Overview of Thrombotic Disorders

By Joel L. Moake, MD, Rice University;Baylor College of Medicine

NOTE: This is the Professional Version. CONSUMERS: Click here for the Consumer Version

Thrombotic Disorders
Overview of Thrombotic Disorders
Antiphospholipid Antibody Syndrome (APS)
Antithrombin Deficiency
Hyperhomocysteinemia
Factor V Resistance to Activated Protein C (APC)
Protein C Deficiency
Protein S Deficiency
Protein Z Deficiency
Prothrombin (Factor II) 20210 Gene Mutation

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

Genetic defects that increase the propensity for venous thromboembolism include

Factor V Leiden mutation, which causes resistance to activated protein C (APC)
Prothrombin 20210 gene mutation
Deficiency of protein C
Deficiency of protein S
Deficiency of protein Z
Antithrombin deficiency

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.

Acquired Causes of Thromboembolism

Condition	Comments
Antiphospholipid antibodies	Autoimmune disorder with increased risk of venous or arterial thrombi
Atherosclerosis	Increases risk of arterial thrombi Higher risk in patients with preexisting stenosis When atherosclerotic plaques rupture, they expose or release tissue factor, activate coagulation, initiate local platelet adhesion and aggregation, and cause thrombosis
Cancer (promyelocytic leukemia; lung, breast, prostate, pancreas, stomach, and colon tumors)	May activate coagulation by secreting a factor X–activating protease, by expressing/exposing tissue factor on exposed membrane surfaces, or both
Heparin-induced thrombocytopenia	Associated with platelet aggregation and increased risk of thrombosis
Hyperhomocysteinemia	Possible cause Due to folate, vitamin B₁₂, or vitamin B₆ deficiency
Infection, if severe (eg, sepsis)	Increases risk of venous thrombosis Increases expression/exposure of tissue factor by monocytes and macrophages
Oral contraceptives that contain estrogen	Low risk with low-dose regimens More frequent in patients who have a genetic abnormality that predisposes to venous thromboembolism and in women who smoke
Tissue injury	Due to trauma or surgery
Venous stasis	Due to surgery, orthopedic or paralytic immobilization, heart failure, pregnancy, or obesity

Symptoms and Signs

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
Leg 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 mesenteric ischemia

Women may have a history of multiple spontaneous abortions.

Diagnosis

Diagnoses are summarized elsewhere in The Manual specific to the location of the thrombus (eg, deep venous thrombosis, pulmonary embolism, ischemic stroke).

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

Family history of venous thrombosis
More than one episode of venous thrombosis
Venous or arterial thrombosis before age 50
Unusual sites of venous thrombosis (eg, cavernous sinus, mesenteric veins)

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: