Thrombophilia overview

# 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  is a component of  Virchow's Triad, which by itself or in synergy with stasis or trauma 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 initiation and 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 may be classified into three groups: inherited or primary hypercoagulable states, acquired or secondary hypercoagulable states, or 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 thrombosis due to abnormalities in the coagulation cascade. The most common genes involved in the pathogenesis of acquired thrombophilias are Factor V Leiden and prothrombin gene mutations.

# Causes
Thrombophilia may be caused by either acquired, inherited, or, more commonly, a combination of both conditions. The most frequent 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 Thrombophilia from other Diseases
Thrombophilias must be differentiated from other diseases that cause the following clinical presentations: family history of thrombosis, especially at an early age (< 45 years), unprovoked thrombosis at an early age (<40-55 for venous thrombosis and <50-55 for arterial thrombosis), recurrent thrombosis including deep venous thrombosis, pulmonary embolism, or superficial venous thrombosis.

# 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 10-60% 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. Acquired thrombophilias are more commonly observed among elderly patients (age > 60) as age is a risk factor for thrombosis. Inherited thrombophilias can be seen among young patients aged <40-55 years old.

## 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
The most common risk factors in the development of acquired thrombophlias are trauma, surgery, immobility, pregnancy, oral contraceptives, hormone replacement therapy, and age. Common risk factors for the development of inherited thrombophilias are a family history of thrombosis at an early age or a family history of inherited thrombophilia. Common genetic risk factors in the development of inherited thrombophilias are mutations in Factor V Leiden and prothrombin G20210A.

# Natural History, Complications and Prognosis
The 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) is low (<0.06%) . 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 from factor V leiden and prothrombin G20210A did not predict for recurrent thrombosis. Christiansen et al and De Stefano et al observed a mild increased risk for recurrent thrombosis in patients with  protein C, protein S, and antithrombin deficiency.  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 an inherited thrombophilia is made with specific laboratory tests for each inherited condition.

## Symptoms
Common symptoms of thrombophilias may include symptoms of Deep venous thrombosis, Pulmonary embolus, and superficial venous thrombosis.

## Physical Examination
Physical examination of patients with thrombophilia is usually remarkable for signs of deep venous thrombosis, pulmonary thrombosis, renal vein thrombosis, cerebral vein thrombosis, superficial vein thrombosis, arterial thrombosis, portal hypertension which can be sign of portal vein thrombosis, warfarin skin necrosis, or livedo reticularis.

## Screening
According to the American Society of Hematology, screening for inherited thrombophilias in adult patients with venous thrombosis in the setting of major transient risk factors which include surgery, trauma, or prolonged immobility is not recommended. However, given the associated risks for recurrent thrombosis, patients who have significant risk factors including a positive family history or concurrent treatment with hormonal therapies should seek expert consultation.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of inherited thrombophilias include specific laboratory findings associated with each inherited thrombophilia.

## Imaging Findings
Ultrasongraphy, computed tomography angiography (CTA or CT Angiography), magnetic resonance angiography (MRA or MR Angiography) and projectional angiography may be diagnostic of acute thrombosis, which is associated with the diagnosis of thrombophilia.

# Treatment

## Medical Therapy
The treatment for thrombophilia depends on the underlying hypercoagulable state and the clinical presentation. The mainstay of therapy for thrombophilia is anticoagulation with either warfarin, low molecular weight heparin, direct Xa inhibitors, or direct thrombin inhibitors. Treatment should be tailored to the individual patient. The risks and benefits, required monitoring, and costs associated with each form of anticoagulation should be discussed with the patient prior to initiation of therapy. All patients on anticoagulation should be monitored for bleeding.

## Surgery
Surgery is not required for treatment for thrombophilia. IVC filter placement may be indicated if the patient has contraindications to or complications from anticoagulation, recurrent thrombosis on anticoagulation, or failure to acheive therapeutic anticoagulation levels.

## Prevention
Prophylaxis with anticoagulation may be recommended for primary prevention of acute thrombosis in certain scenarios. Once diagnosed and successfully treated, patients with thrombophilia are followed-up routinely to monitor anticoagulation and clinically if thrombosis recurrs