HEMATOLOGY

Coagulation cascade

Intrinsic pathway (components already present in the blood)

Minor role in clotting
Subendothelial damage e.g. collagen
Formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK), prekallikrein, and
Factor 12
Prekallikrein is converted to kallikrein and Factor 12 becomes activated
Factor 12 activates Factor 11
Factor 11 activates Factor 9, which with its co-factor Factor 8a form the tenase complex which activates Factor
10

Extrinsic pathway (needs tissue factor released by damaged tissue)

Tissue damage
Factor 7 binds to Tissue factor
This complex activates Factor 9
Activated Factor 9 works with Factor 8 to activate Factor 10

Common pathway
Activated Factor 10 causes the conversion of prothrombin to thrombin
Thrombin hydrolyses fibrinogen peptide bonds to form fibrin and also activates factor 8 to form links between
fibrin molecules
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Fibrinolysis
Plasminogen is converted to plasmin to facilitate clot resorption

Intrinsic pathway Increased APTT Factors 8,9,11,12

Extrinsic pathway Increased PT Factor 7

Common pathway Increased APTT & PT Factors 2,5,10

Vitamin K dependent Factors 2,7,9,10

Coagulation factors are generally serine proteases. But some are

Glycoproteins V & VIII

Transglutaminase XIII

Hageman factor (XII), on contact injured vascular basement membrane, activates both collagen sequence &
kinin system.

Abnormal coagulation

Cause Factors affected

Heparin Prevents activation factors 2,9,10,11

Warfarin Affects synthesis of factors 2,7,9,10

DIC Factors 1,2,5,8,11

Liver disease Factors 1,2,5,7,9,10

Von Willebrand Disease (clinically resembles hemophilia)

RX : Desmopressin (DDAVP-RX of choice) Cryoprecipitate (I, VIII, XIII, vWF); VIII conc.; Desmopressin. The most useful
test in practice is to do the VwB Antigen and activity(RICOF)

Disseminated intravascular coagulation

Simultaneous coagulation and haemorrhage caused by initially formation of thrombi which consume clotting factors
(factors 5,8) and platelets, ultimately leading to bleeding

Causes include:
Infection
Malignancy
Trauma e.g. major surgery, burns, shock, dissecting aortic aneurysm
Liver disease

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 Obstetric complications

Key points
Clinically bleeding is usually a dominant feature, bruising, ischaemia and organ failure
Blood tests: prolonged clotting times, thrombocytopenia, decreased fibrinogen, increased fibrinogen
degradation products
Treat the underlying cause and supportive management

D-I-S-S-E-M-I-N-A-T-E-D

D - Dx: D dimer
I - Immune complexes
S - Snakebite, shock, heatstroke
S - SLE
E - Eclampsia, HELLP syndrome
M - Massive tissue damage
I - Infections: viral and bacterial
N - Neoplasms
A - Acute promyelocytic leukemia
T - Tumor products: Tissue Factor (TF) and TF-like factors released by carcinomas of pancreas, prostate, lung,
colon, stomach
E - Endotoxins (bacterial)
D - Dead fetus (retained)

Platelet function disorder : All (N)

Extrinsic Pathway; Warferin Rx; VII deficiency : All (N), PT rises
Intrinsic Pathway; Heparin; Haemophilia; (VIII, IX,XII) deficiency : All (N), APTT rises
VWD : All (N), APTT, BT rise (F VIIIc abnormal)
Vitamin K deficiency : All (N), APTT, PT rise
Common Pathway; DIC; Acute liver disease : All rises, Platelet, Hb reduce (Initially
factor V & VIII are consumed, then platelets)

* DIC : D dimer may be elevated due to endothelial cell injury *; (And also in PE)
** DIC shows rise of all except Platelet + fibrinogen**
*** APTT indicate intrinsic pathway and PT indicate extrinsic pathway***

DVT pt. + anticardiolipin & lupus anticoagulant ab (+)ve = underlying cz antiphospholipid syndrome.
Recurrent DVT = Factor V Leiden, Protein C, Protein S test to be done

