Thrombophilias, risk factors for thrombosis

Overview

Thrombophilia refers to a group of conditions associated with an increased tendency to form thrombi (blood clots) due to an imbalance between procoagulant and anticoagulant mechanisms. This imbalance may be inherited or acquired and may lead to venous or arterial thrombosis and embolic complications.

Thrombotic disorders are clinically expressed as part of **thromboembolic disease (TED)**, which includes deep vein thrombosis (DVT), pulmonary embolism (PE), thrombophlebitis, and other systemic embolic events.

Hemostasis and its disorders

Hemostasis is the physiological process responsible for stopping bleeding. It involves three simultaneous mechanisms:

• Vascular response (vasoconstriction)
• Platelet function (primary hemostasis)
• Coagulation cascade (secondary hemostasis)

The final result is the formation of a thrombus.

Disturbances of hemostasis arise from an imbalance between procoagulant and anticoagulant factors and are divided into two main groups:

• Hemorrhagic diatheses – increased bleeding tendency (reduced hemostasis)
• Thrombophilic states – increased clot formation (excessive hemostasis)

Primary and secondary hemostasis

• Primary hemostasis – vasoconstriction, platelet adhesion and aggregation

 Disorders: thrombocytopenia, thrombocytopathies, vascular disorders (e.g. vitamin C deficiency, vasculitis)

• Secondary hemostasis – coagulation cascade

 Disorders:
 * Congenital: hemophilia A (factor VIII), hemophilia B (factor IX), afibrinogenemia
 * Acquired: vitamin K deficiency, liver failure

Fibrinolysis represents the third stage of hemostasis, responsible for clot breakdown.

Thrombophilic states

Thrombophilias may be classified as inherited or acquired.

Inherited thrombophilias

These result from genetic defects in coagulation or fibrinolytic factors:

• Factor V Leiden mutation (activated protein C resistance)
• Prothrombin gene mutation
• Protein C deficiency
• Protein S deficiency
• Antithrombin III deficiency
• Hyperhomocysteinemia

Acquired thrombophilias

Acquired hypercoagulable states are often explained by **Virchow’s triad**:

• Stasis of blood flow

 * Immobilization
 * Postoperative state
 * Pregnancy and postpartum period

• Endothelial injury

 * Trauma
 * Surgery
 * Inflammation
 * Varicose veins
 * Sepsis

• Hypercoagulability

 * Malignancy
 * Oral contraceptives
 * Pregnancy
 * Nephrotic syndrome
 * Obesity
 * Smoking

Additional major risk factors include:

• Age > 40 years
• Female sex (estrogen-related risk)

Thromboembolic disease (TED)

Thromboembolic disease represents a spectrum of conditions caused by thrombosis and embolization.

It includes:

• Deep vein thrombosis (DVT)
• Pulmonary embolism (PE)
• Thrombophlebitis
• Post-thrombotic syndrome
• Mesenteric vascular occlusion
• Disseminated intravascular coagulation (DIC)

In clinical practice, TED often refers primarily to DVT and its complications such as pulmonary embolism.

Pathophysiology

Thrombosis develops through:

• Endothelial injury
• Blood stasis
• Hypercoagulable state

Initial platelet adhesion forms a “white thrombus,” followed by fibrin deposition and propagation into a mixed thrombus.

Subsequent inflammation of the vessel wall may lead to organization and partial recanalization, though venous valves are often permanently damaged.

Deep vein thrombosis (DVT)

Deep vein thrombosis is the formation of a thrombus in the deep venous system, most commonly in the lower limbs (calf, popliteal, femoral, iliac veins).

It is the most common source of pulmonary embolism.

Pathophysiology

The development of DVT is classically explained by Virchow’s triad:

• Hemodynamic changes (stasis)
• Endothelial damage
• Hypercoagulability

Clinical features

Typical symptoms include:

• Unilateral limb swelling
• Pain and tenderness
• Increased skin temperature
• Dilated superficial veins
• Livid discoloration

Peripheral pulses are usually preserved.

Diagnosis

• Clinical examination
• D-dimers (high sensitivity, low specificity)
• Duplex ultrasonography (first-line imaging)
• CT venography in selected cases

Treatment

Goals:

• Prevent pulmonary embolism
• Prevent thrombus extension
• Promote thrombus resolution

Treatment options:

• Low molecular weight heparin (LMWH)
• Unfractionated heparin
• Warfarin (long-term therapy)
• NOACs (e.g. rivaroxaban, apixaban)
• Thrombolysis in severe cases
• Caval filter in contraindications to anticoagulation

Complications

• Pulmonary embolism
• Post-thrombotic syndrome
• Chronic venous insufficiency

Prevention

• Early mobilization
• Compression stockings
• Hydration
• Anticoagulant prophylaxis in high-risk patients

Pulmonary embolism (PE)

Pulmonary embolism is a life-threatening condition caused by obstruction of the pulmonary arteries, most commonly by thromboembolism originating from deep veins of the lower limbs.

Sources of emboli

• Deep veins of lower extremities (most common)
• Pelvic veins
• Right heart
• Inferior vena cava
• Central venous catheters

Non-thrombotic emboli include:

• Fat embolism
• Air embolism
• Amniotic fluid embolism
• Tumor embolism
• Septic emboli

Risk factors

Same as for venous thrombosis:

• Previous DVT/PE
• Surgery (especially orthopedic)
• Trauma
• Malignancy
• Pregnancy and oral contraceptives
• Immobilization
• Obesity
• Smoking
• Inherited thrombophilias

Clinical presentation

Symptoms vary from asymptomatic to sudden death:

• Sudden dyspnea (most common)
• Tachypnea
• Chest pain (pleuritic or substernal)
• Tachycardia
• Hemoptysis (rare)
• Syncope in severe cases

Diagnosis

• CT pulmonary angiography (gold standard)
• Ventilation-perfusion scan
• D-dimers
• ECG (signs of right heart strain)
• Echocardiography
• Blood gas analysis (hypoxemia, hypocapnia)

Treatment

• Anticoagulation (heparin, LMWH, warfarin, NOACs)
• Thrombolysis (alteplase) in massive PE
• Surgical or catheter embolectomy in selected cases
• Supportive therapy (oxygen, inotropes)

Prevention

• Early mobilization
• Anticoagulant prophylaxis
• Mechanical compression
• Caval filters in selected patients

Conclusion

Thrombophilias and thrombosis risk factors represent a central mechanism in venous thromboembolic disease. Understanding the balance between coagulation and anticoagulation, along with Virchow’s triad, is essential for prevention, diagnosis, and management of thrombotic complications.

References

• Češka R. et al. Internal Medicine, Triton, Prague, 2020.
• Widimský J., Malý J. Diagnosis and treatment of pulmonary embolism, Cor et Vasa.
• WikiLectures: Deep Vein Thrombosis
• Vaněk I. Cardiovascular Surgery, Karolinum, 2003.