The Incidence of Pulmonary Embolism Has Increased with the Increased Use of Computed Tomography (CT) Pulmonary Artery Angiogram for the Diagnosis of Pulmonary Embolism (see Computed Tomography Pulmonary Artery Angiogram)
Risk Factor Can Be Identified in >80% of Patients with Venous Thrombosis
More than One Factor May Often Be Present
50% of Thrombotic Events in Patients with Inherited Hypercoagulable States are Associated with an Additional Risk Factor (Pregnancy, Surgery, Prolonged Immobilization, Oral Contraceptives)
Associated with Decreased Serum Iron Levels and Increased Plasma Factor VIII Levels (Thorax, 2012) [MEDLINE]
Physiology
Associated with Decreased Serum Iron Levels (Due to Inadequate Replacement of Hemorrhagic Iron Loss) and Increased Plasma Factor VIII Levels (Thorax, 2012) [MEDLINE]
Second Most Common Inherited Hypercoagulable State (After Factor V Leiden)
Diagnosis
Abnormal Aactivated Protein C (APC) Resistance Assay
Race/Ethnicity
Epidemiology
Data from the California Patient Discharge Dataset Indicate that Race/Ethnicity are Associated with the Risk of Venous Thromboembolism (Thromb Res, 2009) [MEDLINE]
Asians/Pacific Islanders and Hispanics Have a Lower Incidence of Venous Thromboembolism, as Compared to Non-Hispanic Whites
Blacks/African Americans Have a Higher Incidence of Venous Thromboembolism of Venous Thromboembolism, as Compared to Non-Hispanic Whites
Multivariable Cox Proportional Hazards Regression Model Study of the Relationship Between Race/Ethnicity and Risk of Cancer-Associated Thrombosis (Data from the California Cancer Registry) (Blood Adv, 2022) [MEDLINE]: n = 942, 109 (with the 13 Most Common, First Primary Malignancies)
Blacks/African Americans Had a Higher Incidence of Cancer-Associated Thrombosis for All Tumor Types (Except Multiple Myeloma), as Compared with Non-Hispanic Whites, After Adjusting for Potential Confounders
Asians/Pacific Islanders Had a Lower Incidence of Cancer-Associated Thrombosis, as Compared with Non-Hispanic Whites, After Adjusting for Potential Confounders
The Main Driver for the Racial/Ethnic Differences was the Incidence of Acute Pulmonary Embolism
Authors Speculated the Association of Race/Ethnicity with Incidence of Cancer-Associated Thrombosis May Be Partially Because of Underlying Thrombotic Predisposition Which Varies by Ancestry, But They Also Considered the Potential Impact of Social Determinants of Health Which Might Impact the Findings
Hospitalization for Atrial Fibrillation/Flutter (within Prior 3 Months) is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
Hypertension is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Demonstrated that Diabetes Mellitus Increased the Risk of Venous Thromboembolism (Adjusted Hazard Ratio 1.5) (Arch Intern Med, 2002) [MEDLINE]
Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
Diabetes Mellitus is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
Pregnancy Itself is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
Postpartum Period is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
Incidence of Deep Venous Thrombosis is Roughly Equal Throughout Pregnancy
First Trimester: 22%
Second Trimester: 41%
Third Trimester: 37%
Incidence of Acute Pulmonary Embolism During Pregnancy
Prepartum: 34%
Postpartum: 66% (with 82% of these occurring following C-section)
Physiology
Increased Risk of Deep Venous Thrombosis in Left Leg During Pregnancy (Possibly Due to Left Common Iliac Vein Compression by the Overlying Right Iliac Artery)
Diagnosis
Some Cases Manifest Abnormal Activated Protein C (APC) Resistance Assay
Treatment
Aspirin Does Not Affect the Risk of Deep Venous Thrombosis in Pregnancy (Even in the Presence of Antiphospholipid Antibody Syndrome)
