Approach to bleeding disorders (coagulopathy): Clinical sciences

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Introduction0:00–0:25

Coagulopathy refers to dysfunction in any step of the coagulation cascade, resulting in impaired blood clot formation. The most important coagulopathies include medication-induced coagulopathy, an acquired factor inhibitor, hemophilia A, hemophilia B, severe von Willebrand disease, chronic liver disease, and vitamin K deficiency.

Unstable0:25–1:34

Now, if your patient presents with a chief concern suggesting a bleeding disorder, perform an ABCDE assessment to determine if the patient is unstable or stable.
If unstable, stabilize their airway, breathing, and circulation. Next, obtain IV access, give IV fluids, and consider transfusion of blood products, such as packed red blood cells, fresh frozen plasma, or cryoprecipitate.
Finally, put your patient on continuous vital sign monitoring and, if needed, provide supplemental oxygen! Now, here’s a clinical pearl to keep in mind!
Unstable patients with bleeding disorders might present with hemorrhagic shock, so you must quickly locate the source of bleeding in order to stabilize the patient!
They may have neurologic changes from intracranial bleeding; hematemesis or hematochezia from gastrointestinal bleeding; or vaginal bleeding from postpartum hemorrhage.
If unclear, consider obtaining a CT angiography or endoscopy, and consulting the surgery team for interventions to stop the bleeding.
Okay, let’s go back to the ABCDE assessment and look at stable patients, and start with a focused history and physical exam.

Stable1:34–2:19

Your patient is likely to report easy bruising possibly in combination with a history of deep soft tissue bleeding, such as muscle hematomas and joint hemarthrosis.
They might also have a history of excessive bleeding after trauma or surgery, which is typically delayed hours to days after the event; as well as a family history of abnormal bleeding.
Additionally, the physical exam typically reveals ecchymoses and hematomas; and you may even find evidence of current bleeding.
With these history and physical findings, consider a bleeding disorder. Once you consider a bleeding disorder, order a CBC with peripheral smear, CMP, and a coagulation profile, including PT, aPTT, fibrinogen, and D-dimer.

Coagulopathy2:19–3:14

The CBC typically reveals normal platelet count, meaning there’s no consumption of platelets and the patient’s bone marrow is unaffected.
Next, the peripheral smear shows normal red blood cells with no schistocytes, which rules out the presence of microangiopathic hemolytic anemias, such as disseminated intravascular coagulation!
Moreover, normal fibrinogen and D-dimer levels confirm the absence of blood clot formation! However, prolonged PT, aPTT, or both, are highly suggestive of coagulopathy, so be sure to rule out medications associated with coagulopathy!

Medication-Induced Coagulopathy3:14–3:51

For example, heparins, like unfractionated heparin and low molecular weight heparin, bind to antithrombin, enhancing its inactivation of coagulation factors.
Next, warfarin, which is a vitamin K antagonist, inhibits the production and activation of factors II, VII, IX, and X in the liver.
Other important anticoagulant medications include factor Xa inhibitors like rivaroxaban and direct thrombin inhibitors like argatroban.
If these medications are present, diagnose medication-induced coagulopathy! Now, once you rule out medications as a cause of coagulopathy, your next step is to perform a one-to-one mixing study.

Mixing study - Factor Inhibitor3:51–4:15

In this diagnostic procedure, you are mixing the patient's abnormal plasma with normal donor plasma. Once mixed, order a PT and aPTT, and check to see if clotting times improve!

Acquired Factor Inhibitor4:15–4:59

If the clotting times don’t improve, diagnose coagulopathy due to an acquired factor inhibitor! In this case, autoantibodies present in your patient’s blood are directed against the clotting factors in both the patient’s and the donor’s plasma, inhibiting their activity.
As a result, either the PT or aPTT will remain prolonged. Acquired factor inhibitors are associated with certain medications, like antibiotics and immunomodulatory drugs; with several underlying conditions, including malignancies, autoimmune diseases like rheumatoid arthritis and lupus; and with pregnancy and the postpartum period..

