morphological typing of anaemia is useful to
narrow down the possible differential diagnosis and
restrict the ambit of subsequent investigation
Identifying the aetiology of anaemia
Each morphological type is associated with a set of
differential diagnosis. An algorithmic approach to
aetiological diagnosis is recommended.
Microcytic Hypochromic anaemia
The differential diagnoses to be considered in a case of
Microcytic hypochromic anaemia are as under
 Iron deficiency anaemia
 Thalassemia especially thalassemia trait since the
more profound forms will come to fore through
clinical and other hematological changes
 Anaemia of chronic disorder
 Rarely sideroblastic anaemia
The algorithmic approach to Microcytic hypochromic
anaemia involves MCV< 80fl as first step. Then
estimate serum ferritin. If ferritin is low it is Iron
Deficiency. If it is normal or high it could be anaemia of
chronic disease or Thalassemia trait. In iron deficiency
anaemia the serum iron levels are low with high total
iron bindimg capacity and low transferrin saturation. In
anaemia of chronic disease serum iron, TIBC and
transferring saturation are low.
Red cell indices on automated cell counters can help
distinguish iron deficiency anemia from thalassemia trait.
In Thalassemia trait the total RBC count ( t RBC ) rises
with the falling MCV, whereas in iron deficiency anemia
the total RBC count falls with decreasing MCV. Also in
iron deficiency there is anisocytosis and so the RDW CV
(red cell distribution with coefficient of variation ) is
high where as it is near normal in thalassemia trait. Thus
an MCV <78 fl with t RBC < 4.8 million/cumm and
RDW CV > 18% suggests iron deficiency and MCV <78
fl with t RBC > 4.8 million/cumm and RDW CV< 18%
suggests thalassemia trait. These cut offs have been
calculated for Indian ethnic group. A simple index
Mentzer index can also be used.
MCV / RBC(106) >14 suggestive of iron deficiency
MCV / RBC(106) 12-14 (indeterminate)
MCV / RBC(106) <14 suggestive of thalassemia
disorders
The diagnosis of thalssemia trait can be confirmed by
raised HbA2 levels >3.5% and Iron deficiency by low
ferritin or low transferrin saturation.
In iron deficiency anaemia (IDA) the peripheral smear
shows microcytic hypochromic red cells with pencil
cells, occasional target cells. Anisocytosis is a feature in
IDA. There is reactive thrombocytosia in IDA. In
thalassemia trait there is microcytic hypochromic change
without anisocytosis and target cells are more prominent.
In thalassemia major the diagnosis stares at the clinician.
The anaemia starts when the child is 6-7 months old
when there is a shut down of the synthesis of Hb F and as
there is a severe paucity of beta chain synthesis which is
required for the synthesis of the major adult haemoglobin
i.e Hb A. The child has severe anaemia, hemolytic facies
with frontal bossing and splenomegaly. The PBS shows
severe anisopoikilocytosis with microcytic hypochromic
change. The smear has numerous nucleated red cells and
basophilic stippling. The diagnosis is confirmed by very
high HbF levels and presence of trait in both parents.
Normocytic Normochromic Anemia: (MCV 80-100 fl)
The common causes for normocytic normochromic
anaemia are:
• Some Hemolytic Anaemias
• Anaemia of Chronic Disorders
• Anaemia of chronic Liver disease
• Anaemia of Chronic renal failure
• Aplastic Anaemia
• Anaemia accompanying Myelodysplastic syndrome
and myeloproliferative disorders
The algorithmic approach to Normocytic Normochromic
anaemia is as follows. Do a reticulocyte count. If it is
raised ( >2%) then it is either a post haemorrhage case or
a haemolytic anaemia. Estimate LDH levels. If they are
increased it is a haemolytic anaemia and if normal it is
posthaemorrhagic. Unconjugated hyperbilirubinaemia,

increased urinary urobilinogen and normal levels of AST
and ALT confirm haemolytic anaemia. After assessment
of the red cell morphology on peripheral smear further
workup for cause of anaemia should be done. If there is
normocytic normochromic anaemia with polychromasia
and schistocytes (fragmented red cells) then patient has a
micro angiopathic hemolysis. If sperocytes are seen then
hereditary spherocytosis or autoimmune anaemia is
likely. If non spherocytic, non schistocytic hemolysis is
present then enzyme deficiencies or sickle cell disease
are the likely cause.
If the smear shows normocytic normochromic anaemia
without polychromasia and poikilocytosis then anaemia
of chronic disease (ACD), chronic renal failure, aplastic
anaemia and chronic liver disease are the likely cause.
Infection, malignancy chronic inflammatory diseases,
and CRF should be looked for. A BM Biopsy for is
required to diagnose aplastic anaemia as cellurarity is
reduced.
The Macrocytic anaemias are those which have MCV of
> 100fl. The common causes are:
• Megaloblastic Anemia
• Myeloproliferative disorders
• Myelodysplastic syndrome
• Hypothyroidism
• Scurvy
• Chronic Liver Disease
• Extreme polychromatophilia following an acute
haemolytic crisis
In patient with Macrocytic Anaemias (>100fl) the first
test is to do reticulocyte count. If it is raised it is either
haemolytic anaemia or a post haemorrhagic case.
Workup for cause is already discussed earlier with
normocytic normochromic anaemia with increased retic
count.
Pathology 175
In macrocytic anaemias with normal retic count, if the
peripheral smear shows macrocytes, macroovalocytes,
poikilocytosis, and presence of hypersegmented
neutrophils the likely diagnosis is megaloblastic
anaemia. The diagnosis can be confirmed by a bone
marrow examination which shows megaloblastic 1
erythroid hyperplasia with giant metamyelocytes. Other
approach is to give a therapeutic trial of inj B12 and folic
acid as their deficiency causes this anaemia. If there is a
rise in reticulocyte count on day 5 to day 8 of therapy
then the diagnosis can be confirmed and treatment
MEDICINE AND ALLIED
continued. Also the serum levels of B12 and folic acid
can be done to confirm diagnosis but they are expensive
tests and not available in routine laboratories.
If the peripheral smear shows only macrocytes without
features of megaloblastic anaemia described above then
the likely causes are hypothyroidism, liver disease,
myeloproliferative neolplasms, myepodysplastic
syndrome and scury. Appropriate investigations to
diagnose these conditions are required.
Conclusion
Anaemia is a common clinical sign signifying presence
of an underlying disease. A four step process is
recommended to scientifically approach the anemia to
diagnose the immediate etiology and the underlying
cause. The approach economizes on use of laboratory
and prevents errors.
 176 Textbook of Family Medicine
Chapter 4
MANAGEMENT OF ANEMIA
1 A K Tripathi,
IRON DEFICIENCY ANEMIA (IDA)
MEDICINE AND ALLIED
Table 1: Causes of iron deficiency anemia
1. Blood loss
a. Acute blood loss: accident and surgery
b. Chronic blood loss: gastritis, peptic ulcer,
hookworm infestation, hemorrhoids, and
menstrual loss
2. Increased demand
Infancy, adolescence, and pregnancy
3. Malabsorption
Post-gastrectomy, sprue, and Crohn’s disease
4. Inadequate diet
Clinical Features
Besides having general symptoms of anemia, patients
with IDA may specifically have pagophagia, i.e. craving
for ice. Additionally patient may complain of dysphagia
due to formation of post cricoid web (Plummer Vinson
or Patterson Kelly syndrome). Plummer Vinson or
Patterson Kelly syndrome includes;
• Iron deficiency anemia
• Angular stomatitis
• Glossitis
• Dysphagia
Post cricoid web is a premalignant lesion and there is an
increased risk of oral sqamouus cell cancer and
oesophageal cancer at post cricoids tissue web.
Other clinical findings include cheilosis and spoon-
shaped nails (koilonychia). Mild splenomegaly can
occur in iron deficiency anemia, although it is
uncommon.
Treatment
Oral Iron Therapy
The drug of choice is ferrous sulfate 200 mg thrice a day
(elemental iron 60 mg thrice a day) orally taken in
between meals. About 15-20 percent patients may
develop intolerance to oral iron in the form of abdominal
pain, nausea, vomiting, diarrhea or constipation. In such
cases, the dose may be reduced or the salt is changed to
ferrous gluconate, ferrous fumarate, sodium ironeditate
or carbonyl iron. The treatment with oral iron is usually
given for a long duration and is sustained for 6-12
S K Sharma
months even after normalization of hemoglobin.avoid
giving antacids concomitantly.
Parenteral Iron Therapy
Intravenous iron therapy is indicated in following
conditions;
a) Patient is unable to tolerate oral iron
b) Patient has malabsorption
c) The needs for iron are relatively acute as in
pregnancy or following bleed
Previously used iron compound, iron dextran has
been associated with the risk of anaphylaxis which is
almost never seen with newer preparations like
sodium ferric gluconate and iron sucrose.
Total dose iron/ (TDI) in mg.=(15-Hb of patient) *
body weight in kg *3.this can be given as slow
intravenous infusion over 8-10 hours.
Red Blood Cell Transfusion
Red cell transfusion is indicated in patients with severe
anemia where cardiorespiratory conditions warrant
immediate intervention. In these situations, whole blood
must be avoided since it may cause volume overload.
Whole blood is needed if there is continued and
excessive blood loss.
MEGALOBLASTIC ANEMIA
In tropical countries, megaloblastic anemia occurs
mostly due to folic acid deficiency because of
malnutrition and during pregnancy.
Causes of cobalamin and folic acid deficiency
Table 2: Causes of cobalamin deficiency
1. Decreased intake: vegans
2. Decreased absorption:
a. Intrinsic factor deficiency: pernicious anemia
and postgastrectomy
b. Diseases of terminal ilium: sprue, Crohn’s
disease, and intestinal resection
c. Bacterial proliferation
d. Fish tapeworm (Diphyllobothrium latum)
infestation

