In healthy people, homeostatic balance 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 [DVT]), arteries (eg, myocardial infarction, ischemic stroke), 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, embolic stroke).
Etiology of Thrombotic Disorders
Genetic defects that increase the propensity for venous thromboembolism include
Factor V Leiden mutation, which causes resistance to activated protein C (APC)
Protein Z, a vitamin K-dependent protein, helps inactivate coagulation factor Xa. Deficiency or dysfunction of protein Z predisposes to venous thrombosis (mainly in patients who also have other clotting abnormalities). However, measurement of its activity is not available in most laboratories.
Acquired defects also predispose to venous and arterial thrombosis (see table Acquired Causes of Thromboembolism).
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 and pulmonary embolism (PE). Superficial thrombophlebitis can also develop. Other consequences may include arterial thrombosis (eg, causing stroke or mesenteric ischemia). Symptoms depend on the location of the clot, as in the following examples:
Chest pain and shortness of breath: Possible PE or myocardial infarction
Leg pain, warmth, redness, and swelling: DVT
Weakness/numbness of one side of the body, problems speaking, and problems with balance and walking: Possible ischemic stroke
Abdominal pain: Possible splanchnic arterial or venous thrombosis
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.
Diagnosis of Thrombotic Disorders
Diagnostic evaluations of thrombotic disorders are summarized elsewhere in THE MANUAL specific to the location of the thrombus (eg, deep venous thrombosis, pulmonary embolism, ischemic stroke). 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, infection, medical illness, generalized atherosclerosis). If no predisposing factor is readily apparent, further evaluation should be considered in patients with
A family history of venous thrombosis (first-degree relative with venous thromboembolism before age 50 years)
More than one episode of venous thrombosis
Venous or arterial thrombosis before age 50 years
Unusual sites of venous thrombosis (eg, cavernous sinus, splanchnic veins)
As many as half of all patients with spontaneous DVT have a genetic predisposition. However, in many such instances, identification of an inherited thrombophilic state does not influence therapy. Therefore, society guidelines suggest targeted testing in patients at high risk of inherited thrombophilia (1, 2).
Testing for predisposing congenital and acquired factors includes specific assays that measure the quantity or activity of natural anticoagulant molecules in plasma, and screening for specific gene defects, as follows:
Clotting assay for lupus anticoagulant
Clotting assay for resistance to activated protein C
Genetic test for factor V Leiden
Genetic test for prothrombin gene mutation (G20210A)
Factors VIII, IX, and XI activity
Functional assay of antithrombin
Functional assay of protein C
Functional assay of protein S
Antigenic assays of total and free protein S.
Measurement of plasma homocysteine levels
Immunoassays for antiphospholipid antibodies
Diagnosis references
1. National Institute on Health and Care Excellence (NICE): Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. NICE guideline [NG 158]. March 26, 2020.
2. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830
Treatment of Thrombotic Disorders
Treatment is summarized elsewhere in THE MANUAL specific to the location of the thrombus.
DOACs include factor Xathrombinapixaban, rivaroxaban) can be used in acute treatment without initial parenteral anticoagulation. In contrast to warfarin, DOACs have fewer drug-drug interactions and their effectiveness is not influenced by diet.
factor Xa inhibitors) as well as non-specific prohemostatic agents such as prothrombin complex concentrates which contain factors VII, IX, X, and prothrombin (1, 4, 5
A major current disadvantage of DOACs is their expense.
Treatment references
1. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report [published correction appears in Chest 2022 Jul;162(1):269]. Chest 2021;160(6):e545-e608. doi:10.1016/j.chest.2021.07.055
2. Ortel TL, Neumann I, Ageno W, et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020;4(19):4693-4738. doi:10.1182/bloodadvances.2020001830
3. National Institute on Health and Care Excellence (NICE): Venous thromboembolic diseases: diagnosis, management and thrombophilia testing. NICE guideline [NG 158]. March 26, 2020.
4. 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.
5 Frontera JA, Lewin JJ 3rd, Rabinstein AA, et al. Guideline for Reversal of Antithrombotics in Intracranial Hemorrhage: A Statement for Healthcare Professionals from the Neurocritical Care Society and Society of Critical Care Medicine. Neurocrit Care. 2016;24(1):6-46. doi:10.1007/s12028-015-0222-x
