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Gene & Protein in Disease Sickle cell disease’s journey

with endothelial activation and vaso-occlusion poses a stimulates nociceptive fibers resulting in pain. Pain begins
strain on the cardiovascular system. In addition, the high from early infancy and continues in childhood as well as
cardiac output-induced increase in pulmonary pressure, adulthood and is the major cause of hospitalizations as
the sickling-induced hypoxemia, and the chronic volume well as a negative impact on the quality of life of SCD
overload intensify left ventricular failure as well as patients. Some patients present with as high as 6 (or
pulmonary venous hypertension, resulting in pulmonary more) episodes in a year, whereas others may suffer the
hypertrophy. The role of free heme released due to complication less frequently or not at all. In addition to
hemolysis has been implicated in pulmonary arterial pain, micro-occlusion also results in ischemia, edema,
vasculopathy and the role of chronic stress (due to anemia, necrosis, and organ damage. The edema and pain of
endothelial dysfunction, and chronic inflammation) has extremities result in one of the cardinal presentations in
been implicated in pathologic remodeling of the heart infancy, the “hand-foot syndrome.” While infants express
in SCD patients, characterized by chamber structure the pain through irritability and what appear to be
changes, diffuse fibrosis, and diastolic dysfunction. features of regression (e.g., no weight bearing, no walking
All of the aforementioned pathophysiological changes or crawling), vaso-occlusive pain in older children and
contribute to the onset of cardiopulmonary dysfunction adults could affect any part of the body. The pain is
and poor outcomes in SCD patients. 21,23,27,30,33 unpredictable in terms of both onset and resolution, but
Hypercoagulability is one of the cardinal features some known triggers are fever, dehydration, infections,
of SCD. This is attributed to multiple factors, with HbS acidosis, abrupt weather changes or pollutants, and
being the major one. The HbS induces hemolysis and the any factor stabilizing deoxyhemoglobin. Acute pain
prevalent oxidative stress activates hemostasis, coagulation progresses into chronic pain. 1,3,7,9,13,17
cascade, and fibrinolysis and depletes coagulation
inhibitors. A chronic activation of coagulation takes place 5.2. Hemolysis and anemia
in patients with SCD as against normal individuals with Symptomatic anemia is the most common symptom in
HbA, due to increased production and hence increased SCD and more so in HbSS patients. Hemoglobin levels for
plasma levels of prothrombin fragment 1.2, fibrinopeptide asymptomatic patients vary according to phenotype with
A, thrombin-antithrombin complexes, D-dimers and steady-state levels ranging from 60 – 80 g/L in HbSS and
plasmin-antiplasmin complexes. 34-41 Among these, it is HbSβ to 100 – 110 g/L in HbSC and HbSβ . It is the fall
0
+
the D-dimer that is reported to show a significant increase from the steady state levels that triggers hypoxic symptoms
during pain crises as compared to the time without acute such as aplastic crisis or shock-like states like splenic
events in the previous year. 42 sequestration crisis. 7
5. Clinical features The most common cause of an aplastic crisis in SCD
children is a parvovirus B19 infection. HbAA children
The most common manifestations of SCD (homozygous) with parvovirus 19 infection might experience a slight drop
as anemia, vaso-occlusion, and hemolysis, which can be in hematocrit, but HbSS children might face a significant
exacerbated by oxidative stress, hypercoagulable state, drop in hematocrit due to the decreased RBC life span of
inflammatory response, and defective arginine metabolism. 10 – 20 days, and the viral infection takes 4 – 7 days to
Infants with homozygous mutation are asymptomatic in resolve, necessitating a transfusion. 7,31
the first few months of life because of the effect of HbF
but once the disease is expressed, they will be fraught with Acute splenic sequestration crisis in SCD follows from
the above-mentioned complications for life and worsening a cycle of hypoxia, RBC polymerization, and reduced
with age. In addition to the vaso-occlusive crisis, hemolysis, blood flow in the narrow capillaries of the splenic bed,
and anemia, SCD includes a host of complications such resulting in splenomegaly, sudden pooling of blood in
as ACS, avascular necrosis, splenic sequestration, stroke, the capillary bed and hence shock and circulatory failure.
pulmonary hypertension, gallstones, thromboembolic This emergency condition of splenic sequestration needs
complications, and end-organ damage, which involve immediate attention, as it could cause death within 1 – 2 h
virtually every organ and organ system. 4,5,7,17,43-50 due to circulatory failure. 7,11,17,19,20,49
5.1. Vaso-occlusive pain crisis 5.3. ACS

The most common complication of SCD is the ACS is a dangerous complication of SCD seen as new
unpredictable, episodic, recurring, excruciating pain of radiodensity/densities on chest imaging along with
bone and joints caused by vaso-occlusion. Sickle RBCs respiratory symptoms and fever. Around 50% of SCD
occlude microvasculature, and the micro-occlusion patients experience more than one episode of ACS, and

Volume 4 Issue 1 (2025) 4 doi: 10.36922/gpd.4361