Table 3: Causes of folic acid deficiency
1. Decreased intake: unbalanced diet and alcoholism
2. Increased demand: pregnancy, infancy, and
hemolysis
3. Decreased absorption: sprue, and celiac disease
4. Drugs: phenytoin, methotrexate, pyremethamine,
and trimethoprim
Clinical Manifestations
The clinical manifestations are mainly due to the
involvement of hematological, gastrointestinal and
nervous systems. Patients are anemic and they may also
have mild jaundice due to raised plasma unconjugated
bilirubin. Purpura may rarely occur due to
thrombocytopenia. Spleen may be enlarged. Anorexia,
weight loss, diarrhea, and smooth and beefy red tongue
are important and significant gastrointestinal
manifestations. Neurological manifestations such as
paresthesia, ataxia, sensory-motor paraparesis (subacute
combined degeneration), forgetfulness, psychosis are
found only in cobalamin deficiency and may occur even
in the absence of anemia.
Treatment
Packed red cell transfusion is needed in case of severe
anemia with cardiac symptoms. In addition, treatment is
directed against the cause of the disease like antibiotics
for bacterial overgrowth in the intestine.
Cobalamin deficiency: Parenteral therapy with intra-
muscular cyanocobalamin is preferred since deficiency is
mostly due to malabsorption. The treatment begins with
a dose of 1000 µg (1 mg) per week for 8 weeks followed
by 1000 µg each month. The treatment is life long in
case of pernicious anemia.
Folate deficiency: The usual dose of folic acid is 1 mg
per day orally. However, higher dosage upto 5 mg daily
may be needed in cases of malabsorption. Folinic acid is
used in methotrexate-induced anemia.
APLASTIC ANEMIA
Aplastic anemia is characterized by pancytopenia
(anemia, leukopenia and thrombocytopenia) and
hypocellular bone marrow. In the majority of patients,
the cause is not discernible (idiopathic) while the major
known causes are drugs, radiation and viral infections .
Pathogenesis
The pathogenesis of bone marrow aplasia is generally
believed to be immune mediated. However, some genetic
factors may predispose the individual to develop an
abnormal T cell immune response to exogenous stimuli
(drugs, viruses) and subsequent marrow failure.
Pathology 177
Table 4: Types of aplastic anemia
a. Idiopathic
b. Secondary
Drugs: chloramphenicol, sulphonamides,
indomethacin, gold, cytotoxic drugs, and
anticonvulsants.
1
Radiation
Chemicals: DDT and benzene
Viruses: hepatitis viruses, parvovirus, HIV-1,
Epstein-Barr virus
MEDICINE AND ALLIED
Pregnancy
Paroxysmal nocturnal hemoglobinuria (PNH)
c. Inherited
Fanconi’s anemia
Clinical Features
The common presentations are bleeding and symptoms
of anemia. The excessive tendency to bleed is due to
thrombocytopenia which may present as easy bruising,
epistaxis, gum bleeding, heavy menstrual flow and
petechiae (small pinpoint hemorrhage in skin and
mucous membrane). Intracranial and retinal hemorrhages
may also occur. Neutropenia may predispose patients to
develop infections. Lymphadenopathy and splenomegaly
are absent.
Investigations
a. Peripheral blood smear shows normocytic or
macrocytic anemia, decreased granulocyte and
platelet count. Immature cells are absent.
Reticulocytes are absent or few.
b. The diagnosis is confirmed by the bone marrow
aspiration and biopsy.
c. Other investigations include viral markers,
chromosomal studies, and tests for paroxysmal
nocturnal hemoglobinuria (PNH). Chromosomal
studies are done in children and younger adults to
rule out inherited disorders like Fanconi’s anemia.
Treatment
Bone marrow transplantation: Allogeneic bone marrow
transplantation (BMT) from HLA matched siblings is
curative and the preferred mode of therapy in young
patients (<40 years). However, this is limited by the high
cost, non-availability of matched donors and the
significant morbidity and mortality. Moreover, this
facility is available only at a few centers.
Immunosuppressive therapy: Immunosuppressive agents
such as anti-thymocyte globulin (ATG) or anti-
lymphocyte globulin (ALG) along with cyclosporine is
the treatment of choice for patients who cannot be given
BMT.
Other drugs: The role of anabolic steroids is not clear,
though some patients may respond to them.
 178 Textbook of Family Medicine
Supportive therapy:
a) Severe anemia is managed with packed red cell
transfusion.
1 b) Platelet concentrates are used to maintain platelet
count at or more than 10,000/ µL. Aspirin and
NSAIDs which inhibit platelet function should be
avoided.
c) Infections should be aggressively dealt with
broad-spectrum antibiotics and anti-fungal agents.
MEDICINE AND ALLIED
Granulocyte transfusion has also been used in
overwhelming infections. Aseptic precautions
must be observed to prevent infections.
HEMOLYTIC ANEMIA
The average life span of RBC is 90-120 days and around
1 percent of RBCs are destroyed in the spleen and
replaced by the bone marrow every day. Hemolytic
anemia results due to increased premature destruction of
RBCs if the bone marrow is not able to replenish them
adequately.
Hemolysis may be extravascular or less commonly
intravascular. The hemoglobin, released following RBC
breakdown is immediately bound to a plasma protein,
haptoglobin. The hemoglobin also binds with albumin to
form methemalbumin. In case of severe hemolysis the
haptoglobin binding capacity of plasma is exceeded.
Hence, free hemoglobin passes through renal glomeruli
and is converted to ferritin and hemosiderin in proximal
tubules and passed in the urine (hemosiderinuria). Excess
hemoglobin that is not absorbed by proximal tubules is
passed as such in the urine (hemoglobinuria).
Unconjugated bilirubin is raised due to increased
hemolysis (prehepatic or hemolytic jaundice).
Table 5: Findings suggestive of hemolysis
Increased RBC destruction:
a. High serum indirect bilirubin
b. Low serum haptoglobin
c.
d.
High serum LDH
Hemoglobinuria and hemosiderinuria
(in intravascular hemolysis)
e. Decreased RBC life span
Increased RBC production:
a. High reticulocyte count
b. Nucleated RBCs in peripheral smear
c. Erythroid hyperplasia in bone marrow
Hemolytic anemia can be acquired or hereditary.
Hemolysis can occur due to defects in the RBC
(intracorpuscular or intrinsic defects) or due to causes
other than in RBC (extracorpuscular or extrinsic defects).
Tbale 6: Classification of hemolytic anemias
Congenital (intrinsic)
1. Membrane defects: hereditary spherocytosis and
hereditary elliptocytosis
2. Hemoglobinopathies:
a. Abnormal chain synthesis; thalassemia
b. Amino acid substitution: sickle cell disease
(Hb S), HbC, HbD
3. Enzyme defects: Glucose-6-phosphate
dehydrogenase and pyruvate kinase deficiency
Acquired (extrinsic)
1. Immune: Autoimmune hemolytic anemia (AIHA)
2. Non-immune:
a. Mechanical: Disseminated intravascular
coagulation (DIC), toxemia of pregnancy, and
artificial heart valve
b. Malarial and clostridium infections
c. PNH (intrinsic)*
 Pathology 179

Chapter 5
PLATELETS: THROMBOCYTOPENIA
Vibha Dutta
1
Platelets are formed by megakaryocytes in the bone Bleeding Time (BT) is prolonged when platelet counts is
marrow. They are the most conspicuous and largest cell ≤ 75,000/mL. Prolonged BT with normal platelet count
of the bone marrow and generate their progeny by indicates qualitative disorder. In disorders of secondary

MEDICINE AND ALLIED

cytoplasmic fragmentation. The sites of hemostasis BT is normal.
thrombocytopoiesis are Bone marrow - 90%
Diseases of platetets can be due to decreased count due
Extramedullary sites (spleen and lungs) – 10%. Platelets to either decreased production, increased destruction,
are fragments of membrane bound cytoplasm and are abnormal distribution/pooling, or artifactual or due to
without a nucleus. The size is 2-3µm and they ppear hereditary or acquired platelet function disorders.
grayish blue with purple red granules on giemsa stain.
Normal function of platelets: Platelets ordinarily CAUSES OF THROMBOCYTOPENIA
circulate in the bloodstream in a quiescent state but 1. DECREASED PRODUCTION
undergo activation following damage to the vessel wall,
leading to the rapid formation of a platelet aggregate or  Hypoplasia of megakaryocytes
vascular plug and occlusion of the site of damage. The  Intrauterine drugs & infection
more rapid that vascular plug formation occurs, the lower  Radiation, chemicals, alcohol, idiopathic
the amount of blood that is lost. To facilitate a rapid  Ineffective thrombopoiesis
response, platelets are enriched in signalling proteins and  B12 & folic acid def
surface receptors, and activation is associated with the  Stem cell disorders
generation of the positive feedback or mediators ADP  May Hegglin, Wiskott Aldrich synd
and thromboxane (Tx)A 2 , and release of the adhesion  Hereditary thrombocytopenias
proteins fibrinogen and von Willebrand factor (VWF),
which support aggregate formation and the generation of 2. INCREASED DESTRUCTION
thrombin through the coagulation cascade. The
By immunologic process
importance of platelets in haemostasis is illustrated by
the excessive bleeding associated with defects in platelet  Autoimmune
function or platelet number. On the other hand, the  ITP
activation of platelets in diseased blood vessels (e.g. at  Pregnancy
sites of plaque rupture) can lead to arterial thrombotic  Drugs
disorders such as stroke and myocardial infarction, two  Lymphoproliferative dis
of the major disorders due to hyperaggregation .  Collagen vascular dis
 Alloimmune
Tests for Platelets: Platelet Count, Peripheral smear,
 Neonatal
Bleeding time (BT), Platelet aggregation Study, in vitro
 Post-transfusion purpura
platelet function analyzer 100
Increased consumption
 Peripheral Blood smear
 DIC
Finger prick – clumps + 5-10 indl platelets/OIF
 TTP
EDTA blood – 10-20 individual platelets/OIF
 HUS
Normal platelet count : 1.5 - 3.5 lakh/µl  Prosthesis

