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CHAPTER 19 Immunology
341
3. What other signs/symptoms may be present in this type
of reaction?
4. Briey outline your immediate management.
5. Before the patient is discharged, what actions would you
ensure had been taken?
OSCE Scenario 19.2
A 20-year-old male undergoes a rst renal transplant from
a well-matched deceased donor. He has no preformed cytotoxic antibodies.
1. What immunosuppressive regime would you commence in the post-operative period?
e serum creatinine falls to 130 µmol/L by the 6th
post-operative day. On the 8th post-operative day, there
is reduced urine output and the creatinine has risen to
200 µmol/L. e ciclosporin level in the blood is within
therapeutic limits.
2. What are the possible diagnoses?
3. Name two investigations which you would perform to
conrm the diagnosis. In which order would you perform them?
4. What histological features suggest the diagnosis of acute
rejection?
5. If cell-mediated rejection is conrmed, how would you
treat it?
6. If the kidney fails to respond to planned treatment, what
further treatment would you institute?
OSCE Scenario 19.3
You have recently incised and drained an abscess on the
neck of a 48-year-old man, which did not exhibit the usual
features of an inamed abscess. e microbiologist reports
seeing acid- and alcohol-fast bacilli on the Gram stain.
1. What infection does this suggest? When you see the
patient in clinic he tells you he has recently had a cough
and shortness of breath. An X-ray and sputum culture
performed by his GP has revealed a Pneumocystis
pneumonia.
2. What possible underlying condition do you now
suspect?
3. Summarize the immune response.
4. Explain to the examiners the dierence between the
humoral and cell-mediated immune systems.
5. What is complement?
OSCE Scenario 19.4
A 42-year-old male is having a blood transfusion following
a major colorectal procedure; the nurse looking aer him
comes to tell you that the patient has just nished the rst
bag of blood but he has a temperature of 38°C and is very
ushed and complaining of back and ank pain.
1. What is the possible diagnosis?
2. Explain how it occurs and what type of immune reaction it is.
3. What is a Coombs test? Which will be the most relevant
in this case?
OSCE Scenario 19.5
A 27-year-old female visits you in the transplant clinic; she
is very upset regarding some unwanted facial hair growth,
acne and excess growth of her gums. She had a cadaveric
renal transplant four months ago and it has been functioning very well.
1. Which immunosuppressant drug has these side eects?
2. Explain how this drug works to prevent gra rejection.
3. Another patient attends who has had a working transplant for over 15 years. ey are complaining of fevers,
night sweats and palpable lumps in the right side of
their neck. What is the likely diagnosis and how has the
drug mentioned in question 1 led to this complication?
Answers in Appendix pages 476–478
Please check your eBook at https://studentconsult.inkling.com/ for more self-assessment questions. See inside cover for
registration details.
20
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Haemopoietic and
Lymphoreticular System
HAEMOPOIESIS
Haemopoiesis is the production of blood cells. Sites of haemopoiesis include:
• fetus: bone marrow, spleen and liver
• at birth: marrow
• adult life: red marrow remains only in axial skeleton,
ribs, skull and proximal ends of humerus and femur.
Red Blood Cell (Erythrocyte)
• Non-nucleated blood cells that are biconcave and
deformable.
• Most abundant blood cell, forming 45% of the total blood
volume, i.e. haematocrit or packed-cell volume (PCV).
• Function: to carry oxygen.
• Mature erythrocytes survive for 18–120 days in the circulation before being removed by macrophages in the
spleen and, to a lesser extent, bone marrow and liver.
• Within the macrophage the erythrocyte is broken down
to haem and globin.
• Amino acids of globin enter the general amino acid pool
of the body.
• Haem is broken down with release of iron, which
attaches to transferrin.
• Transferrin is an iron-binding beta globulin responsible
for iron transport and delivery to receptors on erythroblasts or to iron stores. e remainder of the haem is
converted to bilirubin.
• Renal secretion of erythropoietin stimulates red cell
production to keep pace with rate of destruction.
• Erythropoiesis requires an adequate dietary intake
of iron, vitamin B12 and folate: depletion of these will
reduce erythropoiesis.
Reticulocytes
• About 1% of red cells in the circulation are reticulocytes, which stain purplish because of residual RNA.
• e proportion of reticulocytes in the bloodstream
increases when bone marrow production of erythrocytes increases, e.g. aer haemorrhage.