There is a High (6.3%) Risk of Venous Thromboembolism in Hospitalized Liver Disease Patients, Despite Abnormal Coagulation Parameters (Chest, 2010) [MEDLINE]
Bedrest >3 Days is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
Critical Illness (Especially with Mechanical Ventilation)
Epidemiology
Risk of Deep Venous Thrombosis in Mechanically-Ventilated Patients is 5-10%, Despite Adequate DVT Prophylaxis (J Intensive Care Med, 2006) [MEDLINE] (Crit Care MED, 2005) [MEDLINE] (NEJM, 2011) [MEDLINE]
Extended Travel (“Travelers’ Thrombosis”)
Epidemiology
Travel (Air, Train, Auto) for >4 hrs is Associated with Increased Risk of Deep Venous Thrombosis (Aviat Space Environ Med, 2014) [MEDLINE]
Incidence of Pulmonary Embolism Following Air Travel is Correlated with the Distance Traveled (NEJM, 2001) [MEDLINE]
Extended Travel is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
Lower Extremity Fracture/Injury
Epidemiology
Lower Extremity Fracture is a Strong Risk Factor for Venous Thromboembolism (with Odds Ratio >10) (Eur Heart J, 2020) [MEDLINE]
Infection
General Comments
Infection (Particularly Pneumonia, Urinary Tract Infection, and Human Immunodeficiency Virus Infection) is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
Multicenter Prospective Study of Risk Factors for and Incidence of Venous Thromboembolism in Severe Sepsis/Septic Shock (Chest, 2015) [MEDLINE]
Despite Guideline-Recommended DVT Prophylaxis, the Incidence of Venous Thromboembolism was 37.2% in Patients with Severe Sepsis/Septic Shock
Most Venous Thromboembolism Events were Clinically Significant (Defined as Pulmonary Embolism, Proximal DVT, and/or Symptomatic Distal DVT) and were Associated with an Increased Length of Stay (18.2 ± 9.9 days vs 13.4 ± 11.5 days, P < 0.05)
Mortality was Higher in Patients with Acute Venous Thromboembolism, But this Did Not Reach Statistical Significance
Insertion of a CVC and Longer Mechanical Ventilation Duration were Significant Venous Thromboembolism Risk Factors
There was No Difference in the Incidence of Venous Thromboembolism Incidence Between Patients Receiving Pharmacologic Prophylaxis vs Sequential Compression Devices (37.3% vs 36.3%)
There was No Difference in the Incidence of Venous Thromboembolism Incidence Between Patients Receiving Low Molecular Weight Heparin Prophylaxis vs Unfractionated Heparin Prophylaxis (33.3% vs 41.3%)
In a Multicenter Prospective Cohort Study of Patients with Acute Respiratory Distress Syndrome (ARDS), Patients with SARS CoV-2-Associated ARDS Had a Significantly Higher Incidence of Acute Pulmonary Embolism, as Compared to Non-SARS CoV-2-Associated ARDS (11.7% vs 2.1%, p < 0.008) (Intensive Care Med, 2020) [MEDLINE]
High Relative Incidence of Vascular Thrombotic Events Soon After SARS CoV-2 Diagnosis Declines More Rapidly for Arterial Thromboses than for Venous Thromboembolism (Circulation, 2022) [MEDLINE]
However, Incidence of Vascular Thrombotic Events Remains Elevated Up to 49 wks After SARS CoV-2 Diagnosis
Varicella-Zoster Virus Infection-Associated Stroke and Deep Venous Thrombosis Have Been Rarely Reported in Children (Pediatr Infect Dis J, 2015) [MEDLINE]
Malignancy
General Comments
Malignancy Imparts a 4 to 7-Fold Increased Risk of Developing Venous Thromboembolism, as Compared to the General Population (Med Insights Oncol, 2014) [MEDLINE]
Cancer (Particularly Metastatic Cancer) is a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
Incidence of Cancer-Associated Thrombosis Varies by Tumor Type, Stage at Diagnosis, Type of Therapy, and Patient Comorbidities (Blood Adv, 2022) [MEDLINE]