Heparin

n
LMWH (and also Fondaperinux) :- (-) Xa (indirect inactiv of Xa)
n
HMWH: - binds antithrombinHeparin-antithrombin complex (-) IIa, IXa, Xa (indirect inactiv of thrombin)

n
Both unfractionated and low-molecular weight heparin can cz hyperkalaemia. It caused by inhibit of aldosterone
n
secret

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WARFERIN ALL

Warferin, inhibit vitamin K to become active hydroquinone form (hydroquinone form acts as co-factor in the
formation of factor II, VII, IX and X (mnemonic = 1972) and protein C)

Factors that may potentiate warfarin

Liver disease
P450 enzyme inhibitors, e.g.: amiodarone, ciprofloxacin
Cranberry juice
Drugs which displace warfarin from plasma albumin, e.g. NSAIDs
Inhibit platelet function: NSAIDs

Side-effects
Haemorrhage
Teratogenic
Skin necrosis: when warfarin is first started biosynthesis of protein C is reduced. This results in a temporary
procoagulant state after initially starting warfarin, normally avoided by concurrent heparin administration.
Thrombosis may occur in venules leading to skin necrosis

Protein-C is used as co-factor in activation of thrombomodulin

Blood products used in warfarin reversal
Immediate or urgent surgery in patients taking warfarin(steps 1 & 2):
1. Stop warfarin
2. Vitamin K (reversal within 4-24 hours)
-IV takes 4-6h to work (at least 5mg)
-Oral can take 24 hours to be clinically effective

3. Human Prothrombin Complex Concentrate (reversal within 1 hour)

-Bereplex 50 u/kg
-Rapid action but factor 6 short half life, therefore give with vitamin K

4. Fresh frozen plasma

Used less commonly now as 1st line warfarin reversal
-1
-30ml/kg
-Need to give at least 1L fluid in 70kg person (therefore not appropriate in fluid overload)
-Need blood group
-Only use if human prothrombin complex is not available

4. Human Prothrombin Complex (reversal within 1 hour)

-Bereplex 50 u/kg
-Rapid action but factor 6 short half life, therefore give with vitamin K

**Massive bleeding= stop warin, IV vitamin K & either PCC or FFP (PCC preferable, if available),

**If question says Bleeding due to Excessive Warferinisation then Factor IX concentrate (IX, X, XI ) to be given

Antistatin: direct factor Xa inhibitor

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 Hirudin+ Argatroban: Direct inactivation of thrombin

Anaemias

Chr.dis : S. Fe low; SpO2 low. S.ferritin raised TIBC low

Haemolytic : S. Fe not low
Chr. Blood loss : S. Fe low S. ferritin low; TIBC high
Fe deficiency : S. ferritin low; TIBC high
Megaloblastic : Not assoc. with Fe metabolism (gastritis; pernicious, B12 def.)
Autoimmune haemolytic : Direct coombs test positive (& also in Reynauds disease)

Vit B12 deficiency macrocytic anaemia and thrombocytopenia

Sickle cell anaemia

Disorder of varying degrees. It may present in childhood with anaemia and mild jaundice. In the older patient, vaso-
occlusive problems occur due to sickling in the small vessels of any organ, mimicking many medical and surgical
emergencies. Typical infarctive sickle crises (Vasoactive crisis; aplastic crisis; sequestration crisis) includes
bone pain, pleuritic pain, hemiparesis, fits, splenic infarcts, and priapism, Autosplenectomy occurs
Autosomal recessive
Single base mutation
Deoxygenated cells become sickle in shape
Causes: short red cell survival, obstruction of microvessels and infarction
Sickling is precipitated by: dehydration, infection, hypoxia
Manifest at 6 months age
Africans, Middle East, Indian
Diagnosis: Hb electrophoresis

Sickle crises
Bone pain
Pleuritic chest pain: acute sickle chest syndrome commonest cause of death
CVA, seizures
Papillary necrosis
Splenic infarcts
Priapism
Hepatic pain

Hb does not fall during a crisis, unless there is

Aplasia: parvovirus
Acute sequestration
Haemolysis

Long-term complications
Infections: Streptococcus pnemoniae
Chronic leg ulcers

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 Gallstones: haemolysis
Aseptic necrosis of bone
Chronic renal disease
Retinal detachment, proliferative retinopathy

