Hypercoagulable State

What Is It, Causes, Pregnancy, Diagnosis, Treatment, and More

Author: Anna Hernández Castillo, MD

Editors: Antonella Melani, MD,Ian Mannarino, MD, MBA

Illustrator: Abbey Richard

Modified: 24 Nov 2020

What is a hypercoagulable state?

A hypercoagulable state, also known as thrombophilia, is an increased tendency to develop blood clots (thrombosis) due to the presence of one or more predisposing factors, which can either be inherited or acquired. Normally, developing clots is a good thing; it ensures that the body is able to patch up and heal lacerations and injuries. 

However, when blood clots develop within blood vessels, it’s a problem. As a result, individuals in a hypercoagulable state are at increased risk of developing thromboembolic events such as deep vein thrombosis or pulmonary embolism. Deep vein thrombosis refers to a clot that develops in a deep vein of the lower or upper limbs, which can present with pain and swelling in the affected limb. Parts of these venous blood clots can break off and travel to the lungs, causing pulmonary embolism. On the other hand, arterial clots can travel to other organs, such as the brain, heart, liver, and kidneys, cutting off blood flow to those organs and causing infarction. 

What can cause hypercoagulation?

Blood clotting results from the interaction between blood vessels, platelets and coagulation factors. Coagulation factors circulate in the blood in their inactive form to prevent coagulation from occurring when it’s not necessary. When there’s an injury, coagulation factor VII binds to the cells of the exposed vessel wall, triggering the activation of the coagulation cascade. This allows the subsequent activation of the rest of the clotting factors, which ultimately leads to the formation of thrombin (factor II). Thrombin converts fibrinogen into fibrin (factor I), which forms a tightly connected mesh that stabilizes the platelet plug. 

To limit the formation of clots to the site of injury and prevent them from growing too big, the coagulation cascade is regulated by different anticoagulant mechanisms. Protein C, along with protein S, form a complex that inactivates factors V and VIII. On the other hand, antithrombin III directly decreases the production of thrombin and inactivates factor X. 

Any condition that causes an imbalance between thrombogenic and antithrombogenic mechanisms predisposes an individual to either an increased risk of bleeding or a hypercoagulable state.

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What is a primary hypercoagulable state?

Primary hypercoagulable states are inherited clotting disorders in which there’s a defect in a natural anticoagulant mechanism. Inherited disorders include factor V Leiden, prothrombin gene mutation, protein C and S deficiency, and antithrombin III deficiency

The most common cause of hereditary thrombophilia is factor V Leiden. In normal conditions, protein C regulates the coagulation cascade by inhibiting two factors, factor V and factor VIII. In factor V Leiden, there is a point mutation in the gene coding for factor V, which causes resistance to the anticoagulant effects of activated protein C. This leads to unregulated production of thrombin and consequently, an increased risk of clot formation.

Other causes of decreased anticoagulant function include antithrombin III deficiency and protein C or protein S deficiency. These conditions can be inherited defects or secondary to systemic disorders such as decreased production (in liver disease), increased loss of proteins through the kidneys (nephrotic syndrome), or consumption by active thrombosis.

What is a secondary hypercoagulable state?

Secondary hypercoagulable state occurs when thrombophilia is caused by acquired factors or conditions that can increase the risk of thrombosis. They include cancer, smoking, obesity, pregnancy, major trauma or surgery, inflammatory or autoimmune disorders, prolonged immobilization, and taking certain medications such as oral contraceptives

Cancer causes hypercoagulability through increased production of procoagulant factors and cytokines, as well as through the interaction of malignant cells with the inner lining of the blood vessels. 

Other conditions—such as smoking, inflammation, surgery or trauma—damage the blood vessels, triggering the persistent activation of the coagulation cascade. Additionally, inflammatory disorders can cause systemic activation of the coagulation cascade, decreased natural anticoagulant mechanisms, and impaired removal of blood clots. 

Antiphospholipid syndrome is an autoimmune disorder caused by the presence of auto-antibodies directed to phospholipids, which are components of the cell membrane. The most frequently found antibodies are lupus anticoagulant, anticardiolipin, and anti-beta-2-glycoprotein. Individuals with antiphospholipid syndrome have a high risk of developing arterial and venous thrombosis, as well as obstetric complications like miscarriage

Prolonged immobilization can worsen a hypercoagulable state by slowing blood flow in the veins, especially those of the lower extremities, therefore increasing the risk of deep venous thrombosis

Taking certain medications can cause acquired thrombophilia. Estrogen-containing medications such as contraceptives can increase the levels of coagulant factors VII and X, as well as decrease the levels of anticoagulant proteins. Heparin induced thrombocytopenia is an acquired thrombophilia that can be seen in some individuals taking heparin, which is commonly used to prevent the development of thrombosis in hypercoagulable states. Paradoxically, heparin can induce an immune reaction that triggers the activation of platelets and the release of procoagulant cytokines. These changes can lead to the formation of thrombi in blood and a low platelet count (thrombocytopenia) due to increased consumption.