Risk of Venous Thrombembolism in Course of Cancer is Highest During the Initial Hospitalization, at the Onset of Chemotherapy, and at the Time of Disease Progression
Presence of a Central Venous Catheter Further Compounds the Risk of Malignancy-Associated Venous Thromboembolism
Most Cancers (78%) are Diagnosed Before the Diagnosis of the Deep Venous Thrombosis
Common Sites of Malignancies at Time of Venous Thromboembolism Diagnosis
Lung Cancer (see Lung Cancer): 17% of cases develop venous thromboembolism
Pancreatic Cancer (see Pancreatic Cancer): 10% of cases develop venous thromboembolism
Colorectal Cancer (see Colorectal Cancer): 8% of cases develop venous thromboembolism
Renal Cancer (Renal Cancer): 8% of cases develop venous thromboembolism
Prostate Cancer (Prostate Cancer): 7% of cases develop venous thromboembolism
Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Demonstrated that Obesity Increased the Risk of Venous Thromboembolism Using Age/Race/Sex-Adjusted Hazard Ratios for BMI (BMI <25 = 1.0, BMI 25-30 = 1.5, BMI 30-35 = 2.2, BMI 35-40 = 1.5, and BMI ≥40 = 2.7) (Arch Intern Med, 2002) [MEDLINE]
Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
Obesity Increased the Risk of Pulmonary Embolism (Relative Risk 2.03), But Decreased the Mortality of Pulmonary Embolism in Hospitalized Patients (Thromb Res, 2011) [MEDLINE]
Obesity is a Weak Risk Factor for Venous Thromboembolism (with Odds Ratio <2) (Eur Heart J, 2020) [MEDLINE]
Renal Disease
Chronic Kidney Disease (CKD) (Especially with Hemodialysis) (see Chronic Kidney Disease)
Incidence of Venous Thromboembolism (DVT or PE) was 13.3 per 1000 Person-Years with Incidence Rate Ratio of 3.58 (2.33-5.34, CI 95%) (Ann Rheum Dis, 2016) [MEDLINE]
Superficial Venous Thrombosis May Occur in Patients with Inherited/Acquired Hypercoagulable States
Superficial Venous Thrombosis a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
Clinical
Occult Deep Venous Thrombosis: occult deep venous thrombosis is present in 7-32% of superficial thrombophlebitis cases (suggests that screening of these patients with lower extremity dopplers may be warranted)
Recurrence of Superficial Venous Thrombosis: 24% of cases have recurrent superficial venous thrombosis (Thromb Haemost, 1999) [MEDLINE]
Later Development of Deep Venous Thrombosis: 32% of superficial venous thrombosis cases develop deep venous thrombosis at median interval of 4 years (Thromb Haemost, 1999) [MEDLINE]
Dutch Population-Based Case-Control Study of Danish Adults (Over 7 Year Period) [MEDLINE]: n= 38,765 Danish adults who developed venous thromboembolism (with n = 387,650 controls)
Systemic vs Non-Systemic Steroids: risk of venous thromboembolism was highest with use of systemic glucocorticoids, as compared to a relatively lower risk with inhaled or gastrointestinal glucocorticoids
Time of Onset-Related Effect: risk of venous thromboembolism was highest with new use of glucocorticoids (incidence ratio 3.06), as compared to continuing or past use
Dose-Effect: risk of venous thromboembolism increased with increasing cumulative doses of the glucocorticoids
Possible Study Flaws Include that the Study Did Not Fully Account for All of the Confounding Risks of Venous Thromboembolism Related to the Underlying Disease Itself (For Which the Glucocorticoids were Prescribed): consequently, the underlying disease may have increased the risk of venous thromboembolism or the increased risk of immobility (which could indirectly increase the risk of venous thromboembolism)
United States Population-Based Retrospective Cohort Study of the Risks of Short-Term Corticosteroid Use in Adults (BMJ, 2017) [MEDLINE]
One in Five American Adults in a Commercially-Insured Plan were Given at Least One Outpatient Short-Term Corticosteroid Course During the Three Year Study (2012-2014): mostly for upper respiratory tract infections, spinal conditions, and allergies
Within 30 Days of Initiation, Short-Term Use of Corticosteroids Increased the Risk of Sepsis (Incidence Rate Ratio 5.30, 95% CI: 3.80-7.41), Venous Thromboembolism (Incidence Rate Ratio 3.33, 95% CI: 2.78-3.99), and Fractures (Incidence Rate Ratio 1.87, 95% CI: 1.69-2.07): increased risk persisted at prednisone equivalent doses of <20 mg/day (incidence rate ratio 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture)
Erythropoiesis-Stimulating Agents
Epidemiology
Erythropoiesis-Stimulating Agents are a Moderate Risk Factor for Venous Thromboembolism (with Odds Ratio >2-9) (Eur Heart J, 2020) [MEDLINE]
Risk of Venous Thromboembolism is Higher in Multiple Myeloma Patients Who Receive Thalidomide or Lenalidomide (Especially in Combination with Dexamethasone or Chemotherapy) (Leukemia, 2008) [MEDLINE]
In a Systematic Review and Meta-Analysis, NSAID’s Increased the Risk of Venous Thromboembolism with Relative Risk of 1.80 (95% CI: 1.28-2.52) (Rheumatology, 2015) [MEDLINE]
Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
Longitudinal Investigation of Thromboembolism Etiology (LITE) Study Indicated that Alcohol Use, Hypertension, Hyperlipidemia, Physical Inactivity, and Tobacco Abuse were Not Associated with an Increased Risk of Venous Thromboembolism (Arch Intern Med, 2002) [MEDLINE]
Meta-Analysis Indicated that Obesity (Risk 2.33), Hypertension (Risk 1.51), Diabetes Mellitus (Risk 1.42), Smoking (Risk 1.15), and Hypercholesterolemia (Risk 1.16) Increased the Risk of Venous Thromboembolism (Circulation, 2008) [MEDLINE]
Note: Some Vascular Laboratories Misleadingly Use the Term “Superficial Femoral Vein” (Giving the Incorrect Impression that This is a Superficial Vein), Instead of the Terms, Common Femoral Vein/Femoral Vein (JAMA, 1995) [MEDLINE] (J Clin Ultrasound, 2011) [MEDLINE]
Deep Femoral Vein
Popliteal Vein
Distal
Crural Calf Veins
Anterior Tibial Vein: less common site of distal deep venous thrombosis
Posterior Tibial Vein: more common site of distal deep venous thrombosis
Peroneal Vein: more common site of distal deep venous thrombosis
Muscular Calf Veins: less common site of distal deep venous thrombosis
Most Common Site for Central Venous Catheter (CVC)-Related Deep Venous Thrombosis
Lower Extremity Deep Venous Thrombosis
Calf Vein (Distal) Deep Venous Thrombosis
Progression
Left Untreated, Distal Deep Venous Thrombosis Will Progress to Proximal Deep Venous Thrombosis in Approximately 33% of Cases
If it Does Progress, Distal Deep Venous Thrombosis Usually Progresses within the First 2 wks After Diagnosis
If Extension Does Not Occur in the First 2 wks, it is Unlikely to Occur
Limited Muscular Calf Vein Distal Deep Venous Thrombosis Has a Low Risk of Extension without Treatment (Risk of Extension: 3%), as Compared to Extensive Thrombosis of Multiple Calf Veins (Risk of Extension: 15%)
Risk of Pulmonary Embolism with Distal Deep Venous Thrombosis is Approximately 50% the Risk of Proximal Deep Venous Thrombosis Embolization (BMJ, 2011) [MEDLINE]
Proximal Deep Venous Thrombosis
Thrombi in Lower Extremities Develop within Minutes, Then Organize, and Fibrinolyse (Stabilizing within 7-10 Days)
*Risk of (Symptomatic or Asymptomatic) Pulmonary Embolism with Proximal Deep Venous Thrombosis is Approximately 50%
Highest Risk Period for Embolization of Proximal Deep Venous Thrombosis is within the First Few Days After Deep Venous Thrombosis Formation
Upper Extremity Deep Venous Thrombosis
