1. Introduction and Scope

1.1 Global and ICU-Specific Epidemiology

Venous thromboembolism (VTE), which encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE), affects approximately 1 to 2 per 1,000 individuals annually. This incidence rises significantly in older populations, reaching about 5 per 1,000 in those over 75 years of age. In the intensive care unit (ICU), the burden is substantially higher, with clinically detected VTE occurring in 5–15% of patients despite routine prophylaxis. Autopsy studies suggest the true incidence of subclinical events may exceed 20%.

• ICU Drivers: Key contributors in the ICU include prolonged immobilization, sedation, systemic inflammation from conditions like sepsis, and endothelial activation from central venous catheters.
• Mortality: The 30-day mortality for PE is approximately 10.6% overall, but can surge to 25–30% in cases of massive PE causing hemodynamic shock.
• Long-term Sequelae: VTE recurrence occurs in 5–10% of patients within one year, and up to 50% of DVT survivors develop post-thrombotic syndrome, a chronic condition causing pain, swelling, and skin changes.

1.2 Demographic Disparities and Trends

VTE risk and outcomes are modified by race, age, and sex. While overall VTE rates have declined with improved prophylaxis strategies, ICU-specific rates remain high, particularly in septic and post-operative patients.

• Race: Black patients have a 30–60% higher incidence of VTE compared to White patients, a disparity influenced by genetic factors, comorbidities, and potential differences in prophylaxis access.
• Sex: Men experience a slightly higher rate of VTE recurrence, while women’s risk is modulated by hormonal factors such as estrogen exposure and pregnancy.
• Age: Age is the most potent nonmodifiable risk factor, with VTE incidence doubling after the age of 60.

2. Major and Minor Risk Factors

VTE risk is determined by a combination of inherited predispositions and acquired clinical conditions. In the ICU, acquired factors are the predominant drivers.

2.1 Inherited Thrombophilias

Genetic mutations like Factor V Leiden and the prothrombin G20210A gene mutation create a state of hypercoagulability. However, they typically require an acquired trigger (like surgery or immobilization) to precipitate a VTE event. Screening is generally reserved for patients with unprovoked VTE at a young age (<50 years) or a strong family history, and is not a routine part of acute ICU management.

2.2 Acquired Risk Factors

Most VTE events in the ICU are driven by acquired conditions. Malignancy is a particularly potent risk factor, as tumor cells can release tissue factor and procoagulant microparticles that directly activate the coagulation cascade.

2.3 Social Determinants of Health

Beyond clinical factors, social determinants critically influence VTE prevention and outcomes. Barriers to medication access, such as the cost of Direct Oral Anticoagulants (DOACs), can impede effective therapy. Low health literacy may hinder a patient’s ability to recognize signs of bleeding or adhere to complex regimens. Gaps in transitional care, including poor medication reconciliation at discharge, are a major driver of VTE recurrence and hospital readmission. Multidisciplinary care models that include pharmacists and social workers are effective at improving adherence and promoting health equity.

3. Pathophysiology of Thrombus Formation

3.1 Virchow’s Triad: Stasis, Endothelial Injury, Hypercoagulability

The formation of a venous thrombus is classically explained by Virchow’s Triad, which describes the interplay of three contributing factors. In the critically ill patient, these three elements often converge, creating a perfect storm for VTE development.

3.2 Molecular Pathways in Chronic Disease States

Specific chronic diseases amplify prothrombotic mechanisms through distinct molecular pathways:

• Cancer: Tumor cells release tissue factor and procoagulant microparticles, triggering the extrinsic coagulation cascade.
• Heart Failure: Elevated systemic venous pressure and reduced blood flow promote profound stasis.
• Renal Disease: Uremia can alter platelet function and enhance fibrin generation.
• Autoimmune Disorders: In antiphospholipid syndrome (APS), autoantibodies directly injure the endothelium and activate complement.
• Inflammation: Pro-inflammatory cytokines like Interleukin-6 (IL-6) stimulate the liver to produce excess fibrinogen and factor VIII, tipping the hemostatic balance toward thrombosis.

