There are over 200 different cell types in the human body, each specialised to carry out a particular function, or form a particular tissue. The main types of cells in the human body are listed below:

•Stem cells

•Red blood cells (erythrocytes)

•White blood cells (leukocytes)

•Platelets

•Nerve cells (neurons)

•Neuroglial cells

•Muscle cells (myocytes)

•Cartillage cells (chondrocytes)

•Bone cells

•Skin cells

•Endothelial cells

•Epithelial cells

•Fat cells (adipocytes)

•Sex cells (gametes)

——————————————

•Stem cells are pluripotent cells that have the potential to become any type of cell in the body through a process called differentiation. Stem cells have the ability to divide and replicate themselves for long periods of time. There are two types of stem cells, embryonic stem cells and adult stem cells.

•Red blood cells are known as erythrocytes, and are the most common type of blood cell. They are shaped like a biconcave disc. The main role of red blood cells is to transport oxygen around the body using haemoglobin.

•White blood cells, also known as leukocytes, are a vital component of the immune system. There are five different types, which fall under two main categories; granulocytes and agranulocytes. As suggested by their names, granulocytes contain granules in the cytoplasm as agranulocytes do not. Granulocytes include neutrophils, eosinophils and basophils. Agranulocytes include lymphocytes and monocytes.

•Platelets are fragments of cells rather than true cells, but are vital in the control of bleeding. They are fragments of large cells called megakaryocytes. They have surface proteins which allow them to bind to one another, and to bind to damaged blood vessel walls.

•Nerve cells, commonly known as neurons, transmit information throughout the body in the form of electrical signals or nerve impulses. Structurally, they have four specific regions; the cell body, dendrites, the axon and axon terminals. Neurons can have multiple, two or one dendrite(s) which makes them multipolar, bipolar or unipolar respectively. 

•Neuroglial cells, more commonly known as glial cells or glia, are cells of the nervous system that modulate synaptic action and rate of impulse propagation, provide a scaffold for neural development, and aid recovery from neural injuries. There are four types of glial cells in the central nervous system; astrocytes, oligodendrocytes,microglial cells, and ependymal cells.

•There are 3 types of muscle cells, known as myocytes, in the human body. These types are skeletal, cardiac and smooth muscle. Skeletal and cardiac muscle cells are known as striated, due to the aligned arrangement of myosin and actin proteins within them. Actin and myosin allow muscle contraction by sliding past one another, as described by sliding filament theory.

•Cartillage cells, also known as chondrocytes, make up cartilage, a firm tissue that is vital to the body’s structure. Chondrocytes produce and maintain the extracellular matrix of cartilage, comprising collagen, proteoglycan and elastin fibers.

•There are four types of bone cells in the body; osteoblasts, osteoclasts, osteocytes and lining cells. Osteoclasts are large multinucleated cells that are involved in bone resorption. Osteoblasts have the opposite function, they are involved in the generation of new bone. Osteocytes can sense mechanical strain being placed on the bone, and secrete growth factors which activate bone growth in response. Lining cells line the surface of the bone and are responsible for the release of calcium from the bone into the bloodstream when it falls too low.

•There are many different types of cells in the epidermis (top layer) of the skin. The epidermis contains many types of cells, including keratinocytes, melanocytes, Langerhans cells and Merkel cells.

•Endothelial cells are the cells that form the lining of blood vessels and are connected to one another via intercellular junctions. Endothelial cells are highly adaptable, being able to migrate and adjust their numbers and arrangements to accommodate the body’s needs.

•Epithelial cells make up the linings of cavities in the body, forming sheets called epithelia. They are connected by tight junctions, adherens, desmosomes and gap junctions.

•Fat cells, also referred to as adipocytes and lipocytes are the cells of the body that are specialised to store energy in the form of adipose tissue, or fat. There are two types of fat cell, white fat cells and brown fat cells.

•Sexual reproduction is the result of the fusion of two different types of sex cells called gametes. Male sex cells are commonly known as sperm cells, or spermatozoa, and female gametes are known as eggs or ova. When they fuse together, fertilization occurs and a zygote is formed.

Signs that lead up to a stroke!

 

Stroke Risk and Its Management in Patients With Sickle Cell Disease

Fenella J. Kirkham

 

Clinical Presentation of Stroke in Sickle Cell Disease

There is a broad spectrum of acute presentation with CVA and other neurological complications in patients with SCD ( Table 1 ). Clinical stroke, with focal signs lasting more than 24 hours (Figure 1A),[4] is 250 times more common in children with SCD than in the general pediatric population,[5] and commonly presents 'out of the blue' in an apparently well child.[1] Patients with SCD also have transient ischemic attacks with symptoms and signs resolving within 24 hours,[3] although many of these individuals are found to have had recent cerebral infarction or atrophy on imaging (Figure 1B).[4] The insidious onset of 'soft neurological signs', such as difficulty in tapping quickly, is usually associated with cerebral infarction.[6,7] In addition, seizures[8] (Figure 1C), coma[9] (Figure 1D) and headache[10] (Figure 1E) are common presentations of stroke and cerebrovascular disease in children with SCD. Hyperventilation, for example during an electroencephalogram, occasionally provokes transient or permanent neurological deficits, usually involving the posterior circulation territory.[11] Altered mental status—with or without reduced level of consciousness, headache, seizures, visual loss or focal signs—can occur in numerous contexts, including infection (Figure 1D), shunted hydrocephalus[12] (Figure 1E), acute chest syndrome (ACS)[13,14,15] (Figure 1F), aplastic anemia secondary to parvovirus,[16,17] after surgery,[10,18,19] transfusion[20] or immunosuppression[21,22] (Figure 1G), and apparently spontaneously[23] (Figure 1H). In one large series of patients with ACS, 3% of children had neurological symptoms at presentation, and such symptoms developed in a further 7-10% as a complication of ACS.[13] These patients are classified clinically as having had a CVA,[2,3] although there is a wide differential of focal and generalized vascular and nonvascular pathologies—often distinguished using acute magnetic resonance techniques[23] (Figure 1)—with important management implications.[11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27]

ncpn556304.fig1.gif

(Enlarge Image)

Axial T2-weighted MRI (unless otherwise stated). (A) Large middle cerebral territory infarct in a previously asymptomatic girl with sickle cell anemia (SCA). (B) Left occipital infarct with moderate lobar atrophy (arrow) in a boy with HbSβ0-thalassemia who presented with two episodes of reversible ischemic neurological deficit (left and right hemiparesis). (C) Covert ('silent') infarctions (arrow) in a child with SCA and focal tonic seizures. (D) Infarction in both anterior and posterior arterial border zones in an 8-year-old boy with previously uncomplicated SCA who developed seizures and coma after surgery to drain a painful swelling of his left cheek, which was sustained after a fall and was associated with fever. (E) CT scan of a child with hemoglobin sickle cell disease who had a shunt placed in infancy. The scan was performed 10 days after presentation with headache, and shows definite cerebral edema; the dense appearance of the straight sinus (arrow) raises the possibility of venous sinus thrombosis, but is not diagnostic. (F) Signal change in the left posterior occipital (arrow) and bilateral high parietal regions ('reversible posterior leukoencephalopathy') with hippocampal involvement in a woman with previously uncomplicated SCA who presented aged 18 years with acute chest syndrome. (G) Signal change in the grey and white matter ('reversible posterior leukoencephalopathy'; arrows) in a 9-year-old boy with SCA who had been treated with ciclosporin for nephrotic syndrome. (H) Intracerebral hemorrhage (arrow) in a previously well child with SCA who presented with acute headache.

In addition to those who have had obvious acute neurological events, by adolescence up to 25% of children with homozygous sickle cell anemia have covert or 'silent' infarction on MRI, characteristically in the anterior or posterior border zones[28,29,30,31] (Figure 1C), without having had a clinical stroke. Voxel-based morphometry (Figure 2) shows that, compared with controls, there is evidence of damage in the white matter of the border zones, even in patients with sickle cell anemia who have normal T2-weighted MRI.[31] Neurological examination is usually normal,[6,7] although these patients might have had subtle transient ischemic attacks, headaches or seizures.[32] Cognitive difficulties,[33,34] which commonly affect attention[33] and executive function,[35] are common in SCD, sometimes from infancy;[36] they can be progressive,[37,38] and are associated with covert brain damage.[31,33,37,39]

 

ncpn556304.fig2.gif

(Enlarge Image)

Voxel-based morphometry comparison of white matter density between controls and patients with sickle cell anemia and covert infarction. Regions of reduced white matter density in patients with sickle cell anemia and covert infarction are displayed on the mean white matter segment. The white matter abnormality distribution is similar to that in the patient with overt stroke shown in Figure 1D.

Brain Pathology in Patients With Sickle Cell Disease

In parallel with the wide range of clinical neurological presentations of CVA in patients with SCD, a number of apparently discrepant findings have been described in the pathological literature. In patients who have presented with acute stroke, large infarcts in an arterial territory or in the border zones between anterior and middle cerebral arteries have been described,[40,41] in association with endothelial hyperplasia, fibroblastic reaction, hyalinization and fragmentation of the internal elastic lamina, and thrombi in large and small vessels.[41] Not all patients who die after developing neurological symptoms have large-vessel disease, however.[18] In addition to the typical small necrotic lesions in the border between the cortex and the subcortical white matter, acute demyelination[18] and venous sinus thrombosis[42,43] have also been documented.

Imaging

When a child with SCD presents with acute neurological problems, the priority is to conduct an exchange transfusion. As these patients are often admitted to a peripheral hospital without facilities for emergency imaging under general anesthesia, the literature on acute imaging is scanty. CT often does not show abnormalities within the first 24 hours after the onset of neurological symptoms. By contrast, diffusion-weighted MRI[22,23,44] (Figure 3A) can show ischemic regions within minutes—that is, before irreversible infarction has occurred—and T2-weighted MRI is usually abnormal within a few hours.

ncpn556304.fig3.gif

(Enlarge Image)

Diffusion and perfusion MRI. (A) Diffusion MRI shows abnormalities (arrows) in the patient with ciclosporin toxicity (Figure 1G). (B) Perfusion MRI abnormality throughout the right hemisphere and posteriorly on the left in an 11-year-old boy with sickle cell anemia who developed headaches after a chest crisis and was found to have high internal carotid artery and middle cerebral artery velocities on transcranial Doppler ultrasound (right vessels 200 cm/s; left vessels 161 cm/s).

In patients presenting with clinical stroke, neuroimaging might reveal a large infarct in the distribution of the middle cerebral artery,[45] or an abnormality in the basal ganglia, or deep white or grey matter of the border zones.[46] The involvement of these territories indicates proximal arterial pathology, whereas parieto-occipital or thalamic involvement should suggest venous sinus thrombosis.[25] Subarachnoid and intracerebral hemorrhage also occur, often in the context of acute hypertension,[20] or as a result of venous sinus thrombosis,[25] rupture of aneurysms (usually located at the bifurcations of major vessels, particularly in the vertebrobasilar circulation)[47] or rupture of fragile collaterals.[48]

 

Although it was assumed in the past that stroke in SCD was the result of sickling of red blood cells in the small cerebral vessels, this does not seem to be the direct cause in most cases. Between 60% and 90% of children with SCD and acute stroke in an arterial distribution have abnormal findings on conventional angiography or magnetic resonance angiography (MRA),[49] and there is also an association with seizures[8] (Figure 4). Typical abnormalities include stenosis (Figure 5A,B) or occlusion (Figure 5C) of the distal internal carotid or middle cerebral arteries,[10,50,51,52] which can be diagnosed as high time-averaged maximum velocity on transcranial Doppler ultrasound (TCD; Figure 4), a clinically important risk factor for stroke (see below).[53] Vertebral or internal carotid dissection,[12] moyamoya syndrome[48] (bilateral severe stenosis or occlusion of the internal carotid arteries with collateral formation; Figure 5D) and, occasionally, rarer patterns such as small-vessel vasculitis have also been documented. Moyamoya syndrome is associated with an increased risk of stroke recurrence.[48,54] Venous sinus thrombosis[24,25,42,43] (Figure 1E, Figure 6) is probably underdiagnosed because many patients do not undergo acute vascular imaging; if emergency MRA is available and the results are found to be normal, magnetic resonance or CT venography should be considered.

