In healthy people, homeostatic balance Overview of Hemostasis Hemostasis, the arrest of bleeding from an injured blood vessel, requires the combined activity of Vascular factors Platelets Plasma coagulation factors Regulatory mechanisms counterbalance... read more exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip the balance in favor of coagulation, leading to the pathologic formation of thrombi in veins (eg, deep venous thrombosis Deep Venous Thrombosis (DVT) Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more 
[DVT]), arteries (eg, myocardial infarction Acute Myocardial Infarction (MI) Acute myocardial infarction is myocardial necrosis resulting from acute obstruction of a coronary artery. Symptoms include chest discomfort with or without dyspnea, nausea, and diaphoresis.... read more 
, ischemic stroke Ischemic Stroke Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes... read more 
), or cardiac chambers. Thrombi can obstruct blood flow at the site of formation or detach and embolize to block a distant blood vessel (eg, pulmonary embolism Pulmonary Embolism (PE) Pulmonary embolism (PE) is the occlusion of pulmonary arteries by thrombi that originate elsewhere, typically in the large veins of the legs or pelvis. Risk factors for pulmonary embolism are... read more 
, embolic stroke).
Etiology of Thrombotic Disorders
Genetic defects that increase the propensity for venous thromboembolism include
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Factor V Leiden mutation, which causes resistance to activated protein C Factor V Resistance to Activated Protein C (APC) Mutations of factor V make it resistant to its normal cleavage and inactivation by activated protein C, and they predispose to venous thrombosis. (See also Overview of Thrombotic Disorders.)... read more (APC)
Acquired defects also predispose to venous and arterial thrombosis (see table Acquired Causes of Thromboembolism Acquired Causes of Thromboembolism In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more ).
Other disorders and environmental factors can increase the risk of thrombosis, especially if a genetic abnormality is also present.
Symptoms and Signs of Thrombotic Disorders
Common manifestations of a thrombotic disorder include unexplained deep venous thrombosis Deep Venous Thrombosis (DVT) Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more and pulmonary embolism Pulmonary Embolism (PE) Pulmonary embolism (PE) is the occlusion of pulmonary arteries by thrombi that originate elsewhere, typically in the large veins of the legs or pelvis. Risk factors for pulmonary embolism are... read more (PE). Superficial thrombophlebitis can also develop. Other consequences may include arterial thrombosis (eg, causing stroke Ischemic Stroke Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes... read more or mesenteric ischemia Acute Mesenteric Ischemia Acute mesenteric ischemia is interruption of intestinal blood flow by embolism, thrombosis, or a low-flow state. It leads to mediator release, inflammation, and ultimately infarction. Abdominal... read more 
). Symptoms depend on the location of the clot, as in the following examples:
Most of the inherited disorders do not begin to cause an increased risk of clotting until young adulthood, although clots can form at any age. Women may have a history of multiple spontaneous abortions Spontaneous Abortion Spontaneous abortion is noninduced embryonic or fetal death or passage of products of conception before 20 weeks gestation. Threatened abortion is vaginal bleeding without cervical dilation... read more .
Diagnosis of Thrombotic Disorders
Diagnoses are summarized elsewhere in THE MANUAL specific to the location of the thrombus (eg, deep venous thrombosis Deep Venous Thrombosis (DVT) Deep venous thrombosis (DVT) is clotting of blood in a deep vein of an extremity (usually calf or thigh) or the pelvis. DVT is the primary cause of pulmonary embolism. DVT results from conditions... read more , pulmonary embolism Pulmonary Embolism (PE) Pulmonary embolism (PE) is the occlusion of pulmonary arteries by thrombi that originate elsewhere, typically in the large veins of the legs or pelvis. Risk factors for pulmonary embolism are... read more , ischemic stroke Ischemic Stroke Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes... read more ). Patients who have a thromboembolic event in the absence of an overt clinical explanation may have one of the genetic or acquired predisposing entities described below. It is often valuable to enlist the input of a hematologist in order to sort out the daunting array of diagnostic possibilities.
Predisposing factors
Predisposing factors should always be considered. In some cases, the condition is clinically obvious (eg, recent surgery or trauma, prolonged immobilization, cancer, generalized atherosclerosis). If no predisposing factor is readily apparent, further evaluation should be conducted in patients with
As many as half of all patients with spontaneous DVT have a genetic predisposition.
Testing for predisposing congenital factors includes specific assays that measure the quantity or activity of natural anticoagulant molecules in plasma, and screening for specific gene defects, as follows:
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Clotting assay for lupus anticoagulant
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Clotting assay for resistance to activated protein C
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Genetic test for factor V Leiden
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Genetic test for prothrombin gene mutation (G20210A)
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Functional assay of antithrombin
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Functional assay of protein C
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Functional assay of protein S
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Antigenic assays of total and free protein S.
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Measurement of plasma homocysteine levels
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Immunoassays for antiphospholipid antibodies
Treatment of Thrombotic Disorders
Treatment is summarized elsewhere in THE MANUAL specific to the location of the thrombus.
Anticoagulation is often required, typically beginning with parenteral heparin or low molecular weight heparin, and then followed by oral warfarin or one of the direct oral anticoagulants (DOACs). Drugs include factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and a direct thrombin inhibitor (dabigatran). Unlike warfarin, the direct oral anticoagulants do not require regular laboratory monitoring. DOACs can be reversed either by time (they have brief in vivo half-lives) or in some cases by recently developed agents (idaricizumab for dabigatran; andexanet for rivaroxaban or apixaban [1, 2 Treatment references In healthy people, homeostatic balance exists between procoagulant (clotting) forces and anticoagulant and fibrinolytic forces. Numerous genetic, acquired, and environmental factors can tip... read more ]).
A major current disadvantage of DOACs is their expense.
Treatment references
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1. Cuker A, Burnett A, Triller D, et al: Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol 94:697–709, 2019.
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2. Levy JH, Douketis J, and Weitz JI: Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol 15: 273–281, 2018.
