Thrombophilia



THROMBOPHILIA

“The Lost Chance”, oil on canvas, Charles Burton Barber, 1881

When we assess patients for thromboembolic disease it is important to consider the possible underlying causes for their condition. A first presentation of a thromboembolic event represents an opportunity to consider and explore possible previously hidden underlying pathologies. One important aspect of this assessment will be a careful consideration of the risk factors the patient may have. In acquired conditions this can be quite obvious, and further haematological investigation may not be necessary, however in hereditable conditions, an obvious precipitant may not be apparent. In these cases we must not lose our chance to investigate a possible underlying hypercoaguable state, lest our patient be “left out in the cold”, just like Charles Burton Barber’s poor cat!

THROMBOPHILIA

Introduction

Thrombophilia describes a hypercoagulable state, i.e. a disorder of haemostasis in which there is a tendency for the occurrence of thrombosis.

The causes can be inherited or acquired.

The Inherited Thrombophilia Conditions:

Heritable thrombophilia (or hypercoagulable state) describes an inherited tendency for venous thrombosis (DVT, with or without associated PE).

Deficiency of the natural anticoagulant antithrombin was the first reported inherited risk factor for venous thromboembolism (Egeberg, 1965). Since then a range of other inherited conditions leading to thrombophilia have been described thus explaining many cases of venous thromboembolism that were previously unexplained.

Inherited thrombophilic disorders can be identified in up to 50% of patients presenting with VTE

In the 1980s and 1990s thrombophilia testing became common practice in unselected patients and their relatives despite the fact that there was no evidence that testing had clinical utility. It is now apparent that unselected testing for heritable thrombophilia typically does not predict likelihood of recurrence in unselected patients with symptomatic venous thrombosis.

The challenge therefore is to define those groups who should have a thrombophilia screen for hereditary conditions.

The decision to test selected patients should ideally be based on whether or not test results are likely to influence later treatment decisions.

Note that current negative testing does not necessarily exclude a heritable risk through as yet unrecognised mechanisms.

Pathology

Causes:

The acquired causes are well known and include:

1. A past history of DVT/PE, (the strongest risk factor).

2. Decreased mobility:

● Especially in the setting of prolonged travel such as plane flights.

3 Trauma

4. Recent operation, (especially pelvic, orthopedic)

5. Pregnancy or recent delivery

6. Oral contraceptive

7. Smoker

8. Obesity

9. Predisposing medical conditions:

● Malignancies, including hematological

● Acquired procoagulation syndromes:

♥ Anti-phospholipid syndrome, (Lupus anticoagulant and Anti- cardiolipin antibodies)

Heritable thrombophilia conditions include:

1. Anti-thrombin III deficiency

2. Protein C deficiency

3. Protein S deficiency

4. Factor V Leiden mutation (or Activated Protein C (APC) resistance).

5. Prothrombin (20210A gene mutation).

6. Increased plasma concentration of fibrinogen or other coagulation factors.

7. Hyper-homocysteinaemia, (may be partly determined by environment).

Clinical assessment

Testing for thrombophilia conditions should be done according to clinical risk stratification as follows:

Indicated:

Considerer tests for hereditable thrombophilia conditions in the following groups:

1. A family history of unprovoked recurrent venous thrombosis.

2. Recurrent unexplained venous thrombosis

3. Thrombosis in unusual sites, (venous sinus thrombosis, intra-abdominal thrombosis)

4. Prior to commencement of OC or HRT, in women with first degree relatives with a known thrombophilia defect.

5. Pregnant women with a previous event due to a minor provoking factor, e.g. travel, should be tested (and considered for prophylaxis if a thrombophilia is found).

6. Neonates and children with purpura fulminans should be tested urgently for protein C and S deficiency

7. Adults who develop skin necrosis in association with oral vitamin K antagonists are tested for protein C and S deficiency after vitamin K antagonists treatment is withdrawn.

Not indicated:

1. Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis

2. Indiscriminate testing for heritable thrombophilia in unselected patients presenting with a first episode of venous thrombosis is not indicated

● Inherited thrombophilia is only weakly associated with recurrence in patients with a first venous thrombosis.

Investigations

Tests for heritable thrombophilia are often used inappropriately and non-selectively.

For patients suspected of having a thrombophilia condition consider the following tests:

1. FBE

2. Clotting profile

● INR

● APPT

3. Fibrinogen

4. Anti-phospholipid syndrome tests:

● Lupus anticoagulant

● Anti-cardiolipin antibodies

When considering a hereditary cause:

5. Factor VIII levels

6. Factor V (Leiden factor) mutation:

● Activated Protein C (APC) resistance (if this level is low, then DNA genetic testing of the cells will be done for Leiden factor).