Role of Peripheral Blood smear (PBS) - careful 3. ABNORMAL DISTRIBUTION

examination for size ( ≥4µm macrothrombocytes), and  Splenomegaly caused by congestive, neoplastic
granularity (Gray platelet syndrome). Rule out spurious or infiltrative causes
thrombocytopenia. Giant platelets are often seen in ITP,  Hypothermia
Bernard-Soulier syndrome. PBS examination is essential  Dilution of platelets after massive transfusion
to exclude TTP. 4. ARTIFACTUAL
 Giant platelets
 Platelet satellism
 Pseudothrombocytopenia
 180 Textbook of Family Medicine
The figure 1 shows giant platelets and satelletism of
platelets
1 excessive bruising, and seek medical attention. ITP is
MEDICINE AND ALLIED
The commonest disease associated with reduced platelet
count is immune destruction of platelets in the
reticuloendothelial tissues. Primary immune
thrombocytopenia (ITP), previously called idiopathic
thrombocytopenic purpura, is an autoimmune bleeding
disorder that affects both children and adults. Until fairly
recently, it was considered an autoantibody disorder in
which platelets, opsonized with antiplatelet antibody,
were removed prematurely by the reticuloendothelial
system Many patients have no clinical problems but
bleeding may occur. ITP is unpredictable in its clinical
course. To date, treatment has aimed at reducing the
platelet destruction, mainly through immunosuppression.
However, new thrombopoietin receptor agonists have
been developed that enhance bone marrow platelet
production. These newer targeted treatments are likely to
be associated with less toxicity due to
mmunosuppression than traditional therapies
Clinical features: The two principal forms of ITP,
paediatric and adult, are quite distinct in their underlying
cause and presentation, In children, ITP may follow a
viral illness or immunization. The profound
thrombocytopenia may be associated with extensive
petechiae, purpura and bruises. There may also be
bleeding from mucous membranes such as the nose or
mouth. Despite the severity of the clinical features, most
children need little treatment, and undergo spontaneous
remission in the majority of cases. Around 15% will
develop a more chronic form of the disease. ITP in adults
is much more insidious. There is generally no prodromal
illness and the patient may be aware of petechiae or
often diagnosed by chance, for example during hospital
admission for surgery or complete blood count (CBC) is
checked for other reasons. This is particularly true if the
platelet count is not very low and there are no skin
manifestations of thrombocytopenia
The autoantibodies involved in ITP are generally IgG,
but IgA and IgM autoantibodies have been reported.
Opsonized platelets are removed prematurely by the
reticuloendothelial system via an Fc - dependent
mechanism. In addition, the autoantibodies may impair
megakaryocyte growth and development, platelet release
and may also induce apoptosis of megakaryocytes. The
overall result of this is failure of platelet production. For
the majority of patients, ITP is a fairly minor disorder.
Serious bleeding is not common and clinical sequelae of
the disease are generally absent in patients with platelet
counts above 30000/ cumL. Despite significant advances
in our understanding of ITP, the diagnosis remains one
of exclusion in both paediatric and adult ITP. A thorough
history should be obtained, looking for diseases that
might cause thrombocytopenia. The patient should be
asked about bleeding during previous surgery or
dentistry. The sites of bleeding should be determined. In
children, the possibility of child abuse should be
considered, although abused children will not generally
have petechial haemorrhages or purpura, though they
may have bruising.
Basic evaluation of ITP
Patient history
Family history
Physical examination
Full blood count
Peripheral blood film
Blood group (Rh) and reticulocyte count
Direct antiglobulin test
Quantitative immunoglobulin measurement
Bone marrow examination *
Tests that may be useful in selected cases
Antiphospholipid antibody (including anticardiolipin and
lupus anticoagulant)
Antithyroid antibody and thyroid function
Pregnancy test
Antinuclear antibodies
Viral PCR for parvovirus and cytomegalovirus
Bone marrow examination : is one of the mainstays of
diagnosis was of ITP. The rationale behind this was the
possibility of a patient having a marrow disorder such as
leukaemia, lymphoma or infiltration. It was believed that
detection of these by performing a bone marrow aspirate

and trephine biopsy would aid diagnosis and
management. The bone marrow in these patients shows
normal erythroid and myeloid precursors and an increase
in number of megakaryocytes. However, studies to date
have
shown quite clearly that in patients with isolated
thrombocytopenia, and with no atypical symptoms or
signs, no cases of bone marrow pathology were detected.
For this reason, recent guidelines do not recommend
performing a bone marrow examination in such
individuals. If patients fail to respond to, or relapse
following, first - line treatment, then a bone marrow
examination should be carried out. Similarly, if there is
any hepatomegaly, splenomegaly, lymphadenopathy or
any clinical or laboratory feature suggesting the presence
of a disease other than ITP, a bone marrow examination
should be performed. Bone marrow examination should
also be performed if the patient is above the age of 60
years, since myelodysplasia becomes more likely, and
myelodysplastic syndrome may resemble ITP. Finally, a
bone marrow examination should possibly be carried out
if splenectomy is being contemplated.
Treatment The majority of children require no medical
treatment, and can be managed using a ‘ watch - and -
wait ’ policy. In children with severe bleeding symptoms
treatment should be given. It should also be considered
in children with moderate bleeding or those at increased
risk of bleeding If treatment is deemed to be required,
options include IVIg, anti - D and corticosteroids. The
other drugs used in adult ITP are not suitable for
childhood disease due to their toxicities and long – term
sequelae. IVIg raises the platelet count in more than 80%
of children and does so more rapidly than steroids or no
therapy. Transient side - effects are seen in 75% of
children. Intravenous anti – D immunoglobulin can be
given to Rh(D) - positive children as a short infusion and
is useful in the outpatient setting. Mild extravascular
haemolysis is common, with a mean drop in
haemoglobin of 1 g/dL. Like IVIg, anti - D is a pooled
blood product but it is derived from a smaller donor pool.
The safety profile of anti - D is good with no reported
transmission of infection to date. However, there have
been reports of severe intravascular haemolysis leading
to disseminated intravascular coagulation, most of which
have been fatal. Prednisolone at a dose of 1 – 2 mg/ kg
daily for a maximum of 14 days is effective in around
75% of children within 72 hours. More prolonged high -
dose corticosteroid regimens are associated with
increased toxicity. There are data to suggest that higher
doses of prednisolone (4 mg/kg) for shorter courses may
be more effective and associated with fewer side –
effects.
Pathology 181
ITP in pregnancy
Thrombocytopenia occurs in 5% of pregnancies, but
most of these cases are gestational rather than immune -
mediated. The diagnosis of ITP involves the exclusion of
other causes of thrombocytopenia during pregnancy.
Patient history, physical examination, blood count and
1
blood film examination are used as in non - pregnant
patients. The work - up of a pregnant patient with ITP is
essentially the same as that of a non – pregnant patient.
There are some conditions specific to pregnancy and
MEDICINE AND ALLIED
these should be considered when investigating a pregnant
patient with thrombocytopenia
Laboratory Investigation of ITP in pregnancy
ITP in pregnancy, as with other types of ITP, is a
diagnosis of exclusion. All investigations carried out in
pregnancy are aimed at excluding conditions that may
result in thrombocytopenia. Some disorders such as
thrombotic thrombocytopenic purpura and HELLP
syndromes require urgent diagnosis and treatment since
the mortality rates are high.
Management of ITP in pregnancy
There should be close collaboration between the
obstetrician, haematologist, obstetric anaesthetist and
neonatologist. Treatment is largely based on the risk of
maternal haemorrhage. Throughout the first two
trimesters, treatment is initiated when the patient is
symptomatic and/or when platelet counts fall below 20
000/cumL, or when it is necessary to produce an increase
in platelet count to a level considered safe for procedures
such as obstetric delivery or epidural anaesthesia.
Patients with platelet counts of 20 – 30 000/cumL or
more do not require routine treatment. Delivery: A
platelet count above 50 000/cumL is generally acceptable
for standard vaginal or Caesarean delivery and for
epidural anaesthesia.
Management of the neonate (of mothers with ITP )
ITP in the neonate (from mothers with ITP) accounts for
3% of all cases of thrombocytopenia at delivery. The
fetal or neonatal platelet count cannot be reliably
predicted from the maternal platelet count. After
delivery, a cord blood platelet count should be
determined in all cases. Intramuscular injections (such as
vitamin K) in the fetus should be avoided until the
platelet count is known. Those infants with subnormal
counts should be observed clinically and
haematologically as the platelet count tends to fall
further to a nadir between days 2 and 5 after birth.
 182 Textbook of Family Medicine

Rare causes of thrombocytopenia and their features  Type II HIT:

are given in the following paragraphs. Platelet factor 4 binds tightly to heparin
Antibodies are formed against this complex
Drug induced thrombocytopenia: Immune mediated
platelet damage The complex binds to FcR and cause platelet
1  unexpected, isolated thrombocytopenia
activation and its accelerated clearance
Clinical Features
 recovery is within 5-7 days after drug is
withdrawn  Type II HIT is mild and transient
 Mechanism - drug-dependent antibodies against  Type II HIT occurs 5-12 days after starting the
platelet neo-epitopes therapy (<50% of pre-heparin values).
 Laboratory tests - drug-dependent antibodies
MEDICINE AND ALLIED

assays  Thrombosis occurs because of platelet

 Drugs are: quinidine, quinine, rifampicin, and activation
Septran  Frequency is decreasing with shorter durations
of treatment and increased use of LMW
heparins
Thombocytopenia:TTP-HUS Hereditary Thrombocytopenias
TTP (Thrombotic thrombocytopenic purpura)  Autosomal dominant
 The sporadic - antibody or toxin inhibiting the May-Hegglin anomaly
activity of ADAMTS13. Type 2b vWD
 The chronic, recurrent form - congenital  X-Linked
deficiency of the enzyme Wiskot-Aldrich
 Autosomal recessive
HUS (Hemolytic uremic syndrome)
Bernard-Soulier
 Predominantly affects children aged 4-12
months To conclude platelets are fragments of cytoplasm having
 Shigella-like toxins cause many cases of HUS few organelles and granules. They are forerunners in
 Diarrhea and abdominal cramps maintaining hemostasis after injury. Both qualitative &
Heparin-induced thrombocytopenia quantitative deficiency produces bleeding disorder which
can be diagnosed by simple lab tests.
Mechanism:
 Type I HIT:
Heparin binds to Platelets
 Pathology 183

Chapter 6
BLEEDING DISORDERS
Jyoti Kotwal 1
Definition: Spontaneous excessive multiple site bleeding Acquired antibodies Antibodies to V,VIII, XIII,
is considered as a probable bleeding disorder accclerated clearance of Ab-

MEDICINE AND ALLIED

To understand bleeding disorders we need to recapitulate factor complexes
what are the components of normal haemostasis as any DIC Acute : sepsis, malignancies,
perturbance in them would cause bleeding. trauma, Obs complications
Chronic : malignancies giant
Components/factors of haemostasis hemangiomas, missed
Platelet abortions
Vascular Drugs Antiplatelet, anticoagulants,
Coagulation (coagulation inhibitors/ antithrombin, thrombolytic,
fibrinolysis) myelosuppressive,
hepatotoxic, nephrotoxic
Clinical approach to a patient with bleeding should Vascular purpura, steroids, vit C def,
address the following questions child abuse, thromboembolic
1. Is the bleeding significant ? phenomena
2. Local Vs Systemic ?
3. Platelet Vs Coagulation disorder ? Inherited/congenital disorders of hemostasis
4. Inherited Vs Acquired • Factor deficiency - VIII,IX, II,V, VII,X,XI,XIII,
vWD
Laboratory Approach works at: • Platelet disorders -Glanzmann , Bernard -Soulier,
granule disorders
1. Demonstration of the defect • Fibrinolytic disorders - α - antiplasmin def, PAI-1
2. Identification of the defect(s) def
3. Assessment of severity • Vascular - Haemorrhagic Telangiectasia
4. Consequential studies eg. carrier detection • Connective tissue - Ehler Danlos syndrome
5. Monitoring of treatment Acquired
• Thrombocytopenias
Table 1: Causes of Bleeding
Acquired • Liver disease
Thrombocytopenias Auto,alloimmune, Drug • Renal failure
induced, hypersplenism, • Vit K deficiency
hypoplastic • Hematological disorders
Liver disease • Acquired antibodies to Coag factors
Cirrhosis, liver failure • DIC
Renal failure • Drugs
Vit K deficiency Malabsorption syndromes, • Vascular
malnutrition, long antibiotic Inherited/congenital
therapy, Hemorrhagic disease
of new born • Factor deficiency
• Platelet disorders
Hematological disorders • Fibrinolytic disorders
Leukemia, MDS, Ess. • Vascular
thrombocythemias, • Connective tissue disorders
Monoclonal gammopathies
 184 Textbook of Family Medicine

