Annals of Clinical and Medical

Case Reports

Research Article ISSN 2639-8109 Volume 13

Red Blood Cell Transfusions May Have the Stongest Analgesic Effect during Acute
Painful Crises in Sickle Cell Diseases
Helvaci MR1*, Cayir S2, Halici H2, Sevinc A1, Camci C1, Abyad A3 and Pocock L4
1
Specialist of Internal Medicine, MD, Turkey
2
Manager of Writing and Statistics, Turkey
3
Middle-East Academy for Medicine of Aging, MD, Lebanon
4
Medi-WORLD International, Australia
Received: 28 Feb 2024 Copyright:
*
Corresponding author:
Accepted: 17 Apr 2024 ©2024 Helvaci MR. This is an open access article
Mehmet Rami Helvaci,
Published: 22 Apr 2024 distributed under the terms of the Creative Commons
Specialist of Internal Medicine, MD, 07400, Alanya,
J Short Name: ACMCR Attribution License, which permits unrestricted use, dis-
Turkey
tribution, and build upon your work non-commercially

Keywords: Citation:
Sickle cell diseases; Acute painful crises; Helvaci MR, Red Blood Cell Transfusions May Have the
Hardened red blood cells; Capillary endothelial Stongest Analgesic Effect during Acute Painful Crises in
inflammation; Capillary endothelial edema; Tissue Sickle Cell Diseases. Ann Clin Med Case Rep.
hypoxia; Sudden death 2024; V13(12): 1-12