ncpn556304.fig4.gif

(Enlarge Image)

Transcranial Doppler velocities. Abnormal right middle cerebral artery (220 cm/s) and normal left middle cerebral artery (130 cm/s) in a 10-year-old girl with sickle cell anemia, focal tonic seizures (right side), transient ischemic attacks and headaches, on an exchange-transfusion program. Magnetic resonance angiography shows right proximal stenosis of the middle cerebral artery (bottom panel).

ncpn556304.fig5.gif

(Enlarge Image)

Magnetic resonance angiography (MRA). (A) Grade 1 turbulence in an asymptomatic child with sickle cell anemia and silent infarction. (B) Grade 2 turbulence in the right terminal internal carotid artery, A1 segment of the right anterior cerebral artery, right middle cerebral artery (M1 and M2 segments) and in the M1 segment of the left middle cerebral artery in a boy with HbSβ0-thalassemia (Figure 1B). (C) Middle cerebral artery occlusion in the girl with the large middle cerebral artery territory occlusion (Figure 1A). (D) Moyamoya in a child with sickle cell anemia and recurrent transient ischemic attacks.

ncpn556304.fig6.gif

(Enlarge Image)

Magnetic resonance venogram showing obliteration of the left transverse, sigmoid and straight sinuses in a patient with sickle cell anemia. The patient presented with headache, vomiting, drowsiness, papilledema and a sixth nerve palsy.

 

Risk Factors for Stroke in Sickle Cell Disease

There seems to be a familial predisposition to stroke[55] and to high blood flow velocities[56] in SCD, indicating that genetic factors probably contribute to stroke risk. Siblings might, however, also share adverse environmental conditions, including poverty, air pollution and poor nutrition. There is considerable current interest in epistatic polymorphisms as additional risk factors for stroke in SCD. The A3 and A4 alleles of the GT-repeat polymorphism of the angiotensinogen gene seem to be associated with a fourfold increase in risk of clinical stroke in SCD, perhaps because of an effect on blood pressure.[57] Factor V Leiden and the thermolabile variant of the methylenetetrahydrofolate reductase gene are rare in Afro-Caribbean populations, and at present there is little evidence for a link between stroke and these or any other genetically determined or acquired prothrombotic disorders in patients with SCD.[57]

In recent years, evidence for human leukocyte antigen (HLA)-linked susceptibility for stroke has been found for the class I HLA-B and class II HLA-DRB loci in children with SCD. Hoppe and her co-workers[58] used a candidate gene approach in patients screened with MRI as part of the US-based CSSCD. Dividing patients on the basis of the MRI findings into three groups—those with normal imaging, those with infarction clearly involving the territories of the large vessels (with or without additional small-vessel involvement), and those with infarction not involving the territories of the large vessels (presumed small-vessel disease)—the authors found that polymorphisms in specific HLA types and in genes involved in inflammation, cellular adhesion, blood pressure regulation and lipid metabolism were differentially associated with the two stroke phenotypes. Another group has demonstrated that large-vessel disease in SCD is related to variations in genes that code for factors involved in the responses to inflammation, hypoxia, adhesion and coagulation.[59]

Sickle erythrocytes adhere more avidly to vascular endothelial cells than do normal erythrocytes, and in SCD evidence has also accrued for neutrophil and platelet adhesion to the vascular endothelium, and activation of pathways leading to inflammation and thrombosis. Vascular cell adhesion molecule 1 (V-CAM1) is of particular interest in SCD as this molecule seems to coordinate the inflammatory response by recruiting leukocytes, and mice depleted of V-CAM1 have a high leukocyte count—a risk factor for stroke in humans.[27] Interestingly, there is a high frequency of single nucleotide polymorphisms (SNPs) in the VCAM1 gene in people of Afro-Caribbean origin, and one of these variant alleles (Gly1238Cys) has been shown to associate with protection from stroke in the Jamaican population, as compared with the wild-type allele.[60]

 

Sebastiani et al. have recently used Bayesian modeling to examine the association of SNPs in candidate genes with sickle-cell-related stroke.[61] They found 31 SNPs in 11 genes, including bone morphogenetic protein 6 (BMP6), three genes involved in the transforming growth factor β (TGFβ) signaling pathway, and SELP (P-selectin; also known as granule membrane protein 140 and antigen CD62), which is known to be associated with stroke in the general population; all of these factors seemed to directly affect stroke risk. They also identified SNPs in a further nine genes, including endothelin-1, which is close to BMP6 on chromosome 6 and is upregulated during acute hypoxia, that seemed to be acting indirectly. When validated in a separate population, this combination of genes, interacting with the percentage of hemoglobin F, was found to have 98.2% accuracy for distinguishing patients with stroke from those without stroke, with all seven of the studied strokes correctly classified.