Evaluation of bleeding disorders • Laboratory evaluation

• History - Screening tests
- Age at onset • PT( Prothrombin time)
- Sex of the individual
1 - Family history
• PTTK(aPTT)- partial thromboplastin
time with kaolin ( activated partial
- Drug intake ( history of intake of NSAIDS is thromboplastin time)
important cause as they effect platelet function) • Platelet count
- Acquired causes Bleeding time ( by temlate method and
not finger prick)
MEDICINE AND ALLIED

Table 2: Various features of history to distinguish the

types and causes of bleeding Confirmatory tests
Vessel wall Platelets Coagulation
Table 4: Common tests for hemostasis
Bleed Localized Generalized Generalized
Test Normal range
Duration If Since birth( If Since birth If Recent onset
cong) (cong (acquired)
Platelet count 150-450x103/ml
IF Recent disorder) PT 13-17 sec
onset If Recent
(steroids, onset PTTK / aPTT 25-36 sec
scurvy, ITP vs Other Bleeding time (template) 3-9 min
autuimmune causes
Ds) TT 15-18 sec
Specific Associated Drug Umbilical cord Plasma Fibrinogen 150-350 mg/dL
history autoimmune ingestion stump bleed F XIII
FDP levels 0-5 mg/ml
H/o viral Delayed wound
illness healing F I
Pptd by Spontaneous, Stress Collection of blood sample
antiplatelet induced
drugs 1. Minimum circulatory stasis
2. Clean venous puncture
• Clinical examination 3. Proper anticoagulant
– Type of bleed
4. Proportion of blood to anticoagulant
– Sites involved
– Evidence of pre existing illness 5. Separation of plasma and storage
6. Effect of stress, pregnancy, drugs
Table 3: Table shows how to distinguish between types 7. Effect of PCV on the proportion of plasma to
of bleeding disorders on clinical features anticoagulant
Findings Coagulation Platelets / 8. Anticoagulant is 3.8% Sodium citrate. Blood is
vascular added in ratio 1: 9 (one part anticoagulant and 9
Petechiae Rare Characteristic parts blood)

Ecchymoses Large & single Small &

multiple
Deep hematomas Characteristic Rare
Hemarthrosis Characteristic Rare
Delayed bleed Common Rare
Superficial Minimal Persist/profuse
bleeding
Sex Males (80-90%) Common in
females
Positive Family Common Rare
History
 Pathology 185

COAGULATION CASCADE

INTRINSIC
FXII
EXTRINSIC
1
FXIIa Surface Active FVII
Components
Ca TF
FXI HMW
+2

FXIa or VIIa/TF FVIIa

MEDICINE AND ALLIED

Ca+

FIX Ca +

FIXa
T Ca
+2

VIII VIIIa VIIIa/IXa/PL

or
VIIa/TF
Middle FX Ca+

Components FXa Ca+

T
V Va Va/Xa/PL
PT Ca
+2
Common T
Pathway FG
F

EXTRINSIC PATHWAY

Prothrombin T FVII
Time (PT) FVIIa
+
Ca
2

VIIa/TF
Middle FX Ca
2
+

FXa Ca
2
+

T
V Va Va/Xa/PL

PT Ca
2
+

Common
T
FG
F
 186 Textbook of Family Medicine

PT -  – Liver disease
APTT, TT, Plt – N – Lupus anticoagulant
Factor VII deficiency PT,PTTK & Plt normal + bleeding
* Oral Anticoagulants BT -Normal
1 * Vit K deficiency
* Liver disease
1. Factor XIII def
2. α 2-antiplasmin def
* DIC 3. Dysfibrinogenemia
4. Herd hemorrhagic telengiectasia
APTT -  BT – increased . Do plt count
PT, TT, Plt - N
If plt count dec, work up for causes of
MEDICINE AND ALLIED

Factor deficiency ( VIII, IX, XI, XII) thrombocytopenia

* vWD IF plt count is normal
* Inhibitors
Estimate Ristocetin co factor (RCF) if abnormal the diag
* Heparin therapy
is von willibrand dis ( vWD)
* DIC
* Liver disease If RCF is Normal patient has platelet function
disorders
PT prolonged; PTTK – N; Platelets - N In an asymptomatic patient if routine screening tests
• BLEEDING + show prolonged APTT
– Severe factor VII def
• NO BLEEDING –
Inhibitor - lupus anticoagulant
– Mild factor VII def –
Factor XII deficiency
– Oral anticoagulants –
Mild congenital factor deficiency
( mild to mod Haemophilia A/B)
PT –N; PTTK– prolonged; Platelets -N Confirmatory tests
• Bleeding present
– Injury related only • Factor assays
• Severe factor XI def • Tests for coagulation inhibitors
• Mild – mod Hemophilias A/B • Tests for fibrinolysis
– Unprovoked bleed • Platelet function studies
• Minor • EM for platelets
– vWD Pre-op screening for hemostasis
• Major
Many physicians are of the opinion that if preoperative
– severe hemophilia
– Severe vWD type 3 Bleeding time (BT) and clotting time ( CT) are normal
then no bleeding disorder exists. There can be no bigger
– Acquired inhibitor Factor
myth than this. BT especially by finger prick and CT are
VIII
highly insensitive tests and bleeding time will be
– Acquired vWD
abnormal when platelet count is< 40000/cumm or if
• No bleeding
there is a severe platelet function defect and clotting time
– Factor deficiency XII, HK/PK
will be abnormal in severe hemophilia. These tests will
– Lupus anticoagulant-LAC
– Presence of Heparin miss out mild to moderate thrombocytopenia and mild to
moderate Haemophilia which may cause bleeding during
PT- prolonged; PTTK- prolonged; Plt -N surgery. Thus history forms a major part of preop
• BLEEDING + screening with the tests to be first done being PTTK and
– Afibrinogenemia platelet count. Given below are recommendation for pre
– Severe deficiency of Factor II, V, X op screening proposed by Rappaport in 1983 which are
– Combined factor deficiency V & VIII, now followed world over.
def of vit K dep factors
Level Bleeding Surgical Screening recommended
– Acq inhibitors to factor II, V history procedure
– Acq factor X def (amyloidosis) I Negative Minor None
II Negative Major Plt count, PTTK
•No bleeding III Equivocal Major++ PT, PTTK, Plt count, BT (template)
– Hypofibrinogenemia Factor XIII, ECLT (Euglobin clot
– Mild def of factor II, V, X lysis time)
PT-prolonged, PTTK- prolonged, PLT - reduced IV Positive Major or All level III; if Neg add factor VIII,
minor IX, XI assay, TT &
• BLEEDING OR NO BLEEDING 2 – antiplasmin assay
– DIC
 Pathology 187

Chapter 7
DISSEMINATED INTRAVASCULAR 1
COAGULATION (DIC)
A K Tripathi, Kamal K Sawlani

MEDICINE AND ALLIED

Disseminated intravascular coagulation is characterized Investigation
by widespread coagulation in the microcirculation
The DIC is suspected when there is a suggestive clinical
leading to consumption of coagulation factors and
situation along with following laboratory findings:
platelets.
a. Low platelet count
Clinical Features
b. Increased PT and APTT
• Spontaneous oozing from venipuncture sites or c. Low plasma fibrinogen level
wounds is an important clue to the diagnosis of
DIC. d. Elevated plasma FDP (d-Dimer assay)
e. Schistocytes (fragmented RBC) on peripheral blood
• DIC can present as recurrent deep or superficial
smear.
vein thrombosis, particularly in cancer patients.
• Microangiopathic hemolysis can lead to anemia. Management
This includes the following steps:
1. Prompt management of underlying disorders such as:
Table 1: Causes of DIC
a. antibiotics in septicemia
Infections b. delivery of fetus in obstetric complications
• Gram-negative bacterial infections
• Gram-positive bacterial infections 2. Patients with bleeding manifestations should receive
• Fungal infections fresh frozen plasma (FFP) to replace coagulation
• Malaria factors and platelet transfusion to correct
Obstetric
thrombocytopenia.
• Retained dead fetus
• Amniotic fluid embolism
3. Heparin is indicated in patients where the
• Abruptio placentae
predominant manifestation includes thrombosis and
Malignancies gangrene. Role of heparin in patients with bleeding
• Lung, pancreas, prostate cancer manifestations is controversial. However, it may be
• Acute promyelocytic leukemia given in such situations where the bleeding is not
Tissue injury controlled despite adequate replacement with FFP
• Burns and platelets.
• Head injury
 188 Textbook of Family Medicine

Chapter 8

1 SPLENOMEGALY
A K Tripathi, Kamal K Sawlani
MEDICINE AND ALLIED

The spleen is normally not palpable. If palpable, it is Table 2: Causes of massive splenomegaly
enlarged. The direction of enlargement is towards right • Chronic myeloid leukemia
iliac fossa. The maximum diameter of spleen on • Portal hypertension
ultrasonographic assessment is around 13 cm. Massive • Myelofibrosis
splenomegaly is defined as the spleen palpable more than • Malaria
8 cm below costal margin. • Kala azar

Table 1: Causes of splenomegaly

Hyperplasia in response to infection
• Malaria and kala azar
• Infectious mononucleosis, cytomegalovirus
infection, HIV infection, and viral hepatitis
• Endocarditis, tuberculosis, typhoid fever, and
septicemia
• Histoplasmosis
Hyperplasia due to excessive function of red cell removal
• Spherocylosis, thalassemia, and early sickle cell
disease
Hyperplasia in response to immune disorder
• Felty’s syndrome, SLE, and sarcoidosis
Extramedullary hematopoiesis
• Myelofibrosis and marrow infiltration
Congestive splenomegaly
• Portal hypertension (cirrhosis, hepatic vein
obstruction, portal vein thrombosis)
Clinical manifestations
The symptoms due to splenomegaly are abdominal
discomfort and pain. Massive splenomegaly may cause
early satiety and abdominal bloating due to abdominal
compression. Splenic infarction may result in severe pain
radiating to the left shoulder.
Diagnosis
A detailed history and clinical examination are helpful in
knowing the underlying cause of splenomegaly. The
following investigations can be helpful in making a
diagnosis;
1. Complete blood count
2. Bone marrow examination
3. Imaging (ultrasonography, CT scan)
4. Screening for infections and autoimmune diseases
5. Endoscopy of the upper gastrointestinal tract.