1. Abstract painful crises, multiorgan failures, and sudden deaths in the SCD.
1.1. Background: The hardened red blood cells (RBC)-induced RBC support may have the stongest analgesic effect, and decrease
capillary endothelial damage, inflammation, edema, and fibrosis the risk of multiorgan failures and sudden death by decreasing the
are initiated at birth, and terminate with disseminated tissue hy- density of causative hardened cells from the circulation during
poxia, acute painful crises, multiorgan failures, and sudden death such severe crises.
even at childhood in the sickle cell diseases (SCD). 2. Introduction
1.2. Methods: All cases with the SCD were included into the study. Chronic endothelial damage may be the major cause of aging and
1.3. Results: We studied 222 males and 212 females with similar death by causing end-organ failures in human being [1]. Much
mean ages (30.8 vs 30.3 years, p>0.05, respectively). Dissemi- higher blood pressures (BPs) of the afferent vasculature may be the
nated teeth losses (5.4% vs 1.4%, p<0.001), ileus (7.2% vs 1.4%, major accelerating factor by causing recurrent injuries on vascular
p<0.001), cirrhosis (8.1% vs 1.8%, p<0.001), leg ulcers (19.8% vs endothelial cells. Probably, whole afferent vasculature including
7.0%, p<0.001), digital clubbing (14.8% vs 6.6%, p<0.001), coro- capillaries are mainly involved in the process. Thus the term of
nary heart disease (18.0% vs 13.2%, p<0.05), chronic renal disease venosclerosis is not as famous as atherosclerosis in the literature.
(9.9% vs 6.1%, p<0.05), chronic obstructive pulmonary disease Due to the chronic endothelial damage, inflammation, edema, and
(25.2% vs 7.0%, p<0.001), and stroke (12.1% vs 7.5%, p<0.05) fibrosis, vascular walls thicken, their lumens narrow, and they
were all higher but not acute chest syndrome (2.7% vs 3.7%, lose their elastic natures, those eventually reduce blood supply to
p>0.05) or pulmonary hypertension (12.6% vs 11.7%, p>0.05) the terminal organs, and increase systolic and decrease diastolic
or deep venous thrombosis and/or varices and/or telangiectasias BPs further. Some of the well-known accelerating factors of the
(9.0% vs 6.6%, p>0.05) in males, significantly. inflammatory process are physical inactivity, sedentary lifestyle,
animal-rich diet, smoking, alcohol, overweight, chronic inflam-
1.4. Conclusion: Infections, medical or surgical emergencies, or
mations, prolonged infections, and cancers for the development
emotional stress-induced increased basal metabolic rate aggra-
of terminal consequences including obesity, hypertension (HT),
vates the sickling and capillary endothelial inflammation and ede-
diabetes mellitus (DM), cirrhosis, chronic obstructive pulmonary
ma, and may terminate with disseminated tissue hypoxia, acute
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disease (COPD), coronary heart disease (CHD), chronic renal ments were performed on the silent phase. Check up procedures
disease (CRD), stroke, peripheric artery disease (PAD), mesenter- including serum iron, iron binding capacity, ferritin, creatinine,
ic ischemia, osteoporosis, dementia, early aging, and premature liver function tests, markers of hepatitis viruses A, B, and C, a
death [2, 3]. Although early withdrawal of the accelerating factors posterior-anterior chest x-ray film, an electrocardiogram, a Dop-
can delay terminal consequences, after development of obesity, pler echocardiogram both to evaluate cardiac walls and valves, and
HT, DM, cirrhosis, COPD, CRD, CHD, stroke, PAD, mesenteric to measure systolic BPs of pulmonary artery, an abdominal ultra-
ischemia, osteoporosis, and dementia-like end-organ insufficien- sonography, a venous Doppler ultrasonography of the lower limbs,
cies and aging, the endothelial changes cannot be reversed due to a computed tomography (CT) of brain, and a magnetic resonance
their fibrotic natures, completely. The accelerating factors and ter- imaging (MRI) of hips were performed. Other bones for avascu-
minal consequences of the vascular process are researched under lar necrosis were scanned according to the patients’ complaints.
the titles of metabolic syndrome, aging syndrome, and accelerated So avascular necrosis of bones was diagnosed by means of MRI
endothelial damage syndrome in the literature [4-6]. On the oth- [12]. Associated TM were detected with serum iron, iron binding
er hand, sickle cell diseases (SCD) are chronic inflammatory and capacity, ferritin, and hemoglobin electrophoresis performed via
highly destructive processes on vascular endothelium, initiated HPLC, since the SCD with associated TM show a milder clinic
at birth and terminated with an advanced atherosclerosis induced than the sickle cell anemia (SCA) (Hb SS) alone [13]. Systolic
end-organ insufficiencies in much earlier ages of life [7, 8]. He- BPs of the pulmonary artery of 40 mmHg or higher are accepted
moglobin S causes loss of elastic and biconcave disc shaped struc- as pulmonary hypertension (PHT) [14]. The criterion for diagnosis