Low hemoglobin, high white cell count, previous transient ischemic event, hypertension and history of chest crisis all seem to be risk factors for overt ischemic stroke in SCD ( Table 2 ).[3,27] For hemorrhagic stroke, only low hemoglobin and high white cell count were found to be predictors in the CSSCD ( Table 2 ).[3] A recent study comparing hemorrhagic with ischemic stroke in children, however, did not confirm these two variables as risk factors, and instead highlighted the importance of recent transfusion and corticosteroids, perhaps in relation to acutely increased blood pressure.[20] Large-vessel disease might be associated with markers of increased hemolysis, such as lactate dehydrogenase[62] and reticulocyte count.[63] Patients presenting with neurological symptoms after chest crisis are more likely to have an atypical stroke syndrome or stroke mimic—such as hemorrhagic stroke,[14] posterior circulation stroke,[14,63,64] symptomatic or asymptomatic (covert) single or multiple small infarcts or 'lacunae',[14] reversible posterior leukoencephalopathy,[14] global or focal edema,[63] laminar necrosis[14] or acute necrotizing encephalomyelitis[15]—than they are to have a typical infarctive stroke; thrombocytopenia was the only predictor for neurological symptoms in a large series of patients with ACS.[13] Covert infarction is also associated with high pocked red cell count in infancy, compatible with early splenic infarction, as well as low hemoglobin and high white cell count; interestingly, covert infarction is less common in individuals with frequent pain, but more common in those with a past history of seizures[32] ( Table 2 ). Progressive covert infarction is more common in patients with a persistently high white cell count,[54] suggesting a role for chronic inflammation. Factors associating with low IQ and other cognitive problems in SCD include hematological variables such as low hemoglobin,[29,65,66] high white cell count[66,67] and thrombocytosis,[29] in addition to parenchymal brain damage,[32,34,37,39] large-vessel disease,[63,68] perfusion abnormality[67] (Figure 3B) and nutritional factors (see below).

In African Americans, there is a high prevalence of individuals with only two or three α globin genes (compared with the normal complement of four). This α thalassemia seems to reduce the risk of stroke, probably through an increase in hemoglobin levels.[69] High hemoglobin F levels seem to ameliorate the risk of overt stroke and silent infarction,[70] at least in childhood. The β globin haplotypes might also alter risk, probably by influencing hemoglobin F levels, although the data are conflicting. Increasing hemoglobin F levels provides the rationale for the use of hydroxyurea to ameliorate disease severity ( Table 2 ).

Recent data indicate that nocturnal hypoxemia, related in part to anemia, might increase the risk of CNS events in patients with SCD.[12] Platelet and leukocyte activation, which might affect endothelial function, are inversely related to mean overnight oxygen saturation in children with SCD,[71] and there is evidence for increased levels of markers of cellular and endothelial adhesion.[72] The mean overnight oxygen saturation seems to be associated with the severity of intracranial vasculopathy determined by turbulent flow on MRA,[63,73] which is in turn related to regional cerebral perfusion.[9] Brain areas with low perfusion are at risk of ischemia, which might be exacerbated if there is also hypoxemia. It is not yet clear if this effect is secondary to sustained hypoxemia or obstructive sleep apnea, which have been documented in reports of children with arterial ischemic stroke. Although the numbers of patients studied to date have been small, adenotonsillectomy—commonly used to treat obstructive sleep apnea or recurrent tonsillitis—might not reduce the risk of CNS events,[12] perhaps because hypoxemia commonly persists after surgery. There is some evidence that asthma predisposes to chest crisis and CVA,[74] and the complex relationships between these comorbidities are currently under intense investigation. A pilot feasibility and safety trial of overnight respiratory support has commenced.[75]

Acute and chronic infections have long been recognized as precipitants for the neurological complications of SCD; however, there are few data on the effects of penicillin prophylaxis or vaccination against Streptococcus pneumoniae or Haemophilus influenzae, which are now the standard of care. For the neonatally screened East London SCD cohort, the introduction of penicillin prophylaxis from infancy was associated with 95.2% stroke-free survival at 15 years,[76] which seems to be an improvement compared with previous reports.[3,77] Aspirin might prevent stroke, silent infarction and cognitive impairment by mechanisms that include reduction of inflammation and the antiplatelet effect. A pilot trial has commenced;[75] however, until a phase III randomized trial has been completed, aspirin must be used with caution in patients with existing ischemic stroke and cerebrovascular disease because of the risk of hemorrhage. Blood pressure is relatively low in patients with SCD in comparison with controls, but relative hypertension is associated with increased risk of ischemic stroke.[3] The effect of controlling blood pressure on stroke risk has not, however, been examined systematically.

There are few data on the role of nutrition in determining the risk of overt and silent stroke in SCD, although there is increasing evidence for an effect in elderly adults. If nutritional factors do indeed contribute to stroke risk in patients with SCD, this might explain certain geographical variations that have been observed. For example, although Greek patients with HbSβ0-thalassemia have silent infarction, high TCD velocities and cognitive problems seem to be rare;[78] this rarity might be related to the Mediterranean diet. Short stature was a risk factor for low IQ in the Jamaican cohort,[79] but these patients did not undergo MRI, so the existence of any interaction with covert infarction could not be determined. In the East London cohort, low IQ was associated with infarction on MRI and with cerebrovascular disease and, in addition, was independently predicted by short stature from the age of 3 years.[80] The data on the relationships between anthropometric measurements and the risks of large-vessel disease or overt stroke are limited.

There is considerable evidence that high levels of homocysteine, related to genetic factors as well as vitamin intake, predispose to cerebrovascular disease, including accelerated atherosclerosis, dissection, thrombosis, embolism and venous sinus thrombosis. Some studies have shown high homocysteine levels in children with SCD,[81,82] which seem to be correctable with vitamin B supplementation,[82] although there is controversy over the relevance of these findings to vascular disease. Homocysteine levels might be reduced by folate, vitamin B12, pyridoxine (vitamin B6) and riboflavin (vitamin B2) supplementation. The importance of diagnosing pernicious anemia, particularly in patients on folate supplementation, was underscored by a recent case report.[83] Iron deficiency is a common comorbidity of SCD in young children in the developing world.[84] This deficiency is likely to have a complex effect on phenotype, reducing the degree of hemolysis and potentially its associated complications,[62] but possibly having a detrimental effect on cognitive function in infancy.[36]