7. Protein C.

8. Protein S.

9. Anti-thrombin activity.

Further test that may be specifically requested include:

10. Prothrombin gene G20210A

11. Methylene tetrahydrofolate reductase.

12 Homocysteine

Cautions:

Antithrombin concentration is reduced in acute thrombosis, by heparin treatment and in pre-eclampsia.

Proteins C and S are vitamin K dependent and their concentrations are reduced by warfarin treatment.

It is especially important therefore to record any anti-coagulation the patient may be on, including warfarin, heparin or clexane, (fractionated heparin)

● If the patient is taking warfarin, the Protein C and S levels may be affected.

● If the patient is receiving heparin or clexane, the anti-thrombin III levels may be affected, as may the lupus antibody testing.

Note that if the patient is receiving any of these anticoagulants, procoagulation screens can still be done, but it is important that this fact is recorded on the request slip.

It should also be noted that the same thrombophilic disorder can have very different clinical penetrance within families; such that test results give little guidance in determining a management plan for an individual patient (they have more relevance in determining risk on a population basis). 3

Management

In general terms:

● Initiation and intensity of anticoagulant therapy following a diagnosis of acute venous thrombosis should be the same in patients with and without heritable thrombophilia

● Decisions regarding duration of anticoagulation (lifelong or not) in unselected patients should be made with reference to whether or not a first episode of venous thrombosis was provoked or not, other risk factors, and risk of anticoagulant therapy-related bleeding, regardless of whether a heritable thrombophilia is known.

Treatment decision are complex decisions and should always be made in consultation with a specialist clinical haematologist.

Appendix 1

The coagulation cascade and fibrinolytic system:

Extrinsic clotting pathway Intrinsic clotting pathway, (F12)

(F3, tissue thromboplastin)

F7 F8, 9, 10

X Xa F5

Prothrombin (F2) Thrombin

Plasminogen Fibrinogen (F1) Fibrin

(Stable clot)

tPA

(from

endothelium)

Plasmin

FDPs

(including

D-Dimers)

TM = thrombomodulin, APC = activated protein C, PS = protein S, PS-C4BP = Protein S-C4b complement complex.

Appendix 2: Notes on conditions

Inherited:

Anti-thrombin III deficiency

Antithrombin III is a potent inhibitor of the coagulation cascade.

It is synthesized in the liver and in endothelial cells.

It acts as an anticoagulant by directly binding with and inactivating the serine proteases which include Factors, IXa, Xa, XIa and IIa (thrombin).

Protein C deficiency

Protein C has anti-coagulating activity.

Protein C is a vitamin K-dependent glycoprotein synthesized in the liver.

It is activated by the catalyzing action of thrombin (in the presence of thrombomodulin), into activated protein C (APC).

Activated protein C then exerts anticoagulant activity primarily through inactivation of coagulation factors Va and VIIIa, which are required for thrombin generation.

A deficiency of protein C therefore will lead to a procoagulation tendency.

Protein S deficiency

Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the endothelium.

In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b.

It functions as a cofactor to Protein C in the inactivation of Factors Va and VIIIa. Only the free form has cofactor activity.

A deficiency of protein S therefore will lead to a procoagulation tendency.

20210A gene mutation

The prothrombin 20210 G/A gene mutation, is associated with elevated levels of prothrombin (i.e. factor II) in plasma.

This results in a significantly increased the risk of developing venous thrombosis.

Factor V Leiden Mutation

In Factor V Leiden Mutation, activated protein C tends to have problems deactivating the factor V protein. The factor V is abnormal and is less able to be deactivated by APC. In other words it has activated protein C resistance.

There is therefore more factor V available to convert prothrombin to thrombin and a hypercoagulable state ensues.

Hyper-homocysteinaemia, (may be partly determined by environment)

High plasma homocysteine levels are a risk factor for deep-vein thrombosis.

It is uncertain how hyperhomocysteinemia leads to venous thrombosis and atherosclerosis. One hypothesis is that homocysteine has a direct toxic effect on the vascular endothelium and on the clotting cascade.

Acquired:

Anti-phospholipid syndrome

This disease may be primary (idiopathic) or it may be secondary to various auto-immune diseases, most commonly, SLE.

Characteristic laboratory abnormalities in APS include persistently elevated levels of antibodies directed against membrane phospholipids (e.g. anticardiolipin antibody or lupus inhibitor antibody).

Although antiphospholipid antibodies are clinically linked to APS, it is unclear whether they are involved in the pathogenesis of disease or whether they are merely an epiphenomenon

The exact mechanism of thrombosis in APS is not clear, though there are a number of different theories.

Arterial as well as venous thrombosis can occur in this condition.

Recurrent first trimester abortions are a common feature of this disease.

The disease is much more common in females.

Patients with the syndrome who have suffered from a thrombosis episode are considered for long term warfarin therapy or heparin therapy when pregnant.

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