This is a very good question. Although leg ulcers are one of the clinical manifestations of the hemolytic sub-phenotype there is no one specific marker for leg ulcers that I know of currently. However, the hemolysis-endothelial dysfunction subphenotype often exhibits markers of high hemolytic rate, including low hemoglobin level, high plasma hemoglobin, LDH, bilirubin, and arginase, culminating in low nitric oxide bioavailability and a high prevalence of pulmonary hypertension, leg ulceration, priapism, and stroke. Co-inheritance of α-thalassemia trait with SCD reduces the hemolytic rate, reducing the risk of hemolysis-associated complications and increasing the risk of viscosity-related complications (Kato et al. Blood reviews 2007). Those are likely a group of patients at highest risk. We found that a low global arginine bioavailability ratio (plasma arginine/(ornithine+citrulline)) was often found in patients with the hemolytic subphenotype, and was associated with pulmonary hypertensin risk and increased mortality. But we did not specifically look at leg ulcers. -Claudia

First and foremost, hemolysis is driving vaso-occlusion and the pathophysiology. Markers of hemolysis include the reticulocyte count, hemoglobin, hematocrit, and serum LDH. Heme is released into plasma during hemolysis. Heme induces an inflammatory response in the vasculature and promotes vaso-occlusion in the prodromal phase of a pain crisis.

Secondly, Sickle cell pain includes three types: acute recurrent painful crises, chronic pain syndromes and neuropathic pain. Chronic pain syndromes are associated with or accompany avascular necrosis and leg ulcers.

From my clinical experience sickle leg ulcer do not correlate with severe disease, there indicators of severe disease like frequency of crises, haemoglobin levels, LDH etc may not be as in important in predicting who will develop leg ulcers.

Samir k. Ballas

Predisposing factors for leg ulcers:

Age older than 10 years

Males

Severe anemia

Areas or countries where patients walk bare-footted

Trauma

Lack of alpha gene deletion i.e alpha gene deletion is protective

Homozygosity for the beta CAR haplotype

Leg ulcer in sickle cell disease , from our experience in our center cuts across the spectra of sickle cell patients that we manage. The presence of Ulcers is not one of the markers of the severity of the disease like cerebro vascular accidents, acute chest syndrome etc so its makes it difficult to predict clinically who develops it or who doesn't. This illustrates the importance of this question. I believe its not something that can only be detected by checking for cell markers or biochemical levels of substances or genetic studies for the regulatory genes, the influence of the environment may also be an important predisposing factor.

How do you treat leg ulcers?

In my experience with patients with thalassemia, they responded very well with sessions of hyperbaric oxygen.

I will like to know how sickle cell pain is managed in the community

In our experience in DRC, lesg ulcers are rarely observed in young children (< 10 yrs); but we suspect also the role of some enviromental factors: little trauma and insect bites. Leg ulcers are treated with local application of bees honey and results seem enough good; but we need a large numlber of cases to confirm a such result.

I think the idea of having a biomarker to predict whether a sicke cell disease patient is most likely to develop chronic leg ulcers is very interesting. There are as such no such biomarkers available. Considering that in the pathophysiology of the disease there could be hemolysis or in cases of co-inheritance of α-thalassemia trait with Sickle Cell Disease wherein the hemolysis related complications may be decreased, however, there could be increased viscosity risk which may predispose patients to develop chronic leg ulcers, I have an idea that pulse wave velocity measurements may serve as a risk predictor of chronic leg ulcers. However, this needs to be tested. Pulse-wave velocity measurements basically help in assessing the arterial stiffness, but it is known to be altered in patients with hemolysis or in patients with increased viscosity. Physicians may use this technology during the course of treatment of patients and see whether it may be of any value. Physicians who do not have this technology perhaps may just feel the femoral, anterior tibial or pedal pulses. It is just a thought.

It needs to be clarified that, although the concept of pulse wave velocity is known since a long time and several scientists have investigated its role in various conditions like hypertension, atherosclerosis, hemolysis and increased viscosity etc. Some investigators have found the value of pulse wave velocity in assessment of psychiatric disorders. My intention of suggesting pulse wave velocity in a condition such as sickle cell disease where the physicians encounter hemolysis or increased viscocity, was to test or to evaluate the use of pulse wave velocity in predicting chronic leg ulcers in patients who may manifest increased viscocity. This concept of pulse wave velocity in predicting chronic leg ulcers in patients with sickle cell disease has to be evaluated in large clinical trials before this can be used for such conditions. This answer was in response to the original question by Dr. Madu Anazoe "Are there are any markers that predict whether a sickle cell disease patient is most likely to develop chronic leg ulcers? Since there are no such marker available, the idea of the answer was to identify pulse wave velocity as a possible marker to predict chronic leg ulcers. I had also suggested that people who do not have access to pulse wave velocity technology can also get some experience in predicting increased viscosity by just feeling the anterior tibial or pedal pulses. Even this concept has to be further evaluated clinically before it can be widely practiced. I hope this clarifies my answer.

Thank you Omer, I will seriously give it a thought as well as discuss with the sonographers to see whether we can indirectly measure the pulse wave velocity in the arteries of the lower limb.

Madu,

I am glad to know that you will give a serious thought as well as discuss with sonographers regarding pulse wave velocity. This is a very precise measurement. You would need to perform PWV on a good number of normal individuals and then perform it on patients with SCD manifesting increased viscocity or hemolysis and notice for yourself the subtle changes in PWV you see in both groups. You can target any blood vessel such as carotid, radial, femoral, anterior tibial or pedal arteries etc. Besides the viscocity of blood you can also use this technique for measurement of arterial thickness. Please do try this out with all seriousness and I wish you my best.

Omer

In Brazil we use Nanoskin Matrix extracellular, very excellent results and complete cicatrization .

Dear some cytokines could be biomarkers for predicting leg ulcers in sickle cell patients.