tures of red blood cells (RBC). Probably loss of elasticity instead of COPD is a post-bronchodilator forced expiratory volume in one
of shape is the major problem because sickling is rare in peripher- second/forced vital capacity of lower than 70% [15]. Acute chest
ic blood samples of the cases with associated thalassemia minors syndrome (ACS) is diagnosed clinically with the presence of new
(TM), and human survival is not affected in hereditary spherocy- infiltrates on chest x-ray film, fever, cough, sputum production,
tosis or elliptocytosis. Loss of elasticity is present during whole dyspnea, or hypoxia [16]. An x-ray film of abdomen in upright
lifespan, but exaggerated with inflammations, infections, and ad- position was taken just in patients with abdominal distention or
ditional stresses of the body. The hardened RBC induced chronic discomfort, vomiting, obstipation, or lack of bowel movement,
endothelial damage, inflammation, edema, and fibrosis terminate and ileus was diagnosed with gaseous distention of isolated seg-
with tissue hypoxia all over the body [9]. As a difference from ments of bowel, vomiting, obstipation, cramps, and with the ab-
other causes of chronic endothelial damage, SCD keep vascular sence of peristaltic activity. CRD is diagnosed with a persistent
endothelium particularly at the capillary level [10, 11], since the serum creatinine level of 1.3 mg/dL or higher in males and 1.2
capillary system is the main distributor of the hardened RBC into mg/dL or higher in females. Cirrhosis is diagnosed with physical
the tissues. The hardened RBC induced chronic endothelial dam- examination findings, laboratory parameters, and ultrasonographic
age builds up an advanced atherosclerosis in much earlier ages of evaluation. Digital clubbing is diagnosed with the ratio of distal
life. Vascular narrowings and occlusions induced tissue ischemia phalangeal diameter to interphalangeal diameter of higher than
and end-organ insufficiencies are the final consequences, so the 1.0, and with the presence of Schamroth’s sign [17, 18]. An ex-
mean life expectancy is decreased by 25 to 30 years for both gen- ercise electrocardiogram is performed in cases with an abnormal
ders in the SCD [8]. electrocardiogram and/or angina pectoris. Coronary angiography
3. Material and Methods is taken for the exercise electrocardiogram positive cases. So CHD
was diagnosed either angiographically or with the Doppler echo-
The study was performed in Medical Faculty of the Mustafa Ke-
cardiographic findings as movement disorders in the cardiac walls.
mal University between March 2007 and June 2016. All patients
Rheumatic heart disease is diagnosed with the echocardiograph-
with the SCD were included. The SCD were diagnosed with the
ic findings, too. Stroke is diagnosed by the CT of brain. Sickle
hemoglobin electrophoresis performed via high performance liq-
cell retinopathy is diagnosed with ophthalmologic examination in
uid chromatography (HPLC). Medical histories including smok-
patients with visual complaints. Mann-Whitney U test, Independ-
ing, alcohol, acute painful crises per year, transfused units of RBC
ent-Samples t test, and comparison of proportions were used as the
in their lives, leg ulcers, stroke, surgical operations, deep venous
methods of statistical analyses.
thrombosis (DVT), epilepsy, and priapism were learnt. Patients
with a history of one pack-year were accepted as smokers, and 4. Results
one drink-year were accepted as drinkers. A complete physical ex- The study included 222 males and 212 females with similar ages
amination was performed by the Same Internist, and patients with (30.8 vs 30.3 years, p>0.05, respectively). Prevalences of associat-
disseminated teeth losses (<20 teeth present) were detected. Pa- ed TM were similar in both genders, too (72.5% vs 67.9%, p>0.05,
tients with an acute painful crisis or any other inflammatory event respectively). Smoking (23.8% vs 6.1%) and alcohol (4.9% vs
were treated at first, and the laboratory tests and clinical measure- 0.4%) were higher in males (p<0.001 for both) (Table 1). Trans-
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fused units of RBC in their lives (48.1 vs 28.5, p=0.000), dissem- PHT (12.6% vs 11.7%, p>0.05) or DVT and/or varices and/or tel-
inated teeth losses (5.4% vs 1.4%, p<0.001), ileus (7.2% vs 1.4%, angiectasias (9.0% vs 6.6%, p>0.05) in males, significantly. Al-
p<0.001), cirrhosis (8.1% vs 1.8%, p<0.001), leg ulcers (19.8% though the mean age of mortality (30.2 vs 33.3 years) was lower
vs 7.0%, p<0.001), digital clubbing (14.8% vs 6.6%, p<0.001), in males, the difference was not significant, probably due to the
CHD (18.0% vs 13.2%, p<0.05), CRD (9.9% vs 6.1%, p<0.05), small sample size of the study cases (Table 2). Interestingly, mean
COPD (25.2% vs 7.0%, p<0.001), and stroke (12.1% vs 7.5%, ages of the stroke (33.5 years), COPD (33.6 years), digital club-
p<0.05) were all higher but not ACS (2.7% vs 3.7%, p>0.05) or bing (35.4 years), CHD (35.7 years), cirrhosis (37.0 years), and
CRD (39.4 years) were the highest among the other atherosclerotic
consequences in the SCD (Table 3).

