Approach to hypercoagulable disorders: Clinical sciences

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Introduction 0:00–0:49

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.

H&P 0:49–1:37

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.

Consider VTE 1:37–2:11

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.

Provoked VTE 2:11–2:55

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.

Unprovoked VTE 2:55–3:49

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.

Labs 3:49–5:51

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!
Okay, now let’s take a look at lab results, starting with cases where inherited hypercoagulable labs are abnormal. There are 5 possible outcomes, starting with Factor V Leiden.

Factor V Leiden Mutation 5:51–6:36

If the DNA test identifies the R506Q gene mutation, diagnose factor V Leiden! This mutation was discovered in Leiden, the Netherlands, and is sometimes referred to as activated protein C resistance.
This is because activated protein C normally degrades factor Va. However, this mutation inhibits the ability of protein C to bind factor V and inhibit it, leading to enhanced factor Va activity and increasing the risk of thrombosis.
Second, if the DNA testing reveals the prothrombin G20210A gene mutation, diagnose prothrombin gene mutation! This mutation is a gain of function mutation that increases prothrombin concentration and activity, increasing the risk of thrombosis.

Prothrombin Mutation 6:36–6:57

Third, if labs reveal low protein C activity, diagnose protein C deficiency, which can occur due to over 100 different genetic mutations.

Protein C Deficiency 6:57–7:40

These mutations can reduce either the level or function of this protein, which is an anticoagulant that inactivates coagulation factors Va and VIIIa.
Now, keep in mind that the synthesis of protein C in the liver is vitamin K-dependent. So, if you start your patient on vitamin K antagonists, like warfarin, protein C will get depleted more rapidly than the vitamin K-dependent coagulation factors.
This can cause a transient hypercoagulable state that can result in warfarin-induced skin necrosis! Fourth, if the labs reveal low protein S activity, diagnose protein S deficiency.

Protein S Deficiency 7:40–8:01

Protein S is also a vitamin K-dependent anticoagulant that acts as a cofactor for activated protein C. Inherited mutations in protein S reduce its level or function, increasing the risk of thrombosis.
Finally, the fifth and the last inherited hypercoagulable disorder is antithrombin deficiency! In this case, the labs reveal decreased antithrombin activity.

Antithrombin Deficiency 8:01–8:54

Previously called antithrombin III and also known as heparin cofactor I, antithrombin is a protease inhibitor that inactivates several coagulation factors, including thrombin and factor Xa.
There are hundreds of genetic mutations that lead to either reduced production or reduced activity of antithrombin that increase the risk of thrombosis.
Here’s a final clinical pearl to keep in mind! The anticoagulant heparin binds to antithrombin and induces a conformational change that dramatically accelerates antithrombin activity.
This means your patient with antithrombin deficiency could present with heparin resistance! Okay, let’s go back to the lab results, and take a look at the lab results where the acquired hypercoagulable labs are abnormal, and discuss antiphospholipid syndrome!

Antiphospholipid Syndrome 8:54–9:44

If your patient’s antiphospholipid antibody lab tests are positive for anticardiolipin, anti-beta2-glycoprotein-I, or lupus anticoagulant antibodies; consider antiphospholipid syndrome.
In patients with an acute infection, these antibodies could be transient and variable, so you should always repeat the antiphospholipid antibody labs in 12 weeks.
If any of the antiphospholipid antibodies continue to be positive, diagnose antiphospholipid syndrome, which can occur as a primary condition or as a result of another systemic autoimmune disease, including systemic lupus erythematosus.
Alright, as a quick recap…Hypercoagulable disorders include conditions associated with an increased tendency of blood clotting, due to either an inherited or acquired cause.

Review 9:44–10:37

If you diagnose unprovoked VTE, assess whether or not your patient requires screening for hypercoagulable conditions. If screening indications are present, order factor V Leiden, prothrombin gene mutation, protein C activity, protein S activity, and antithrombin activity to screen for inherited causes; and anticardiolipin antibody, anti-beta2-glycoprotein-I antibody, and lupus anticoagulant to screen for acquired antiphospholipid syndrome.
An abnormal lab result is diagnostic for any of the inherited disorders, but diagnosis of antiphospholipid syndrome requires persistence of antibodies, so repeat testing after 12 weeks.
Approach to hypercoagulable disorders: Video | Osmosis