Hematology I

Lecture 15

Thrombosis

Professor Trujillo Cañete Ana Maria ,MD

Haematologist
Associate professor
 Thrombosis
 Physiological purpose:

◦To arrest haemorrhage

 Minor spontaneous bleedings (epistaxis)
 Trauma
 Delivery
 Menstruation
Thrombophilia
 Thrombophilia is a heritable or acquired
disorder of

the haemostatic mechanism predisposing to

thrombosis, typically venous.

 Pathological thrombosis (arterial and cardiac)

Causes:
 Abnormalities of the cell wall
 Atrial fibrillation (cardiac thrombi)
 Aneurysms (cardiac or arterial)
 Intra-arterial lines or injection
 Abnormalities of the clotting cascade (very rarely)
 Thrombocytosis and Polycythaemia
 Risk factors for arterial thrombosis
 Atheroma

◦ Associated with:
 Hyperlipidaemia
 Smoking
 Hypertension
 Diabetes mellitus
 Minor risk factors (obesity etc)

 Other forms of arterial disease

◦ Vasculitis (rarely)
Pathological venous thrombosis
◦ Causes
 Prolonged immobility (bed rest, air travel)
 Pelvic obstruction
 Nephrotic syndrome
 Dehydration
 Polycythaemia
 Thrombocytosis
 Varicose veins
 Lupus anticoagulant (anti-PL antibody)
 Estrogen therapy
 Pregnancy and the puerperium
 Post surgery (especially hip and abdominal)
 Major trauma
 Malignancy (especially pancreas)
 Abnormalities of the clotting cascade.
 VENOUS THROMBOEMBOLISM
 Common medical condition associated with significant morbidity.

 Largely preventable

 Occur in any vein(most commonly in the legs).

 Types

-superficial vein thrombosis

-deep vein thrombosis (serious condition).

complicated by pulmonary embolism(important causes of morbidity and mortality in
hospitalized patients).
VENUS THROMBI
 Composed predominantly of fibrin and red cells

 Activation of blood coagulation exceeds the ability of the natural

anticoagulant mechanisms and the fibrinolytic system to prevent
clot formation.

 Stasis and vascular injury are the most frequent precipitants of

venous thromboembolism.

 Vessel wall injury is an important factor predisposing the patient to

venous thromboembolism after major hip or knee surgery.
 CLINICAL FEATURES
• Most are asymptomatic .

• Symptoms and signs are caused by obstruction to venous

outflow, inflammation of the vessel wall or perivascular

tissues, or embolization of thrombus into the pulmonary

circulation.
Thrombophilia
Fibrinolysis
Thrombophilia:
ETIOLOGY
 Malignancy:
Mucin and proteases released from a tumour may
activate factor X

 Blood disorders with increased viscocity:

◦ Polycythaemia
◦ Thrombocytosis
◦ Sickle cell disease
◦ Paraproteinaemias
Thrombophilia: ETIOLOGY
 Estrogen therapy:
◦ Causes increases in factors ll, Vll, Vlll, lX and X
◦ Low dose oestrogen containing contraceptives are associated with
much lower risk

 Lupus anticoagulant:
◦ Found in SLE, other immune and viral disorders
◦ Anti-PL antibody
◦ Prothrombotic tendency, and spontaneous abortion.
Abnormalities of the clotting
cascade
1-Factor V Leiden (the commonest inherited
prothrombotic disease)

2-Prothrombin variant
3-Antithrombin lll deficiency
4-Protein C deficiency
5-Protein S deficiency
6-Abnormalities of fibrinogen and plasminogen
(very rare)
 Factor V Leiden
Activated protein C (+ cofactor protein S) inactivate Va and
Vlla.
The process is triggered by the binding of thrombin to its
endothelial receptor (thrombomodulin).

Factor V Leiden is a mutant form of factor V, which is

resistant to inactivation by activated protein C.
Prothrombin variant
A mutation in the 3’ untranslated region of the
prothrombin gene, leads to elevated levels of
prothrombin, and a 2-3 fold increased risk of
venous thrombosis.
Protein C and Protein S deficiency
Protein C deficiency is quite common.
Protein S deficiency is rare.
Both are autosomal dominant conditions
Associated with defective inactivation of factors Va and Vlla.
Neonatal purpura fulminans
 Rare, life-threatening condition, caused by congenital or
acquired deficiencies of protein C or S.
 The condition is often fatal unless there is early recognition

of the clinical symptoms, prompt diagnosis, and judicious

replacement therapy is initiated.
Plasminogen variants
Thrombi are dissolved by plasmin.
It dissolves fibrin to release fibrin degradation
products.
Also degrades fibrinogen and factors V and Vlll.
Plasminogen variants yield less active plasmin,
and are associated with an increased risk of
thrombosis.
 Screening test
 C. Blood count ,ESR
 Blood film examination
 Pt and APTT