Is pregnancy a hypercoagulable state?

During pregnancy, there’s a higher risk of venous thromboembolism. This is in part due to hormonal and physical changes that occur during the pregnancy and peripartum. There’s an increase in most of the clotting factors, as well as a decrease in the anticoagulant mechanisms, such as resistance to activated protein C and decreased levels of protein S. In addition, the increased pressure of the womb slows down the venous return into the heart, making the blood more likely to clot.

How do you test for hypercoagulability?

Testing for hypercoagulability generally begins after the development of a thrombotic event. Most of the time, thrombi are caused by the presence of more than one acquired risk factor. In these cases, performing blood tests to look for hereditary thrombophilias is not needed. 

Clinical practice guidelines recommend screening for hypercoagulable states only in individuals with a high suspicion of an inherited clotting disorder. Factors that suggest this include a family history of thromboembolism, a personal history of thrombosis at a young age or in usual blood vessels, and a history of frequent miscarriages. Common lab tests for screening include looking at the levels of anticoagulant proteins in the blood, as well as genetic tests to identify the inherited mutation, such as factor V Leiden and G20210A mutation in the prothrombin gene. 

In those who have experienced miscarriages along with thrombotic events, antiphospholipid syndrome should be suspected. In these cases, tests to look for an antiphospholipid antibody such as lupus anticoagulant should be performed.

How do you manage a hypercoagulable state?

Management of hypercoagulability is generally recommended only after the development of a thromboembolic event, even for individuals with a known inherited clotting disorder. 

Acute thromboembolic events can be treated with short-term anticoagulant therapy, using medications like low molecular weight heparin (LMWH), warfarin, or direct anticoagulants such as dabigatran or rivaroxaban. In severe cases, the clot can be surgically removed through thrombectomy or dissolved with thrombolytic medications such as urokinase or streptokinase. After managing the thromboembolic event, individuals with high thrombotic risk of recurrence can be prescribed long-term anticoagulant therapy like warfarin or heparin, so as to inhibit the clotting cascade and prevent clot formation.

Anticoagulant medications may also be recommended for prevention in people with several hypercoagulable risk factors, such as during pregnancy or after a major surgery. However, the decision to offer preventive anticoagulant treatment should be individualized in each person according to their thrombotic risk. For instance, individuals with a mild hereditary thrombophilia, such as factor V Leiden, may not need preventive anticoagulant treatment in the absence of other risk factors, since they have a low thrombotic risk. On the other hand, pregnant females with antiphospholipid syndrome may take low molecular weight heparin or aspirin during pregnancy to prevent the development of thromboembolic complications.

Finally, it’s important to remove or avoid risk factors that may contribute to the hypercoagulable state, when possible. These measures may include changing oral contraceptives pills to another birth control method, quitting smoking or avoiding prolonged immobilization.

What are the most important facts to know about a hypercoagulable state?

Individuals with a hypercoagulable state have an increased tendency to form blood clots, generally due to an imbalance between prothrombotic and anticoagulant mechanisms. Primary hypercoagulable states are inherited disorders that include factor V Leiden, prothrombin gene mutation, protein C and S deficiency, and antithrombin III deficiency. Primary hypercoagulable states should be suspected in young individuals with a positive family history, recurrent thromboembolic events, or blood clots in usual territories. Secondary hypercoagulable states are acquired conditions or risk factors that increase the risk of thrombosis through various mechanisms. Some of them are antiphospholipid syndrome, cancer, and prolonged immobilization, among others. Diagnosis of hypercoagulability can include blood tests to look at the levels of anticoagulant proteins, as well as genetic testing to identify the most common inherited thrombophilias. Treatment may include anticoagulant therapy, thrombolysis or thrombectomy, as well as removing or avoiding the risk factors that contribute to the hypercoagulable state, when possible. 

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Related links

Anticoagulants: Heparin
Anticoagulants: Warfarin
Clinical Reasoning: Thrombophilia
High Yield: Deep vein thrombosis and pulmonary embolism
High Yield: Thrombophilic disorders

Resources for research and reference

Khan, S. & Dickerman, J. D. (2006). Hereditary thrombophilia. Thrombosis Journal, 4(15). DOI: 10.1186/1477-9560-4-15

Margetic S. (2010). Diagnostic algorithm for thrombophilia screening. Clinical Chemistry and Laboratory Medicine, 48(Suppl 1): S27-S39. DOI: 10.1515/CCLM.2010.362

Nakashima, M. O. & Rogers, H. J. (2014). Hypercoagulable states: an algorithmic approach to laboratory testing and update on monitoring of direct oral anticoagulant. Blood Research, 49(2): 85–94. DOI: 10.5045/br.2014.49.2.85

Palta, S., Saroa, R., & Palta, A. (2014). Overview of the coagulation system. Indian Journal of Anaesthesia, 58(5):515–23. DOI: 10.4103/0019-5049.144643 

Senst, B., Tadi, P., Goyal, A., & Jan, A. (2020). Hypercoagulability. In StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved August 25, 2020, from