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Research Article | DOI: https://doi.org/10.31579/2641-5194/065
1 Specialist of Internal Medicine, MD, Turkey.
2 Manager of Writing and Statistics, Turkey.
3 Ministry of Health of Turkey, MD, Turkey.
4 Specialist of Emergency Medicine, MD, Turkey.
5 Middle-East Academy for Medicine of Aging, MD, Lebanon.
6 Medi-WORLD International, Australia.
*Corresponding Author: Mehmet Rami Helvaci, Specialist of Internal Medicine, MD, Turkey.
Citation: Mehmet R. Helvaci, Kubra Piral, Kubra Seckin, Esin Esra Tanaydin, Ayse Deniz Karabacak, et all, (2023), An Exaggerated Capillary Endothelial Edema May be the Cause of Sudden Deaths in Sickle Cell Diseases. J. Gastroenterology Pancreatology and Hepatobilary Disorders, 7(3); DOI:10.31579/2641-5194/065
Copyright: 2023, Mehmet Rami Helvaci. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 01 June 2023 | Accepted: 09 June 2023 | Published: 21 June 2023
Keywords: sickle cell diseases; sickled or just hardened red blood cells; capillary endothelial damage; exaggerated capillary endothelial edema; sudden deaths
Background: Sickle cell diseases (SCDs) are inborn and severe inflammatory processes on vascular endothelium, particularly at the capillaries which are the actual distributors of the sickled or just hardened red blood cells (RBCs) into the tissues.
Methods: All patients of the SCDs were included.
Results: We studied 222 males and 212 females with similar ages (30.8 vs 30.3 years, p>0.05, respectively). Disseminated teeth losses (5.4% vs 1.4%, p<0.001), ileus (7.2% vs 1.4%, p<0.001), cirrhosis (8.1% vs 1.8%, p<0.001), leg ulcers (19.8% vs 7.0%, p<0.001), digital clubbing (14.8% vs 6.6%, p<0.001), coronary heart disease (18.0% vs 13.2%, p<0.05), chronic renal disease (9.9% vs 6.1%, p<0.05), chronic obstructive pulmonary disease (25.2% vs 7.0%, p<0.001), and stroke (12.1% vs 7.5%, p<0.05) were higher in males but not acute chest syndrome (2.7% vs 3.7%), pulmonary hypertension (12.6% vs 11.7), deep venous thrombosis and/or varices and/or telangiectasias (9.0% vs 6.6%), or mean age of mortality (30.2 vs 33.3 years) (p>0.05 for all).
Conclusion: The sickled or just hardened RBCs-induced capillary endothelial damage, inflammation, edema, and fibrosis are initiated at birth, and terminate with disseminated tissue hypoxia, multiorgan failures, and sudden deaths even at childhood. Although RBCs suspensions and corticosteroids in acute and aspirin plus hydroxyurea in acute and chronic phases decrease severity of the destructive process, survivals are still shortened in both genders, dramatically. Infections, medical or surgical emergencies, or emotional stresses-induced increased basal metabolic rate aggravates the sickling and capillary endothelial edema, and may terminate with multiorgan failures-induced sudden deaths in the SCDs.
