INTRODUCTION:

The World Health Organization mentioned that stroke is one of the foremost diseases which cause disabilities and deaths¹. Blood circulation supplies nutrients and oxygen throughout the body including the brain. Once the blood supply stops or is insufficient in the brain, cells are starved of oxygen, and damage and stroke happen. Signs of disease arise based on the area of the brain which affected. If the affected area responsible the for face it would cause a drooping face, it occurs in the area associated with limbs it will cause a weakness in the arms or legs, if it occurs in the area linked with speech it will cause speech problems, or other signs like vision change, body imbalance, misperception, and cognition loss. Endothelial damage, a heightened inflammatory response, platelet activation or aggravation, and activation of both the intrinsic and extrinsic coagulation pathways are symptoms of sickle cell disease. The unwanted events could be barely noticed, but often are severe and disabling².

“In 2019, the five leading risk factors for stroke were high systolic blood pressure³, high body-mass index, high fasting plasma glucose, ambient particulate matter pollution, and smoking (25·3 million.”⁴ Based on recurrence, the status of recurrence risk “Stroke patients are at high risk of recurrence, which increases from 3% (after 30 days) to 40% (after 10 years)”. Observation of an individual and providing is needed “FAST” (F is for Face: is their face drooping on one side or can they smile.; A is for Arms: is their weakness in the arms or can they lift them both.; S is for Speech: is their speech slurred; T is for Time: if you spot any one of these signs then it’s time to call an ambulance). Due to the young age of the patients and the negative effects of stroke on quality of life, morbidity, and mortality, prevention, identification, and therapy of stroke in SCD patients are of increasing interest.^5,6

Types of Strokes:

Strokes are put into two groups (i.e., ischemic stroke or hemorrhagic stroke) based on the problem associated with vessels of the circulatory system. When there is a blockage so-called an ischemic stroke, or if there is a rupture/bleed of the blood vessel so-called a hemorrhagic stroke. In most of the cases due to blockages of blood vessels, accumulation of fatty material in blood vessels that block the blood supply to the brain, is thought of as a “brain attack” just like a heart attack. Also, the clot may occur within the brain or moved from another part of the body neck, or heart when there is an improper heartbeat termed ‘atrial fibrillation. “Mini-stroke or Transient Ischemic Attack (TIA)” is known only when signs disappear within a few minutes or 24 hours, but that is an indicator to an individual suspected to have a full stroke, so recommended to visit a hospital for early identification of disease and to find preventive measures and/or appropriate treatments^6,7.

Pathogenesis:

Before discussion of interlink between stroke and sickle cell disease there is a need of go through pathogenesis of each disease, because of familiarized important factors which involved in disease occurrence.

Pathogenesis of stroke:

The key pathway of ischemia is narrow or blocked arteries to/within the brain which lead to insufficient blood flow in cerebral tissues, energy failure, and neuronal cell death. Ischemic insult, causes the acute events of low oxygen (O₂) and glucose. The condition lead to depletion of Adenosine Triphosphate (ATP) and failure of ionic pump. This induces further series of events including down flown of ions concentration gradients, swelling of cells (cytotoxic oedema), releasing of excitatory amino acids (EAA), cells switching to anaerobic metabolism instead of aerobic, as a results in metabolic acidosis, and others which finally led to necrosis or apoptosis.^8,9

Ischemia also resulted in an upregulation of stress signals like reactive oxygen species (ROS)/reactive nitrogen species (RNS) which might exacerbate tissue injury. These signals mediate the inflammation responses, activate damaging proteases (e.g., matrix metalloproteinases (MMPs)), followed by secondary damage involving brain oedema and hemorrhage. Without forget the influenced role of mitogen activated protein kinase (MAPK) as well as activation of other factors for retrieval mechanisms such as protein kinase B (PBK or AKT), up-regulation of trophic factor, neurogenesis, angiogenesis and synaptogenesis.^8,9 The (figure 1) below represent pathogenesis of ischemia.

Pathogenesis of sickle cell disease:

Sickle-cell anemia is a hereditary disease whereby the red blood cells (RBCs) hemoglobin’s is affected, and leading to cells with curved/semicircle shape. The normal hemoglobin A (HbA) is a proteinous molecule composed of two alpha and two beta subunits/chains (i.e.,141 amino-acids of alpha chain, and 146 amino-acids of beta-chains). Sickle cell disease is a result from 11^th chromosomal mutation of single amino-acid -(noncharged hydrophobic valine for negatively charged hydrophilic glutamate at position 6)- on the subunit (β-globin) of haemoglobin A (HbA) and forming haemoglobin S (HbS).^10–14 This HbS is bio-chemically not stable molecule, decreased solubility when deoxygenated, become curved/semicircle in shapes, clogging in blood vessels, breaking easily and causes hemolysis. The pathophysiology of disease as shown (figure 2)^15–19.