Infiltration of spleen
• Leukemias, lymphomas, Myeloproliferative
disorders, amyloidosis, and storage diseases
(Gaucher’s disease, Niemann-Pick disease).
• Sarcoidosis and amyloidosis

Chapter 9
THROMBOPHILIA: HYPERCOAGULABLE
STATES
Jyoti Kotwal
Introduction
Thrombophilia (sometimes hypercoagulability or a
prothrombotic state) is an abnormality of blood
coagulation that increases the risk of thrombosis (blood
clots in blood vessels). Such abnormalities can be
identified in 50% of people who have an episode of
thrombosis (such as deep vein thrombosis in the leg) that
was not provoked by other causes. A significant
proportion of the population has a detectable
abnormality, but most of these only develop thrombosis
in the presence of an additional risk factor.
There is no specific treatment for most thrombophilias,
but recurrent episodes of thrombosis may be an
indication for long-term preventative anticoagulation The
first major form of thrombophilia, antithrombin
deficiency, was identified in 1965, while the most
common abnormalities (including factor V Leiden) were
described in the 1990s.
Signs and symptoms
The most common conditions associated with
thrombophilia are deep vein thrombosis (DVT) and
pulmonary embolism (PE), which are referred to
collectively as venous thromboembolism (VTE). DVT
usually occurs in the legs, and is characterized by pain,
swelling and redness of the limb. It may lead to long-
term swelling and heaviness due to damage to valves in
the veins. The clot may also break off and migrate
(embolize) to arteries in the lungs. Depending on the size
and the location of the clot, this may lead to sudden-
onset shortness of breath, chest pain, palpitations and
may be complicated by collapse, shock and cardiac
arrest.
Venous thrombosis may also occur in more unusual
places: in the veins of the brain, liver (portal vein
thrombosis and hepatic vein thrombosis), mesenteric
vein, kidney (renal vein thrombosis) and the veins of the
arms. Whether thrombophilia also increases the risk of
arterial thrombosis (which is the underlying cause of
heart attacks and strokes) is less well established.
In the Armed forces as many soldiers spend prolonged
periods of time in high altitude, which is a prothrombotic
milleu. The soldiers may present with intractable
Pathology 189
1
MEDICINE AND ALLIED
headace or dizziness due to cortical vein thrombosis. It is
important to distinguish this situation from simple high
altitude cerebral edema in this setting.
Thrombophilia has been linked to recurrent miscarriage,
and possibly various complications of pregnancy such as
intrauterine growth restriction, stillbirth, severe pre-
eclampsia and abruptio placentae. Protein C deficiency
may cause purpura fulminans, a severe clotting disorder
in the newborn that leads to both tissue death and
bleeding into the skin and other organs. The condition
has also been described in adults. Protein C and protein S
deficiency have also been associated with an increased
risk of skin necrosis on commencing anticoagulant
treatment with warfarin or related drug
Causes
Thrombophilia can be congenital or acquired. Congenital
thrombophilia refers to inborn conditions (and usually
hereditary, in which case "hereditary thrombophilia" may
be used) that increase the tendency to develop
thrombosis, while, on the other hand, acquired
thrombophilia refers to conditions that arise later in life.
Congenital
The most common types of congenital thrombophilia are
those that arise as a result of overactivity of coagulation
factors. They are relatively mild, and are therefore
classified as "type II" defects. The most common ones
are factor V Leiden (a mutation in the F5 gene at position
1691) and prothrombin G20210A, a mutation in
prothrombin (at position 20210 in the 3' untranslated
region of the gene) in the western world. In India the
prothrombin gene mutation is not a common cause for
inhereted thrombophilia.
The rare forms of congenital thrombophilia are typically
caused by a deficiency of natural anticoagulants. They
are classified as "type I" and are more severe in their
propensity to cause thrombosis. The main ones are
antithrombin III deficiency, protein C deficiency and
protein S deficiency. Milder rare congenital
thrombophilias are factor XIII mutation and familial
dysfibrinogenemia (an abnormal fibrinogen). It is unclear
whether congenital disorders of fibrinolysis (the system
 190 Textbook of Family Medicine
that destroys clots) are major contributors to thrombosis
risk. Congenital deficiency of plasminogen, for instance,
mainly causes eye symptoms and sometimes problems in
other organs, but the link with thrombosis has been more
1 uncertain.
Blood group determines thrombosis risk to a significant
extent. Those with blood groups other than type O are at
a two- to fourfold relative risk. Those with type O have
lower levels of the blood protein von Willebrand factor
as well as factor VIII, which confers protection from
MEDICINE AND ALLIED
thrombosis.
Acquired
A number of acquired conditions augment the risk of
thrombosis. A prominent example is antiphospholipid
syndrome, which is caused by antibodies against
constituents of the cell membrane, particularly lupus
anticoagulant (first found in people with the disease
systemic lupus erythematosus but often detected in
people without the disease), anti-cardiolipin antibodies,
and anti-β2-gycoprotein 1 antibodies; it is therefore
regarded as an autoimmune disease. In some cases
antiphospholipid syndrome can cause arterial as well as
venous thrombosis. It is also more strongly associated
with miscarriage, and can cause a number of other
symptoms (such as livedo reticularis of the skin and
migraine).
Heparin-induced thrombocytopenia (HIT) is due to an
immune system reaction against the anticoagulant drug
heparin (or its derivatives). Though it is named for
associated low platelet counts, HIT is strongly associated
with risk of venous and arterial thrombosis. Paroxysmal
nocturnal hemoglobinuria (PNH) is a rare condition
resulting from acquired alterations in the PIGA gene,
which plays a role in the protection of blood cells from
the complement system. PNH increases the risk of
venous thrombosis but is also associated with hemolytic
anemia (anemia resulting from destruction of red blood
cells). Both HIT and PNH require particular treatment.
Hematologic conditions associated with sluggish blood
flow can increase risk for thrombosis. For example,
sickle-cell disease (caused by mutations of hemoglobin)
is regarded as a mild prothrombotic state induced by
impaired flow. Similarly, myeloproliferative disorders, in
which the bone marrow produces too many blood cells,
predispose to thrombosis, particularly in polycythemia
vera (excess red blood cells) and essential
thrombocytosis (excess platelets). Again, these
conditions usually warrant specific treatment when
identified.
Cancer, particularly when metastatic (spread to other
places in the body), is a recognised risk factor for
thrombosis. A number of mechanisms have been
proposed, such as activation of the coagulation system by
cancer cells or secretion of procoagulant substances.
Furthermore, particular cancer treatments (such as the
use of central venous catheters for chemotherapy) may
increase the risk of thrombosis further.
Nephrotic syndrome, in which protein from the
bloodstream is released into the urine due to kidney
diseases, can predispose to thrombosis; this is
particularly the case in more severe cases (as indicated
by blood levels of albumin below 25 g/l) and if the
syndrome is caused by the condition membranous
nephropathy. Inflammatory bowel disease (ulcerative
colitis and Crohn's disease) predispose to thrombosis,
particularly when the disease is active. Various
mechanisms have been proposed for this.
Pregnancy is associated with an increased risk of
thrombosis. This probably results from a physiological
hypercoagulability in pregnancy that protects against
postpartum hemorrhage.
Oestrogen, when used in the combined oral contraceptive
pill and in perimenopausal hormone replacement
therapy, has been associated with a two- to sixfold
increased risk of venous thrombosis. The risk depends on
the type of hormones used, the dose of estrogen, and the
presence of other thrombophilic risk factors. Various
mechanisms, such as deficiency of protein S and tissue
factor pathway inhibitor, are said to be responsible.
Obesity has long been regarded as a risk factor for
venous thrombosis. It more than doubles the risk in
numerous studies, particularly in combination with the
use of oral contraceptives or in the period after surgery.
Various coagulation abnormalities have been described
in the obese. Plasminogen activator inhibitor-1, an
inhibitor of fibrinolysis, is present in higher levels in
people with obesity. Obese people also have larger
numbers of circulating microvesicles (fragments of
damaged cells) that bear tissue factor. Platelet
aggregation may be increased, and there are higher levels
of coagulation proteins such as von Willebrand factor,
fibrinogen, factor VII and factor VIII. Obesity also
increases the risk of recurrence after an initial episode of
thrombosis.
Other Causes
A number of conditions that have been linked with
venous thrombosis are possibly genetic and possibly
acquired. These include: elevated levels of factor VIII,
factor IX, factor XI, fibrinogen and thrombin-activatable
fibrinolysis inhibitor, and decreased levels of tissue
factor pathway inhibitor. Activated protein C resistance
that is not attributable to factor V mutations is probably
caused by other factors and remains a risk factor for
thrombosis.

