Development of a Target Concentration Intervention to Individualize Paroxysmal Nocturnal Hemoglobinuria Treatment With Pegcetacoplan

Paroxysmal Nocturnal Hemoglobinuria (PNH)

In medical school, the rarer the disease the more interested I was in reading about it. But, once in practice, we realize we don’t see those “rare birds,” and so I settled into routine and only focused on the common diseases. However, those rare birds are still in our primary care offices, and they may present with symptoms that baffle us if we don’t have these rare conditions on our radar. Perhaps we don’t need to become experts in these rare conditions, but we do need to know how they might present in the primary care setting and from there we can refer them to the appropriate specialty care.

Paroxysmal nocturnal hemoglobinuria is one such rare condition. So, how might this present in a primary care office? Let’s start off with the keyword "hemoglobinuria." There is hemoglobin in the urine so the urine will be a dark color — dark red or brown. However, this is not hematuria, which is red blood cells in the urine. This is just hemoglobin, which means the red blood cells are being hemolyzed in the blood and then the leaked hemoglobin is spilling into the urine.

People with this condition have a genetic defect, and the mutation typically shows up between 30 and 40 years of age. These individuals can’t make GPI, which acts as an anchor protein on the red cell membrane. Important proteins attach to this anchor and tell the complement system not to attack these red cells. Remember that the complement system defends us by attacking and lysing bacteria. So, if the red cells do not have the protein that tells the complement system that they are the good guys, then the complement system will attack and lyse the red cells.

The red cells are lysed, and the hemoglobin is released and then spills into the urine. Overnight, the urine gets concentrated, and so it darkest in the morning. That is why initially we called PNH "nocturnal" because we thought it only happened at night. But this lysis can happen anytime. It's just easier to see the dark urine color in the morning.

The loose hemoglobin also binds to nitric oxide and uses up a lot of it. Nitric oxide helps smooth muscles relax, and, without it, the smooth muscles in the gastrointestinal system can’t relax. So, patients may complain of dysphagia, esophageal spasm, and abdominal pain. The hemoglobin and iron can damage the kidney, and their renal function tests may be abnormal. And that anchor protein defect also leads to more platelet activation and aggregation, so blood clots are more common. In fact, 40% of these patients have blood clots over their lifetime. They tend to be more venous clots, and they can be anywhere, although the most common site is the hepatic vein.

Before these events happen, patients may come in with complaints of fatigue or generalized malaise (due to their hemolytic anemia). They may mention dark urine (due to the hemoglobinuria), and they may mention dysphagia or esophageal spasms or abdominal pain. On lab tests, you will see a positive urine test for blood, low hemoglobin, and renal insufficiency. We need to remember that often these rare conditions present with very vague and common symptoms; but, if we can identify that pattern then get the patient onto the right path, we can truly change that person's life.

There are treatments available. This article talks about such advances in therapy for paroxysmal nocturnal hemoglobinuria.