ANAEMIA
Anaemia is the reduction of the concentration of haemoglobin in the circulation below the normal range. e
normal range for a male is 13–18 g/dL and for the female
11.5–16.5 g/dL. ere are three main causes of anaemia:
• blood loss
• haemolysis
• impairment of red cell formation/function.
Blood Loss
• Immediately aer acute haemorrhage the haemoglobin
level is normal.
• In the absence of i.v. uid replacement there is a slow
expansion in plasma volume over the next 2–3 days.
• Acute haemorrhage results eventually in a normochromic, normocytic anaemia.
• Reticulocytosis occurs; maximal at 1 week.
• ere is a mild neutrophil leucocytosis with occasional
metamyelocytes.
• Chronic blood loss leads to hypochromic microcytic
iron deciency anaemia.
Haemolysis
Haemolytic anaemias are a group of diseases in which red
cell life span is reduced.
• Haemolysis is usually associated with increased
erythropoiesis.
• Laboratory evidence of increased red cell destruction is
demonstrated by:
• increased serum unconjugated bilirubin
• reduced serum haptoglobin
• morphological evidence of red cell damage, e.g.
spherocytes, red cell fragments, sickled cells
• reduced life span of red cells, e.g. demonstrated by
tagging with radioactive chromium.
• Laboratory evidence of increased erythropoiesis is demonstrated by:
• reticulocytosis in peripheral blood
• erythroid hyperplasia in the bone marrow.
342
CHAPTER 20 Haemopoietic and Lymphoreticular System
343
Clinical Features of Haemolytic States
ese result from:
• red cell destruction
• compensatory erythropoiesis.
Red cell destruction results in:
• pallor
• mild jaundice
• pigment stones may form in the gall bladder
• splenomegaly may occur.
Haemolytic states may result in:
• expansion of marrow cavities with thinning of cortical
bone in congenital forms
• frontal bossing of the skull may occur, due to widening
of the marrow space between inner and outer tables of
the skull.
ere are a number of haemolytic conditions but only two,
which are surgically relevant, will be described here, i.e.
sickle cell anaemia and hereditary spherocytosis.
Sickle Cell Anaemia
• Due to presence of haemoglobin variant HbS in red cells.
• Deoxygenated HbS is 50 times less soluble than deoxygenated HbA; polymerizes on deoxygenation into long
bres, which deform the red cell into the typical sickle
shape.
• e presence of HbS is the result of a defect in gene coding for glutamic acid, the latter being replaced by valine.
• In heterozygous individuals, both HbA and HbS are
formed, and the individual has sickle-cell trait. Patients
with sickle-cell trait are usually haematologically normal and usually asymptomatic.
• In the presence of sickle-cell trait, red cells do not usually sickle until the oxygen saturation falls below 40%,
which is rarely reached in venous blood.
• In surgical practice, the anaesthetist needs to be aware
of the trait so that hypoxia is avoided intra-operatively.
• In homozygous individuals, HbA is not formed. e red
cells readily deform and sickle cell anaemia develops.
• In the homozygous form, cells sickle at the oxygen tension normally found in venous blood.
• Increased rigidity of the cells causes them to plug small
blood vessels with infarction and painful crises.
• Patients may develop acute abdominal and chest
pain that mimics other intra-abdominal and thoracic
catastrophes.
• Bone pain and priapism may also occur.
• e anaemic patient responds poorly to infection; septicaemia and osteomyelitis may develop, the latter being
attributable on occasion to salmonella.
• e spleen may calcify and atrophy due to repeated
infarction.
• Pigment gallstones may occur.
Hereditary Spherocytosis (Congenital
Acholuric Jaundice)
• Due to defect in red cell membrane.
• Spherocytes are identied by blood lm.
• Clinical features include family history, pallor, mild
jaundice and splenomegaly.
• Raised serum bilirubin and increased reticulocyte count.
• Cholecystitis may occur as result of pigment stones.
• Splenectomy is the treatment of choice, being delayed
until aer the age of 10 years, as post-splenectomy sepsis is less aer this age.
• Splenectomy does not cure spherocytosis but prevents the
abnormally shaped cells being destroyed by the spleen.
• Following splenectomy:
• haemoglobin level rises
• jaundice disappears
• the life span of red cells increases to near-normal levels.