There is an association between the blood levels of
homocysteine and thrombosis, although this has not been
reported consistently in all studies. Homocysteine levels
are determined by mutations in the MTHFR and CBS
genes, but also by levels of folic acid, vitamin B6 and
vitamin B12, which depend on diet. In the Indian setting
aquired hyperhomocysteinemia due to nutritional
deficiency is an important cause
High altitude stay for a prolonged period leads to
increased haemoglobin (causing hyperviscocity), with
increased levels of fibrinogen, plasminogen activator
inhibitor(PAI-1), platelet activation factors and platelet
count. All these predispose to them developing a
prothrombotic mileu in the blood. Thus asymptomatic
thrombophiliacs and normal individuals develop
thrombosis at high altitude.The incidence of thrombosis
in young soldiers is 30 times higher in high altitude as
compared to low altitude.
Mechanism
Thrombosis is a multifactorial problem because there are
often multiple reasons why a person might develop
thrombosis. These risk factors may include any
combination of abnormalities in the blood vessel wall,
abnormalities in the blood flow (as in immobilization),
and abnormalities in the consistency of the blood.
Thrombophilia is caused by abnormalities in blood
consistency, which is determined by the levels of
coagulation factors and other circulating blood proteins
that participate in the "coagulation cascade".
Normal coagulation is initiated by the release of tissue
factor from damaged tissue. Tissue factor binds to
circulating factor VIIa. The combination activates factor
X to factor Xa and factor IX to factor IXa. Factor Xa (in
the presence of factor V) activates prothrombin into
thrombin. Thrombin is a central enzyme in the
coagulation process: it generates fibrin from fibrinogen,
and activates a number of other enzymes and cofactors
(factor XIII, factor XI, factor V and factor VIII, TAFI)
that enhance the fibrin clot. The process is inhibited by
TFPI (which inactivates the first step catalyzed by factor
VIIa/tissue factor), antithrombin (which inactivates
thrombin, factor IXa, Xa and XIa), protein C (which
inhibits factors Va and VIIIa in the presence of protein
S), and protein Z (which inhibits factor Xa).
In thrombophilia, the balance between "procoagulant"
and "anticoagulant" activity is disturbed. The severity of
the imbalance determines the likelihood that someone
develops thrombosis. Even small perturbances of
proteins, such as the reduction of antithrombin to only
70–80% of the normal level, can increase the thrombosis
risk; this is in contrast with hemophilia, which only
arises if levels of coagulation factors are markedly
decreased.
Pathology 191
In addition to its effects on thrombosis, hypercoagulable
states may accelerate the development of atherosclerosis,
the arterial disease that underlies myocardial infarction
and other forms of cardiovascular disease. This is
specifically significant with hyperhomocysteinemia.
Diagnosis
1
Tests for thrombophilia include complete blood count
(with examination of the blood smear), prothrombin
time, activated partial thromboplastin time, thrombin
time and reptilase time, lupus anticoagulant, anti-
MEDICINE AND ALLIED
cardiolipin antibody, anti beta 2 glycoprotein 1 antibody,
activated protein C resistance, fibrinogen tests, factor V
Leiden and prothrombin mutation, and basal
homocysteine levels. Testing may be more or less
extensive depending on clinical judgement and
abnormalities detected on initial evaluation.
There are divergent views as to whether everyone with
an unprovoked episode of thrombosis should be
investigated for thrombophilia. Even those with a form
of thrombophilia may not necessarily be at risk of further
thrombosis, while recurrent thrombosis is more likely in
those who have had previous thrombosis even in those
who have no detectable thrombophilic abnormalities.
Recurrent thromboembolism, or thrombosis in unusual
sites (e.g. the hepatic vein in Budd-Chiari syndrome), is
a generally accepted indication for screening. It is more
likely to be cost-effective in people with a strong
personal or family history of thrombosis, In contrast, the
combination of thrombophilia with other risk factors may
provide an indication for preventative treatment, which is
why thrombophilia testing may be performed even in
those who would not meet the strict criteria for these
tests. Searching for a coagulation abnormality is not
normally undertaken in patients in whom thrombosis has
an obvious trigger. For example, if the thrombosis is due
to immobilization after recent orthopedic surgery, it is
regarded as "provoked" by the immobilization and the
surgery, and it is less likely that investigations will yield
clinically important results.
The guidelines of the International society on thrombosis
should be followed for testing. . It is recommended that
testing be done only after appropriate counseling, and
hence the investigations are usually not performed at the
time when thrombosis is diagnosed but at a later time. In
particular situations, such as retinal vein thrombosis,
testing is discouraged altogether because thrombophilia
is not regarded as a major risk factor. In other rare
conditions generally linked with hypercoagulability, such
as cerebral venous thrombosis and portal vein
thrombosis, there is insufficient data to state for certain
whether thrombophilia screening is helpful, and
decisions on thrombophilia screening in these conditions
are therefore not regarded as evidence-based. If cost-
effectiveness (quality-adjusted life years in return for
expenditure) is taken as a guide, it is generally unclear
 192 Textbook of Family Medicine
whether thrombophilia investigations justify the often
high cost, unless the testing is restricted to selected
situations.
Recurrent miscarriage is an indication for thrombophilia
1 screening, particularly antiphospholipid antibodies (anti-
cardiolipin IgG and IgM, as well as lupus anticoagulant),
factor V Leiden and prothrombin mutation, activated
protein C resistance and a general assessment of
coagulation through an investigation known as
thromboelastography.
MEDICINE AND ALLIED
Women who are planning to use oral contraceptives do
not benefit from routine screening for thrombophilias, as
the absolute risk of thrombotic events is low. If either the
woman or a first-degree relative has suffered from
thrombosis, the risk of developing thrombosis is
increased. Screening this selected group may be
beneficial, but even when negative may still indicate
residual risk.. Professional guidelines therefore suggest
that alternative forms of contraception be used rather
than relying on screening.[
Thrombophilia screening in people with arterial
thrombosis is generally regarded unrewarding and is
generally discouraged, except possibly for unusually
young patients (especially when precipitated by smoking
or use of estrogen-containing hormonal contraceptives)
and those in whom revascularization, such as coronary
arterial bypass, fails because of rapid occlusion of the
graft.
Timing for tests: The samples for testing for tests like
protein C, protein S, anti thrombin 3 etc should be
collected at least 12 weeks after the thrombotic event, as
all the factors may be consumed in the thrombus and the
patient may be falsely labeled as inherted thrombophilia
and unnecessarily get life long anticoagulants. The blood
samlpes should be collected 2 weeks after stopping
anticoagulants. If the patient can not be taken off
anticoagulants fof clinical reasons than sample for
antithrombin 3 can be collected while on warfarin.
Patient is then shifted to heparin and the sample for other
tests ( for vitamin K dependent factors like protein C and
S are collected). The samples for mutation analysis can
be collected at any time.
Treatment
There is no specific treatment for thrombophilia, unless it
is caused by an underlying medical illness (such as
nephrotic syndrome), in which case the treatment of the
underlying disease is needed. In those with unprovoked
and/or recurrent thrombosis, or those with a high-risk
risk form of thrombophilia, the most important decision
is whether to use anticoagulation medications, such as
warfarin, on a long-term basis to reduce the risk of
further episodes. This risk needs to weighed against the
risk that the treatment will cause significant bleeding, as
the reported risk of major bleeding is over 3% per year,
and 11% of those with major bleeding may die as a
result.
Apart from the abovementioned forms of thrombophilia,
the risk of recurrence after an episode of thrombosis is
determined by factors such as the extent and severity of
the original thrombosis, whether it was provoked (such
as by immobilization or pregnancy), the number of
previous thrombotic events, male sex, the presence of an
inferior vena cava filter, the presence of cancer,
symptoms of post-thrombotic syndrome, and obesity..
These factors tend to be more important in the decision
than the presence or absence of a detectable
thrombophilia.
Those with antiphospholipid syndrome may be offered
long-term anticoagulation after a first unprovoked
episode of thrombosis. The risk is determined by the
subtype of antibody detected, by the antibody titer
(amount of antibodies), whether multiple antibodies are
detected, and whether it is detected repeatedly or only on
a single occasion.
Women with a thrombophilia who are contemplating
pregnancy or are pregnant usually require alternatives to
warfarin during pregnancy, especially in the first 13
weeks, when it may produce abnormalities in the unborn
child. Low molecular weight heparin (LMWH, such as
enoxaparin) is generally used as an alternative. Warfarin
and LMWH may safely be used in breastfeeding.
Prognosis
In people without a detectable thrombophilia, the
cumulative risk of developing thrombosis by the age of
60 is about 12%. About 60% of people who are deficient
in antithrombin will have experienced thrombosis at least
once by age 60, as will about 50% of people with protein
C deficiency and about a third of those with protein S
deficiency. People with activated protein C resistance
(usually resulting from factor V Leiden), in contrast,
have a slightly raised absolute risk of thrombosis, with
15% having had at least one thrombotic event by the age
of sixty. In general, men are more likely than women to
experience repeated episodes of venous thrombosis.
People with factor V Leiden are at a relatively low risk
of thrombosis, but may develop thrombosis in the
presence of an additional risk factor, such as
immobilization. Most people with the prothrombin
mutation (G20210A) never develop thrombosis.
 Pathology 193

Chapter 10
LEUKEMIAS
A K Tripathi 1
 It is malignant transformation of hematopoietic cells Diagnosis
leading to increased number of white blood cells in
Peripheral blood examination reveals the presence of
blood and/or bone marrow.

MEDICINE AND ALLIED

blast cells with high, low or normal total leukocyte
 Depending on the onset and the course of the disease,
count. There is also the evidence of anemia and
leukemia is classified as acute or chronic.
thrombocytopenia. The bone marrow examination shows
ACUTE LEUKEMIAS hypercellularity along with the presence of >20 percent
leukemic blast cells. Presence of Auer rods in cytoplasm
Classification of blast cells is diagnostic of AML.
Acute leukemias are classified on the basis of cell of Treatment
origin, morphology and immunophenotypic The management of acute leukemia consists of
characteristics supportive and specific treatment.
a) Supportive treatment: The chance of life-
Table 1: Classification of acute leukemias
threatening bleeding becomes more when platelet
Acute myeloid leukemia count is <10,000/µl. Infections are treated with
(French-American-British classification) parenteral broad spectrum antibiotics and anti-
• M0 undifferentiated fungal drugs if required Anemia is managed with
• M1 Myeloblastic infusion of red cell concentrate. Platelet
• M2 Myeloblastic with differentiation transfusion is needed to treat bleeding
manifestations and to maintain platelet count
• M3 Promyelocytic
above 10,000-20,000/µL..
• M4 Myelo-monocytic
b) Specific treatment: The objective of specific
• M5 Monoblastic treatment is to eliminate leukemic cells without
• M6 Erythroleukemia affecting the normal cells.
• M7 Megakaryoblastic c) Chemotherapy: The first step is to achieve
Acute lymphoblasic leukemia remission (normal blood counts, normal bone
• Pre B cell ALL marrow, and normal clinical status). The initial
• T cell ALL induction phase is followed by the consolidation
phase and the maintenance phase. shows drugs
• B cell ALL
used in acute leukemias.

