Background

• Venous thromboembolism (VTE) refers to the formation of blood clots in the veins, typically occurring in the deep veins of the legs (deep vein thrombosis or DVT) and potentially leading to a life-threatening complication known as pulmonary embolism (PE). VTE is a significant medical condition that affects millions of people worldwide and has the potential for serious morbidity and mortality if not properly managed. 
• Thromboembolic disease is the third most prevalent abrupt cardiovascular ailment, following cardiac ischemic conditions and stroke.  
• The scope of illness varies from clinically unnoticed to clinically insignificant to substantial embolism resulting in demise, and in fact DVT and PE often go undetected because they may not be suspected clinically. 

Epidemiology

• VTE is a global health issue, and its prevalence varies across different populations and regions. It is estimated that VTE affects millions of people worldwide each year. The exact prevalence can be challenging to determine accurately due to varying study methodologies, but it is generally considered a common condition. 
• The incidence of VTE varies by age, sex, and underlying risk factors. VTE is more common in older adults, with the incidence increasing with age. It affects both men and women, although certain risk factors, such as pregnancy and the use of hormone therapy, can increase the risk in women.  
• There are several risk factors associated with an increased likelihood of developing VTE. These include advanced age, immobility or prolonged periods of inactivity, surgery especially orthopedic and abdominal procedures, trauma, obesity, pregnancy and the postpartum period, cancer, hormone therapy such as oral contraceptive therapy.  

Anatomy

Pathophysiology

• Hypercoagulability refers to a state of increased coagulation or clotting tendency. Various factors can contribute to hypercoagulability, including inherited or acquired conditions, hormonal imbalances, malignancies, pregnancy, certain medications, and underlying medical conditions like antiphospholipid syndrome. Hypercoagulability increases the risk of clot formation and inhibits the natural mechanisms that prevent excessive clotting. 
• Venous stasis refers to the slowing or stagnation of blood flow within the veins. It can occur due to conditions that impede the normal movement of blood, such as immobility, prolonged bed rest, long-distance travel, or conditions that affect the functioning of the venous valves or muscle pump. 
• As the blood clot spreads, it undergoes proximal expansion, which can result in detachment or fragmentation and travel to the blood vessels in the lungs. This results in blockage of the pulmonary arteries, and the platelets release vasoactive substances (such as serotonin), which raises the resistance in the blood vessels of the lungs. 
• The blockage in the arteries raises the amount of unused space in the air sacs of the lungs and causes a change in the distribution of blood flow. As a result, gas exchange is impaired because certain areas of the lungs have less ventilation compared to blood supply. 

Etiology

• Factors that increase the risk of thromboembolic disease can be categorized into several groups, which include factors related to the patient, medical conditions, surgical factors, and disorders affecting the blood. The risk of developing thromboembolic disease is cumulative. 
• Patient-related factors that contribute to the risk include being over the age of 40, being obese, having varicose veins, taking estrogen in high doses (such as oral contraceptives or hormone replacement therapy), and being immobile. 
• Medical conditions such as cancer, congestive heart failure, nephrotic syndrome, recent heart attack, inflammatory bowel disease, paralysis due to spinal cord injury, and fractures in the pelvic, hip, or long bones increase the risk of developing thromboembolic disease.

Genetics

Prognostic Factors

• The size and location of the blood clot are important prognostic factors. Clots that extend into proximal veins are generally associated with a higher risk of complications compared to those limited to distal veins. Extensive clot burden or involvement of multiple veins increases the risk of complications, such as recurrent VTE or post-thrombotic syndrome. 
• The history of previous VTE events is an important prognostic factor. Individuals who have experienced one or more episodes of VTE are generally at a higher risk of recurrent VTE compared to those without a previous history. Recurrent VTE may influence the duration and intensity of anticoagulation therapy and require more aggressive preventive measures. 
• The presence of PE, particularly if it is massive or accompanied by hemodynamic instability, is a significant prognostic factor. PE can impair blood flow to the lungs, leading to respiratory and cardiovascular compromise.  

Clinical History

• As individuals age, the risk of developing VTE increases. Older adults may also have decreased mobility, leading to venous stasis, and an increased likelihood of undergoing surgical procedures, which further increases the risk of VTE. 
• VTE can also occur in middle-aged adults, typically between the ages of 40 and 60. While the risk is generally lower compared to older adults, several factors can contribute to VTE in this age group. These factors may include hormonal changes associated with the use of oral contraceptives or hormone replacement therapy, pregnancy, or the presence of other risk factors such as obesity, smoking, or underlying medical conditions. 

