Thrombophilia overview

Thrombophilia Microchapters
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Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Thrombophilia from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
Laboratory Findings
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Asiri Ediriwickrema, M.D., M.H.S. [2]

Overview

Thrombophilia is a complex condition which increases the risk of thrombosis or thromboembolic disease. The predisposition to clotting, or thrombotic risk, can be multi-factorial, and is due to an abnormality in coagulation described as hypercoagulability. Hypercoagulability by itself or in synergy with the other components of Virchow's Triad can predispose to clot formation. The thrombotic risk associated with thrombophilic states is variable and depends on the underlying coagulopathy. Thrombophilias are classified as either inherited or a primary hypercoagulable state, acquired or a secondary hypercoagulable state, or mixed/unknown. Factor V Leiden and prothrombin gene mutations are the most common forms of inherited hypercoagulable states. Patients with thrombophilia can have a family history of thrombosis, or present with frequent or unprovoked blood clots (primarily as deep vein thrombosis or pulmonary embolism), thrombosis at a young age, or blood clots in multiple or unusual sites. Thrombophilia screening is controversial, but may aid in managing the duration of anticoagulation in affected patients and primary prevention in relatives.

Historical Perspective

Rudolf Virchow described hypercoagulability in the mid 1800s, however, it was not until 1965 that the first descriptions of inherited thrombophilia were published'. Later, in the 1990s, the more common mutations associated with primary hypercoagulable states were identified.

Classification

• Thrombophilias are typically classified into three categories:

1. Inherited or a primary hypercoagulable state
2. Acquired or a secondary hypercoagulable state
3. Mixed/unknown

• Certain conditions are associated with greater thrombotic risks and both venous and arterial clots.

Pathophysiology

• The pathogenesis of thrombophilia is multi-factorial. It is characterized by hypercoagulability, which by itself or in synergy with endothelial injury or stasis (Virchow's Triad) can predispose to clot formation.
• Multiple genetic mutations and predisposing conditions have been associated with the increased risk of thrombus formation due to abnormalities in the coagulation cascade. .

Causes

• Thrombophilia may be caused by either acquired, inherited, or, more commonly, a combination of both conditions.
• The most common forms of inherited thrombophilia are Factor V Leiden (20-50% prevalence in patients with recurrent venous thrombosis) and prothrombon G20210A (5-20% prevalence in patients with recurrent venous thrombosis).

Differentiating Inherited Thrombophilia from other Diseases

• Inherited thrombophilia must be differentiated from acquired thrombophilia, as it may influence the selection and duration of anticoagulation.
• Inherited thrombophilias should be suspected in patients with the certain clinical presentations.
• Screening for inherited thrombophilias is controversial and should be performed in the appropriate clinical context.

Epidemiology and Demographics

• Due to the multitude and complexity of inherited thrombophilias, the true prevalence is unknown, and current data may be providing an underestimate. Comparison among different epidemiologic studies becomes difficult due to variation in study design and inclusion criteria.
• Prevalence of common inherited thrombophilias is variable among both healthy patients and patients with recurrent thrombosis.
• According to epidemiologic and modeling studies obtained from certain sources, the prevalence of inherited thrombophilias was estimated to be between 0.01-7% in caucasians.
• In certain studies, the prevalence of inherited thrombophilias, specifically, activated protein C resistance and prothrombin G20210A, rises to approximately 24-37% in patients with documented venous thrombosis compared to less than 10% among controls.
• The incidence of inherited thrombophilia in incident venous thrombosis is approximately 150-840 per 100,000 person years.
• The incidence of inherited thrombophilia in recurrent venous thrombosis is approximately 3,500-10,500 per 100,000 person-years.

Age

• Patients of all age groups may develop thrombophilias.
• Inherited thrombophilias are more commonly observed among patients aged <40-55 years old.
• Acquired thrombophilias are more commonly observed among elderly patients (age > 60) as age is a risk factor for thrombosis.

Gender

• Epidemiologic studies have provided mixed results regarding the effect of gender on venous thrombosis. Certain groups observed increased risk of thrombosis in younger females and older males, whereas other groups found similar frequencies in both genders.
• A prospective follow up study performed by Christiansen et al, revealed an age corrected hazard ratio of 2.7 of recurrent thrombosis in male patients with inherited thrombophilias compared to women.
• In patients with inherited thrombophilias, a prospective follow up study performed by Christiansen et al revealed an age corrected hazard ratio of 2.7 for recurrent thrombosis in male patients compared to women.

Race

• The factor V leiden G1691A and prothrombin G20210A mutations are exceedingly rare in non-white populations.

Risk Factors

• Inherited thrombophilias should be suspected in certain clinical presentations.
• Refer to the thrombophilia classification page for a list conditions associated with acquired thrombophilias, and to the page on causes of thrombophilia by organ system.

Natural History, Complications and Prognosis

• Refer to the clinical symptoms section regarding early clinical features of patients with thrombophilia.
• Annual thrombotic risks are variable and depend on the underlying thrombophilia.
• If left untreated, the annual incidence of incident thrombosis in asymptomatic patients with factor V leiden and prothrombin G20210A (<0.06%) is low. The risk is approximately equivalent to treatment with oral contraceptives (OCPs). Whereas the annual incidence of significant bleeds is approximately 2-3%.
• Studies performed by Christiansen et al and Baglin et al revealed that inherited thrombophilia did not predict for recurrent thrombosis.
• OCPs, hormone replacement therapy, and pregnancy can significantly increase thrombotic risk in patients with thrombophilia.
• Certain high risk thrombophilias require indefinate anticoagulation.

Diagnosis

Diagnostic Criteria

• The diagnosis of [disease name] is made when at least [number] of the following [number] diagnostic criteria are met:

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

Symptoms

• [Disease name] is usually asymptomatic.
• Symptoms of [disease name] may include the following:

• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
• [symptom 6]

Physical Examination

• Patients with [disease name] usually appear [general appearance].
• Physical examination may be remarkable for:

• [finding 1]
• [finding 2]
• [finding 3]
• [finding 4]
• [finding 5]
• [finding 6]

Screening

• The American Society of Hematology recommends against thrombophilia screening in adult patients with venous thrombosis in the setting of major transient risk factors.
  • Major transient risk factors including: surgery, trauma, or prolonged immobility.
  • However, patients who have significant risk factors including a positive family history or concurrent treatment with hormonal therapies should seek expert consultation.
• Thrombophilia screening can be expensive, and are often performed at inappropriate times.

Laboratory Findings

• There are no specific laboratory findings associated with [disease name].

• A [positive/negative] [test name] is diagnostic of [disease name].
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of [disease name].
• Other laboratory findings consistent with the diagnosis of [disease name] include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Imaging Findings

• There are no [imaging study] findings associated with [disease name].

• [Imaging study 1] is the imaging modality of choice for [disease name].
• On [imaging study 1], [disease name] is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• [Disease name] may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

• There is no treatment for [disease name]; the mainstay of therapy is supportive care.

• The mainstay of therapy for [disease name] is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action 1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for [disease name].
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of [disease name].
• [Surgical procedure] can only be performed for patients with [disease stage] [disease name].

Prevention

• There are no primary preventive measures available for [disease name].

• Effective measures for the primary prevention of [disease name] include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with [disease name] are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].