Other supplements might improve endothelial function in patients with SCD. Morris et al. have shown that pulmonary pressures were reduced by arginine supplementation in patients with pulmonary hypertension;[85] however, there are currently no data on cerebrovascular disease or neurological complications. Intake of antioxidants such as aged garlic, ascorbic acid and vitamin E might affect intermediate risk factors, such as oxidative damage,[86,87] hematology,[87,88]blood pressure[87] and the hypoxic hyperventilatory response;[63,89] however, there are no data on the effects of supplementation on endothelial function, cerebrovascular disease or the risk of neurological events. Although increased hemolysis is a theoretical concern with high-dose vitamin C,[90] there is no evidence that it is an actual side effect.[91] Zinc supplementation, which reduces red blood cell dehydration, might be associated with reduced hemolysis and other crises,[92] but there are no data on its effects on neurological disease. There are very few data on other nutritional supplements, such as fish oil,[91] which might be of benefit to the general population at risk of vascular disease. Trials of appropriate nutritional supplementation from infancy would be justified as there is evidence for low levels of key components in individuals with SCD despite adequate dietary intake as in the general population, indicating that consumption needs to be increased in this group of individuals. Currently, as there are no known nutritional risk factors, health professionals caring for patients with SCD should encourage consumption of a wide variety of foodstuffs as part of a healthy diet, including at least five portions of fruit or vegetables per day.

 

Recent data from the CSSCD showed that covert infarction seen on MRI was associated with an increased risk of overt stroke (1.03 per 100 patient-years) and progression of covert infarction (7.06 per 100 patient-years).[28] The Silent Infarct Transfusion Trial, in which children with covert infarction seen on MRI will be randomized to blood transfusion or observation, is currently enrolling patients and will report after 2011.[75]

 

TCD is a safe, noninvasive, well tolerated, relatively low-cost procedure in which the velocity of blood flow can be measured in intracranial vessels using an ultrasound probe placed over the temporal bone to screen for cerebrovascular disease.[53] In a comparison with conventional angiography, TCD showed a sensitivity of 90% and specificity of 100% for the diagnosis of abnormality.[93] Follow-up studies have indicated that blood velocities over 200 cm/s (abnormal) and between 170 cm/s and 200 cm/s (conditional) in the internal carotid or middle cerebral artery of children with SCD predict stroke risks of 40% and 7%, respectively, over the subsequent 3 years,[53] presumably because high velocities indicate the development of severe middle cerebral artery narrowing secondary to turbulence or fixed stenosis. TCD might become abnormal before MRA does;[94] however, although it is more expensive and can require general anesthesia in young children, MRA is very useful in confirming the presence and extent of cerebrovascular disease.[10,50,51,52,94]

 

Stroke Prevention in Patients With Sickle Cell Disease

The Royal College of Physicians (UK) has recently published guidelines on the management of stroke in childhood, which address the issues of primary and secondary prevention of stroke in SCD ( Box 1 ).[95]

If no treatment was offered after a first ischemic stroke in children with sickle cell anemia, the risks of recurrence documented by cohort studies have been between 20% and 92%.[27,96,97,98,99] Two studies found a high risk of recurrence in children who had arteriographic abnormalities.[99,100] Ever since transfusion therapy was shown to be effective at reducing recurrent events,[99,100] it has been the mainstay of treatment for stroke in SCD.[101] The aim of transfusion is to reduce the percentage of HbS and increase levels of HbA, thereby reducing the deleterious effects of sickling while improving tissue oxygenation. For acutely sick patients, such as those with severe chest crisis or neurological symptoms, treatment is usually simple or partial exchange blood transfusion.[101] Although there has never been a controlled trial of transfusion, a chronic intermittent transfusion program, aiming to keep the HbS level below 30%, decreases the risk of stroke recurrence to between 10% and 20%.[2,101,102] There is ongoing controversy over whether allowing the HbS percentage to drift up towards 50% with less-frequent blood transfusions,[101] or switching to hydroxyurea[101,103,104] after a few years, is safe. Moyamoya syndrome is a risk factor for stroke recurrence despite regular transfusion,[48,54] although this risk seems to be reduced after extracranial-intracranial bypass or indirect revascularization.[101,105] Bone marrow or cord blood transplantation is an option for children with a matched sibling donor.[101,106,107,108] These procedures might, however, result in acute neurological complications including subarachnoid hemorrhage[109] and border zone edema in the context of hypertensive encephalopathy,[109] and serial MRI scans in individuals with pre-existing cerebral damage might show new lesions as well as extension of existing abnormality.[109] Further studies of these procedures are needed as some researchers have not found progression,[107] and the cerebrovascular disease can stabilize as demonstrated on both MRA[110] and TCD.[111]

The peak age for hemorrhage in SCD is 20-30 years, and these young adults usually have aneurysms,[47] which are amenable to extirpation by coil embolization or surgery;[112] these procedures reduce the risk of recurrence. By contrast, aneurysms and other cerebrovascular diseases are rarely found in children with SCD and intracranial or subarachnoid hemorrhage—conditions that seem to be common in those exposed to corticosteroids and rapid blood transfusion.[20] Care with corticosteroid use and judicious blood transfusion to achieve small increases in hemoglobin without acute hypertension might reduce the incidence of hemorrhagic stroke.[20]

 

There is Class A evidence for the role of blood transfusions in preventing first stroke in children with sickle cell anemia and high blood flow velocities on TCD. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) showed a clear benefit for prophylactic transfusion in children with blood flow velocities of more than 200 cm/s.[113] A large proportion of the treated patients apparently received unnecessary transfusion, however, as only 15% of the nontransfused children went on to have a stroke despite very high velocities. This is an important issue, as transfusion is associated with risks of infection and alloimmunization,[114] and many children and their families find regular blood transfusion and chelation therapy burdensome. The subsequent STOP II has, however, shown that it is essential to continue to transfuse long-term even if TCD velocities return to the normal range, as the risks of stroke or reversion to high-risk TCD velocities are unacceptably high.[115] Reductions in the incidence of stroke in SCD recorded in California[116] and East London[117] are probably related to the introduction of TCD screening and prophylactic transfusion. TCD screening is currently not universally available, however, and cannot, therefore, be mandated at present.[117,118] In addition, there is evidence that adults with SCD do not have high TCD velocities, and programs of TCD screening and prophylactic transfusion are probably not appropriate for older age groups.