Physical Examination

• Palpation: Palpate the affected limb for tenderness, pain, or cord-like structures, which may suggest deep vein thrombosis (DVT). 
• Compare the temperature of the affected limb with the contralateral limb to identify any temperature asymmetry. 
• Individuals suffering from deep vein thrombosis (DVT) often experience isolated swelling, discomfort, heat, and redness in the affected area. The patient typically describes the pain associated with DVT as “cramp-like” located in the lower leg or thigh of the impacted limb (although it can occur in any limb). They may display a limited range of motion in the limb, inability to walk, or pain that spreads. 
• Patients with sudden pulmonary embolism (PE) may exhibit chest pain when breathing, difficulty breathing, exhaustion, back discomfort, loss of consciousness, or even fatality if severe (e.g., PE associated with unstable blood flow or strain on the right side of the heart). Symptoms may include rapid heartbeat, rapid breathing, fever, and potentially reduced oxygen levels. 

Age group

Associated comorbidity

• Chronic Kidney Disease (CKD): CKD is a risk factor for VTE due to multiple factors, including abnormalities in coagulation and platelet function, inflammation, and impaired renal clearance of clotting factors. Patients with end-stage renal disease on dialysis are at particularly high risk of VTE. 
• Obesity: Adipose tissue, especially visceral adipose tissue, is associated with a proinflammatory state and an imbalance in procoagulant and anticoagulant factors. Obesity can also lead to increased venous stasis and impaired venous return, promoting clot formation. 
• Cancer: Cancer, particularly certain types such as pancreatic, lung, gastrointestinal, ovarian, or hematological malignancies, is associated with an increased risk of VTE. Cancer can lead to a hypercoagulable state through various mechanisms, including the release of procoagulant substances, activation of the coagulation system, and compression of blood vessels by tumors. 

Associated activity

Acuity of presentation

• Many cases of VTE present with subacute symptoms, meaning the symptoms develop gradually over time. The symptoms may include pain, swelling, and tenderness in the affected leg (in the case of DVT), as well as warmth and redness over the affected area. Subacute presentation allows for earlier detection and treatment initiation compared to asymptomatic cases. 
• VTE can be asymptomatic, meaning that the individual does not experience any noticeable symptoms. These cases are often discovered incidentally during imaging tests conducted for other reasons. Asymptomatic VTE is more common in lower-extremity deep vein thrombosis (DVT) and may be seen in individuals with a history of prior VTE or known risk factors. 

Differential Diagnoses

• Muscular strain: Muscle injuries or strains can cause localized pain, swelling, and limited mobility, which may mimic the symptoms of DVT.  
• Cellulitis: Skin infection and inflammation can lead to redness, warmth, swelling, and pain, resembling the signs of DVT. However, cellulitis typically has more diffuse involvement of the affected area, with visible skin changes and associated symptoms like fever. 
• Superficial thrombophlebitis: It involves inflammation and clot formation in superficial veins, usually visible under the skin. It can cause localized pain, redness, and swelling.  

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

• Anticoagulant Therapy: The initial focus is on preventing the clot from growing larger and reducing the risk of further clot formation. Pharmacological treatment with anticoagulant medications is the mainstay of therapy during the acute phase.  
• Transition to Oral Anticoagulants: Once the acute phase is managed, many patients transition from injectable anticoagulants to oral anticoagulants for long-term treatment.  
• Thrombolytic Therapy: In severe cases where there is a large clot burden or hemodynamic instability, thrombolytic therapy may be considered. Thrombolytics, such as tissue plasminogen activator (tPA), help dissolve the clot more rapidly.  
• Supportive Measures: Non-pharmacological approaches, such as compression stockings, elevation of the affected limb, and early mobilization, are often recommended to improve blood flow and reduce the risk of complications. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

use-of-non-pharmacological-approach-for-treating-venous-thromboembolism

• Elevating the affected limb: Elevating the affected leg, especially when sitting or lying down, can help reduce swelling and improve blood flow. Raising the leg above heart level can facilitate venous return and reduce the risk of blood clot progression.  
• Compression therapy: Compression therapy involves the use of compression stockings or bandages to apply pressure on the legs, promoting blood flow and preventing blood pooling. It is commonly used in conjunction with pharmacological therapy and is especially beneficial for patients with acute VTE or those at risk of developing post-thrombotic syndrome.  
• Physical activity and exercise: Regular physical activity and exercise promote blood circulation and help prevent blood stasis. Engaging in activities such as walking, swimming, or cycling can improve overall cardiovascular health and reduce the risk of developing blood clots.  

• Hydration: Staying adequately hydrated is important for maintaining healthy blood flow and preventing blood from becoming too viscous. It is advisable to drink plenty of fluids, especially during long periods of immobility or in hot environments. 
• Quit Smoking: Smoking has been associated with an increased risk of blood clots. Quitting smoking is beneficial not only for reducing the risk of VTE but also for overall cardiovascular health. 

Use of Anticoagulant agents

Anticoagulants help to prevent the formation of blood clots or reduce the size of existing clots, thereby reducing the risk of VTE, which includes deep vein thrombosis (DVT) and pulmonary embolism (PE). 