Chronic endothelial damage may be the main underlying cause of aging and death by causing end-organ failures [1]. Much higher blood pressures (BPs) of the afferent vasculature may be the chief accelerating factor by causing recurrent injuries on vascular endothelium. Probably, whole afferent vasculature including capillaries are mainly involved in the destructive process. Thus the term of venosclerosis is not as famous as atherosclerosis in the literature. Due to the chronic endothelial damage, inflammation, edema, and fibrosis, vascular walls thicken, their lumens narrow, and they lose their elastic natures which eventually reduce blood flow to the terminal organs, and increase systolic and decrease diastolic BPs further. Some of the well-known accelerating factors of the harmful process are physical inactivity, sedentary lifestyle, animal-rich diet, smoking, alcohol, overweight, chronic inflammations, prolonged infections, and cancers for the development of terminal consequences including obesity, hypertension (HT), diabetes mellitus (DM), cirrhosis, chronic obstructive pulmonary disease (COPD), coronary heart disease (CHD), chronic renal disease (CRD), stroke, peripheric artery disease (PAD), mesenteric ischemia, osteoporosis, dementia, early aging, and premature death [2, 3]. Although early withdrawal of the accelerating factors can delay terminal consequences, after development of obesity, HT, DM, cirrhosis, COPD, CRD, CHD, stroke, PAD, mesenteric ischemia, osteoporosis, aging, and dementia-like end-organ insufficiencies, the endothelial changes can not be reversed due to their fibrotic natures, completely. The accelerating factors and terminal consequences of the harmful process are researched under the titles of metabolic syndrome, aging syndrome, and accelerated endothelial damage syndrome in the literature [4-6]. On the other hand, sickle cell diseases (SCDs) are inborn and severe inflammatory and highly destructive processes on vascular endothelium, initiated at birth and terminated with an advanced atherosclerosis-induced end-organ failures in much earlier ages of life [7, 8]. Hemoglobin S causes loss of elastic and biconcave disc shaped structures of red blood cells (RBCs). Probably loss of elasticity instead of shape is the major problem because sickling is rare in peripheric blood samples of the patients with associated thalassemia minors (TMs), and human survival is not affected in hereditary spherocytosis or elliptocytosis. Loss of elasticity is present even at birth, but exaggerated with inflammations, infections, and emotional stresses of the body. The sickled or just hardened RBCs-induced chronic endothelial damage, inflammation, edema, and fibrosis terminate with disseminated tissue hypoxia all over the body [9]. As a difference from other causes of chronic endothelial damage, SCDs keep vascular endothelium particularly at the capillaries which are the actual distributors of the sickled or just hardened RBCs into the tissues [10, 11]. The sickled or just hardened RBCs-induced chronic endothelial damage builds up an advanced atherosclerosis in much earlier ages of life. Vascular narrowings and occlusions-induced tissue ischemia and end-organ failures are the terminal results, so the life expectancy is decreased by 25 to 30 years for both genders in the SCDs [8].
The clinical study was performed in Medical Faculty of the Mustafa Kemal University between March 2007 and June 2016. All patients of the SCDs were included. The SCDs are diagnosed with the hemoglobin electrophoresis performed by means of high performance liquid chromatography (HPLC). Smoking and alcohol habits, acute painful crises per year, transfused units of RBCs in their lives, leg ulcers, stroke, surgical operations, deep venous thrombosis (DVT), epilepsy, and priapism were learnt. Cases with a history of one pack-year were accepted as smokers, and one drink-year were accepted as drinkers. A complete physical examination was performed by the Same Internist, and patients with disseminated teeth losses (<20>
The study included 222 males and 212 females with similar ages (30.8 vs 30.3 years, p>0.05, respectively). Prevalences of associated TMs were similar in both genders, too (72.5% vs 67.9%, p>0.05, respectively). Smoking (23.8% vs 6.1%) and alcohol (4.9% vs 0.4%) were higher in males (p<0>Table 1). Transfused units of RBCs in their lives (48.1 vs 28.5, p=0.000), disseminated teeth losses (5.4% vs 1.4%, p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>p<0>p>0.05 for all) (Table 2). Beside that the mean ages of terminal consequences were shown in Table 3.