 

Conclusions

Although it is now possible to prevent ischemic stroke in SCD with lifelong regular blood transfusions, this is a heavy burden for a child and there is a need for further research to determine modifiable risk factors for this and other complications.p

An amazing sicklecell power point!

A Sickle Cell Power Point

Why Cartilage Damage is WORSE than CRISIS

Connective Tissue Structure
and Support

Cartilage is connective tissue that is less rigid than bone and
less exible than muscles

Connective tissue is essential for our
bodies to function properly. Bone
connective tissue provides structure and
support, adipose (or fat) connective tissue
insulates and provides energy, and blood
connective tissue distributes oxygen to
our tissues and removes carbon dioxide.
Another integral type of connective tissue
is cartilage.
The main structural components of our
bodies are bone, muscle, and cartilage.
Bones are rigid, while muscles bend,
stretch, and are exible. Cartilage
connective tissue is the perfect halfway
point between these other tissues. It is
not as rigid or as hard as bone, and it is
also less exible than muscle. Therefore,
we nd cartilage in places where we need
some support and structure, but a bit of
exibility as well. This includes places
such as our joints, our ears, and our nose,
as well as in between the vertebrae in our
spinal column.

Chondroblasts and
Chondrocytes
Connective tissue is comprised of living
cells within an extracellular (or outside
the cell) matrix. The extracellular matrix in
cartilage is produced by specialized cells
called chondroblasts. Chondroblasts that
are caught in the matrix are called
chondrocytes. These cells lie in spaces
called lacunae. Chondrocytes, also called
chondrocytes in lacunae, determine how
'bendy' our cartilage is.
When looking through a microscope,
chondrocytes look similar to eyeballs
oating in goo. Have you ever served
eyeball soup for Halloween? This is the
perfect way to describe cartilage
connective tissue. The eyeballs are our
chondrocytes, and the soup is the matrix
they live in. That's the easiest way to
determine what type of cartilage you're
talking about - the number of 'eyeballs' in
the soup.

Elastic Cartilage
There are three types of cartilage found in
the human body. Elastic cartilage is the
most exible, which means it contains the
most chondrocytes. This is the type of
cartilage found in your ear. If you look at
this slide, which is what elastic cartilage
looks like under a microscope, you'll note
quite a few chondrocytes.

Fewer chondrocytes in hyaline cartilage make it less exible
than elastic cartilage

Hyaline Cartilage
Hyaline cartilage is the second most
exible, and this cartilage is found in your
nose and at the end of your ribs. Again,
note the chondrocytes in this tissue; you'll
notice there are fewer than in the elastic
cartilage tissue slide.

Fibrocartilage
Fibrocartilage is the cartilage with the
fewest number of chondrocytes, which
means it bends the least. This is the type
of cartilage found in your knee, as well as
in between the vertebrae in your spine.
Note how many chondrocytes are on this
slide - only three! This makes sense, right?

We have more than cartilage damage to worry about!

Connective Tissue of the Skeletal System

Connective tissues primary function in the skeletal system is to connect muscles to bone and to connect joints together.  This dense connective tissues is comprised of fibers called collagen.  Mature connective tissue has fewer cells than other tissues and needs less blood, oxygen, and other nutrients.  Each collagen bundle is comprised of several fibers, and these fibers contain fibrils.  The fibrils contain the actual collagen molecules.

Tendons

The Golgi Tendon Organ

Tendons connect muscles to bone and are an extension of the muscle fibers.  They are slightly more elastic than ligaments but cannot shorten as muscles do.  Within the muscles and tendons there is a built in sensory mechanisms called the Golgi tendon organ.  The Golgi tendon organ acts as a “safety valve” and provides feedback about the bodies position and protects the muscle and connective tissue.  This safety valve is called the feedback loop.  In essence, when tension becomes to great, greater than the brain can recall; the Golgi tendon organ’s signal inhibits the contraction stimulus and reduces the risk of injury.

Ligaments

Ligaments of the skeletal system connect bones to bones at a joint.  Ligaments contain collagen and also contain an elastic fiber called elastin.  Ligaments do have some elasticity to allow joint movement, but it is very limited.

Cartilage

Cartilage of the skeletal system is the firm, elastic, flexible, white material found at the ends of the ribs, between the vertebrae, at joint surfaces, and in the nose and ears.  Cartilage functions as both a shock absorber, and to provide structure.  Cartilage also functions as a lubricant in the working parts of a joint.  Unlike tendons and ligaments, cartilage has no blood supply of its own.  It receives oxygen and nutrients through diffusion.  Because of this, damage to cartilage takes a very long time to heal.

IT IS NOT IN YOUR HEAD...JUST YO CELLS.

Sickle cell disease may affect brain function in adults
who have few or mild complications of the inherited
blood disease, according to results of the first study to
examine cognitive functioning in adults with sickle cell
disease. The multicenter study, funded by the National
Heart, Lung, and Blood Institute (NHLBI), part of the
National Institutes of Health, compared brain function
scores and imaging tests in adult patients with few
sickle cell complications with results in similar adults
who did not have the blood disease.

Researchers report that the brain function scores in
sickle cell patients were, on average, in the normal
range. However, twice as many patients as healthy
adults (33 percent versus 15 percent) scored below
normal levels. Those who were more likely to score
lower were older and had the lowest levels of
hemoglobin, the protein in red blood cells that carries
oxygen in the blood, compared to sickle cell
participants who scored higher. Findings from brain
magnetic resonance imaging scans did not explain
differences in scores.

Researchers at 12 sites within the NHLBI-supported
Comprehensive Sickle Cell Centers conducted the
study. Their results are published in the May 12 issue of
the Journal of the American Medical Association. An
editorial accompanies the article.

"This study suggests that some adult patients who
have sickle cell disease may develop cognitive
problems, such as having difficulty organizing their
thoughts, making decisions, or learning, even if they do
not have severe complications such as stroke related to
sickle cell disease," said NHLBI Acting Director Susan
B. Shurin, M.D. "Such challenges can tremendously
affect a patient's quality of life, and we need to address
these concerns as part of an overall approach to
effectively managing sickle cell disease."