Surgical complications
Bowel ischaemia
Cholecystitis
Avascular necrosis

Management
Supportive
Hydroxyurea
Repeated transfusions pre operatively
Exchange transfusion in emergencies

Sickle cell trait

Heterozygous state
Asymptomatic
Symptoms associated with extreme situations ie anaesthesia complications
Protective against Plasmodium falciparum

Drugs causing Aplastic Anaemia

Indomethacin
Sulphonamides
Penicillamine

Chronic Alcoholic develops Megalolblastic Anaemia (Hb & MCV)

Thrombocytopenia

Causes of severe thrombocytopenia

ITP
DIC
TTP
haematological malignancy

Causes of moderate thrombocytopenia

heparin induced thrombocytopenia (HIT)
drug-induced (e.g. quinine, diuretics, sulphonamides, aspirin, thiazides)
alcohol
liver disease
hypersplenism
viral infection (EBV, HIV, hepatitis)

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 pregnancy
SLE/antiphospholipid syndrome
vitamin B12 deficiency

Hereditary Spherocytosis

Most common disorder of the red cell membrane, it has an incidence of 1 in 5000. The abnormally shaped erythrocytes
are prone to splenic sequestration and destruction. This can result in hyperbilirubinaemia, jaundice and splenomegaly. In
older patients an intercurrent illness may increase the rate of red cell destruction resulting in more acute symptoms.
Severe cases may benefit from splenectomy

Some PBF Findings

AML : Blast cells with Auer bodies

CML, Myelofibrosis : Philadelphia chromosome (due to long arm deletion in chr-22)

CLL : Numerous small, mature lymphocytes

Infectious Mono. : Atypical Lymphocytosis; (Monospot test +ve)

DIC : Schistocyte(RBCs undergoing fragmentation)

Splenectomy** : Howell-Jolly bodies;

Pappenheimer bodies;
Poikilocytes (Target cells);
Irregular contracted erythrocytes(siderotic granules)

Hairy Cell Leukaemia : Hairy cell

Pb poison; Anaemia; Septicaemia : Basophilic Stippling; Clover leaf morphology(Pb poisoning)

Sickle cell; Thalassemia; Hemolytic : Traget cell

st
** In 1 few days after splenectomy target cells, siderocytes and reticulocytes will appear in circulation. Immediately
following splenectomy a granulocytosis (mainly neutrophils) is seen, it is replaced by lymphocytosis & monocytosis over
following weeks. Platelet count is usually raised & this may b persistent, oral antiplatelet agents may b needed.

XI deficiency is called Haemophilia C. Ashkenazi Jews are sufferer

Presence of Lupus anticoagulant: Antiphospholipid Syndrome

WHOLE BLOOD FRACTIONS

Fraction Key points

Packed red cells Used for transfusion in chronic anaemia and cases where infusion of large volumes of fluid may

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 result in cardiovascular compromise. Product obtained by centrifugation of whole blood.

Platelet rich Usually administered to patients who are thrombocytopaenic and are bleeding or require surgery. It is
plasma obtained by low speed centrifugation.

Platelet Prepared by high speed centrifugation and administered to patients with thrombocytopaenia.
concentrate

Fresh frozen Prepared from single units of blood.

plasma Contains clotting factors, albumin and immunoglobulin.
Unit is usually 200 to 250ml.
Usually used in correcting clotting deficiencies in patients with hepatic synthetic failure who
are due to undergo surgery.
-1
Usual dose is 12-15ml/Kg .
It should not be used as first line therapy for hypovolaemia.

Cryoprecipitate Formed from supernatant of FFP.

Rich source of Factor VIII and fibrinogen.
Allows large concentration of factor VIII to be administered in small volume.

SAG-Mannitol Removal of all plasma from a blood unit and substitution with:
Blood Sodium chloride
Adenine
Anhydrous glucose
Mannitol
Up to 4 units of SAG M Blood may be administered. Thereafter whole blood is preferred. After 8
units, clotting factors and platelets should be considered.

BAINBRIDGE REFLEX release Aldosterone to increase HR mediated via atrial stretch receptors that occurs following
rapid infusion of blood.