Thrombophilia
Thrombosis
- Solid masses formed in the circulation from blood constituents
- Results in ischaemia from local vascular obstruction or distant embolisation
Arterial thrombosis
- Risk factors are related to the development of atherosclerosis. These include;
- Positive family history
- Male sex
- Hyperlipidaemia
- Diabetes mellitus
- Gout
- Polycythaemia
- Hyperhomocycteinaemia
- Smoking
- ECG abnormalities
- Elevated Factor VII
- Elevated fibrinogen
- Lupus anticoagulant
- Collagen vascular diseases
- Behcet’s disease
- Positive family history
Venous thrombosis
- Virchow’s triangle suggests there are 3 components important to thrombus formation;
- Slowing down of blood flow
- Hypercoagulability
- Vessel wall damage
- Slowing down of blood flow
- Risk factors
- Related to stasis
- Cardiac failure
- Stroke
- Prolonged immobility
- Pelvic obstruction
- Nephrotic syndrome
- Dehydration
- Hyperviscosity – polycythaemia
- Cardiac failure
- Related to coagulation
- Hereditary disorders
- Factor V
Leiden - Protein C deficiency
- Protein S deficiency
- Antithrombin deficiency
- Prothrombin mutations
- Factor V
- Acquired
- Pregnancy
- Oestrogen therapy
- Surgery
- Trauma
- Malignancy
- Thrombocythaemia
- Pregnancy
- Hereditary disorders
- Related to unknown factors
- Age
- Obesity
- Sepsis
- Paroxysmal nocturnal haemoglobinuria
- Behcet’s disease
- Age
- Related to stasis
Hereditary disorders of haemostasis
Factor V
- Incidence of 5% in Caucasions
- Protein C breaks down activated Factor V so activated Protein C should slow the clotting reaction
- A missense mutation of the factor V gene (arginine replaced by glutamine) renders it 10 times less sensitive to Protein C inactivation
- Increased risk of venous but not arterial thrombosis
- Patients who are heterozygous have a 5-8 fold increased risk of thrombosis
- Patients who are homozygous have a 30-140 fold risk
Antithrombin III deficiency
- Autosomal dominant inheritance
- Affects 1 in 2000
- The deficiency can either result in Type I (decreased quantity) or Type II (reduced biological activity)
- Heterozygotes have 50% of normal levels of ATIII, homozygotes are lethal
Protein C deficiency
- Autosomal dominant inheritance with variable penetration
- Patients have a tendency to develop skin necrosis when put on warfarin at first. Possibly due to a further reduction in Protein C in the first day or two of therapy before there is a reduction in the Vit K dependant clotting factors
Protein S deficiency
- Also autosomal dominant inheritance
- Clinically indistinguishable from Protein C deficiency
Prothrombin allele G20210A
- Carried by 2% of population
- Leads to increased plasma prothrombin levels and a two-fold increased thrombotic risk
Hyperhomocysteinaemia
- May be genetic or aquired and are associated with an increased risk of venous and arterial thrombosis
Acquired risk factors
Postoperative venous thrombosis
- More likely to occur in the elderly, obese, those with a previous family history and those in whom major abdominal or hip operations have been performed
Venous stasis and immobility
- Possibly responsible for post-operative venous thrombosis, and venous thrombosis associated with congestive CF, MI and varicose veins
Malignancy
- Risk increased with all cancers, particularly ovary, brain and pancreas
- The tumours produce Tissue factor and a pro-coagulant that directly activated factor X
Mucin secreting adenocarcinomas are associated with an increased risk of DIC
Inflammation
- Up regulates pro-coagulant factors and down regulates anti-coagulant factors, particularly Protein C
- Thrombosis is particularly associated with IBD, Behcet’s disease, SLE, systemic TB and diabetes
Blood disorders
- Increased incidence of thrombosis in polycythaemia vera and thrombocythaemia due to increased viscosity, thrombocytosis and altered platelet membrane receptors and responses
Oestrogen therapy
- Increases plasma levels of Factors II, VII, VIII, IX and X and decreases levels of antithrombin and tissue plasminogen activator in the vessel wall
Antiphospholipid syndrome
- Also called lupus anticoagulant syndrome
- May be defined as the occurrence of thrombosis or recurrent miscarriage in association with laboratory evidence of persistent antiphospholipid antibodies
- One antiphospholipid antibody is the ‘lupus anticoagulant’ which was initially detected in SLE and is identified by a prolonged APTT which doesn’t correct with a 50:50 mixture of normal plasma
- Also associated with other antiphospholipid antibodies e.g. anti-cardiolipin and anti-β2-glycoprotein
- The disease can be idiopathic or associated with other autoimmune diseases
