Hypercoagulable State · What Is It, Causes, Pregnancy, Diagnosis, Treatment, and More

A hypercoagulable state, also known as thrombophilia, is an increased tendency to develop blood clots (i.e., 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, as 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 (DVT) or pulmonary embolism (PE). DVT 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 and causing infarction.  

Blood clotting results from the interaction between blood vessels, platelets and coagulation factors. Coagulation factors are proteins circulating in the blood in their inactive form, to prevent coagulation from occurring when it’s not necessary. When there’s an injury, a platelet plug forms first (i.e., primary hemostasis); subsequently, coagulation factor VII binds to tissue factor (i.e., factor III) expressed on the exposed vessel wall, triggering the activation of the coagulation cascade (i.e., secondary hemostasis). This allows the subsequent activation of the rest of the clotting factors, which ultimately leads to the formation of thrombin (i.e., factor IIa). Thrombin converts fibrinogen into fibrin (i.e., factor Ia), 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 and protein S form a complex that inactivates factors V and VIII. On the other hand, antithrombin III directly decreases the production of thrombin (i.e., factor IIa) and inactivates thrombin and several other activated factors, including factor Xa.  

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.  

Primary hypercoagulable states are inherited clotting disorders characterized by a defect in a natural anticoagulant mechanism. Inherited disorders include factor V Leiden, prothrombin gene G20210A mutation, protein C and S deficiency, and antithrombin III deficiency.  

The most common cause of hereditary thrombophilia is factor V Leiden. In normal conditions, activated 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 an unregulated production of thrombin and, consequently, an increased risk of clot formation. 

The G20210A mutation in the prothrombin gene is the second most common hereditary risk factor for venous thromboembolism. It results in elevated prothrombin (i.e., factor II) levels, contributing to a hypercoagulable state. 

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 (e.g., liver disease), increased loss of proteins through the kidneys (e.g., nephrotic syndrome), or consumption by active thrombosis. 

Secondary hypercoagulable states occur 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 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 autoantibodies directed against phospholipids, which are components of the cell membrane. The most frequently found are lupus anticoagulants, anticardiolipin antibodies, and anti-beta-2-glycoprotein antibodies. 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 clotting 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 the blood and a low platelet count (i.e., thrombocytopenia) due to increased consumption. 

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 unusual 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 a possible 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. 

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 initially treated with short-term anticoagulant therapy, using medications like low molecular weight heparin (LMWH), warfarin, or direct oral anticoagulants (DOACs) 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 DOACs, 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, have a low thrombotic risk and may not need preventive anticoagulant treatment in the absence of other risk factors. On the other hand, pregnant females with antiphospholipid syndrome may be prescribed 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.