Risk of Pulmonary Embolism with Upper Extremity DVT: 10-25% of cases (BMJ, 2004) [MEDLINE] (Exp Oncol, 2006) [MEDLINE] (J Thromb Haemost, 2008) [MEDLINE]
Source of Pulmonary Embolism
In Situ Pulmonary Artery Thrombosis
Rare
Lower Extremity Deep Venous Thrombosis
Accounts for >95% of Pulmonary Embolism Cases
Larger Lower Extremity Veins (Iliac, Femoral, Popliteal) are the Source of Most Clinically Significant Pulmonary Emboli
Increased Pulmonary Vascular Resistance Due to Mechanical Obstruction of Pulmonary Vascular Bed and Hypoxic Pulmonary Vasoconstriction
Obstruction of Only 33% of Pulmonary Vasculature Produces Pulmonary Hypertension (Due to Pulmonary Arterial Vasoconstriction Induced by Serotonin and Thromboxane (Cardiovasc Res, 2000) [MEDLINE] – In Addition, When Obstruction of the Pulmonary Vascular Bed Approaches 75%, the Right Ventricle Must Generate a Systolic Pressure >50 mmHg to Preserve Adequate Pulmonary Artery Blood Flow
Cardiovascular Consequences – Right Ventricular Dilation/Flattening of the Interventricular Septum
Decreased Flow from the Right Ventricle and Right Ventricular Dilation, Resulting in Decreased Left Ventricular Preload
Decreased Left Ventricular Stroke Volume and Decreased Cardiac Output, Resulting in Hypotension
Increased Alveolar Dead Space Fraction
Physiology
Due to Occluded Vasculature with Remaining Ventilation
Clinical
Most Patients with Acute Pulmonary Embolism Have Alveolar Dead Space Fraction >20% and Positive D-Dimer
Most Patients with Normal Alveolar Dead Space (<20%) and Negative D-Dimer Do No Have Acute Pulmonary Embolism
Resolution of Acute Pulmonary Embolism
Embolus in the Pulmonary Vasculature Lyses over Hours-Days
References
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Epidemiology
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A meta-analysis of the risk of venous thromboembolism in inflammatory rheumatic diseases. Arthritis Res Ther. 2014 Sep 25;16(5):435. doi: 10.1186/s13075-014-0435-y [MEDLINE]
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Deep Vein Thrombosis as Initial Manifestation of Whipple Disease. Case Rep Gastroenterol. 2016 Nov 7;10(3):640-645. eCollection 2016 Sep-Dec [MEDLINE]
Consider Behcet’s disease in young patients with deep vein thrombosis. Respir Med Case Rep. 2016 Apr 14;18:41-4. doi: 10.1016/j.rmcr.2016.04.002. eCollection 2016 [MEDLINE]
Cerebral venous sinus thrombosis in Behçet’s disease: a retrospective case-control study. Clin Rheumatol. 2017 Jun 14. doi: 10.1007/s10067-017-3718-2 [MEDLINE]
Behcet Disease Initially Presenting as Deep Venous Thrombosis: A Case Report. J Pediatr Hematol Oncol. 2017 Apr 21. doi: 10.1097/MPH.0000000000000830 [MEDLINE]
Clinical associations with venous thromboembolism in anti-neutrophil cytoplasm antibody-associated vasculitides. Rheumatology (Oxford). 2017 May 1;56(5):704-708. doi: 10.1093/rheumatology/kew465 [MEDLINE]
Venous thrombosis and relapses in patients with Behçet’s disease. Descriptive analysis from Spanish network of Behçet’s disease (REGEB cohort). Clin Exp Rheumatol. Nov-Dec 2018;36(6 Suppl 115):40-44 [MEDLINE]
Higher Dose of Tofacitinib for Rheumatoid Arthritis Poses Risks. JAMA. 2019 Apr 2;321(13):1245. doi: 10.1001/jama.2019.2986 [MEDLINE]
High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020 Jun;46(6):1089-1098. doi: 10.1007/s00134-020-06062-x [MEDLINE]
Racial disparities in cancer-associated thrombosis. Blood Adv. 2022;6(10):3167-3177. doi:10.1182/bloodadvances.2021006209 [MEDLINE]
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Physiology
General
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Other
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