4. Clinical Manifestations

4.1 Deep Vein Thrombosis (DVT)

The classic signs of DVT—unilateral leg swelling, warmth, erythema, and calf pain—are neither sensitive nor specific, with a diagnostic accuracy of only 50-70%. Therefore, objective testing is mandatory for diagnosis. Proximal DVTs (involving the popliteal, femoral, or iliac veins) carry the highest risk of embolizing to the lungs. In the ICU, clinical signs can be masked by generalized edema or obesity, and catheter-associated upper extremity DVTs may present subtly as arm swelling or difficulty with IV infusions.

4.2 Pulmonary Embolism (PE)

PE presents with acute respiratory and hemodynamic compromise, with severity dictating the clinical picture. Common symptoms include sudden-onset dyspnea, pleuritic chest pain, tachypnea, and hypoxia. A massive PE can cause hypotension, syncope, and obstructive shock from acute right ventricular failure. In the ICU, any sudden decline in oxygenation, new or refractory hypotension, or unexplained tachycardia should prompt an immediate evaluation for PE.

4.3 Atypical and Asymptomatic Presentations in ICU

Up to half of all VTE events in the ICU may be clinically silent. Diagnoses are often made based on a rising D-dimer, incidental findings on imaging performed for other reasons (e.g., a CT scan), or through surveillance protocols. Maintaining a low threshold for imaging is critical to avoid missed or delayed diagnoses in this high-risk population.

5. Key Decision Points

5.1 Initial Risk Assessment

Early and dynamic risk stratification is crucial for guiding VTE prophylaxis in the ICU. This assessment must incorporate clinical factors (age, obesity, cancer), ICU-specific elements (vasopressors, central lines), and mobility status. While risk scores like the Padua Prediction Score are useful for general medical patients, their limitations in the ICU setting must be recognized. The standard of care for most high-risk ICU patients is combined prophylaxis with both mechanical devices (e.g., sequential compression devices) and pharmacologic agents, unless a high bleeding risk presents a contraindication. Clinical pharmacists play a key role in balancing thrombosis versus bleeding risk and recommending appropriate dosing adjustments.

5.2 Early Recognition Strategies

Structured daily reviews and predefined triggers for imaging can enhance early VTE detection. This includes daily multidisciplinary discussions of VTE risk, reviewing laboratory trends, and having clear protocols for imaging in response to unexplained hypoxia, hemodynamic instability, or acute limb changes. Access to bedside ultrasound can dramatically accelerate the evaluation for DVT.

6. Summary and Clinical Pearls

Acute VTE is a common and preventable cause of significant morbidity and mortality in critically ill patients. Effective management requires a deep understanding of its epidemiology, the convergence of Virchow’s triad in the ICU, key risk factors, and the importance of vigilant clinical assessment.

• Incidence: VTE affects 1–2 per 1,000 in the general population but rises to 5–15% clinically (and >20% subclinically) in the ICU.
• Key Drivers: Risk is driven by immobilization, surgery, cancer, advanced age, race, and critical illness itself. Social determinants of health are crucial for long-term adherence and outcomes.
• Pathophysiology: The triad of stasis, endothelial injury, and hypercoagulability is central to VTE formation in the ICU.
• Clinical Vigilance: Best practice involves combining validated risk scores, readily available bedside imaging, and structured daily multidisciplinary rounds to ensure timely prevention and detection.

Key Clinical Pearls for Practice

1. Silent DVT is Common: Consider weekly surveillance ultrasound in the highest-risk, long-stay ICU patients (e.g., severe trauma, post-operative paralysis) to detect asymptomatic DVT.
2. Reassess Risk Dynamically: VTE and bleeding risks are not static. Reassess them daily and after any major clinical change, such as a new invasive procedure, a change in hemodynamic status, or development of sepsis.
3. Plan for Discharge: Embed screening for social determinants of health (e.g., medication affordability, health literacy) into the discharge planning process to create a safe transition and improve long-term adherence to anticoagulation.