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Thrombophilia

Thrombophilia/ Hyper coagulable States Thrombosis


Inherited or Acquired Haemostatic disorders
↑ Risk of developing Thrombotic complications (compared with general)
Clinical
History of Recurrent Thrombosis
Thrombosis at early age DVT of legs
Familial Tendency Unusual sites
Thrombosis at unusual sites Upper extremity thrombosis
Underlying disease/ conditions associated with thrombo-embolic disorder Cerebral vein
Adrenal infarction
Thrombosis Budd-Chiari syndrome
Solid masses/ plugs formed in circulation from blood constituents Renal vein thrombosis
Platelets, Fibrin – Form basic structure Visceral vein thrombosis
Outcome Retinal vein thrombosis
Ischaemia from local vascular obstruction Priapism
Distant Embolization
Complications Virchow
MI (Myocardial Infarction) Causes of Thrombosis (3 main groups)
Cerebro-Vascular disease ↓ Blood Flow
Peripheral Artery Disease (Arterial Thrombosis) Change in vessel wall (vessel wall damage)
Venous Thrombosis Change in blood composition (hypercoagulability)
Thrombophilia/ Hypercoagulable state – Venous Thrombosis Most risk factors for venous thrombosis
(unless otherwise stated) Stasis
Changes in overall total blood coagulabality
Blood Coagulation Pathway (Arterial Thrombosis – Vessel wall Damage)
↑ Risk of Thrombosis (Venous)
Haemostatic balance between procoagulant, anticoagulant forces Mechanisms/ Pathogenesis of Thrombosis
shift in favour of coagulation Abnormal Blood Flow Abnormal Vasculature Abnormal Coagulation
↓ Ac&vity of An&coagulant Mechanism leads to Sickle cell disease Hyperlipidemia AT
↑ Blood clot forma0on CCF Atherosclerosis Protein C deficiency
Thrombosis Obesity DM Protein S deficiency
If caused by Inherited defect, resulting hypercoagulable state Hyperviscosity Vasculitis Nephrotic syndrome
is a lifelong ↑ risk of thrombosis Trauma

Haemostatic Balance Arterial Thrombosis


Procoagulant Anticoagulant Pathogenesis Risk Factors
PAI-I Protein S Atherosclerosis (AS) Family History
Antiplasmin Protein C ↓ Male
Tissue Factor TFPI Plaque Rupture Hyperlipidemia
Clotting Factors Fibrinolytic system ↓
Hyperhomocysteinaemia
Endothelial Injury
AT III ↓ Serum Folate, B12, B6

Blood Exposure HPT, DM, Gout
Regulation of Blood Coagulation (Subendothelial Collagen, TF) Polycythemia
Require strict regulation (considerable biological potential) ↓ Cigarette smoking
Plasma proteins, Protein-cell interactions – involved in constant sensoring Formation of Platelet Collagen vascular disease
Nidus, Adhere, Aggregation
Efficient control

Circulating Inhibitors Platelet Deposition
Fibrinolytic pathway ↓
Release PDGF

Proliferation of
smooth muscle, fibroblasts
(in Arterial Intima)

Thickening of Blood Vessel

Venous Thrombosis
Acquired Risk Factors Inherited Risk Factors
Advanced age Factor V Leiden mutation
Heart disease, Myocardial infarct PT20210A (Abnormal Prothrombin)
Immobility Antithrombin deficiency
Lupus Anticoagulants Protein C deficiency
Malignancy Protein S deficiency
Obesity Fibrinolytic disorders – Abnormal
Oral contraceptives (oestrogen) Plasmin
Pregnancy, Puerperium
Clinical Trauma, Surgery
Varicose Veins
Deep Vein Thrombosis (DVT) of the legs (common site)
Pulmonary Embolism – outcome of distal thrombosis Nephrotic syndrome
Depends on site of Thrombosis Hyperhomocysteinaemia
Lower Limb – DVT – Pain, Swelling of Lower Limb (+ve *Homan’s sign) Hyperviscosity states
Abdomen – Intra-abdominal thrombosis Myeloproliferative diseases
(mesenteric thrombosis, b owel ischaemia) – Pain in abdomen Paroxysmal Nocturnal
Chest Pain – Pulmonary Embolism Haemoglobinuria
Consequent of DVT Behcet’s syndrome
Chronic Leg Ulcer
Post Phlebitic Limb Syndrome (limb - dis coloration, pain, swelling)
(Post-Thrombotic Syndrome)
*Homan’s sign – Forceful Dorsiflexion of Foot will cause pain in Calf
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Acquired (↑ Common than Inherited) Inherited

