Thrombotic microangiopathy: Clinical sciences

Thrombotic microangiopathy, or TMA for short, is a rare but life-threatening blood condition characterized by uncontrolled formation of thrombi in the small blood vessels. These blood clots consume platelets, leading to thrombocytopenia. They also create turbulent shearing forces that destroy passing red blood cells, leading to microangiopathic hemolytic anemia, or MAHA. Now based on the underlying pathophysiology, there are several different types of TMA! The first one is thrombotic thrombocytopenic purpura, which is associated with von Willebrand factor-dependent coagulation and impaired function of a metalloprotease called ADAMTS13. Next, there’s atypical hemolytic uremic syndrome, which is characterized by uncontrolled complement activation. Finally, there’s classic hemolytic uremic syndrome, which is associated with E. Coli or Shigella infections!

Now, if your patient presents with chief concern suggesting TMA, you should first perform an ABCDE assessment to determine they are unstable or stable. If unstable, stabilize their airway, breathing, and circulation. Next, obtain IV access and consider IV fluids. Finally, put your patient on continuous vital sign monitoring including blood pressure, heart rate, and pulse oximetry. Finally, if needed, don’t forget to provide supplemental oxygen.

Okay, let’s go back to the ABCDE assessment and look at stable patients. In this case, start with a focused history and physical exam. Your patient is likely to report weakness and fatigue. They might also note non-specific symptoms, like fever and headache, often in combination with easy bruising or excessive bleeding. Additionally, some patients could report gastrointestinal symptoms, such as abdominal pain or diarrhea. On physical exam, you might observe purpura, bruising, or mucosal bleeding.

Based on these findings, you should suspect a disorder affecting platelets, such as TMA, so your next step is to order labs, including a CBC with peripheral blood smear; reticulocyte count; LDH, CMP, and haptoglobin; as well as coagulation tests, including PT, PTT, INR, and fibrinogen.

The formation of blood clots throughout the body depletes thrombocytes, causing thrombocytopenia. In small blood vessels, these microthrombi act like saw blades, eventually damaging erythrocytes and causing anemia! On the peripheral smear, you can identify these damaged red blood cells as schistocytes, also known as helmet cells. Now, because the body is losing red blood cells, bone marrow will increase the red blood cell production, by pumping more reticulocytes into the bloodstream! In other words, labs will reveal elevated reticulocyte count! As red blood cells are destroyed, they release LDH, so it will be elevated on labs.

CMP will show elevated creatinine. Red blood cells will also release hemoglobin, which eventually is broken down into unconjugated bilirubin. So, CMP will reveal elevated unconjugated bilirubin levels! But, to prevent further loss of hemoglobin, a small protein named haptoglobin binds it. As a result, the level of free haptoglobin drops, so your patient often presents with undetectable haptoglobin levels. Finally, since there’s no activation of the coagulation cascade, there will be no consumption of clotting factors, thus, PT, aPTT, INR, and fibrinogen will all be normal.

Now, here’s a clinical pearl! In contrast to TMA, in disseminated intravascular coagulation or DIC for short, a trigger over-activates the coagulation and fibrinolytic cascades, leading to widespread thrombosis, which results in severe consumption of both platelets and coagulation factors. As a result, your patient will typically present with thrombocytopenia in combination with a prolonged PT and aPTT.

Now, based on these lab findings, you can diagnose TMA, so your next step is to evaluate your patient’s presentation, paying attention to features that may help to distinguish between TTP and HUS. The main features you should look for include fever, renal failure, abdominal pain and bloody diarrhea, or neurological symptoms like headaches, confusion, stroke, focal deficits, and even coma. In addition, consider your patient’s age, as well as dietary and travel history.

Here’s a clinical pearl! You can predict the likelihood of TTP by using the PLASMIC score, which uses a combination of lab results and history findings. PLASMIC stands for Platelet count; hemoLysis; absence of Active cancer; absence of Stem-cell or Solid-organ transplant; normal MCV; normal INR; and Creatinine less than 2 mg/dL. Each category is scored one point. If the PLASMIC score is greater than 6, there’s a high likelihood of TTP!

Okay, let’s start with features that would make you suspect TTP! This condition mostly occurs in adults, and is characterized by fever, renal failure, and neurological symptoms. Now, what happens is that normally, Von Willebrand factor, or vWf for short, promotes hemostasis and platelet adhesion; while the metalloprotease ADAMTS13 cleaves vWf and prevents uncontrolled platelet adhesion. However, in TTP, ADAMTS13 activity is severely reduced due to inhibitory autoantibodies, leading to an overabundance of Von Willebrand Factor, which eventually results in uncontrolled platelet aggregation and thrombus formation.