Researchers tested cognitive functioning of 149 adult
sickle cell disease patients (between the ages of 19 and
55) and compared them to 47 healthy study
participants of similar age and education levels from
the same communities. All of the participants were
African-American.

More sickle cell disease patients scored lower on
measures such as intellectual ability, short-term
memory, processing speed, and attention, than
participants in the healthy group. The sickle cell
disease participants did not have a history of end-organ failure, stroke, high blood pressure, or other
conditions that might otherwise affect brain function.

"We need to study whether existing therapies, such as
blood transfusions, can help maintain brain function, or
perhaps even reverse any loss of function," noted Elliott
P. Vichinsky, M.D., of the Children's Hospital &
Research Center Oakland, principal investigator of the
study and the lead author of the paper. "These effects
were found in patients who have clinically mild sickle
cell disease, which raises the question of whether
therapies should be given to all patients to help prevent
these problems from developing."

Researchers involved in this study are recruiting
patients with sickle cell disease into a clinical trial to
determine whether blood transfusions may help
preserve cognitive function. Participants will receive
transfusions every three or four weeks for six months
as part of the clinical study. Information about this
study can be found at www.clinicaltrials.gov, search for
NCT00850018.

Sickle cell disease affects about 70,000 Americans. At
one time, many children died from the disease, but new
therapies have enabled sickle cell disease patients to
live well into middle age or beyond. As more people
with sickle cell disease are living into adulthood, health
care providers are uncovering previously unrecognized
complications.

Studies of brain function in children who have sickle
cell disease have suggested that some children with the
disease, even if they have not suffered a stroke, have
experienced silent brain injury. Others without obvious
changes on brain scans may have some level of
cognitive dysfunction that seems to worsen with age.
Stroke is a common complication of sickle cell disease,
and can lead to learning disabilities, lasting brain
damage, long-term disability, paralysis, or death.

Sickle cell disease involves an altered gene that
produces abnormal hemoglobin. Red blood cells with
sickle hemoglobin that have too little oxygen become
C-shaped in addition to becoming stiff and sticky.
These crescent-shaped cells can clump to block blood
flow, causing severe pain and potential organ damage.
In the United States, the disease mainly affects those of
African descent, but it is also found in other ethnic
groups, including those of Hispanic and Middle Eastern
descent.

Sickle Cell and The Brain

 THIS INFO NEEDS TO BE IN THE HANDS OF PARENTS WHEN DISCUSSING WHY THE KIDS AND US ARE EXPERIENCING FORGETFULNESS/ MEMORY LOSS/ SHORT ATTENTION SPANS ETC...I THOUGHT I WAS GOING CRAZY BECAUSE I'M NOT SUPPOSED TO BE FORGETTING AT MY AGE. AND I QUESTIONED MYSELF ABOUT MY CHILD BEING RUDE OR IS HE GOING THROUGH WHAT I AM ‪#‎UFEELME‬?>>>> SICKLECELLAWARENESS:
HOW THIS ILLNESS AFFECTS OUR BRAIN

Sickle cell disease (SCD) is a blood disorder; however, the central nervous system (CNS) is one of the organs frequently affected by the disease. Brain disease can begin early in life and often leads to neurocognitive dysfunction. Approximately one-fourth to one-third of children with SCD have some form of CNS effects from the disease, which typically manifest as deficits in specific cognitive domains and academic difficulties. 
Patients who have sickle cell disease may
develop cognitive problems, such as
having difficulty organizing their thoughts,
making decisions, or learning, even if they
do not have severe complications such as
stroke related to sickle cell disease
We discuss SCD as a neurodevelopmental disorder by reviewing the mechanisms of neurological morbidity in SCD, the timing of these mechanisms, the types of cognitive and behavioral morbidity that is typical, and the interaction of social-environmental context with disease processes. The impact of the disease on families shares many features similar to other neurodevelopmental disorders; however, social-environmental factors related to low socioeconomic status, worry and concerns about social stigma, and recurrent, unpredictable medical complications can be sources of relatively higher stress in SCD. Greater public awareness of the neurocognitive effects of SCD and their impact on child outcomes is a critical step toward improved treatment, adaptation to illness, and quality of life.

BRAIN AND SICKLECELL AND CLOTS

The anterior communicating artery due to its location an aneurysm will go undetected because the person will be a systematic / has no symptoms at all.

Sickle cell disease may affect brain function in adults
who have few or mild complications of the inherited
blood disease, according to results of the first study to
examine cognitive functioning in adults with sickle cell
disease. The multicenter study, funded by the National
Heart, Lung, and Blood Institute (NHLBI), part of the
National Institutes of Health, compared brain function
scores and imaging tests in adult patients with few
sickle cell complications with results in similar adults
who did not have the blood disease.

Researchers report that the brain function scores in
sickle cell patients were, on average, in the normal
range. However, twice as many patients as healthy
adults (33 percent versus 15 percent) scored below
normal levels. Those who were more likely to score
lower were older and had the lowest levels of
hemoglobin, the protein in red blood cells that carries
oxygen in the blood, compared to sickle cell
participants who scored higher. Findings from brain
magnetic resonance imaging scans did not explain
differences in scores.

Researchers at 12 sites within the NHLBI-supported
Comprehensive Sickle Cell Centers conducted the
study. Their results are published in the May 12 issue of
the Journal of the American Medical Association. An
editorial accompanies the article.

"This study suggests that some adult patients who
have sickle cell disease may develop cognitive
problems, such as having difficulty organizing their
thoughts, making decisions, or learning, even if they do
not have severe complications such as stroke related to
sickle cell disease," said NHLBI Acting Director Susan
B. Shurin, M.D. "Such challenges can tremendously
affect a patient's quality of life, and we need to address
these concerns as part of an overall approach to
effectively managing sickle cell disease."