• Heparin: Heparin is an injectable anticoagulant that works by inhibiting the clotting factors in the blood. It is often used in the acute treatment of VTE, such as in hospital settings, and can be administered intravenously (IV) or subcutaneously (under the skin). Heparin may also be used during surgery to prevent clot formation. 
• Low molecular weight heparin (LMWH): LMWH, such as enoxaparin or dalteparin, is a modified form of heparin that has a longer half-life and more predictable anticoagulant effects. It is often used for the prevention and treatment of VTE, including in outpatient settings. LMWH is usually given as a subcutaneous injection once or twice daily. 
• Warfarin: Warfarin is an oral anticoagulant that interferes with the production of clotting factors in the liver. It is commonly used for long-term anticoagulation therapy to prevent recurrent VTE. Warfarin requires regular monitoring of the International Normalized Ratio (INR), a measure of blood clotting time, to ensure proper dosing. 

Use of direct <a class="wpil_keyword_link" href="https://medtigo.com/drug/thrombin-topical" title="thrombin" data-wpil-keyword-link="linked">thrombin</a> inhibitors

• Direct oral anticoagulants (DOACs): DOACs, such as rivaroxaban, apixaban, dabigatran, and edoxaban, are newer oral anticoagulants that directly inhibit specific clotting factors in the blood. They have a more predictable anticoagulant effect than warfarin and do not require regular INR monitoring. DOACs are often used for the treatment and prevention of VTE. 
• Rivaroxaban: It is a factor Xa inhibitor approved for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE). It is also used for the prevention of recurrent VTE. Rivaroxaban is typically prescribed as a once-daily oral medication. 
• Dabigatran: It is a direct thrombin inhibitor used for the treatment and prevention of DVT and PE. While not as commonly prescribed for VTE treatment as the factor Xa inhibitors, it is still an option in certain situations. Dabigatran is typically given as a twice-daily oral medication. 
• Apixaban: It is another factor Xa inhibitor indicated for the treatment and prevention of DVT and PE, as well as the prevention of recurrent VTE. It is generally administered as a twice-daily oral medication. 

Use of Thrombolytic therapy in treatment of Venous Thromboembolism

Thrombolytic therapy accelerates the restoration of pulmonary tissue and swiftly reverses right heart failure. It also enhances blood flow in pulmonary capillaries and expedites the improvement of hemodynamic parameters. 

Thrombolytic agents, also known as fibrinolytic agents, are medications used to dissolve blood clots and restore blood flow. While they are commonly used in the treatment of arterial thromboembolism, such as acute myocardial infarction or ischemic stroke.  

• Alteplase (tPA): Alteplase is a tissue plasminogen activator (tPA) that promotes the conversion of plasminogen to plasmin, which helps dissolve blood clots. It can be administered systemically (intravenously) or directly into the clot (catheter-directed thrombolysis). 
• Tenecteplase: Tenecteplase is a modified form of tPA that has a longer half-life and higher fibrin specificity. It is occasionally used in thrombolytic therapy for VTE, but its use is less common than alteplase. 

use-of-intervention-with-a-procedure-in-treating-of-venous-thromboembolism

• Thrombectomy: It is another minimally invasive procedure used to remove or break up blood clots. It involves the use of specialized devices, such as catheters with rotating blades or suction devices, to physically disrupt or remove the clot. This procedure is usually performed in cases where the clot burden is significant and can’t be adequately addressed with medications alone. 
• Inferior vena cava (IVC) filter placement: IVC filters are small, cage-like devices inserted into the inferior vena cava, a large vein that carries blood from the lower body to the heart. These filters are used in cases where there is a contraindication to anticoagulant therapy or recurrent clotting despite optimal medical treatment. The filter acts as a barrier, trapping blood clots and preventing them from reaching the lungs.  

use-of-phases-in-managing-venous-thromboembolism

• Acute Phase: The acute phase focuses on immediate management and prevention of clot progression. The primary goals are to stabilize the patient, prevent further clot formation, and minimize the risk of complications such as pulmonary embolism (PE). 
• Subacute Phase: Long-term anticoagulation therapy is initiated with oral anticoagulants. The duration of therapy depends on various factors, including the underlying cause of VTE, the presence of ongoing risk factors, and the occurrence of recurrent VTE. 
• Follow-up and Long-Term Management: Regular follow-up visits are essential to assess the patient’s response to treatment, monitor for potential complications, and adjust the treatment plan as needed. 
• Ongoing monitoring of anticoagulation therapy, including laboratory tests like international normalized ratio (INR) for patients on warfarin, is conducted to ensure therapeutic levels and minimize the risk of bleeding. 

Medication

Future Trends

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References

• Thrombosis – StatPearls – NCBI Bookshelf (nih.gov) 
• Thromboembolic Event – StatPearls – NCBI Bookshelf (nih.gov)