Clinical Features Table 2: Drugs commonly used to treat acute

leukemias
 anemia and recurrent infections due to neutropenia. Acute myeloid leukemia
 Malignant cells may also infiltrate various organs • Daunorubicin
leading to lymphadenopathy and hepato- • Cytosine arabinoside
splenomegaly. • Etoposide
 Petechiae, gingival bleeding, epistaxis and • All –trans-retinoic acid*
menorrhagia may occur due to thrombocytopenia. Acute Lymphoblastic leukemia
 bleeding may occur due to disseminated intravascular • Vincristine
coagulation (DIC) which is mainly present in patients • Prednisolone
with acute promyelocytic leukemia (AML-M3). • Daunorubicin
 Gum hyperplasia may be seen in monocytic subtype • L-asparaginase
(M4, M5) of AML. • Methotrexate
• Etoposide
 stomatitis, sternal tenderness, testicular enlargement • Cytosine arabinoside
and infiltration of skin and meninges. • Mercaptopurine
 194 Textbook of Family Medicine
d) Radiotherapy: Cranial irradiation along with
intrathecal methotrexate is given in ALL patients
for CNS prophylaxis.
e) Bone marrow transplantation: Following initial
1 remission of disease with chemotherapy, further
treatment is given to cure the disease. The
options are consolidation chemotherapy and bone
marrow transplantation (BMT). Indications for
BMT are:
MEDICINE AND ALLIED
 Common (pre B) ALL in second remission
 T and B cell ALL in first remission
 AML in first remission.
Prognosis
The cure rate of >90 percent can be achieved by
chemotherapy in children with ALL (pre B type). The
cure rate in AML is around 25-30 percent with
chemotherapy and 50-60 percent with BMT.
CHRONIC MYELOID LEUKEMIA
It occurs as a result of malignant transformation of
pluripotent stem cell leading to accumulation of large
number of immature leukocytes in the blood.
The underlying chromosomal abnormality in CML is the
Philadelphia chromosome (short 22) which results due to
the reciprocal translocation between chromosomes 9 and
22 .
Typically the course of CML consists of three phases.
1. The initial phase is the chronic phase which, without
treatment, may last for 2-3 years.
2. This evolves into an accelerated phase which finally
transforms into a terminal blast phase.
3. The blast phase is like acute leukemia, which is
mostly myeloblastic but in about 20 percent cases, it
can be lymphoblastic.
Clinical Manifestations
Some patients are asymptomatic at the time of diagnosis,
However, The common presenting features are
weakness, tiredness, weight loss and abdominal fullness
due to splenomegaly .
CML affects individuals in the third and fourth decade.
Worsening anemia, splenomegaly, fever, and bony pain
may suggest the transformation into the accelerated
phase. In addition to these, in blast phase, patient may
also exhibit bleeding, severe infection and
lymphadenopathy.
Investigations
 The blood examination reveals high total leukocyte
count normocytic normochromic anemia and high
platelet count.
 Presence of 20 percent or more blast cells in bone
marrow or peripheral blood is diagnostic of the blast
phase of CML.
 The presence of low platelet count denotes worsening
of the disease.
 Large numbers of immature myeloid cells
(metamyelocytes, myelocytes) are seen in the blood
smear.
 The diagnosis of CML is confirmed by the
demonstration of Philadelphia chromosome on
cytogenetic analysis or the presence of bcr-abl fusion
gene by molecular techniques.
• Treatment
• Imatinib mesylate is the drug of choice .
• Imatinib mesylate is a new targeted drug which
specifically inhibits the bcr-abl tyrosine kinase. This
can result in molecular remission in around 60-70
percent patients. The usual dose is 400 mg oral daily.
Newer tyrosine kinase inhibitor, Dasatinib is now
available and is useful in patients who fail to respond
to imatinib.
• The only known curative method of treatment of
CML is allogeneic bone marrow transplantation (Allo
BMT).
• Hydroxyurea is used to control the white blood cell
count and has almost replaced the busulphan used
previously.
• The blast phase is managed as acute leukemia.
Alternatively imatinib in larger dosage (600 mg
daily) or dasatinib can be tried in blast phase.
• The other useful agent is interferon alpha which is
more toxic and less effective than imatinib.
CHRONIC LYMPHOCYTIC LEUKEMIA
The median age at presentation is 65 years. Chronic
lymphocytic leukemia (CLL) is a malignancy of mainly
B cell origin. It has slowly progressive course. CLL is
characterized by the presence of large number of mature
looking small lymphocytes in the blood smear and
lymphoid organs like lymph nodes, liver and spleen.
Clinical Manifestation.
The usual clinical features are painless
lymphadenopathy, splenomegaly and anemia.
Autoimmune hemolytic anemia and thrombocytopenia
may also occur. Binet and Rai staging systems are used
for the prognostic classification of the disease. The onset
is insidious. In many, the disease is asymptomatic and is
diagnosed during incidental blood examination
 Pathology 195

Investigations
• Examination of the blood reveals high lymphocyte
count (WBC usually >20000/µl). Majority of the
cells are mature lymphocytes.
• Bone marrow examination reveals infiltration with
mature lymphocytes.
• Coombs test is positive in autoimmune hemolytic
anemia.
• Thrombocytopenia may occur due to immune
destruction or marrow failure.
Treatment
Most patients do not require treatment in the early stage
of the disease. Those with features of progressive disease
such as symptomatic lymphadenopathy, anemia or
thrombocytopenia need chemotherapy. The therapy of
choice is fludarabine based chemotherapy (fludarabine
1
alone or in combination with cyclophosphamide and/or
anti-CD 20 monoclonal antibody) which provides better
response and survival.
Alternatively oral chlorambucil may be given.

MEDICINE AND ALLIED

• Serum immunoglobulin levels may be low which Prednisolone is administered in cases of autoimmune
gives an idea about the degree of
hemolytic anemia.
immunosuppression.
 196 Textbook of Family Medicine
Chapter 11
1 LYMPHOMA
A K Tripathi
MEDICINE AND ALLIED
HODGKIN’S DISEASE
Hodgkin’s disease (HD) is a lymphoid malignancy
characterized by the presence of Reed- Sternberg cells of
B cell origin. The disease arises usually in single nodal
area and successively spreads to contiguous lymph node
areas. Extra nodal involvement is rare.
Clinical Features
 The most common clinical presentation is painless
lymphadenopathy, generally in neck, supraclavicular
area and axillae. one peak at 20-35 years and second
peak in 50-70 year age group.
 A sizable number of patients have mediastinal
lymphadenopathy.
 About one-third patients have B symptoms—fever,
weight loss and night sweats.
 Unusual symptoms are generalized pruritus and pain
in involved lymph nodes following alcohol
ingestion.
Classification
HD is classified into four types depending on
histological features. Mixed cellularity is the most
common type of HD in India
Table 1: Classification of Hodgkin’s disease
• Nodular sclerosis
• Mixed cellularity
• Lymphocyte-predominant
• Lymphocyte-depleted
Investigations
 The diagnosis of HD is made by lymph node biopsy.
Fine needle aspiration cytology (FNAC) may
provide doubtful results. Presence of Reed-
Sternberg cells (Owl’s eye appearance) is
characteristic of the disease.
 Bone marrow examination, CT chest and abdomen
are done for the staging purposes.
 PET scan (Positron emission tomography) is useful
to document remission.
 Serum LDH is a useful prognostic marker, a high
level being a bad prognostic sign.
 Tests such as complete blood count, ESR, serum
uric acid, liver function and renal function tests are
helpful in planning and monitoring the treatment.
Staging
The disease stage is determined after clinical evaluation
and investigations
Table 2: Ann Arbor staging system
Stage I: Involvement of single lymph node region or
lymphoid structure*.
Stage II: Involvement of two or more lymph node
regions on same side of the diaphragm.
Stage III: Involvement of lymph node regions or
lymphoid structures on both sides of the
diaphragm.
Stage IV: Disseminated disease with liver or bone
marrow involvement.
A. No systemic symptoms
B. Weight loss >10 percent in 6 months, fever, and
night sweats
*The lymphoid structures are defined as spleen, thymus,
Waldeyer’s ring, appendix and Peyer’s patches
Treatment
Localized disease: The patients with localized disease
(IA, IIA) are treated with 3 cycles of chemotherapy
(ABVD- doxorubicin, bleomycin, vinblastine, and
dacarbazine ) followed by radiotherapy of involved nodal
areas.
Extensive disease: Patients with B symptoms or
extensive disease receive complete course (6-8 cycles) of
ABVD chemotherapy.
Long-term cure can be achieved in >90 percent patients
with localized disease and in 50-75 percent patients with
extensive disease.