Table 1: Characteristic features of the study cases

Variables Male patients with SCD* p-value Female patients with SCD
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 TM‡ 72.5% (161) Ns 67.9% (144)
Smoking 23.8% (53) <0.001 6.1% (13)
Alcoholism 4.9% (11) <0.001 0.4% (1)
*Sickle cell diseases †Nonsignificant (p>0.05) ‡Thalassemia minors
Table 2: Associated pathologies of the study cases
Variables Male patients with SCD* p-value Female patients with SCD
Painful crises per year 5.0 ± 7.1 (0-36) Ns† 4.9 ± 8.6 (0-52)
Transfused units of RBC‡ 48.1 ± 61.8 (0-434) 0 28.5 ± 35.8 (0-206)
Disseminated teeth losses
5.4% (12) <0.001 1.4% (3)
(<20 teeth present)
COPD§ 25.2% (56) <0.001 7.0% (15)
Ileus 7.2% (16) <0.001 1.4% (3)
Cirrhosis 8.1% (18) <0.001 1.8% (4)
Leg ulcers 19.8% (44) <0.001 7.0% (15)
Digital clubbing 14.8% (33) <0.001 6.6% (14)
CHD¶ 18.0% (40) <0.05 13.2% (28)
CRD** 9.9% (22) <0.05 6.1% (13)
Stroke 12.1% (27) <0.05 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)

