Key Points
Disease summary:
Pulmonary embolism (PE) and deep vein thrombosis (DVT) are a disease continuum of venous thromboembolism (VTE), a complex and serious multifactorial disorder of blood coagulation influenced by genetic and environmental risk factors, and their interactions.
Clinical presentations:
DVT is the formation of a thrombus in one of the deep veins, most commonly the lower extremities; occasionally, DVT can occur in the deep veins of the upper extremity, or in other locations.
PE is blockage in one or more pulmonary arteries occurring most commonly as a complication of DVT.
Differential diagnosis:
DVT: cardiovascular disorders, septic arthritis, cellulitis, ruptured popliteal cyst, traumatic injury to a vein or artery
PE: any condition with clinical presentation characterized by chest pain, dyspnea, hemoptysis, or syncope
Monogenic forms:
The well-established susceptibility genes for DVT/PE are factor V Leiden, factor II (or prothrombin), SERPINC1 gene (in antithrombin deficiency), PROC gene (in protein C deficiency), PROS1 gene (in protein S deficiency), A1 and B blood groups, and fibrinogen gamma gene.
Family history:
Family history reflects inherited genetic susceptibilities, environmental, cultural, and behavioral factors in VTE. A positive family history is an independent risk factor for VTE, similarly among whites and African Americans, with an almost three times increased risk of VTE for both races. The risk of VTE is even higher among individuals who have a strong family history of VTE, that is, a first-degree relative with a history of VTE before the age of 50 years or a history of VTE among multiple relatives regardless of age. In addition, certain comorbid conditions, such as obesity, diabetes mellitus, hypertension, and cancer, could further increase the risk of VTE associated with a positive family history. Furthermore, there is evidence that only one-third of patients with a positive family history of VTE carry factor V Leiden variants among whites.
Twin studies:
Among white monozygotic twins, the concordance rate with DVT or PE is 22% in males and 0.02% in females.
Environmental and clinical factors:
Advanced age, race (whites and African Americans), previous episodes of VTE, prolonged immobilization, major trauma, spinal cord injury, burns, surgery, central venous catheterization, presence of a pacemaker
Female risk factors: pregnancy and postpartum period, estrogen-containing hormonal contraception, hormone replacement therapy
Obesity, diabetes mellitus
Cancer, myeloproliferative disorders, polycythemia vera, essential thrombocythemia, antiphospholipid syndrome, systemic lupus erythematosus, sickle cell disease
Endocrine disorders: thyroid dysfunction, Cushing syndrome, hyperprolactinemia
Major medical illness: nephrotic syndrome, inflammatory bowel disease, congestive heart failure, chronic obstructive pulmonary disease, paroxysmal nocturnal hemoglobinuria, disseminated intravascular coagulopathy
Pharmacogenomics:
Although the US Food and Drug Administration (FDA) adapted guidelines for the clinical use of warfarin therapy when genotype information on cytochrome P450-2C9 complex (CYP2C9) and vitamin K-epoxide reductase complex subunit 1 (VKORC1) genes is available, the current recommendations for standard clinical practice do not include genetic testing.
Diagnostic Criteria and Clinical Characteristics
PE and DVT are a disease continuum of VTE, a complex and serious multifactorial disorder of blood coagulation influenced by genetic and environmental risk factors, and their interactions. The updated paradigm for causal mechanisms of venous thrombosis is supported by the concept that inflammation and coagulation are interrelated, and incorporates the contributing factors of thrombosis initially postulated in the Virchow triad—abnormal blood flow, endothelial injury followed by accumulation of inflammatory markers, and increased hypercoagulability (also known as thrombophilia) characterized by activation of clotting factors. In 2008, the US Surgeon General called to action to prevent DVT and PE and urged all Americans to be aware of the risk factors, triggering events, and symptoms of DVT and PE, because these conditions represent a major public health problem associated with high morbidity and mortality rates, and substantial societal burden and economic costs. VTE is a common complication of hospitalization in medical and surgical patients. Guidelines for diagnosing VTE have been developed because of the lack of sensitivity and specificity of the clinical presentation of DVT and PE, and the low predictive value of their clinical symptoms, signs, and abnormalities of blood gases, chest radiograph, and electrocardiogram.
Deep vein Thrombosis
Pretest probability assessment of DVT using the Wells score.
d-dimer test (measures plasma levels of a degradation product of cross-linked fibrin) or enzyme-linked immunosorbent assay (ELISA)-based d-dimer tests are used to rule out DVT.