Stroke in Relation to Sickle Cell Disease:

Sickle cell patients might be at risk of getting stroke due to evaluation which showed close association between stroke and sickle cell disease²⁰. The interlink point of these two diseases is enlighten by Clogging in blood vessels, Hypoxemia, Acidosis and Dehydration. All these factors interlink directly between stroke and sickle cell disease in one way or another as summarized in scheme representation (figure 3) below.

Preventive Measures:

What can we do to prevent stroke from happening? Lowering high blood pressure (this is the number one cause a stroke), stopping smoking and alcohol, lowering cholesterol (statins), being more active, eating healthily, keeping good control of blood sugar levels especially in diabetic patients.^21,22 “The strong primary prevention potential for stroke based on avoidance of excess body weight, smoking, heavy alcohol consumption, unhealthy diet, and physical inactivity.”²³ “Implement early-in-life culturally appropriate education about healthy lifestyle into standard education curricula with reinforcement across the lifespan.”²⁴ All these are the preventive measure which could be keep in consideration to avoid stroke problems.²⁵

Therapeutical Interventions:

Management of Stroke:

Stroke is an unexpected condition which required fast treatment actions to minimize damaging of brain and complications. Blood leakage in the brain can lead to swelling, which is a serious problem which may require surgery in some cases.²⁶ In the other part, drugs affecting blood and blood formation like anticoagulants, fibrinolytics (thrombolytics) and antiplatelets might be used after clinical diagnosis.

a) Anticoagulants are drug which act by reducing blood coagulation. They work by preventing recurrence but they do not dissolve the clot which is already formed. Anticoagulants may be used to prevent emboli which are mostly recurring in cerebral embolism, or treating of large embolic which started late (after 1week), and antiplatelets probably used in transient ischemic attack (TIAs).^27,28

b) Fibrinolytics (Thrombolytics) used to break-up thrombi/clot and restored proper flow in blocked vessels. They work by activation of the natural fibrinolytic system. The usage of thrombolytic treatment in an ischemic stroke is controversial, this is probably due to the need of balance between the outcome of improved neurology with the risk of intracranial hemorrhage. The uses of alteplase in ischemic stroke approved, and there is current strong recommendation of using I.V alteplase within 3hours of onset for patient selected carefully, whom all factors of risky for bleeding and intracranial hemorrhage is ruled out. ^27,28 If the blockage detected within the first few hours, a clot busting medication is sometimes given to dissolve the clot “this is called thrombolysis”. If thrombolysis can’t be used, other medications such as aspirin will be given as treatment instead. ^6,7

c) Antiplatelets: are agents which act on platelets and used in treatment of thromboembolic conditions. These medicines don’t adjust stroke due to cerebral thrombosis. Though, aspirin or clopidogrel reported to minimize manifestation of TIAs, full-stroke in people with TIAs, and in people with atrial fibrillation. European study stated that dipyridamole when combined with aspirin at lower dose produces synergism effect in secondary prevention of stroke^27,28.

Rational use of medicines is helpful in prevention of further stroke episodes, and stroke rehabilitation done alongside with doctors, nurses and novel robot rehabs ^6,7,29,30. If stroke causes difficulty swallowing³¹, dieticians’ specialist can recommend special diets or feeding tubes. If the problems with speech and language therapists can help. If it has become difficult to walk or perform daily tasks, physiotherapists and occupational therapists can offer exercises and home adaptations³². Also, after a stroke people often feel low or frustrated that they can’t do the things they used to, and don’t like being dependent on others³³. Counsellors can help talk through these feelings and many patient groups are available for further support.^26,34

Management of Sickle Cell Disease

Currently, the treatment of sickle cell disease³⁵ include medication including pain killers, antibiotics like penicillin prophylaxis, and other medications which used to reduce the sign and symptoms of the disease; or blood transfusion and rarely a bone marrow transplant. They are not performed frequently because of the various risks complicated.^36–40 Apart from that approach, health experts still are doing researches on developing other means of treating sickle cell anemia, such as usage of antisense oligonucleotides.^36,41–43

CONCLUSION:

People with sickle cell disease might face the stroke in their life due to the interlink between sickle cell disease and stroke. The global burden of stroke is like a giant enemy, which affect people of all age, gender, with no exception of geographical region. Therefore, to fight against this problem it requires the collective efforts from Stroke Organization and academia, which have vital tasks in providence of suitable scientific guidance on prevention, practices, management, and therapies. But also, efforts which driven by political will are required, such that the Governments have the major everyday jobs and the power to impact environments (such as issues of pollution), community (such as employments, health care system, education, poverty, standard living houses, etc.), and factors associated with lifestyle (e.g., nutritional issues, smoking, and other physical activities) through legislation, policies, guidelines and taxation.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 05.03.2022 Modified on 08.05.2022

Research J. Pharm. and Tech 2023; 16(6):3004-3008.

DOI: 10.52711/0974-360X.2023.00496