Impairment of Red Cell Formation/Function
is may arise as a result of:
• deciency of essential haematinics, e.g. iron, folate, vitamin B
• chronic disorders, e.g. infections (TB), renal disease,
12
liver disease, neoplasia, collagen disease
• marrow inltration, e.g. carcinoma, myeloma, lymphoma, myelobrosis
• endocrine disease, e.g. hypothyroidism
• cytotoxic and immunosuppressive agents.
Classification of Anaemia
Anaemias may be classied by the morphological appearance of erythrocytes in the stained blood smear.
• Normocytes: red cells with a normal diameter.
• Microcytes: red cells with a reduced diameter.
• Macrocytes: red cells with an increased diameter.
• Normochromic: normal staining of a red cell with a central area of pallor.
• Hypochromic: reduced staining with a large central area
of pallor.
• Haematocrit or PCV: percentage of packed cells in relation to the total volume of blood; normally 45%.
Other important parameters in assessing anaemia are:
• Mean corpuscular volume (MCV), measured in femtolitres (fL):
haematocritL/L
red cell concentrationL
• Mean corpuscular haemoglobin (MCH), in picograms
(pg):
haemoglobin concentrationg/dL
red cell concentrationL
()
()
()
78 98
= fL
221
()
= pg26 332
21
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SECTION III Pathology
TABLE 20.1 Morphological Classification of Anaemia
Morphology Values Cause
Microcytic
Hypochromic
Macrocytic
Normocytic
Normochromic
MCV <78
MCH <28
MCV >98
}
MCV normal Acute blood loss
MCH normal Haemolytic anaemia
Iron deficiency
Thalassaemia
Folate deficiency, vitamin B12 deficiency, alcoholism
Chronic disorders
Leucoerythroblastic anaemias
• Mean corpuscular haemoglobin concentration (MCHC),
in grams per decilitre (g/dL):
haemoglobin concentrationg/dL
haematocritL/L
()
()
= g/d
30 352 LL
A morphological classication of anaemia is shown in
Table 20.1.
Polycythaemia
Polycythaemia is an increase in the concentration of red
cells above normal level. ere is a rise in both total blood
volume and PCV; the latter may be as high as 60%. Features
of polycythaemia include:
• Hb concentration rises to above 18 g/dL
• blood viscosity is high
• polycythaemia may be a primary condition, i.e. polycythaemia rubra vera, or may be secondary, relative or due
to inappropriate secretion of erythropoietin (Box 20.1)
• increase in blood viscosity results in a sluggish blood
ow through heart, brain and limbs, leading to myocardial infarction, stroke and ischaemic limbs
• splenomegaly occurs in 75% of cases
• haemorrhagic lesions may be a feature, especially in the
gastrointestinal tract
• peptic ulceration is common in polycythaemia rubra
vera but the reason is unknown.
WHITE BLOOD CELLS (LEUCOCYTES)
White blood cells form part of the body’s defence mechanisms. ey are divided into two main groups:
• phagocytes, which engulf and destroy bacteria and foreign matter
• lymphocytes, which are responsible for the immune
response.
Types of White Blood Cell
Neutrophils
• Develop from myeloblasts in red bone marrow.
BOX 20.1 Causes of Polycythaemia
• True
• polycythaemia rubra vera
• Secondary: chronic hypoxia stimulates erythropoietin
• high altitude
• respiratory disease
• cyanotic heart disease
• smoking
• haemoglobinopathy.
• Relative: reduced plasma volume, normal red cell mass
• vomiting
• diarrhoea
• burns
• inadequate fluid intake.
• Inappropriate: increase of erythropoietin
• kidney disease, e.g. carcinoma
• renal transplantation
• hepatocellular carcinoma
• giant uterine fibroids
• cerebellar haemangioblastoma
• Have a scavenging function and are important in
defence against bacterial infection.
• Possess a segmented nucleus and abundant cytoplasmic
granules containing enzymes, e.g. alkaline phosphatase
and lysozyme.
• Spend 14 days in the bone marrow, whereas their life
span in blood is 6–12 h.
• Enter tissues by penetrating the endothelium.
Lymphocytes
e role of lymphocytes is described in Chapter 19.
Monocytes
• Develop in red bone marrow from myeloblasts.
• Largest blood cells.
• Function is similar to that of neutrophils.
• Enter the tissues, and phagocytose and digest foreign
and dying material.
CHAPTER 20 Haemopoietic and Lymphoreticular System
345
Eosinophils
• Important in the mediation of the allergic response.
• Important in defence in parasitic infections.
Basophils
• Least frequent leucocytes in blood.