*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

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Table 3: Mean ages of the consequences of the sickle cell diseases to the repeated transfusions-induced blood group mismatch. Ac-
Variables Mean age (year) tually, transfusion of each unit of RBC complicates the following
transfusions by means of the blood subgroup mismacth. Due to
Ileus 29.8 ± 9.8 (18-53)
the significant efficacy of hydroxyurea therapy, RBC transfusions
Hepatomegaly 30.2 ± 9.5 (5-59)
should be kept just for acute events and emergencies in the SCD
ACS* 30.3 ± 10.0 (5-59)
[23, 24]. According to our experiences, simple and repeated trans-
Sickle cell retinopathy 31.5 ± 10.8 (21-46) fusions are superior to RBC exchange in the SCD [25, 26]. First
Rheumatic heart disease 31.9 ± 8.4 (20-49) of all, preparation of one or two units of RBC suspensions in each
Autosplenectomy 32.5 ± 9.5 (15-59) time rather than preparation of six units or higher provides time
Disseminated teeth losses (<20 teeth present) 32.6 ± 12.7 (11-58) to clinicians to prepare more units by preventing sudden death of
Avascular necrosis of bones 32.8 ± 9.8 (13-58) such high-risk patients. Secondly, transfusions of one or two units
Epilepsy 33.2 ± 11.6 (18-54) of RBC suspensions in each time decrease the severity of pain, and
relax anxiety of the patients and their relatives since RBC trans-
Priapism 33.4 ± 7.9 (18-51)
fusions probably have the strongest analgesic effects during the
Left lobe hypertrophy of the liver 33.4 ± 10.7 (19-56)
crises. Actually, the decreased severity of pain by transfusions also
Stroke 33.5 ± 11.9 (9-58)
indicates the decreased severity of inflammation all over the body.
COPD† 33.6 ± 9.2 (13-58) Thirdly, transfusions of lesser units of RBC suspensions in each
PHT‡ 34.0 ± 10.0 (18-56) time by means of the simple transfusions will decrease transfu-
Leg ulcers 35.3 ± 8.8 (17-58) sion-related complications including infections, iron overload, and
Digital clubbing 35.4 ± 10.7 (18-56) blood group mismatch in the future. Fourthly, transfusion of RBC
CHD§ 35.7 ± 10.8 (17-59) suspensions in the secondary health centers may prevent some
DVT¶ and/or varices and/or telangiectasias 37.0 ± 8.4 (17-50)
deaths developed during the transport to the tertiary centers for
the exchange. Finally, cost of the simple and repeated transfusions
Cirrhosis 37.0 ± 11.5 (19-56)
on insurance system is much lower than the exchange that needs
CRD** 39.4 ± 9.7 (19-59)
trained staff and additional devices. On the other hand, pain is the
*Acute chest syndrome †Chronic obstructive pulmonary disease ‡Pul- result of complex and poorly understood interactions between
monary hypertension §Coronary heart disease ¶Deep venous thrombo- RBC, white blood cells (WBCs), platelets (PLTs), and endothelial
sis **Chronic renal disease cells, yet. Whether leukocytosis contributes to the pathogenesis by
5. Discussion releasing cytotoxic enzymes is unknown. The adverse actions of
WBCs on endothelium are of particular interest with regard to the
Acute painful crises are the most disabling symptoms of the SCD.
cerebrovascular diseases in the SCD. For example, leukocytosis
Although some authors reported that pain itself may not be life
even in the absence of any infection was an independent predictor
threatening directly, infections, medical or surgical emergencies,
of the severity of the SCD [20], and it was associated with the
or emotional stress are the most common precipitating factors of
risk of stroke in a cohort of Jamaican patients [21]. Disseminated
the crises [19]. The increased basal metabolic rate during such
tissue hypoxia, releasing of inflammatory mediators, bone infarc-
stresses aggravates the sickling, capillary endothelial damage, in-
tions, and activation of afferent nerves may take role in the patho-
flammation, edema, tissue hypoxia, and multiorgan insufficiencies.
physiology of the intolerable pain. Because of the severity of pain,
So the risk of mortality is much higher during the crises. Actually,
narcotic analgesics are usually required to control them [22], but
each crisis may complicate with the following crises by leaving
according to our practice, simple and repeated RBC transfusions
significant sequelaes on the capillary endothelial system all over
may be highly effective both to relieve pain and to prevent sudden
the body. After a period of time, the sequelaes may terminate with
death that may develop secondary to multiorgan failures on the
sudden end-organ failures and death during a final acute painful
chronic inflammatory background of the SCD.
crisis that may even be silent, clinically. Similarly, after a 20-year
experience on such patients, the deaths seem sudden and unexpect- Hydroxyurea may be the only life-saving drug for the treatment of
ed events in the SCD. Unfortunately, most of the deaths develop the SCD. It interferes with the cell division by blocking the forma-
just after the hospital admission, and majority of them are patients tion of deoxyribonucleotides by means of inhibition of ribonucle-
without hydroxyurea therapy [23, 24]. Rapid RBC supports are otide reductase. The deoxyribonucleotides are the building blocks
usually life-saving for such patients, although preparation of RBC of DNA. Hydroxyurea mainly affects hyperproliferating cells. Al-
units for transfusion usually takes time. Beside that RBC supports though the action way of hydroxyurea is thought to be the increase
in emergencies become much more difficult in terminal cases due in gamma-globin synthesis for fetal hemoglobin (Hb F), its main