Factor Deficiency4:59–5:28

On the flip side, if either the PT or aPTT improve after the mixing study, your patient is presenting with a factor deficiency!
In this case, the presence of normal factors in the donor plasma are able to overcome the factor or factors that are deficient in your patient’s plasma.
To further investigate which factor or factors are deficient in your patient’s plasma, start by assessing which of the coagulation tests is prolonged.
First up, let’s consider a normal PT with a prolonged aPTT, which indicates a problem with the intrinsic coagulation pathway.

aPTT Prolonged5:28–6:19

The intrinsic pathway is called intrinsic because all the factors needed to activate it are found within the blood. It’s initiated when factor XII binds to collagen at the site of an injury.
The other factors involved in this pathway are XI, IX, and VIII. On the flip side, the extrinsic pathway is activated when tissue factor, or factor III, which is found outside the blood, binds to factor VII.
Both pathways lead to the final common pathway, starting with the activation of factor X, and also involving factors V, II, and I.
Okay, once you identify a defect of the intrinsic pathway, order additional labs, including factor VIII activity, factor IX activity, as well as the von Willebrand factor level and activity.

Hemophilia6:19–7:04

If the factor VIII activity is low, diagnose Hemophilia A. On the other hand, if factor IX activity is low, diagnose hemophilia B.
Here’s a high-yield fact! Hemophilia A and B are X-linked recessive disorders that typically affect biological males.
Although other types of hemophilia exist due to deficiencies in other clotting factors, they are much rarer. Finally, if the von Willebrand factor level, activity, or both are low; and factor VIII activity is low, diagnose von Willebrand disease.

Von Willebrand Disease7:04–7:59

Now, von Willebrand disease is often thought of as a platelet function disorder, but in severe cases, it can also lead to coagulopathy.
Here’s a clinical pearl! Von Willebrand factor is a protein that acts as a bridging molecule between platelets and exposed endothelium, facilitating platelet adhesion.
This protein also works as a transport protein for factor VIII in the circulation, protecting factor VIII from inactivation.
Deficiency or dysfunction of the von Willebrand factor leads to inadequate platelet adhesion. In more severe cases, this can decrease factor VIII activity, eventually prolonging the aPTT.
Now, let’s return to our coagulation tests and focus on a prolonged PT, with or without a prolonged aPTT. In this case, an extrinsic pathway defect will prolong the PT, while either a common pathway defect or a combination of extrinsic and intrinsic defects will prolong both.

Chronic Liver Disease7:59–9:31

So, since the liver synthesizes most coagulation factors, your next step is to assess for chronic liver disease. In this scenario, your patient will have a history of chronic liver disease, like advanced fibrosis or cirrhosis, often with manifestations of portal hypertension like splenomegaly, hepatomegaly, and ascites.
Additionally, the CMP may reveal elevated AST, ALT, and bilirubin levels, which suggests hepatocyte damage. With these findings, diagnose coagulopathy due to chronic liver disease!
Now, here’s a high-yield fact! Chronic liver disease increases bleeding risk by several mechanisms.
First, the liver is not making enough thrombopoietin. Low thrombopoietin levels decrease platelet production by the bone marrow.
Additionally, damaged hepatocytes are not producing various clotting factors. Finally, an enlarged spleen sequesters more platelets than usual, which further reduces the number of circulating platelets!

Vitamin K Deficiency9:31–10:29

Finally, if you rule out chronic liver conditions, consider vitamin K deficiency, which is a required cofactor in the synthesis of factors II, VII, IX, and X.
In this case, history may reveal malnutrition, prolonged antibiotic use, or an underlying gastrointestinal disease associated with fat malabsorption.
Additionally, if the labs reveal normal AST, ALT, and bilirubin levels, with low vitamin K levels, diagnose vitamin K deficiency!
Here’s one last clinical pearl to keep in mind! Malnutrition is associated with inadequate vitamin K intake, while some antibiotics deplete the intestinal flora that synthesize vitamin K, and pancreatic, biliary, and intestinal diseases may cause malabsorption of fats and the fat-soluble vitamin K.

Review10:29–11:16

Alright, as a quick recap… Coagulopathy refers to dysfunction of the coagulation cascade, resulting in impaired ability to form blood clots and an increased risk of bleeding.
Once you suspect coagulopathy, rule out medication-induced coagulopathy. Next, perform a one-to-one mixing study.
No improvement in PT or aPTT suggests an acquired factor inhibitor; while the improvement of coagulation studies suggests a factor deficiency!
Moreover, if the aPTT is prolonged, think of hemophilia A, hemophilia B, and severe von Willebrand disease. On the other hand, if the PT is prolonged, consider coagulopathy due to liver
Approach to bleeding disorders (coagulopathy) | Osmosis