• Have similar function to tissue mast cells.
• Important in immediate hypersensitivity reactions, when
they release histamine.
Changes in White Cells in Disease
Leucocytosis
• Leucocytosis is an increase in the number of circulating
white cells. e normal reference range is shown in Box
20.2.
• Leucocytosis may involve any of the white cells, but
polymorphonuclear leucocytosis is the most common,
i.e. neutrophilia.
• e causes of leucocytosis are shown in Box 20.3.
Leucopenia
Leucopenia is a reduction in circulating leucocytes. In
practice the most common form is neutropenia, i.e. deciency of neutrophil granulocytes. Neutropenia may be
selective or part of a pancytopenia (Box 20.4).
Neutropenia
• Neutrophil counts of <0.5 × 109/L may result in:
• severe sepsis, e.g. oral or oesophageal candida, septi-
caemia, opportunistic infections
• this type of disease is seen in patients receiving che-
motherapy for malignant disease or immunosuppressive therapy for organ transplantation.
Platelets
• Platelets are discoid, non-nucleated, granule-containing
cells that form in the bone marrow by fragmentation of
the cytoplasm of megakaryocytes.
• Concentration in normal blood is 160–450 × 109/L.
• Survive in circulation for 8–10 days.
• Contractile and adhesive cells which are important in
haemostasis.
• Adhere to exposed subendothelial tissues, aggregate and
form haemostatic plug.
• Take part in repair process aer vascular injury.
• Platelet-derived growth factor is mitogenic for smooth
muscle and broblasts; it may also be involved in the
development of atherosclerosis.
• A reduction in the number of platelets is called thrombocytopenia (Box 20.5).
BOX 20.2 Reference Range for White Cell
Concentrations
Cell Count (109/L)
Total white cell count 4–11
Neutrophils 2.0–7.5
Lymphocytes 1.0–3.0
Monocytes 0.15–0.6
Eosinophils 0.05–0.35
Basophils 0.01–0.10
BOX 20.3 Causes of Leucocytosis
Cell Cause
Neutrophils Sepsis, e.g. acute appendicitis
Trauma, e.g. major surgery
Infarction, e.g. myocardial infarction
Mesenteric infarction
Malignant disease
Acute haemorrhage
Steroid therapy
Lymphocytes Viral infections, e.g. glandular fever,
CMV, rubella, influenza, hepatitis
Bacterial infections, e.g. pertussis,
TB, brucellosis
Chronic lymphocytic leukaemia
Post-splenectomy (temporary)
Monocytes Sepsis
Chronic infection, e.g. TB
Malignant disease
Eosinophils Allergy, e.g. asthma
Parasitic infection
Malignant disease, e.g. Hodgkin’s
disease
HAEMOSTASIS
Haemostasis is the physiological process by which bleeding
is controlled. It consists of four components:
• vasoconstriction
• platelet activation
• coagulation mechanism
• brinolytic system.
346
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SECTION III Pathology
BOX 20.4 Causes of Neutropenia
Type Cause
Pancytopenia Bone marrow depression, e.g.
cytotoxic drugs
Malignant infiltration
Severe vitamin B12 or folate deficiency
Hypersplenism
Selective Overwhelming sepsis, e.g. septicaemia
Autoimmune
Drug-induced, e.g. indomethacin,
chloramphenicol, co-trimoxazole
BOX 20.5 Causes of Thrombocytopenia
Type Cause
Reduced production Aplastic anaemia
Drugs, e.g. tolbutamide,
alcohol, cytotoxic agents
Viral infections, e.g. EBV, CMV
Myelodysplasia
Bone marrow infiltration, e.g.
carcinoma, leukaemia
Myeloma, myelofibrosis
Megaloblastic anaemia
Hereditary thrombocytopenia
Decreased platelet
survival
Immune Idiopathic thrombocytopenic
purpura
Drugs, e.g. heparin, quinine,
sulphonamides, penicillins,
gold
Infections
Post-transfusion
Non-immune Disseminated intravascular
coagulation
Thrombotic thrombocytopenic
purpura
Hypersplenism Sequestration of platelets
Vasoconstriction
• Due to smooth muscle contraction mediated by:
• local reexes
• thromboxane A2 released by activated platelets
• serotonin released by activated platelets.
Platelet Activation
• Vascular damage promotes haemostasis if the endothelial lining of blood vessels is disrupted.
