Hypercoagulation disorders

ALSO KNOWN AS: Hypercoagulable states, blood-clotting disorders, thrombophilia or thrombotic disorders

RELATED CONDITIONS: Blood clots, deep vein thrombosis, pulmonary embolism

DEFINITION: Hypercoagulation disorders are inherited or acquired conditions that increase one's tendency to develop excessive or abnormal blood clots in the arteries or veins. These disorders increase the risk of blood clots even without injury.

A thrombus is a blood clot that forms and remains in a certain location, such as a blood vessel or the heart. If a thrombus becomes detached and travels through the bloodstream, it is called an embolus. People with hypercoagulation disorders have an increased risk of a deep vein thrombosis (blood clot in the deep leg vein) or a pulmonary embolism (blockage in a lung artery caused by a traveling blood clot), two conditions collectively termed venousthromboembolism.

The majority of hypercoagulation disorders are acquired, frequently as a result of cancer. About 10 percent of patients with otherwise unexplained venous thromboembolism have received a cancer diagnosis within the past year.

Factor V Leiden thrombophilia is the most common inherited hypercoagulation disorder caused by a specific mutation in the F5 gene. Other inherited hypercoagulation disorders include prothrombin thrombophilia, hyperfibrinogenemia (elevated fibrinogen levels), dysfibrinogenemia (abnormally functioning fibrinogen), hereditary antithrombin deficiency, protein C deficiency, and protein S deficiency.

Risk factors: Risk factors for acquired hypercoagulation disorders include cancer, particularly cancer of the brain, gastrointestinal tract, pancreas, blood or bone marrow, kidney, lung, ovaries, or prostate; pregnancy; hormone replacement therapy; oral contraceptive use; heparin-induced thrombocytopenia; antiphospholipid antibody syndrome; deep vein thrombosis; pulmonary embolism; myeloproliferative disorders, including polycythemia vera and essential thrombocytosis; hyperhomocysteinemia (elevated homocysteine levels); diabetes; prolonged bed rest with immobility or inactivity; and smoking.

Risk factors for hereditary disorders include a family history of blood clotting disorders or venous thromboembolism. Hereditary defects in one or more clotting factors may also increase a person’s risk.

Etiology and the disease process: Hemostasis is the body’s natural mechanism to stop bleeding upon injury. Blood clot formation is part of this process and involves a variety of blood cells, platelets, blood proteins, and coagulation (clotting) factors. If there is an inherited or acquired imbalance or malfunction in any of these substances, clot formation becomes abnormal.

Certain chemotherapy drugs, such as asparaginase, can increase the risk of clotting. Estrogen in hormone replacement therapy or oral contraceptives can also increase the risk of excessive clot formation.

Incidence: Between 1 and 8 percent of cancer patients develop venous thromboembolism. Rates of venous thromboembolism in cancer patients seem to be gradually increasing over time. Around 30 percent of patients with hypercoagulation disorders present with the genetic factor V Leiden or a prothrombin G2021A mutation.

Symptoms: Apart from the occurrence of a blood clot, there are no specific signs or symptoms typical of hypercoagulation disorders in general. Symptoms of deep vein thrombosis include pain, swelling, tenderness, a sensation of warmth, and reddened skin in the area of the clot, although not all cases are symptomatic. Symptoms of pulmonary embolism include dry or bloody coughing, shortness of breath, pain in the chest or upper back, light-headedness, dizziness, and fainting.

Screening and diagnosis: Laboratory tests to screen for hypercoagulability include the prothrombin time test to calculate the international normalized ratio (PT/INR) and the activated partial thromboplastin time test (aPTT), which measures overall blood-clotting time. The thrombin time test (TT), which times the part of the clotting process in which fibrinogen changes into the fibrin threads that form the clot; and the fibrinogen antigen and fibrinogen activity assays, which measure how much fibrinogen is present and how well it functions to form a blood clot, respectively. Genetic blood tests may identify certain gene mutations when an inherited hypercoagulation disorder is suspected.