 Anticardiolipin and anti-β -GPI

2
antibodies.
 Thrombin time
 Fibrinogen assay
 Activated protein C resistance (DNA

analysis for factor V Leiden)

 Antithrombin immunological and

functional assays
Anticoagulan
ts
 Anticoagulant therapy
 Drugs that reduce the coagulation of blood

 Antiplatelet drugs (including aspirin )

 Uses of anticoagulants

Heparin Warfarin
 Heparin is used for  Warfarin is used for
short-term action prolonged therapy
 Main indications:  Main indications
◦ Deep vein thrombosis ◦ Deep vein thrombosis
◦ Pulmonary embolism ◦ Pulmonary embolism
◦ Unstable angina ◦ Atrial fibrillation
◦ Arterial occlusion ◦ Prosthetic heart valves
◦ Myocardial infarction
 (prevents re-occlusion
after thrombolysis)
◦ Extracorporeal
circulations
Action of heparin
 Heparan sulphate (a glycosaminoglycan) is expressed on
endothelium, and is a natural co-factor for antithrombin lll.
Heparin is a mixture of a family of glycosaminoglycans. It is
found in masts cells, and is extracted commercially from
bovine lung or porcine intestine. Heparin mimics heparan
sulphate and activates antithrombin lll – and thus inhibits
the catalytic activity of thrombin.
Low molecular weight heparin
(fractionated by molecular weight)

 Advantages:  Examples:
◦ longer acting (sc inj ◦ enoxaparin
x1/day) ◦ tinzaparin
◦ Route: sc injection ◦ dalteparin
◦ APTT not required
◦ uniform responses
◦ suitable for
outpatients
 Disadvantages:
◦ cost
OTHER IV ANTICOAGULANTS

Hirudins  Heparinoids
 Thrombin antagonists
◦ Danaparoid
 Prepared from the
◦ Avoids the risk of
medicinal leech
thrombocytopenia
◦ Lepirudin (iv & sc)
◦ Used mainly in
◦ avoids
orthopedic
thrombocytopenia
surgery in
risk
patients with a
◦ Used in
history of
interventional
thrombocytopenia
cardiology
after heparin.
◦ monitor APTT
WARFARIN
 Warfarin is a structural analogue
of vitamin K
 Warfarin blocks biosynthesis of
clotting factors II, VII, IX, X
 Route: oral (x1 daily)
 Monitor: PT (INR: 2-4)
 Slow onset of action
◦ Preformed clotting factors in the
circulation are cleared slowly
 Drug interactions Reversal: Vit K
injection (im)
 Warfarin
 Problems:
◦ haemorrhage
◦ avoid NSAIDs
◦ teratogenic (1st trim)
◦ Drug interactions
 Prolonged use
◦ DVT: 3 months
◦ PE: 6 months
◦ Recurrent PE: 1 year +
◦ Atrial fibrillation: life long
◦ Prosthetic heart valves: life long
 Therapy in Fibrinolysis

 Naturally occurring fibrinolytic agent is

tissue plasminogen activator(tPA), which
permits the release of plasmin.
 Therapeutically, there are several options:
◦ Streptokinase
◦ Alteplase (recombinant tPA)
◦ Retaplase
 Indications:
◦ Acute myocardial infarction
◦ Pulmonary embolism
◦ Thrombotic stroke
◦ Arterial occlusion
 Fibrinolysis

Streptokinase
 Isolated from streptococci
 The action is blocked by anti-streptococcal
antibodies, which appear in about 4 days.
 An interval of 1 year+ must elapse before
the drug is used again
 Streptokinase is active against circulating
(plasma) plasminogen (not clot-directed)
 Route: iv infusion for 1 hour in myocardial
infarction.
Contraindications for fibrinolysis

 Contraindications include:
◦ Recent haemorrhage, trauma or surgery
◦ Coagulation or other bleeding disorders
◦ Dissection
◦ Coma or previous CVA
◦ Heavy menstruation
◦ Severe hypertension
◦ Lung cavitation
◦ Acute pancreatitis
◦ Pericarditis or bacterial endocarditis
◦ Severe liver disease
◦ Oesophageal varices
◦ Active proliferative diabetic retinopathy
◦ Streptokinase should not be used if there is a
history of previous allergy to streptokinase
Reversal of thrombolytic drugs

Tranexamic acid
 Inhibits plasminogen activation
 May be given po or by iv injection
 Uses: For treatment in the following
circumstances :
◦ Serious haemorrhage (eg following
prostatectomy or dental extraction)
◦ Significant menorrhagia
◦ Life threatening bleeding following
thrombolytic therapy.