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action may be the suppression of leukocytosis and thrombocytosis acetylating agent where an acetyl group is covalently attached to
by blocking the DNA synthesis in the SCD [27, 28]. By this way, a serine residue in the active site of the cyclooxygenase (COX)
the chronic inflammatory and destructive process of the SCD is enzyme. Aspirin’s ability to suppress the production of prostaglan-
suppressed with some extent. Due to the same action way, hydrox- dins (PGs) and thromboxanes (TXs) is due to its irreversible in-
yurea is also used in moderate and severe psoriasis to suppress hy- activation of the COX enzyme required for PG and TX synthesis.
perproliferating skin cells. As in the viral hepatitis cases, although PGs are the locally produced hormones with some diverse effects,
presence of a continuous damage of sickle cells on the capillary including the transmission of pain into the brain and modulation
endothelium, the severity of destructive process is probably exag- of the hypothalamic thermostat and inflammation in the body. TXs
gerated by the patients’ own WBCs and PLTs. So suppression of are responsible for the aggregation of PLTs to form blood clots.
proliferation of them may limit the endothelial damage-induced In another definition, low-dose aspirin use irreversibly blocks the
edema, ischemia, and infarctions in whole body [29]. Similarly, formation of TXA2 in the PLTs, producing an inhibitory effect on
final Hb F levels in hydroxyurea users did not differ from their the PLT aggregation during whole lifespan of the affected PLTs
pretreatment levels [30]. The Multicenter Study of Hydroxyurea (8-9 days). Since PLTs do not have nucleus and DNA, they are
(MSH) studied 299 severely affected adults with the SCA, and unable to synthesize new COX enzyme once aspirin has inhibited
compared the results of patients treated with hydroxyurea or place- the enzyme. The antithrombotic property of aspirin is useful to
bo [31]. The study particularly researched effects of hydroxyurea reduce the incidences of myocardial infarction, transient ischemic
on painful crises, ACS, and requirement of blood transfusion. The attack, and stroke (34). Heart attacks are caused primarily by blood
outcomes were so overwhelming in the favour of hydroxyurea that clots, and low dose of aspirin is seen as an effective medical inter-
the study was terminated after 22 months, and hydroxyurea was vention to prevent a second myocardial infarction [35]. Accord-
initiated for all patients. The MSH also demonstrated that patients ing to the literature, aspirin may also be effective in prevention
treated with hydroxyurea had a 44% decrease in hospitalizations of colorectal cancers [36]. On the other hand, aspirin has some
[31]. In multivariable analyses, there was a strong and independ- side effects including gastric ulcers, gastric bleeding, worsening of
ent association of lower neutrophil counts with the lower crisis asthma, and Reye syndrome in childhood and adolescence. Due to
rates [31]. But this study was performed just in severe SCA cases the risk of Reye syndrome, the US Food and Drug Administration
alone, and the rate of painful crises was decreased from 4.5 to 2.5 recommends that aspirin or aspirin-containing products should not
per year [31]. Whereas we used all subtypes of the SCD with all be prescribed for febrile patients under the age of 12 years [37].
clinical severity, and the rate of painful crises was decreased from Eventually, the general recommendation to use aspirin in children
10.3 to 1.7 per year (p<0.000) with an additional decreased se- has been withdrawn, and it was only recommended for Kawasaki
verity of them (7.8/10 vs 2.2/10, p<0.000) in the previous study disease [38]. Reye syndrome is a rapidly worsening brain disease
[21]. Parallel to our results, adult patients using hydroxyurea for [38]. The first detailed description of Reye syndrome was in 1963
frequent painful crises appear to have reduced mortality rate after by an Australian pathologist, Douglas Reye [39]. The syndrome
a 9-year follow-up period [32]. Although the underlying disease mostly affects children, but it can only affect fewer than one in a
severity remains critical to determine prognosis, hydroxyurea may million children a year [39]. Symptoms of Reye syndrome may
also decrease severity of disease and prolong survival [32]. The include personality changes, confusion, seizures, and loss of con-
complications start to be seen even in infancy in the SCD. For sciousness [38]. Although the liver toxicity typically occurs in the
example, infants with lower hemoglobin values were more likely syndrome, jaundice is usually not seen with it, but the liver is en-
to have a higher incidence of clinical events such as ACS, painful larged in most cases [38]. Although the death occurs in 20-40% of
crises, and lower neuropsychological scores, and hydroxyurea re- affected cases, about one third of survivors get a significant degree
duced the incidences of them [33]. Hydroxyurea therapy in early of brain damage [38]. The cause of Reye syndrome is unknown
years of life may protect splenic function, improve growth, and [39]. It usually starts just after recovery from a viral infection, such
prevent end-organ insufficiencies. Transfusion programmes can as influenza or chicken pox. About 90% of cases in children are as-
also reduce all of the complications, but transfusions carry many sociated with an aspirin use [39, 40]. Inborn errors of metabolism
risks including infections, iron overload, and development of al- are also the other risk factors, and the genetic testing for inborn er-
lo-antibodies causing subsequent transfusions difficult. rors of metabolism became available in developed countries in the
Aspirin is a nonsteroidal anti-inflammatory drug (NSAID) used 1980s [38]. When aspirin use was withdrawn for children in the US
to reduce pain, fever, inflammation, and acute thromboembolic and UK in the 1980s, a decrease of more than 90% in rates of Reye
events. Although aspirin has similar anti-inflammatory effects with syndrome was seen [39]. Early diagnosis improves outcomes, and
the other NSAIDs, it also suppresses the normal functions of PLTs, treatment is supportive. Mannitol may be used in cases with the
irreversibly. This property causes aspirin being different from oth- brain swelling [39]. Due to the very low risk of Reye syndrome
er NSAIDs, which are reversible inhibitors. Aspirin acts as an but much higher risk of death due to the SCD in children, aspirin

