CURRENT SERIES:
The Challenges and Treatment of Sickle Cell Disease

Sickle Cell Disease: Pathophysiology and Presentation

A review of the pathophysiology behind sickle cell disease as well as the resulting clinical symptoms and comorbidities.


Neil B. Minkoff, MD: What’s the underlying pathology or pathophysiology that’s leading to all of this cost?

Ahmar U. Zaidi, MD: Our understanding of what exactly is happening in sickle cell disease has taken off in the past 2 decades. We’ve always known that the polymerization of sickle hemoglobin is the mainstay of what’s causing red blood cells to change their shape. But over the past 20 years we’ve learned that the pathophysiology of sickle cell disease is particularly complicated and involves more than just the erythrocytes, and probably involves the endothelium, white blood cells, platelets, overall inflammation, and thrombophilia. The basic issue with sickle cell disease is what we refer to as vaso-occlusion, and that’s driven by a multitude of factors.

Neil B. Minkoff, MD: What is the hemolysis effect?

Ahmar U. Zaidi, MD: Sickle hemoglobin causes, as we discussed, the formation of a long strand polymer that makes sickle cells rigid. And by default, the erythrocytes are required to be able to change shape as they traverse through the various sized vasculature in our body, and they should be able to make it through different types of environments.

What happens is as sickle cells continue to form these polymers, they become unable to get through, they lose their competency to get through the vasculature. Along with that, from the vaso-occlusion we have this effect of ischemia and reperfusion that causes an environment that’s unfavorable for the red blood cell. The result of this is that as sickle cells age, they don’t make it to the expected red blood cell lifespan that we know of, their lifespan is probably reduced by about 75%.

The red blood cells eventually break open and release the content. And the content inside the red blood cells can be quite toxic to the body. They release a variety of molecules that signal to the body that something bad is happening, and the body reacts to that signaling.

Neil B. Minkoff, MD: How does the body react?

Ahmar U. Zaidi, MD: The way the body reacts to that is by identifying that something has gone wrong in the process of the erythrocyte making it through the body. So what we see is an amped-up immune system, and we start seeing consumption of some of the factors that are good for the vasculature in general. So we see the consumption of things like nitric oxide, which is responsible for causing vasodilation, and we end up getting a vasculature that’s inflamed and constricted that makes it even more difficult for erythrocytes make it through.

Neil B. Minkoff, MD: Which sounds like quite the setting for some pretty dramatic complications.

Ahmar U. Zaidi, MD: Absolutely.

Neil B. Minkoff, MD: What are those sort of comorbidities that are caused by this?

Ahmar U. Zaidi, MD: The top flagship comorbidity that’s associated with sickle cell disease is pain. We see tremendous amounts of unpredictable, complex pain that is treated with large doses of opioids, mostly because we don’t have anything better at this point to treat pain with. We also see a top comorbidity of stroke in these patients. The comorbidities you see are obviously based on where the vasculature is being occluded. It’s distributed by anatomic sites. We see a tremendous amount of lung injury in the form of what we call acute chest syndrome. We see things like leg ulcers, and eventually as patients age, we start seeing multi-organ dysfunction.

Neil B. Minkoff, MD: Is that the usual clinical presentation?

Ahmar U. Zaidi, MD: Even though sickle cell disease is a monogenic disorder, every patient has a very unique phenotype, and we see that there are quite a few modifiers in phenotype. Different patients have different journeys. We see patients who are particularly severe who start presenting early in life, under the age of 1, with tremendous amounts of complications. And then we see patients who may have a beneficial modifier in their pathophysiology that stops the polymerization of sickle hemoglobin, for example. Something like an elevated amount of fetal hemoglobin, and those patients tend to have a milder course. So the patient journey is very individualized based on the environment that their erythrocytes are going through.

John C. Stancil, RPh: I would add that presentation at the hospital or the emergency department with pain crisis is the number 1 reason driver for our medical cost for sickle cell patients. And then that creates that stigma that they’re frequent flyers, they’re drug seeking, which creates a whole other stigma around that population.

Ahmar U. Zaidi, MD: Absolutely. There’s a very interesting study called the PiSCES study by Dr Wally Smith, MD, where he gave pain diaries to his sickle cell patients, and he showed that what we’re seeing as providers is the tip of the iceberg. And really the burden of pain in sickle cell disease is what’s submerged under the water. From the patient perspective, it appears that when you follow the pain diaries, about two-thirds of their pain is actually happening at home. So we’re not even seeing the daily burden that this disease is causing on these patients.

John C. Stancil, RPh: Absolutely.

Ahmar U. Zaidi, MD: We’re only seeing a third of it.

Maria Lopes, MD, MS: This may bring up the opportunity perhaps for Telehealth or diaries that help clarify what is beneath that surface. It may actually lead to the emergency department visit, we can actually do something about that.

Ahmar U. Zaidi, MD: Right.

Maria Lopes, MD, MS: What I was going to comment on was also the chest syndrome, because as you get admitted these patients can also be so labile, and survival and mortality is so high, right? This disease is robbing patients of having a normal life expectancy.

 
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