Acquired Risk Factors for Venous Thrombosis (↑ common in ou r regio n than Caucasian) Factor V Leiden (FVL) (Common – Whites)
Age Hereditary resistance to activated protein C
< 40 y/o – 1:10,000 people/year Defect in Factor V
>75 y/o – 1:100 people/year Render it unable to be degraded by activated protein C
Malignancy Associated with primarily Venous Thrombosis
Solid Tumour Epidemiology
Lymphoma 2-15% of normal pop ulation (white), 40-60% of all hypercoagulable states
Mucin Secreting Adenocarcinomoas Rare in Malaysia
Troussseau syndrome – Migrating nature of venous thrombosis
Cancer patients Prothrombin Gene Mutation
Procoagulant material produced by tumour (AML-M3) Mutation in PT gene : 20210G → A
Mechanical effects due to venous ob struction by tumour Might be involved in Arterial disease
General effect of an acute phase reactants Epidemiology
↓ Mobility, Direct effect of treatment Mutation is present in 1-2% normal population
↓ Protein C, Protein S Perhaps 10-20% in patients with hypercoagulable states
Immobilization
Prolonged bed rest (from complicated operative procedures) Protein C Deficiency
Long haul airline travel (cramped seating – economy class travel) Protein when activated will degrade F VIIIa, F Va
Mechanism Primarily will cause Venous Thrombosis
• Interfering of function of calf mus cles in pumping blood upstream Epidemiology
through veins Incidence in pop ulation – 1:200
• Lead to prolonged stasis, excessive activation of coagulation system 5-10% of Hypercoagulable states
(in relatively static areas associated with valve cusps) Warfarin Induced Skin Necrosis
Nephrotic Syndrome Purpura Fulminans in Neonates
Loss of AT III (Antithrombin) in urine
Haemolytic Disorders
Paroxysmal Nocturnal Haemoglobinuria
(defect in red cell membrane – prone to haemolysis when blood pH changes)
Heparin induce d Thrombocytopenia Thrombosis
Complication of Heparin therapy
Paradoxically, associated with Thrombocytopenia
Acquired Hypercoagula ble states Skin Necrosis
OCP, HRT (Oral Contraceptive Pill)(Hormone Replace ment Therapy)
↑ VII, VIII, XII, VWF, Fibrinogen Protein S Deficiency
Platelet changes Protein S = cofactor for Protein C
3rd generation OCP - ↑ risk of thrombosis
Deficiency of free Protein S can lead to
Myeloproliferative Disorders
Hypercoagulable state (unbound to C4b)
↑ Blood viscosity
Primarily causes Venous Thrombosis
↑ Platelet count, activity
↑ Haematocrit levels (hyperaggregability of platelets, ↑ blood viscosity) Epidemiology
Incidence in pop ulation – 1:?5000
Antiphospholipid Syndrome (APS) (Common Acquired Cause of Thrombosis ) 5-10% of Hypercoagulable states
Can be diagnose d as
Antithrombin Deficiency
Arterial/ Venous Thrombosis
Isolated Thrombocytopenia Antithrombin Inhibits Activated Factors (Thrombin, 7,9,10,11 )
Recurrent miscarriages Thrombin
F XIa
1° or 2° to auto-immune disease (eg. SLE)
F IXa
Acquired Thrombophilia/ Thromb osis (common cause)
F Xa
Investigation
F VIIa
Anti-phospholipid antibodies comprise of a family of antibodies
Important Serine Protease Inhibitor (Serpin) in regulation of blood coagulation
Lupus Anticoagulant (LA) Anticardiolipin Antibodies
Epidemiology
APTT ↑
1-3% of Hypercoagulable states
Mixing Test – Not Corrected
Proceed to confirmatory test
(eg. Lupus Anticoagulant study)

[PL = Phosp holipid]


Mechanism of Thrombogenesis in LA
Inhibition of Endothelial activation of Protein C
Inhibition of Endothelial cell release or production of prostacycline
↓ Protein S
Impaired Fibrinolytic Capacity
(In Vivo disturb anticoagulant activity)

Conclusion
Prolongs clotting time (in vitro)
In vivo effects of this antibody
Suppression of Fibrinolysis
Disturbed Protein C system
Disturbed Endothelial function
Lead to Thrombosis
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Approach
Thrombosis
Arterial (associated with Atherosclerosis, Embolism)
Venous (most Hypercoagulable states)
Site of Thrombosis
DVT
Visceral Thrombosis (PNH, Behcet’s Disease)
Age
Thrombosis (rare in childhood)(1st thrombosis in late teens → thirties)
Neoplasm/ Acquired Hypercoagulable state
(sudden onset of thrombosis in older patient)
Risk Factors for Thrombosis
Immobilization (Older patients after surgery, hospitalization)
Associated disease (SLE, Nephrotic syndrome)
Young patients – should be screened for defe cts
Family History
Many Hypercoagulable states – Inherited
Thrombotic Tendency – variable penetrance
(rate of thrombosis less than 50% expected for Autosomal Dominant traits)

Investigations
General evaluation
(Con firm diagnosis of thromb osis)
Contrast CT
Venography
Duplex and Colour Code d Doppler Ultrasound
Ventilation-Perfussion Scintigraphy
Others
Biochemi cal tests
Con tissue study
Exclude Neoplas m (malignant)

Haemostatic Tests
Coagulation Screening Tests
APTT – Prolonged (in LA – Lupus Anticoagulant)
D-Dimer
+ve due to activation of fibrinolytic system
FBP
Thrombosis in Myeloproliferative disorders
(as a result of thrombocytosis, polycythaemia)(Hct ↑ > 55%)
Acid Lysis Test
+ve (in PNH)
Haemolytic condition associated with thrombosis
(due to clot formation from platelet lysis)

Hypercoagulable State Tests


DNA Study – Genetic/ Molecular Test
FVL
Prothrombin Gene Mutation
Protein C Activity/ Antigen assay
↓ – in Protein C deficiency
Protein S Activity/ Antigen assay
↓ - in Protein S deficiency
AT III Activity/ Antigen assay
↓ in AT deficiency
Homocysteine level
↑ - in Genetic cause of Hyperhomocysteneimia
Factor VIII assay
↑ - in Acquired, Hereditary cause of Thrombosis
APL Antibodies assays
LA Tests
Anticardiolipin Antibodies (IgG, IgM, IgA) are presence

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