• Platelets adhere to the site of damage, aggregate there,
and ultimately form a platelet plug.
Adherence
• Injury to vessel wall results in loss of endothelium and
exposes subendothelial collagen.
• Platelets adhere to the damaged area and there is activation of the intrinsic pathway of coagulation.
• Damaged endothelial cells release von Willebrand’s
factor, which is necessary for platelet adhesion; tissue
thromboplastin is also released, which activates the
intrinsic pathway of coagulation.
• Simultaneously, platelet granules release ADP, which
initiates platelet aggregation.
Aggregation
• romboxane A2 is produced from arachidonic acid
released from platelet phospholipids.
• romboxane A2 induces further ADP release, causing
further platelet aggregation.
Platelet Plug
• Aggregated platelets act as catalysts of coagulation with
local generation of thrombin and conversion of brinogen to brin.
• Aggregated platelets, thrombin and brin fuse to form
platelet plug.
Coagulation Mechanism
• End-point of blood coagulation is conversion of soluble
brinogen to insoluble brin by thrombin.
• Coagulation mechanism involves two interacting systems: intrinsic and extrinsic pathways.
• Activation of Factor X is the result of preceding enzyme
reactions in the two pathways.
• e intrinsic pathway involves normal blood
components.
• e extrinsic pathway requires tissue thromboplastin,
released by damaged cells.
• e pathways are shown in Fig. 20.1.
• All soluble coagulation factors are manufactured in the
liver, with the exception of Factor VIII (endothelium),
calcium, platelet factors and thromboplastin.
CHAPTER 20 Haemopoietic and Lymphoreticular System
Cross-linked fibrin
Antithrombin
Tissue thromboplastin
Intrinsic pathway
347
Extrinsic pathway
+
VII
Vessel injury
Exposed collagen
Prothrombin
IX
Fibrinogen
XIIaXII
XIaXI
phospholipid
Platelet
phospholipid
IXa
+
+ VIIIPlatelet
Inhibitors
Protein C
Protein S
XaX
V
Thrombin
Fibrin
III
Fig. 20.1 The coagulation mechanism.
Fibrinolytic System
• Fibrin is removed by the brinolytic system during the
• Fibrin is broken down to soluble brin degradation
• Plasmin is derived from inactive precursor plasminogen
• Tissue plasminogen activator is released from endothe-
• Control of activation of plasminogen is provided by
• PAI-1 is released by endothelial cells and rapidly inacti-
repair process in blood vessels and healing wounds (Fig.
20.2).
products by plasmin.
by action of plasminogen activators.
lial cells.
plasminogen-activator inhibitor 1 (PAI-1).
vates tissue plasminogen activator.
XIII
Assessment of Coagulation System
Platelet Count
• Normal range 160–450 × 109/L.
• rombocytopenia exists with counts of less than 100 ×
9
/L.
• Counts of 70 × 109/L are usually adequate for surgical
haemostasis.
• Spontaneous bleeding occurs with counts of less than
20 × 109/L.
Bleeding Time
• Time for a small puncture wound in the skin made by
standard technique to stop bleeding.
• Time varies from 1 to 8 min.
348
Plasminogen
Tissue plasminogen
degradation
products
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SECTION III Pathology
activator
PAI-1
Plasmin
Antiplasmin
Fibrin
Fibrin
Fig. 20.2 The fibrinolytic mechanism (PAI-1 =
plasminogen-activator inhibitor 1).
• A time within this range implies:
• adequate platelet count
• normal platelet function
• normal vascular response to injury.
• A prolonged bleeding time implies:
• thrombocytopenia
• platelet defects
• failure of vascular contraction.
Whole-Blood Clotting Time
• Blood clots in glass tube in 5–15 min.
• A clotting time within this range requires:
• integrity of the intrinsic system
• adequate nal common pathway
• normal platelet function.
Prothrombin Times (PT)
• Tests the integrity of the extrinsic pathway and nal
common pathway.
• Deciencies of Factors I, II, V, VII and X will be detected.
BOX 20.6 Assessment of Bleeding States
Test result Conclusion
APTT and PT normal Platelet or vessel defect
APTT and PT abnormal Deficit in common
pathway
APTT normal and PT
abnormal
APTT abnormal and PT
normal
Note: APTT tests the intrinsic system; PT tests the extrinsic
system.
Factor VII deficiency
Deficit in intrinsic
system
Fibrin Degradation Products (FDPs)
• Products released from brinogen and brin by plasmin.