| Variables | Males with SCDs* | p-value | Females with SCDs |
| Prevalence | 51.1% (222) | Ns† | 48.8% (212) |
| Mean age (year) | 30.8 ± 10.0 (5-58) | Ns | 30.3 ± 9.9 (8-59) |
| Associated TMs‡ | 72.5% (161) | Ns | 67.9% (144) |
| Smoking | 23.8% (53) | <0> | 6.1% (13) |
| Alcoholism | 4.9% (11) | <0> | 0.4% (1) |
Table 1: Characteristic features of the study patients
*Sickle cell diseases †Nonsignificant (p>0.05) ‡Thalassemia minor
| Variables | Males with SCDs* | p-value | Females with SCDs |
| Painful crises per year | 5.0 ± 7.1 (0-36) | Ns† | 4.9 ± 8.6 (0-52) |
| Transfused units of RBCs‡ | 48.1 ± 61.8 (0-434) | 0.000 | 28.5 ± 35.8 (0-206) |
Disseminated teeth losses (<20> | 5.4% (12) | <0> | 1.4% (3) |
| COPD§ | 25.2% (56) | <0> | 7.0% (15) |
| Ileus | 7.2% (16) | <0> | 1.4% (3) |
| Cirrhosis | 8.1% (18) | <0> | 1.8% (4) |
| Leg ulcers | 19.8% (44) | <0> | 7.0% (15) |
| Digital clubbing | 14.8% (33) | <0> | 6.6% (14) |
| CHD¶ | 18.0% (40) | <0> | 13.2% (28) |
| CRD** | 9.9% (22) | <0> | 6.1% (13) |
| Stroke | 12.1% (27) | <0> | 7.5% (16) |
| PHT*** | 12.6% (28) | Ns | 11.7% (25) |
| Autosplenectomy | 50.4% (112) | Ns | 53.3% (113) |
| DVT**** and/or varices and/or telangiectasias | 9.0% (20) | Ns | 6.6% (14) |
| Rheumatic heart disease | 6.7% (15) | Ns | 5.6% (12) |
| Avascular necrosis of bones | 24.3% (54) | Ns | 25.4% (54) |
| Sickle cell retinopathy | 0.9% (2) | Ns | 0.9% (2) |
| Epilepsy | 2.7% (6) | Ns | 2.3% (5) |
| ACS***** | 2.7% (6) | Ns | 3.7% (8) |
| Mortality | 7.6% (17) | Ns | 6.6% (14) |
| Mean age of mortality (year) | 30.2 ± 8.4 (19-50) | Ns | 33.3 ± 9.2 (19-47) |
Table 2: Associated pathologies of the study patients
*Sickle cell diseases †Nonsignificant (p>0.05) ‡Red blood cells §Chronic obstructive pulmonary disease ¶Coronary heart disease **Chronic renal disease ***Pulmonary hypertension ****Deep venous thrombosis *****Acute chest syndrome
| Variables | Mean age (year) |
| Ileus | 29.8 ± 9.8 (18-53) |
| Hepatomegaly | 30.2 ± 9.5 (5-59) |
| ACS* | 30.3 ± 10.0 (5-59) |
| Sickle cell retinopathy | 31.5 ± 10.8 (21-46) |
| Rheumatic heart disease | 31.9 ± 8.4 (20-49) |
| Autosplenectomy | 32.5 ± 9.5 (15-59) |
| Disseminated teeth losses (<20> | 32.6 ± 12.7 (11-58) |
| Avascular necrosis of bones | 32.8 ± 9.8 (13-58) |
| Epilepsy | 33.2 ± 11.6 (18-54) |
| Priapism | 33.4 ± 7.9 (18-51) |
| Left lobe hypertrophy of the liver | 33.4 ± 10.7 (19-56) |
| Stroke | 33.5 ± 11.9 (9-58) |
| COPD† | 33.6 ± 9.2 (13-58) |
| PHT‡ | 34.0 ± 10.0 (18-56) |
| Leg ulcers | 35.3 ± 8.8 (17-58) |
| Digital clubbing | 35.4 ± 10.7 (18-56) |
| CHD§ | 35.7 ± 10.8 (17-59) |
| DVT¶ and/or varices and/or telangiectasias | 37.0 ± 8.4 (17-50) |
| Cirrhosis | 37.0 ± 11.5 (19-56) |
| CRD** | 39.4 ± 9.7 (19-59) |
Table 3: Mean ages of the consequences of the sickle cell diseases
*Acute chest syndrome †Chronic obstructive pulmonary disease ‡Pulmonary hypertension §Coronary heart disease ¶Deep venous thrombosis **Chronic renal disease
Acute painful crises are the most disabling symptoms of the SCDs. Although some authors reported that pain itself may not be life threatening directly, infections, medical or surgical emergencies, or emotional stresses are the most common precipitating factors of the crises [19]. Although the sickled or just hardened RBCs-induced capillary endothelial damage, inflammation, and edema are present even at birth, the increased basal metabolic rate during such stresses aggravates the sickling and capillary endothelial damage, inflammation, and edema, and may terminate with disseminated tissue hypoxia and multiorgan failures-induced sudden deaths in the SCDs. So the risk of mortality is much higher during the crises. Actually, each crisis may complicate with the following crises by leaving some sequelaes on the capillary endothelial system all over the body. After a period of time, the sequelaes may terminate with sudden end-organ failures and death during a final acute painful crisis that may even be silent, clinically. Similarly, after a 20-year experience on such patients, the deaths seem sudden and unexpected events in the SCDs. Unfortunately, most of the deaths develop just after the hospital admission, and majority of such cases are without hydroxyurea therapy [20]. Rapid RBCs supports are usually life-saving for such patients, although preparation of RBCs units for transfusion usually takes time. Beside that RBCs supports in emergencies become much more difficult in such terminal patients due to the repeated transfusions-induced blood group mismatch. Actually, transfusion of