Approach to hypercoagulable disorders: Clinical sciences

Hypercoagulable disorders, or thrombophilic disorders, include conditions associated with an increased tendency for blood clotting. Based on the underlying cause, hypercoagulable disorders can be classified as inherited, which are associated with genetic mutations; and acquired, which are characterized by the presence of specific autoantibodies. Inheritable hypercoagulable disorders include factor V Leiden and prothrombin gene mutations, as well as protein C, S, and antithrombin deficiency. On the flip side, the most important example of an acquired hypercoagulable disorder is antiphospholipid syndrome.

Now, if your patient presents with a chief concern suggesting a hypercoagulable disorder, obtain a focused history and physical examination. Your patient will typically report symptoms associated with venous thromboembolism, or VTE for short. For example, they might report pain and swelling in one or more limbs, or they might report shortness of breath, chest pain, and coughing up blood. On physical exam, you might notice edema, erythema, and warmth, as well as tenderness to palpation of the affected area, which are typical findings associated with deep vein thrombosis, or DVT for short. On the other hand, you could also observe tachycardia and decreased oxygen saturation, which are common findings associated with pulmonary embolism.

With these findings, consider VTE. Your next step is to assess for VTE provoking risk factors. These include recent surgery, especially orthopedic and neurovascular procedures; immobilization, for example, if a limb is immobilized after a traumatic injury, or if your patient experiences prolonged immobility during an extended illness; malignancy; or a history of prior thromboembolism. Additionally, don’t forget pregnancy and estrogen therapy in biological females, especially if they are smoking.

If provoking risk factors are present, you are likely dealing with provoked VTE. Because these patients usually have a known risk factor for hypercoagulability, you should focus on treating the underlying cause.

Now, here’s a clinical pearl to keep in mind! Individuals with provoked VTE typically do not require further screening or workup. The only exception is in biological females whose risk factors for VTE are either pregnancy or estrogen therapy, especially in the absence of smoking. While these are known risk factors for provoked VTE, a small percentage of these individuals who do undergo screening are found to have an underlying hypercoagulable disorder.

Okay, if provoking risk factors are not present, diagnose an unprovoked VTE and assess if your patient requires screening for an inherited or acquired hypercoagulable disorder. These include one or more of the following: age less than 45; recurrent thrombosis; and involvement of multiple veins or unusual sites of thrombosis, such as portal, hepatic, mesenteric, and cerebral veins.

Now, here’s another clinical pearl to keep in mind! While most patients with an underlying hypercoagulable disorder will have a history of a thrombotic or unexplained ischemic event, like a stroke, some patients might be asymptomatic. This may mean that they never develop a thrombosis or only develop clinically insignificant thromboses that do not produce symptoms.

If screening indications are present, your next step is to consider a hypercoagulable disorder and order labs! First, check for inherited hypercoagulable disorders, using DNA tests to check for factor V Leiden and prothrombin gene mutations; and order functional assays to test protein C, protein S, and antithrombin activity.

On the flip side, to rule out acquired hypercoagulable disorders, check for antiphospholipid antibodies, including anticardiolipin, anti-beta2-glycoprotein-I, and lupus anticoagulant antibodies.

Now, the term “lupus anticoagulant” is a confusing misnomer because this antibody is not always indicative of lupus. Additionally, it has no anticoagulative effects because the term "anticoagulant" comes from its feature of prolonging the aPTT, probably due to interfering with the phospholipids used in the test. So, lupus anticoagulant antibodies are associated with hypercoagulable states, in spite of their name!

Now here’s a clinical pearl to keep in mind! Sometimes, you’ll only test for either inherited or acquired hypercoagulable disorders, but not both. If your patient has a family history of more than one first-degree relatives diagnosed with venous thromboembolism, you should screen for inherited hypercoagulable disorders. On the flip side, an unexplained arterial thrombosis, three or more spontaneous abortions before 10 weeks of gestation, or 1 or more fetal losses after 10 weeks of gestation, strongly suggest acquired conditions like antiphospholipid syndrome.

And here’s another clinical pearl! Hypercoagulable lab results might be inaccurate if a blood clot is present or if your patient is receiving anticoagulation therapy. So whenever possible, order labs at least 4 weeks after your patient has completed the prescribed course of anticoagulation treatment!