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should be added both into the acute and chronic phase treatments give INR results that are comparable with those obtained in labo-
with an anti-inflammatory dose even in childhood in the SCD [41]. ratory testing. The only common side effect of warfarin is hemor-
Warfarin is an anticoagulant, and first came into large-scale com- rhage. The risk of severe bleeding is low with a yearly rate of 1-3%
mercial use in 1948 as a rat poison. It was formally approved as a [45]. All types of bleeding may occur, but the most severe ones are
medication to treat blood clots in human being by the U.S. Food those involving the brain and spinal cord [45]. The risk is particu-
and Drug Administration in 1954. In 1955, warfarin’s reputation larly increased once the INR exceeds 4.5 [45]. The risk of bleeding
as a safe and acceptable treatment was bolstred when President is increased further when warfarin is combined with antiplatelet
Dwight David Eisenhower was treated with warfarin following a drugs such as clopidogrel or aspirin [46]. But thirteen publications
massive and highly publicized heart attack. Eisenhower’s treat- from 11 cohorts including more than 48.500 total patients with
ment kickstarted a transformation in medicine whereby CHD, more than 11.600 warfarin users were included in the meta-anal-
arterial plaques, and ischemic strokes were treated and protected ysis [47]. In patients with AF and non-end-stage CRD, warfarin
against by using anticoagulants such as warfarin. Warfarin is found resulted in a lower risk of ischemic stroke (p= 0.004) and mortality
in the List of Essential Medicines of WHO. In 2020, it was the (p<0.00001), but had no effect on major bleeding (p>0.05) [47].
58th most commonly prescribed medication in the United States. Similarly, warfarin resumption is associated with significant re-
It does not reduce blood viscosity but inhibits blood coagulation. ductions in ischemic stroke even in patients with warfarin-associ-
Warfarin is used to decrease the tendency for thrombosis, and it ated intracranial hemorrhage (ICH) [48]. Death occured in 18.7%
can prevent formation of future blood clots and reduce the risk of of patients who resumed warfarin and 32.3% who did not resume
embolism. Warfarin is the best suited for anticoagulation in areas warfarin (p= 0.009) [48]. Ischemic stroke occured in 3.5% of pa-
of slowly running blood such as in veins and the pooled blood be- tients who resumed warfarin and 7.0% of patients who did not
hind artificial and natural valves, and in blood pooled in dysfunc- resume warfarin (p= 0.002) [48]. Whereas recurrent ICH occured
tional cardiac atria. It is commonly used to prevent blood clots in in 6.7% of patients who resumed warfarin and 7.7% of patients
the circulatory system such as DVT and pulmonary embolism, and who did not resume warfarin without any significant difference in
to protect against stroke in people who have atrial fibrillation (AF), between (p>0.05) [48]. On the other hand, patients with cerebral
valvular heart disease, or artificial heart valves. Less commonly, it venous thrombosis (CVT) those were anticoagulated either with
is used following ST-segment elevation myocardial infarction and warfarin or dabigatran had low risk of recurrent venous throm-
orthopedic surgery. The warfarin initiation regimens are simple, botic events (VTE), and the risk of bleeding was similar in both
safe, and suitable to be used in ambulatory and in patient settings regimens, suggesting that both warfarin and dabigatran are safe
[42]. Warfarin should be initiated with a 5 mg dose, or 2 to 4 mg and effective for preventing recurrent VTE in patients with CVT
in the very elderly. In the protocol of low-dose warfarin, the tar- [49]. Additionally, an INR value of about 1.5 achieved with an
get international normalised ratio (INR) value is between 2.0 and average daily dose of 4.6 mg warfarin, has resulted in no increase
2.5, whereas in the protocol of standard-dose warfarin, the target in the number of men ever reporting minor bleeding episodes, al-
INR value is between 2.5 and 3.5 [43]. When warfarin is used and though rectal bleeding occurs more frequently in those men who
INR is in therapeutic range, simple discontinuation of the drug for report this symptom [50]. Non-rheumatic AF increases the risk of
five days is usually enough to reverse the effect, and causes INR stroke, presumably from atrial thromboemboli, and long-term low-
to drop below 1.5 [44]. Its effects can be reversed with phytome- dose warfarin therapy is highly effective and safe in preventing
nadione (vitamin K1), fresh frozen plasma, or prothrombin com- stroke in such patients [51]. There were just two strokes in the
plex concentrate, rapidly. Blood products should not be routinely warfarin group (0.41% per year) as compared with 13 strokes in
used to reverse warfarin overdose, when vitamin K1 could work the control group (2.98% per year) with a reduction of 86% in the
alone. Warfarin decreases blood clotting by blocking vitamin K risk of stroke (p= 0.0022) [51]. The mortality was markedly low-
epoxide reductase, an ezyme that reactivates vitamin K1. With- er in the warfarin group, too (p= 0.005) [51]. The warfarin group
out sufficient active vitamin K1, clotting factors II, VII, IX, and had a higher rate of minor hemorrhage (38 vs 21 patients) but the
X have decreased clotting ability. The anticlotting protein C and frequency of bleedings that required hospitalization or transfusion
protein S are also inhibited, but to a lesser degree. A few days was the same in both group (p>0.05) [51]. Additionally, very-low-
are required for full effect to occur, and these effects can last for dose warfarin was a safe and effective method for prevention of
up to five days. The consensus agrees that patient self-testing and thromboembolism in patients with metastatic breast cancer [52].
patient self-management are effective methods of monitoring oral The warfarin dose was 1 mg daily for 6 weeks, and was adjusted to
anticoagulation therapy, providing outcomes at least as good as, maintain the INR value of 1.3 to 1.9 [52]. The average daily dose
and possibly better than, those achieved with an anticoagulation was 2.6 mg, and the mean INR was 1.5 [52]. On the other hand,
clinic. Currently available self-testing/self-management devices new oral anticoagulants had a favourable risk-benefit profile with