- It increases the risk of both venous and arterial thrombosis
- Clinical associations;
DVT ,PE , venous thrombosis of renal, cerebral and mesenteric veins- Arterial thrombosis
- Recurrent foetal loss
- Thrombocytopenia
- Livedo reticularis
Investigation of thrombophilia
- Full assessment should be done in patients with recurrent or spontaneous DVT or PE, those who have thrombosis at a young age, those with a familial tendency for thrombosis and those who develop thrombosis at unusual sites. It may also be indicated in women experiencing recurrent foetal loss
- The following lab tests are used in diagnosis;
- Blood count and ESR – to detect elevation in haematocrit, WCC, platelets, fibrinogen and globulins
- Blood film examination – may show evidence of a myeloproliferative disorder
- PT and APTT – a prolonged APTT is often seen in thrombotic states and may indicate the presence of activated clotting factors
- Anti-cardiolipin and β2-glycoprotein antibodies
- Thrombin time and reptilase (from snake venom) time – prolongation suggests an abnormal fibrinogen
- Fibrinogen assay
- Activated protein C resistance test and DNA analysis for Leiden factor V
- Antithrombin - measurement and function
- Protein C and protein S – measurement and function
- Prothrombin gene analysis for G20210A variant
- Plasma homocysteine estimation
- Test for CD59 and CD55 expression on red cells if paroxysmal nocturnal haemaglobinuria is suspected
- Blood count and ESR – to detect elevation in haematocrit, WCC, platelets, fibrinogen and globulins
Anticoagulant therapy
Heparin
- Potentiates the formation of complexes between antithrombin and activated serine protease coagulation factors, thrombin and Factors IX, X and XI. This complex formation inactivates these factors irreversibly
- Low molecular weight heparin preparations are produced by enzymatic or chemical depolymerisation of unfractionated heparin.
- They have a greater ability to inhibit Factor Xa and thrombin and interact less with platelets so have a lesser tendency to cause bleeding
- They also have a greater bioavailability and a more prolonged plasma half life making once daily treatment fessible
- It is also associated with a lower risk of osteoporosis and thrombocytopenia
- Given IV or sub cut
- Doesn’t cross the placenta so can be given in pregnancy
- If severe bleeding occurs, give protamine to inactivate the heparin
Warfarin
- Is is coumarin derivative
- Vitamin K antagonist so results in decreased activity of factors II, VII, IX and X
- Blocks γ-carboxylation of glutamic acid
- After warfarin is give, Factor XII drops considerably in the first 24hr but prothrombin (Factor II) has a longer half life and only falls by 50% at 3 days. The patient is only fully anti coagulated after this period
- A typically starting regime would be 10mg on day 1 and 5mg on day 2 and 3 and following this time adjusting the dose according to the PT
- The maintenance dose is normally 3-9mg/day but individual responses vary greatly
- Lower loading dosage is recommended for the elderly and those with liver disease
- The INR is based on the ratio between the patients PT to a mean normal PT with correction for the sensitivity of the thromboplastin used. The higher the INR, the greater the bleeding incidence
- Warfarin in teratogenic
- 97% of warfarin is bound to albumin, the rest being free and active
- Drugs that interfere with albumin binding, or excretion of warfarin or that decrease the absorption of Vitamin K
Drug interactions with warfarin
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Increase anticoagulant effect |
Decrease anticoagulant effect |
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Fibrinolytic agents
Lyse fresh thrombi. May be used for an acute MI, major PE or iliofemoral thrombosis
Most effective in the first 6 hours of symptoms
Includes streptokinase and tissue plasminogen activator
Antiplatelet agents
- Asprin is valuable in the secondary prevention of vascular disease
- Is inhibits platelet COX irreversibly thus reducing the production of thromboxane A2
- Low dose therapy is more effective than standard doses at enhancing the prostacyclin:thromboxane A2 ratio and may have greater antithrombotic effect
- Is inhibits platelet COX irreversibly thus reducing the production of thromboxane A2
- Clopidogrel
- ADP receptor antagonist
- Used for the reduction of ischaemic events in patients with ischaemic stroke, MI or peripheral vascular disease
- ADP receptor antagonist
- Glycoprotein IIb/IIIa inhibitors
- Abciximab and tirofiban
- Monoclonal antibodies that inhibit the platelet GPIIb/IIIa receptor
- Abciximab and tirofiban