A complete medical history and physical exam, including a complete blood count, liver function test, urinalysis, comprehensive metabolic panel, and chest X-ray, are used to diagnose these conditions. Further tests are performed to determine the disorder's underlying cause when an abnormality is indicated. Further screening to detect a malignancy is recommended in patients with recurrent venous thromboembolism.

Treatment and therapy: Treatment for hypercoagulation disorders varies depending on the type of disorder. Generally, treatment includes anticoagulant medications to decrease the blood’s clotting ability and reduce the risk of clot formation. The most commonly prescribed anticoagulants are warfarin, a vitamin K antagonist, and heparin, which works by activating antithrombin III, a protein that, in turn, inactivates several coagulation factors. Alternative anticoagulants include heparin derivatives such as fondaparinux and low-molecular-weight heparin; antiplatelet agents such as clopidogrel, prasugrel, and ticagrelor; and direct thrombin inhibitors such as lepirudin, bivalirudin, and argatroban.

The use of anticoagulants in patients with a known malignancy increases the risk of complications, particularly when the malignancy is advanced. Therefore, the potential benefits of each anticoagulant therapy should be weighed against the risks. Some studies have suggested a reduced mortality risk using heparin injections instead of oral anticoagulants. With all anticoagulants, close monitoring is required to evaluate the patient’s response to the medication and make dosage adjustments as needed.

Thrombolytic (fibrinolytic) drugs such as streptokinase and tissue plasminogen activator (tPA) agents such as alteplase, reteplase, and tenecteplase may be injected to dissolve a blood clot in select patients. These drugs are administered in a hospital setting and are effective only when given within six hours after the onset of a clot-induced stroke or heart attack.

Prognosis, prevention, and outcomes: The outcomes of patients with hypercoagulation disorders depend on the rates of venous thromboembolism recurrence associated with the different disorders. Some data indicates that patients with inherited hypercoagulation disorders do not have a reduced survival rate.

Patients with cancer and venous thromboembolism have an increased risk of recurrent thromboembolic events and major bleeding. Thrombosis can potentially complicate the course of cancer treatment by increasing the rate of hospital readmission as well as morbidity and mortality.

Bibliography

Akinbo, David Bolaji, and Olutayo Ifedayo Ajayi. "Thrombotic Pathogenesis and Laboratory Diagnosis in Cancer Patients, an Update." International Journal of General Medicine, 2023, pp. 259-272. doi.org/10.2147/IJGM.S385772.

Antovic, Jovan P., and Margareta Blombäck, editors. Essential Guide to Blood Coagulation. 2nd ed., Wiley, 2013.

"Blood Clotting Disorders (Hypercoagulable States)." Cleveland Clinic, 1 July 2022, my.clevelandclinic.org/health/diseases/16788-blood-clotting-disorders-hypercoagulable-states. Accessed 10 July 2024.

Galioto, Nicholas J., et al. "Recurrent Venous Thromboembolism." American Family Physician, vol. 83, no. 3, 2011, pp. 293–300. www.aafp.org/pubs/afp/issues/2022/0400/p377.html.

Howard, Martin R., and Peter J. Hamilton. Haematology: An Illustrated Colour Text. 4th ed., Churchill, 2013.

Lichtin, Alan, and John Bartholomew, editors. The Coagulation Consult: A Case-Based Guide. Springer, 2014.

Michaelis, Laura C. "Hypercoagulable States Associated with Malignancy." Venous and Lymphatic Diseases. Edited by Robert S. Dieter, et al. McGraw, 2011, pp. 47–62.

Senst, Benjamin. "Hypercoagulability." National Library of Medicine, 22 Aug. 2023, www.ncbi.nlm.nih.gov/books/NBK538251. Accessed 10 July 2024.

Villarreal, Alcibiades E, and Lineth López. “The Brain of the Critically Ill Pregnant Woman.” Chapter 13 - Thrombotic Thrombocytopenic Purpura, Elsevier Inc., 2024, pp. 251–262.

Williams, Angela, et al. Blood and Circulatory Disorders Sourcebook. 5th ed., Omnigraphics, Incorporated, 2020.