• Increased in disseminated intravascular coagulation
(DIC).
Assessment of the dierent pathways involved in coagulation may be made with two simple tests:
• APTT for intrinsic system
• PT for extrinsic system.
Test results and the conclusions that may be drawn from
them are shown in Box 20.6.
DISORDERS OF HAEMOSTASIS
Platelet Disorders
Thrombocytopenia
is may be due to:
• failure of platelet production
• increased destruction or sequestration of platelets.
e causes of thrombocytopenia are shown in Box 20.5.
Activated Partial Thromboplastin Time (APTT)
• Tests the intrinsic system, i.e. all factors except Factor VII.
Kaolin-Cephalin Clotting Time (KCCT)
• Independent of platelet count.
• Tests intrinsic pathway and common pathway.
Abnormal Platelet Function
• May cause bleeding despite a normal platelet count.
• Abnormal platelet function may occur with:
• drugs, e.g. aspirin, non-steroidal anti-inammatory
drugs; carbenicillin, ticarcillin
• uraemia
• septicaemia
• von Willebrand’s disease.
Thrombin Time (TT)
• Increased if there is an inadequate concentration of
brinogen.
• Prolonged by heparin and presence of brin degradation products.
Blood Vessel Wall Abnormalities
ese are rare and may be due to:
• scurvy (vitamin C deciency)
• steroids
CHAPTER 20 Haemopoietic and Lymphoreticular System
349
• Cushing's syndrome
• Henoch–Schönlein purpura.
Disorders of Coagulation
Congenital Coagulation Disorders
ese are uncommon, the commonest being haemophilia
A and von Willebrand’s disease.
Haemophilia A
• Inherited deciency of Factor VIII.
• X-linked recessive disorder aecting males and carried
by females.
• Severity of the disease depends upon the degree of
Factor VIII deciency.
• Prothrombin time (PT) normal but activated partial
thromboplastin time (APTT) prolonged.
von Willebrand’s disease
• Due to deciency of von Willebrand’s factor.
• Transmitted as autosomal dominant condition.
• Vascular endothelium releases decreased amounts of
Factor VIII.
• Platelet count usually normal, but platelet interaction
with endothelium is defective because of deciency of
von Willebrand’s factor.
Acquired Disorders of Coagulation
Vitamin K deficiency
• Vitamin K is present in green vegetables and is synthesized by intestinal bacteria.
• It is fat soluble and requires bile for absorption.
• It is required for formation of Factors II, VII, IX and X.
• Vitamin K deciency may occur in the surgical patient
as a result of:
• obstructive jaundice
• antibiotic therapy, which alters normal intestinal ora
• prolonged parenteral nutrition without vitamin K
supplements.
Liver disease
• Commonly associated with coagulation defects due to
failure of clotting factor synthesis and the production of
abnormal brinogen.
• Vitamin K will not help if there is hepatocellular failure.
• In addition, there may be thrombocytopenia due to
hypersplenism.
Disseminated intravascular coagulation (DIC)
• Results from simultaneous activation of coagulation
and brinolytic systems.
• Activation of coagulation system leads to formation of
microthrombi in many organs with the consumption of
clotting factors and platelets.
• is in turn leads to haemorrhage.
• DIC may arise as the result of the following disorders:
• septicaemia
• malignancy
• trauma
• shock
• liver disease
• acute pancreatitis
• obstetric problems, e.g. toxaemia, amniotic uid
embolism.
• Clinically there is widespread haemorrhage.
• Diagnosis conrmed by presence of:
• thrombocytopenia
• decreased brinogen
• elevated brin degradation products.
Natural Anticoagulants
Antithrombin III
• Inhibitor of thrombin.
• Action potentiated by heparin.
• Congenital antithrombin III deciency is inherited in
an autosomal dominant fashion.
• Heterozygotes may suer from recurrent deep vein
thrombosis (DVT), pulmonary embolism (PE) and
mesenteric thrombosis.
• Homozygotes present in childhood with severe arterial
and venous thrombosis.
Protein C and Protein S
• Both synthesized in the liver and dependent on vitamin
K.
• Protein C degrades Factors Va and VIIIa, and promotes
brinolysis by inactivating plasminogen-activator
inhibitor 1.
• Protein S is a cofactor for protein C and enhances its
activity.
• Hereditary protein C deciency may occur, patients
being more susceptible to:
• pulmonary embolism
• supercial thrombophlebitis
• cerebral venous thrombosis.
Anticoagulant Drugs
e two most commonly used in surgical practice are heparin
and warfarin. Many newer anticoagulants have been developed; the most commonly encountered of these in surgical
practice are clopidogrel and the most recently launched new
oral anticoagulants (NOACs; e.g. rivaroxaban).
Heparin
• Heparin potentiates the action of antithrombin III.
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SECTION III Pathology
• Standard unfractionated heparin is administered intravenously or subcutaneously and has a half-life of about 1 h.
• Low-molecular-weight heparin (LMWH) is used subcutaneously, has a longer biological half-life and does
not require monitoring but is contraindicated in severe
renal failure and cannot be reversed. is is now the
standard treatment for DVT/PE or to reduce the risk
of DVT or PE in patients undergoing major surgery or
patients who are on prolonged bed-rest, e.g. post-myocardial infarction or orthopaedic patients.
• Intravenous heparin is used in patients with thromboembolic disease with severe renal failure precluding
LMWH, or in cases where rapid reversal of heparin
anticoagulation is required, as this can be performed by
stopping the heparin infusion and administering protamine sulphate intravenously.
• Dosage is monitored by performing APTT, which
should be maintained at 2–2.5 × normal.
• Heparin does not cross the placenta and is therefore the
drug of choice when anticoagulation is required during
pregn anc y.
• Side-eects of heparin include:
• thrombocytopenia
• hypersensitivity reactions
• alopecia
• osteoporosis (when used long term).
Warfarin
• Coumarin derivative which is administered orally.
• Vitamin K antagonist – in eect induces a state analogous to vitamin K deciency.
• Interferes with the activities of Factors II, VII, IX and X.
• Delays thrombin generation, thus preventing the formation of thrombi.
• Usual to give a loading dose (10 mg) and to determine
the international normalized ratio (INR; prothrombin
ratio standardized by correcting for the sensitivity of the
thromboplastin used) about 15–18 h later.
• Subsequent doses are based on monitoring of INR.
• Warfarin is usually administered for 3–6 months following DVT or PE.
• Life-long warfarin therapy is required for:
• recurrent venous thromboembolic disease
• some prosthetic heart valves
• congenital deciency of antithrombin III
• deciency of protein C or protein S
• patients with lupus anticoagulant
• valvular heart disease complicated by embolism or
atrial brillation.
• Bleeding is controlled by stopping warfarin and administering fresh frozen plasma or vitamin K, depending on
the degree of urgency.
• If vitamin K is used, there is a period of resistance to
warfarin and control may be dicult initially when the
patient is restarted on warfarin.
• A number of drugs may interfere with the control of
warfarin; these are:
• antibiotics
• laxatives (interfere with vitamin K absorption)
• phenylbutazone (interferes with binding of warfarin
to albumin)
• cimetidine (inhibits hepatic microsomal degradation).
• Warfarin crosses the placenta and is teratogenic, and
therefore should be avoided particularly in the rst trimester of pregnancy.
Clopidogrel
• Antiplatelet agent administered orally.
• Used in patients with ischaemic heart disease, cerebrovascular disease and to prevent thromboembolic events
where warfarin is contraindicated.
• It inhibits activation and aggregation of platelets by
blocking the glycoprotein IIa/IIIb pathway.
• Needs to be stopped for 7 days to reverse the eect.
• No coagulation monitoring test or specic reversal
agent exists.
NOACs (New Oral Anticoagulants, e.g. Rivaroxaban)
• Direct inhibitors of activated Factor X.
• ey are administered orally.
• Used for treatment and prophylaxis of venous thromboembolism and in patients with cerebrovascular disease.
• Eects are mostly reversed (i.e. can perform minor procedures) within 24 h of stopping the drug and totally
reversed in 48 h.
• No coagulation monitoring test or specic reversal
agent exists.
LYMPHOID SYSTEM
Lymph Nodes
Normal Structure and Function
• Lymph nodes are discrete encapsulated, usually kidneyshaped, structures, and range in diameter from a few
mm to several cm.
• Situated along the course of lymphatic vessels and are
numerous where these vessels converge, e.g. the root of
the limbs, the neck, the pelvis, the mediastinum.
• Structure of a lymph node is shown in Fig. 19.2.
• ere are three distinct microanatomical regions within
a lymph node; these are:
• the cortex: contains either primary or secondary
lymphoid follicles
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