Researchers tested cognitive functioning of 149 adult
sickle cell disease patients (between the ages of 19 and
55) and compared them to 47 healthy study
participants of similar age and education levels from
the same communities. All of the participants were
African-American.

More sickle cell disease patients scored lower on
measures such as intellectual ability, short-term
memory, processing speed, and attention, than
participants in the healthy group. The sickle cell
disease participants did not have a history of end-organ failure, stroke, high blood pressure, or other
conditions that might otherwise affect brain function.

"We need to study whether existing therapies, such as
blood transfusions, can help maintain brain function, or
perhaps even reverse any loss of function," noted Elliott
P. Vichinsky, M.D., of the Children's Hospital &
Research Center Oakland, principal investigator of the
study and the lead author of the paper. "These effects
were found in patients who have clinically mild sickle
cell disease, which raises the question of whether
therapies should be given to all patients to help prevent
these problems from developing."

Researchers involved in this study are recruiting
patients with sickle cell disease into a clinical trial to
determine whether blood transfusions may help
preserve cognitive function. Participants will receive
transfusions every three or four weeks for six months
as part of the clinical study. I

LUNGS-Pulmonary Hypertension

Vasculopathy and pulmonary
hypertension in sickle cell disease:

Sickle cell disease (SCD) is an
autosomal recessive disorder in the
gene encoding the β-chain of
hemoglobin. Deoxygenation causes the
mutant hemoglobin S to polymerize,
resulting in rigid, adherent red blood
cells that are entrapped in the
microcirculation and hemolyze.
Cardinal features include severe painful
crises and episodic acute lung injury,
called acute chest syndrome. This
population, with age, develops chronic
organ injury, such as chronic kidney
disease and pulmonary hypertension. A
major risk factor for developing chronic
organ injury is hemolytic anemia, which
releases red blood cell contents into the
circulation. Cell free plasma
hemoglobin, heme, and arginase 1
disrupt endothelial function, drive
oxidative and inflammatory stress, and
have recently been referred to as
erythrocyte damage-associated
molecular pattern molecules (eDAMPs).
Studies suggest that in addition to
effects of cell free plasma hemoglobin
on scavenging nitric oxide (NO) and
generating reactive oxygen species
(ROS), heme released from plasma
hemoglobin can bind to the toll-like
receptor 4 to activate the innate
immune system. Persistent
intravascular hemolysis over decades
leads to chronic vasculopathy, with
∼10% of patients developing pulmonary
hypertension. Progressive obstruction
of small pulmonary arterioles, increase
in pulmonary vascular resistance,
decreased cardiac output, and eventual
right heart failure causes death in many
patients with this complication. This
review provides an overview of the
pathobiology of hemolysis-mediated
endothelial dysfunction and eDAMPs
and a summary of our present
understanding of diagnosis and
management of pulmonary
hypertension in sickle cell disease,
including a review of recent American
Thoracic Society (ATS) consensus
guidelines for risk stratification and
management.

SickleCell and joints

Joints the Skeletal System

A joint, or otherwise known as an articulation; is formed where two bones connect.  There are two major classifications of skeletal system joints: 1) synarthrodial joints, which is a union of two bones by fibrous tissues such that there is no joint cavity and almost no movement possible.  An example would be the skull, and 2) diarthrodial joints, which is a freely moving joint with an articular cavity (which holds the fluid inside the joint).

 

Joints of the Human Body

As a freely moving joint, the diarthrodial joint has an articular cavity encased in a ligamentous capsule, and synovial fluid lubricates the cartilage inside the capsule.  There are six categories of diarthrodial joints:

1) Arthrodial Joint (gliding): They comprise of two flat bone surfaces that press up against each other and allow a limited gliding movement.  They can be found in the wrist and the foot.

2) Ginglymus Joint (hinge): They provide a wide range of movement in one place. An example is the knee joint.

3) Condyloid Joint (ellipsoid): They provide movement in two planes without rotation.  An example is the wrist between the radius and the proximal row of carpal bones.

4) Enarthrodial Joint (multi-axial ball-and-socket): They permit movement in all planes.  An example is the hip joint.

5) Sellar Joint (saddle): This joint provides movement similar to ball-and-socket movement but without rotation. The thumb is the only saddle joint in the body.

6) Trochoidal Joint (pivot): This is a joint that moves by rotating.  One bone articulates just like the hinge on a door in such away that one bone rotates using the other as pivot. An example is the neck.

SickleCell and bones

Bones of the Skeletal System

Cross Section of a Human Bone

All of the 206 bones in our body consist of three layers: the bone marrow, compact bone, and the periosteum. Within the center section of our long bone is a central cavity which holds the bone marrow.  The are two different types of bone marrow: 1) red marrow produces platelets to assist in blood clotting, and red blood cells which fight against infection, and 2) yellow marrow which consists mostly of fat cells.  Surrounding the marrow is a dense rigid bone called the compact bone.  The ridge compact bone is honeycombed with thousands of tiny holes and passages that supply oxygen and nutrients to the bone.  This dense layer of compact bone supports the weight of the body and is mostly comprised of calcium and minerals.  Every bone is then covered by the periosteum which acts as the skin of the bone.  The inner layer of the periosteum contains cells the produce bone.

Our 206 bones of the skeletal system are divided into two categories: 1) the axial skeleton, which is comprised of our trunk and head, and 2) the appendicular skeleton, which is comprised of our arms and legs.  Our bones are further broken down into five main categories:

1) Flat Bones: Provide protection.  They include such bones as the ribs, sternum, and scapula.

2) Short Bones: Provide shock absorption.  They include such bones as the carpals, and tarsals.

3) Long Bones: They provide the structural support of our body.  They include such bones as the tibia, fibula, and ulna.

4) Sesamoid Bones: Provide protection and improve mechanical advantage of musculotendinous units (relating to or affecting both muscle and tendons).  They include such bones as the patella (knee cap).

5) Irregular Bones: Provide a variety of purposes throughout the body.  They include such bones as a vertebra.