Thrombophilia

Thrombophilia
OMIM	188050
DiseasesDB	29080
MeSH	D019851

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-In-Chief: Kashish Goel, M.D.

Synonyms and Keywords: Hypercoagulability, coagulability, hypercoagulable state

Overview

Thrombophilia is defined as an increased risk of thrombosis in the body, due to an abnormality in the system of coagulation. Thrombophilia can be congenital or acquired. More than 50% of the cases of thrombosis are associated with an underlying thrombophilia. Thrombophilias are mostly associated with venous thromboembolism like deep vein thrombosis in lower extremities or pulmonary embolism. Relatively less is known about thrombophilias that predispose to arterial thromboembolism.

Classification

Thrombophilia can be classified in various forms.

• The most common classification is by the nature of the thrombosis: arterial, venous or combined.
• Crowther & Kelton (2003) propose to classify the abnormality by the molecular deficiency, type I being the (severe) deficiencies of inhibitors, and type II being the less severe elevation of coagulation factors.
• Acquired vs. congenital

Pathophysiology

The Virchow's triad has been described classically as the patho-physiologic mechanism responsible for any thrombosis, which includes 3 components:

• Endothelial dysfunction
• Venous stasis
• Hypercoaguability

The mechanism of thrombophilia involves affecting the pathway of thrombosis:

Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31.

Epidemiology and Demographics

Prevalence of various inherited thrombophilias and their clinical impact

Disorder	Healthy subjects/General population (%)	Patients with known thrombosis (%)	Estimated increase in thrombosis risk
Antithrombin deficiency	0.02	1 - 4	10 - 20X
Dysfibrinogenemia	<1	<1	Variable
Protein C deficiency	0.2 - 0.4	3 - 5	10X
Protein S deficiency	0.3 - 0.13	2 - 4	10X
Factor V Leiden	1 - 15	18 - 40	5X
G20210A prothrombin gene mutation	2 - 5	7 - 16	3X
Hyperhomocystenemia	5	10	3X
Elevated factor VIII levels	11	25	5X

Causes

Common types:

• Factor V, Leiden type (5% of the population are heterozygous for FVL).
• Prothrombin mutation (G20210A, 5'UTR).
• High homocysteine levels due to MTHFR mutation or vitamin deficiency (vitamins B6, B12 and folic acid).
• Antiphospholipid antibodies
  • anti-cardiolipin antibodies and/or
  • lupus anticoagulants
• Renal disease (renal loss of antithrombin)

Rare forms:

• Plasminogen and fibrinolysis disorders.
• Paroxysmal nocturnal hemoglobinuria
• Protein C deficiency.
• Protein S deficiency.
• Antithrombin III deficiency.

Differential diagnosis of thrombophilia

(By organ system)

Indications for testing

Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious other cause. For example, if the thrombosis is due to immobilisation after recent orthopedic surgery, it is unlikely that an underlying cause is found. Comprehensive testing in any patient should include complete assessment of risk factors and its effect on long-term therapy. Some of the indications may include:

• Unexplained venous thromboembolism at an age of less than 50 years
• Recurrent spontaneous thrombosis
• Unusual sites like portal, splenic, mesenteric, hepatic or renal veins
• Family history in first-degree relatives
• Recurrent pregnancy losses
• Recurrence of venous thromboembolism while adequately anticoagulated
• Warfarin-induced skin necrosis
• Unexplained arterial thromboembolism in a younger patient without significant arteriosclerosis risk factors and no cardioembolic source

Conversely, although thrombosis itself may occur in any person, repeated (two or more) unprovoked episodes of thrombosis and unusual sites and types of thrombosis (e.g. Budd-Chiari syndrome) may point towards a coagulation disorder.

Increasingly, recurrent miscarriage is seen as an indication for thrombophilia screening.

Tests for thrombophilia include prothrombin time and INR, partial thromboplastin time, thrombin time, fibrinogen levels, antiphospholipid antibody levels (IgG- and IgM-anticardiolipin, dilute Russell viper venom time and lupus anticoagulant), protein C, protein S and antithrombin (both levels and activity), activated protein C resistance (APC resistance), factor V Leiden and prothrombin mutation. Many laboratories add on various other tests, depending on local policy and guidelines.

References

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