Inflammation and Coagulation Activation Influence Clinical Disease Burden in Sickle Cell Disease

Background: Hemoglobin SC sickle cell disease (HbSC-SCD) manifests similar, but milder and less frequent clinical events than HbSS-SCD. Although the cause of such phenotypic variability is unclear, several lines of evidence point to the complex interplay of multiple etiologies in SCD pathology. Serum lactate dehydrogenase (LDH) has emerged as an important clinical surrogate for intravascular hemolysis in evaluating reduced nitric oxide (NO) bioavailability-mediated complications in SCD; most of the data comes from adult studies and shows that higher LDH levels in HbSS patients correlate clinically with pulmonary hypertension, priapism and leg ulcers. One recent publication showed that elevated LDH levels in pediatric HbSS correlate with abnormal transcranial Doppler values. In this study we compare biomarker and clinical profiles in children and adolescents with HbSS vs. HbSC disease with control-range LDH levels. We hypothesized that despite similar LDH levels as the HbSC patient group, HbSS patients would demonstrate marked differences in biomarker and clinical profiles that could implicate important additional pathways of disease mechanisms.

Methods: 48 patients at steady state (age 3–20 years) with control-range LDH levels (<400 IU/l) were divided in two groups: HbSS (n=24) and Hb-SC (n=24). Laboratory evaluations included hematologic indices, and biomarkers pertinent to inflammation and endothelial activation (CRP, sVCAM1, sP-selectin, sE-selectin), and coagulation/fibrinolysis {DDimer, prothrombin fragment (f1.2), tissue plasminogen activator (tPA), Plasmin-antiplasmin complex (PAP), plasminogen activator inhibitor (PAI-1), and phosphatidylserine-positive microparticles (PS+ve MPs)}. Clinical charts were reviewed for microvascular occlusive events including total hospitalizations for VOC and ACS over a 3 year period to include year of study, the year previous to, and the year following date of study. t test was used to compare means (parametric and non-parametric as appropriate).

Results:

Summary: Our data indicate that HbSS children and adolescents with control-range LDH bear greater clinical burden of disease (more hospitalizations for VOC and ACS) as compared to HbSC patients with similar LDH levels (i.e. equivalent levels of intra-vascular hemolysis). The biomarker profile of “steady state” HbSS patients showed:

1. Increased bone marrow (BM) turnover (higher reticulocytes, polymorphonuclear neutrophils, monocytes and platelets);

2. Increased inflammation/endothelial activation (elevated CRP, sP-selectin and sE-selectin); and

3. Coagulation activation (increased f1.2 and DDimers).

However, there was no difference in PS+ve MPs between the HbSS and HbSC groups.

While the increased BM activity supports a greater baseline hemoglobin in HbSS patients with control-range LDH, our data imply that this is not without cost. We suggest that this increase in neutrophils, monocytess and platelets plays a key role in influencing inflammation, endothelial activation and thrombin generation in the microvessel-dependent SCD complications of VOC and ACS. Contrary to our expectations, the increase in thrombin generation noted in our study does not appear to be influenced by the presence of PS+ve MPs. These data provide further evidence to support the study of therapeutic strategies targeting inflammation and coagulation in SCD.