each unit of RBCs complicates the following transfusions by means of the blood subgroup mismacth. Due to the significant efficacy of hydroxyurea therapy, RBCs transfusions should be kept just for acute events and emergencies in the SCDs [21]. According to our experiences, simple and repeated transfusions are superior to RBCs exchange in the SCDs [22]. First of all, preparation of one or two units of RBCs suspensions in each time rather than preparation of six units or higher provides time to clinicians to prepare more units by preventing sudden death of such high-risk cases. Secondly, transfusions of one or two units of RBCs suspensions in each time decrease the severity of pain and relax anxiety of the patients and their relatives because RBCs transfusions probably have the strongest analgesic effects during such crises. Actually, the decreased severity of pain by transfusions also indicates the decreased severity of inflammation in whole body. Thirdly, transfusions of lesser units of RBCs suspensions in each time by means of the simple transfusions decrease transfusions-related complications including infections, iron overload, and blood group mismatch. Fourthly, transfusions of RBCs suspensions in the secondary health centers prevent some deaths developed during the transport to the tertiary centers for the exchange. Finally, cost of the simple and repeated transfusions on insurance system is much lower than the exchange that needs trained staff and additional devices. On the other hand, pain is the result of complex and poorly understood interactions between RBCs, white blood cells (WBCs), platelets (PLTs), and endothelial cells, yet. Whether leukocytosis contributes to the pathogenesis by releasing cytotoxic enzymes is unknown. The adverse actions of WBCs on the capillary endothelium are of particular interest with regard to the cerebrovascular diseases in the SCDs. For instance, leukocytosis even in the absence of an infection was an independent predictor of the severity of the SCDs, and it was associated with the higher risk of stroke [23]. Disseminated tissue hypoxia, releasing of inflammatory mediators, bone infarctions, and activation of afferent nerves may take role in the pathophysiology of the intolerable pain. Because of the severity of pain, narcotic analgesics are usually required to control them [24], but according to our long term experience, simple and repeated RBCs transfusions are much more effective than the narcotics to control the intolerable pain in the SCDs.
Hydroxyurea is the first drug that was approved by Food and Drug Administration in the SCDs [25]. It is an orally-administered, cheap, safe, and effective drug, and it may be the only life-saving drug in the treatment of the SCDs [26, 27]. It interferes with the cell division by blocking the formation of deoxyribonucleotides via inhibition of ribonucleotide reductase. The deoxyribonucleotides are the building blocks of DNA. Hydroxyurea mainly affects hyperproliferating cells. Although the action way of hydroxyurea is thought to be the increase in gamma-globin synthesis for fetal hemoglobin (Hb F), its main action may be the prevention of leukocytosis and thrombocytosis by blocking the DNA synthesis [28, 29]. By this way, the inborn inflammatory and destructive process of the SCDs is suppressed with some extent. Due to the same action way, hydroxyurea is also used in moderate and severe psoriasis to suppress hyperproliferating skin cells. As also seen in the viral hepatitis cases, although presence of a continuous damage of sickled or just hardened RBCs on the capillary endothelium, the severity of destructive process may be exaggerated by the patients’ own WBCs and PLTs. So suppression of proliferation of the WBCs and PLTs may limit the capillary endothelial damage, inflammation, edema, tissue ischemia, and end-organ failures in the body [30]. Similarly, final Hb F levels in the hydroxyurea users did not differ from their pretreatment levels [31]. The Multicenter Study of Hydroxyurea (MSH) studied 299 severely affected adults with the SCA, and compared the results of patients treated with hydroxyurea or placebo [32]. The study particularly researched effects of hydroxyurea on the painful crises, ACS, and requirement of RBCs transfusion. The outcomes were so overwhelming in the favour of hydroxyurea that the study was terminated after 22 months, and hydroxyurea was started for all patients. The MSH also demonstrated that patients treated with hydroxyurea had a 44
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