NON-HODGKIN’S LYMPHOMA (NHL)
Etiology: A variety of etiological factors are associated
with NHL. Viruses such as Epstein-Barr virus, HTLV-1,
HIV, hepatitis C virus and Human herpes virus 8 are
implicated in the occurrence of NHL. Infection with
Helicobactor pylori is related with the genesis of gastric
MALT (mucosa associated lymphoid tissue) lymphoma.
NHL can occur in congenital and acquired
immunodeficiency states, autoimmune disorders, and
following exposure to chemicals, drugs, prior
chemotherapy and radiation therapy.
Table 3: Types of non-Hodgkin’s lymphoma
B cell lymphoma
 Follicular lymphoma
 Small lymphocytic lymphoma
 Marginal zone lymphoma
 Mantle cell lymphoma
 Diffuse large B cell lymphoma
 Burkitt’s lymphoma
 T cell lymphoma
 Peripheral T cell lymphoma
 Anaplastic large cell lymphoma
 Mycosis fungoides/Sezary syndrome
Clinical Features
 The patients may present with localized or
generalized painless lymphadenopathy,
hepatosplenomegaly and constitutional symptoms
such as fever, weight loss and night sweats.
 Extranodal presentations are more common in
NHL than in HD. These include involvement of
bone marrow, gut, lungs, testis, thyroid, skin and
brain.
 Low grade NHL is characterized by low
proliferation rate, insidious onset of symptoms
and slow progression. High grade NHL have
early onset of symptoms with aggressive course
and are fatal if untreated.
Investigations
 The diagnosis of NHL is made by tissue biopsy
(lymph node or extranodal tissue). Fine needle
aspiration cytology (FNAC) may provide
doubtful results.
 Immunophenotyping and cytogenetic analysis are
done to further characterize the type of NHL.
Pathology 197
 Tests such as complete blood count, ESR, serum
uric acid, liver function and renal function tests
are helpful in planning and monitoring of the
treatment.
 Bone marrow examination, CT chest and
abdomen, and lumbar puncture are done for the
1
staging purposes.
Treatment
MEDICINE AND ALLIED
The disease stage is determined after clinical evaluation
and investigations.
Treatment of low grade lymphoma: It depends on the
stage of the disease and clinical status.
 Asymptomatic patients generally do not require
therapy.
 Symptomatic localized (stage I) disease can be
treated with radiotherapy.
 Symptomatic patients with extensive disease (stage
III, IV) are treated with chlorambucil or combination
chemotherapy (CVP; cyclophosphamide, vincristine,
and prednisolone or CHOP; cyclophosphamide,
doxorubiin, vincristine, and prednisolone).
 Other newer effective agents are fludarabine,
monoclonal antibody (anti-CD20) with or without
radionuclides, and lymphoma vaccine.
 The relapse following therapy is common. Hence,
low grade NHL is generally not curable. However,
the cure is now possible in some cases with the use
of radio-immunotherapy.
Treatment of high grade lymphoma: Localized high
grade NHL (stage I and non-bulky stage II) is treated
with three cycles of chemotherapy (CHOP with
monoclonal antibody, anti-CD 20) followed by
radiotherapy. Extensive disease (bulky stage II, stage III,
and stage IV) is treated with six to eight cycles of
chemotherapy. The cure rate is 60-90 percent in stage I
and II and 30-40 percent in stage III and IV. Autologous
bone marrow transplantation is indicated in relapsed
cases.
 198 Textbook of Family Medicine
Chapter 12
1 HEALTHCARE ASSOCIATED INFECTIONS
Vinod Rahgav,
MEDICINE AND ALLIED
Introduction
Healthcare associated infections (HAI)/Hospital
Acquired infections/Nosocomial infections are infections
developing in hospitalized patients from 48 hours after
admission to 30 days after discharge and not in
manifestation or under incubation at the time of
admission.
Reflections on HAI are found in Hippocratic teachings,
hand washing advocacy by Semmelweis to control
puerperal sepsis (1847), Lister’s antiseptic surgery using
phenol (1865) to modern aseptic techniques. HAI are
increasing due to modern therapeutic modalities like
immunomodulatory therapy, irradiation, organ
transplants, implant prostheses, premature neonatal care,
exchange transfusion and advanced geriatric care which
have increased infection-prone hosts.
Epidemiology
Since the first implementation of hospital infection
control program in 1959 in England, HAI still remain a
significant healthcare issue despite active surveillance
and control measures. HAI affect 1.7 million patients,
cost $28–33 billion and contribute to 99,000 deaths in
the US annually. The prevalence is 3-21% and incidence
is 2-12% and more than 25% in developed and
developing countries respectively amongst hospitalized
patients. HAI form a sensitive parameter in modern
healthcare practice so much so that the quality of hospital
infection control program is considered to reflect the
overall standard of care in a healthcare establishment.
Sources of infection
Infected patients, healthcare environment and healthcare
professionals form the sources of infection. Patients form
the largest reservoir of infection in a hospital setup.
Patients and visitors may harbor both virulent and
commensal pathogens as diseased persons or carriers.
Autoinfection due to individual’s own microbial flora
may be caused by Enterococci, Streptococci and
anaerobes. Cross infection from other patients may be
caused by Staphylococci, Streptococci, enteric Gram
Inam Danish Khan
negative bacteria, HIV, hepatitis B and C viruses.
Iatrogenic infection is infection acquired through
diagnostic or therapeutic procedures. Secondary
infections with Clostridium difficile and fungi may occur
after prolonged antibiotic administration. Environmental
infections are derived from environmental sources like
air, water (Legionella), food, hospital dust and inanimate
objects like furniture, linen, utensils and sanitary
installations. Hospital equipment and medications, if not
sterilized properly can be a source of infection.
Healthcare professionals like doctors, nurses and other
ancillary staff may harbor pathogens in their body or
may act as vectors in transmitting pathogens from one
patient to another. Lack and change of trained staff
jeopardizes patient safety.
Modes of transmission
HAI can be transmitted through air (tuberculosis,
measles, chickenpox, SARS and viral haemorrhagic
fevers), droplet nuclei (meningitis, diphtheria, influenza,
mumps, Mycoplasma pneumoniae, Parvovirus B19,
plague, rubella, Gp A Streptococcal and H. influenza
infections), direct contact (cellulitis, furunculosis,
impetigo, Clostridium difficile diarrhoea, E. coli colitis,
multidrug resistant bacterial infections, measles, viral
conjunctivitis, Herpes simplex, Respiratory syncytial
virus and enteroviral infections), feco-oral route
(Shigella, Yersinia enterocolitica, Hepatitis A and
rotaviral infections) and parenteral routes (Enterobacter,
Citrobacter, Serratia, Burkholderia, HIV, Hepatitis B
and C).
Host factors
Increased susceptibility to infections is seen in extremes
of age, metabolic abnormalities (malnutrition, diabetes,
uraemia, jaundice), immunosuppression (genetic
polymorphisms, HIV, cancer, transplant recipients) and
iatrogenic causes (prolonged steroid therapy, radiation
therapy, chemotherapy).
 Pathology 199

Table 1: Host Factors Respiratory Pneumonia S. aureus, Sporadic

infections Klebsiella,
Host profile Common pathogens Pseudomonas,
Neonate Gp B Streptococci, Enterobacter,
Enterococci, Staphylococci,
Streptococcus viridians,
Acinetobacter, E.
coli, Herpes,
Aspergillus
1
Enteric Gram negative
bacteria, Pseudomonas, H. Wound Stitch abscess, S. aureus, S. Sporadic
influenza, Enterobacter, infections infected epidermidis,
Listeria, anaerobes, Candida burns, Streptococcus
Asplenic Streptococcus pneumoniae, H. decubitus pyogenes,

MEDICINE AND ALLIED

influenzae, N. meningitidis, ulcers Enterococci,
Capnocytophaga, Babesia Pseudomonas, E.
coli, anaerobes
Cirrhotic Vibrio, Yersinia, Salmonella,
Gram negative bacteria, Intravascular Central line Coagulase Sporadic/
encapsulated organisms device associated negative Outbreaks
Alcoholic Klebsiella, Streptococcus infections blood stream Staphylococci, S.
infection aureus,
pneumonia
Enterococci,
Diabetic Pseudomonas aeruginosa, E. Gram negative
coli, Mucor bacteria, Candida
On long term M. tuberculosis, fungi, Herpes
Gastrointestinal Acute Salmonella, Sporadic/
steroids infections gastroenteritis Staphylococci, E. Outbreaks
AIDS P. aeruginosa, S. aureus, , food coli, Clostridium
Pneumocystis jiroveci poisoning difficile,
Severely neutropenic Enteric Gram negative Norovirus
bacteria, P. aeruginosa, S. Dialysis Viral hepatitis Hepatitis B, Sporadic
aureus, Candida, Aspergillus, associated B and C Hepatitis C virus
Mucor infections
Hypogammaglobulin Streptococcus pneumoniae, E.
Transfusion HIV-AIDS, HIV, Hepatitis B Sporadic
emic coli
related viral hepatitis and C virus,
T cell abnormalities Listeria, Salmonella, infections B and C Enterobacter,
Mycobacteria, Herpes Citrobacter,
Serratia,
Common types of HAI and associated pathogens Burkholderia,
Acinetobacter
HAI is caused by diverse pathogens which may be highly
or minimally virulent, drug resistant or commensal
bacteria, fungi and viruses. The ability to form biofilms Diagnosis
helps them survive on devices and implants.
Pseudomonas can grow in disinfectants and Clostridium Routine smears, cultures with identification and
difficile spores survive in alcohol. Polymicrobial antimicrobial sensitivity are helpful for sporadic cases.
infections and superinfections may increase the risk of Blood cultures, cultures of sonicates from explanted
complications and mortality due to HAI. prostheses may be required in addition to routine
Table 2: Common types of HAI and associated cultures. Serological tests like Widal and ELISA are
pathogens done. Nucleic acid technology with pathogen/resistance
specific primers may speed up the diagnosis and
HAI Examples Common Presentation characterization of offending organism. In addition,
pathogens source identification through air (Settle plate technique),
Urinary Catheter E. coli, Sporadic/ water, floor (Contact agar plate technique), other
infections related Klebsiella, Outbreaks surfaces, staff (nasopharyngeal swabs) and sterilization
urinary Enterococci,
surveillance cultures is required for outbreaks. Typing
infection Proteus,
Enterobacter, (biotyping, bacteriocin typing, antibiograms, phage
Pseudomonas, typing, molecular typing) is done to characterize
Serratia, outbreaks.
Providencia,
Candida, mixed
flora
 200 Textbook of Family Medicine

Management and Prevention HAI Surveillance, Outbreak Investigation and

Presumptive treatment of patients and carriers with broad
spectrum antimicrobials is followed by sensitivity tested
regimens. Source control may mandate surgical
1 intervention in addition. Infection prone hosts may be
nursed in contained sterile environments. Early
identification of pathogens and antimicrobial treatment
guided by susceptibility testing helps reduce nosocomial
hazard in hospitals. Staphylococcal nasal colonization
can be eradicated using mupirocin, rifampicin and
MEDICINE AND ALLIED
Control
HAI surveillance, outbreak investigation and control
forms a diligent activity under an interdisciplinary
Hospital Infection Control Committee (HICC)
comprising of microbiologists, epidemiologists,
physicians, surgeons, administrators, nurses and
engineers at all large healthcare setups. Guidelines for
admission, nursing procedures, sterilization, surveillance
and control and antimicrobial stewardship are handled by

doxycycline. HICC. Surveillance programs based on algorithmic

computation of hospital databases using pre-designed
While all healthcare associated infections can be
softwares (WHONet, MedMined, SafetySurveillor,
prevented, in developed and developing countries, 20%
and 40% HAI respectively may be preventable. ICNet, Infection Control Assist, NOSO-3 etc) and
Multilateral preventive approach coupled with follow up automated systems (Vitek-2) for device-related HAI
surveillance and monitoring programs are indispensable. (Ventilator associated pneumonia, central line associated
Risk of HAI can be curtailed by day care surgeries, bloodstream infection, catheter related urinary infection),
process (Hand hygiene) and outcome measures depict
reduction in invasive procedures, avoiding surgical
complications, autologous transfusions, early HAI rates which are reviewed temporally and compared
with benchmarks. Data is analyzed in view of duration
ambulation, short hospital stay and anti-infection
engineering. Health education of healthcare and exposure of patients. With advancing research, total
professionals, patients and community at large, along HAI control may be the promise of the future.
with behaviour modification like hand hygiene,
respiratory hygiene and changing gloves between
patients, proper handling and transportation of specimens
is pivotal to control HAI. Healthcare staff should wear
personal protective equipment and be covered by
immunoprophylaxis or chemoprophylaxis. Isolation of
infected patients along with standard, airborne, droplet
and contact precautions as well as barrier nursing and
restricted access may be instituted. Screening of blood
and organ donors can prevent transfusion transmitted
infections. Pre and post employment surveillance may
identify carriers. Hospital environmental protection may
be achieved by stringent surface sanitization including
wet dusting to reduce dust, proper air handling,
sterilization and disinfection procedures, hospital waste
management and anti-infection engineering. Devices
coated with anti infective surfaces should be used.
Legislation may influence infection control practices.
Apex bodies like Centre for Disease Control (CDC) and
National Nosocomial Infection Surveillance (NNIS) in
the US oversee HICCs. Total quality management with
internal and external quality control measures should be
incorporated at every step.