Venous compression ultrasonography is the imaging test of choice to diagnose DVT.
When DVT is symptomatic, the clinical presentation is nonspecific. Signs and symptoms include pain, tenderness along the distribution of the veins, edema, and erythema. DVT can be asymptomatic or recurrent, or result in emboli to the pulmonary arteries. Long-term complication of DVT is post-thrombotic syndrome (PTS), and even ulceration. DVT can be asymptomatic in almost 50% of the cases; 30% of patients with DVT will have a recurrent episode within the next 10 years. If DVT remains unrecognized and untreated, it could result in emboli to the pulmonary arteries and the development of PE, the most life-threatening complication of DVT. Much less commonly, DVT could result in phlegmasia alba dolens, a rare complication of DVT during pregnancy, or in phlegmasia cerulean dolens, a near-total venous occlusion caused by massive iliofemoral venous thrombosis.
Pulmonary Embolism
Pretest probability assessment of PE using the Wells score or the revised Geneva score.
d-dimer test or ELISA-based d-dimer test are used to rule out PE.
Contrast-enhanced computed tomography (CT) arteriography and multi-detector computed tomography angiography (MDCTA) are considered the first-line imaging techniques to diagnose PE.
PE is a life-threatening condition occurring most commonly (70%) as a complication of proximal vein thrombosis in approximately 50% of patients with documented proximal DVT. PE is characterized by an embolus which originates in the deep veins of the leg or pelvis, travels through the right side of the heart, and reaches the lung causing partial or complete blockage of the pulmonary arteries. PE is, however, most commonly asymptomatic, and its first diagnosis is often made until autopsy. Symptoms and signs of PE are nonspecific, and characterized by dyspnea, pleuritic chest pain, hemoptysis, and tachypnea. Chronic thromboembolic pulmonary hypertension is a long-term complication of PE resulting in chronic right heart failure. Severe cases with massive PE can lead to sudden death from right ventricular failure one in five individuals. It is estimated that about 30% of patients who develop clinically apparent PE die, although a large proportion of these patients die from other causes.
Screening and Counseling
VTE is a complex trait with a multifactorial non-Mendelian mode of inheritance that involves multiple genes—thrombosis-susceptibility genes, environmental risk factors, as well as gene-gene and gene-environment interactions. Genetics factors are estimated to explain at least 60% of the heritability of VTE. Inherited thrombophilia is a genetic predisposition to venous thrombosis, and when associated with a DVT or PE event occurring in the absence of a known precipitating environmental factor, is referred to as idiopathic or unprovoked VTE. Inherited thrombophilia should be suspected when a patient has recurrent VTE, has a family history of relatives with DVT or PE, has an early-onset episode of VTE occurring before the age of 45 years, has DVT at an unusual site, or has no other obvious acquired risk factors, or if the patient is a woman who has a history of early pregnancy loss, late pregnancy loss, or severe pre-eclampsia.
The objective of screening for inherited thrombophilia is to identify individuals at risk for VTE. There is a strong evidence, however, that screening for thrombophilic disorders in the general population is not cost-effective because the incidence rate of symptomatic VTE in the general population is low, the clinical penetrance of symptomatic VTE among carriers of the most common thrombophilic conditions is incomplete, and there is no available long-term prophylactic therapy which is safe and cost-effective. Screening for primary prevention is recommended only for selected groups at high risk for VTE such as women considering oral contraceptives or hormone replacement therapy if they have a positive family history of VTE in a first-degree relative. Selective screening is also recommended, for example, during pregnancy or the puerperium for women with previous VTE history.
The inheritance pattern of most inherited thrombophilic conditions is autosomal dominant. The clinical expression of thrombophilia is variable and influenced by the type of genetic factors, the number of risk alleles, and the interaction between genetic and environmental risk factors. In addition, family history of VTE is an independent risk factor for VTE. There is a significant genotype-phenotype correlation in VTE as suggested by the association between the severity of the disease and the type of thrombophilic mutations. Individuals referred for genetic counseling and their family members might be informed on advantages and disadvantages of genetic testing for thrombophilia, inheritance pattern of VTE, the risk of developing venous thrombosis, risk factors associated with VTE such as oral contraceptive use or obesity, and available prophylactic modalities for the prevention of VTE.