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Volume 13 Issue 12 -2024 Research Article

significant reductions in stroke, ICH, and mortality, and with sim- exact cause and significance is unknown, the chronic tissue hy-
ilar major bleeding as for warfarin, but increased gastrointestinal poxia is highly suspected [67]. In the previous study, only 40%
bleeding [53]. Interestingly, rivaroxaban and low-dose apixaban of clubbing cases turned out to have significant underlying dis-
were associated with increased risks of all cause mortality com- eases while 60% remained well over the subsequent years [18].
pared with warfarin [54]. The mortality rate was 4.1% per year But according to our experiences, digital clubbing is frequently
in the warfarin group, as compared with 3.7% per year with 110 associated with the pulmonary, cardiac, renal, and hepatic diseases
mg of dabigatran and 3.6% per year with 150 mg of dabigatran and smoking which are characterized with chronic tissue hypoxia
(p>0.05 for both) in patients with AF in another study [55]. On [5]. As an explanation for that hypothesis, lungs, heart, kidneys,
the other hand, infections, medical or surgical emergencies, or and liver are closely related organs which affect their functions in
emotional stress-induced increased basal metabolic rate acceler- a short period of time. On the other hand, digital clubbing is also
ates sickling, and an exaggerated capillary endothelial edema-in- common in the SCD, and its prevalence was 10.8% in the present
duced myocardial infarction or stroke may cause sudden deaths in study. It probably shows chronic tissue hypoxia caused by dissem-
the SCD. So lifelong aspirin with an anti-inflammatory dose plus inated endothelial damage, inflammation, edema, and fibrosis at
low-dose warfarin may be a life-saving treatment regimen even the capillary level in the SCD. Beside the effects of SCD, smoking,
at childhood both to decrease severity of capillary endothelial in- alcohol, cirrhosis, CRD, CHD, and COPD, the higher prevalence
flammation and to prevent thromboembolic complications in the of digital clubbing in males (14.8% vs 6.6%, p<0.001) may also
SCD [56]. show some additional role of male gender in the systemic athero-
COPD is the third leading cause of death with various underlying sclerotic process.
etiologies in whole world [57, 58]. Aging, physical inactivity, sed- Leg ulcers are seen in 10% to 20% of the SCD, and the ratio was
entary lifestyle, animal-rich diet, smoking, alcohol, male gender, 13.5% in the present study [83]. Its prevalence increases with ag-
excess weight, chronic inflammations, prolonged infections, and ing, male gender, and SCA [69]. Similarly, its ratio was higher in
cancers may be the major underlying causes. Beside smoking, reg- males (19.8% vs 7.0%, p<0.001), and mean age of the leg ulcer
ular alcohol consumption is also important for the pulmonary and cases was higher than the remaining patients (35.3 vs 29.8 years,
systemic inflammatory process of the COPD, since COPD was one p<0.000) in the present study. The leg ulcers have an intractable
of the most common diagnoses in alcohol dependence [59]. Fur- nature, and around 97% of them relapse in a period of one year
thermore, 30-day readmission rates were higher in the COPD pa- [68]. As an evidence of their atherosclerotic nature, the leg ulcers
tients with alcoholism [60]. Probably an accelerated atherosclerot- occur in the distal segments of the body with a lesser collateral
ic process is the main structural background of functional changes blood flow [68]. The hardened RBC induced chronic endothelial
that are characteristics of the COPD. The inflammatory process of damage, inflammation, edema, and fibrosis at the capillary level
vascular endothelium is enhanced by release of various chemicals may be the major causes, again [69]. Prolonged exposure to the
by inflammatory cells, and it terminates with an advanced fibrosis, hardened bodies due to the pooling of blood in the lower extrem-
atherosclerosis, and pulmonary losses. COPD may actually be the ities may also explain the leg but not arm ulcers in the SCD. The
pulmonary consequence of the systemic atherosclerotic process. hardened RBC induced venous insufficiencies may also accelerate
Since beside the accelerated atherosclerotic process of the pulmo- the process by pooling of causative bodies in the legs, and vice
nary vasculature, there are several reports about coexistence of versa. Pooling of blood may also have some effects on develop-
associated endothelial inflammation all over the body in COPD ment of venous ulcers, diabetic ulcers, Buerger’s disease, digital
[61, 62]. For example, there may be close relationships between clubbing, and onychomycosis in the lower extremities. Further-
COPD, CHD, PAD, and stroke [63]. Furthermore, two-third of more, probably pooling of blood is the cause of delayed wound
mortality cases were caused by cardiovascular diseases and lung and fracture healings in the lower extremities. Smoking and alco-
cancers in the COPD, and the CHD was the most common cause hol may also have some additional atherosclerotic effects on the
in a multi-center study of 5.887 smokers [64]. When the hospitali- ulcers in males. Hydroxyurea is the first drug that was approved by
zations were researched, the most common causes were the cardi- Food and Drug Administration in the SCD [70]. It is an orally-ad-
ovascular diseases, again [64]. In another study, 27% of mortality ministered, cheap, safe, and effective drug that blocks cell divi-
cases were due to the cardiovascular diseases in the moderate and sion by suppressing formation of deoxyribonucleotides which are
severe COPD [65]. On the other hand, COPD may be the pulmo- the building blocks of DNA [11]. Its main action may be the sup-
nary consequence of the systemic atherosclerotic process caused pression of hyperproliferative WBCs and PLTs in the SCD [71].
by the hardened RBC in the SCD [57]. Although presence of a continuous damage of hardened RBC on
Digital clubbing is characterized by the increased normal angle vascular endothelium, severity of the destructive process is proba-
of 165° between nailbed and fold, increased convexity of the nail bly exaggerated by the patients’ own immune systems. Similarly,
fold, and thickening of the whole distal finger [66]. Although the lower WBCs counts were associated with lower crises rates, and if

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Volume 13 Issue 12 -2024 Research Article

a tissue infarct occurs, lower WBCs counts may decrease severity advanced atherosclerosis, tissue hypoxia, and infarcts [81]. Excess
of pain and tissue damage [30]. According to our experiences, pro- weight induced hyperglycemia, dyslipidemia, elevated BPs, and
longed resolution of leg ulcers with hydroxyurea may also suggest insulin resistance may cause tissue inflammation and immune cell
that the ulcers may be secondary to increased WBCs and PLTs activation [82]. For example, age (p= 0.04), high-sensitivity C-re-
counts induced exaggerated capillary endothelial inflammation active protein (p= 0.01), mean arterial BPs (p= 0.003), and DM (p=
and edema instead of the fibrosis, yet. 0.02) had significant correlations with the CIMT [80]. Increased
Cirrhosis was the 10th leading cause of death for men and the 12th renal tubular sodium reabsorption, impaired pressure natriuresis,
for women in the United States in 2001 [6]. Although the improve- volume expansion due to the activations of sympathetic nervous
ments of health services worldwide, the increased morbidity and system and renin-angiotensin system, and physical compression
mortality of cirrhosis may be explained by prolonged survival of kidneys by visceral fat tissue may be some mechanisms of the
of the human being, and increased prevalence of excess weight increased BPs with excess weight [83]. Excess weight also causes
all over the world. For example, nonalcoholic fatty liver disease renal vasodilation and glomerular hyperfiltration which initially
(NAFLD) affects up to one third of the world population, and it serve as compensatory mechanisms to maintain sodium balance
became the most common cause of chronic liver disease even at due to the increased tubular reabsorption [83]. However, along
childhood, nowadays [72]. NAFLD is a marker of pathological with the increased BPs, these changes cause a hemodynamic bur-
fat deposition combined with a low-grade inflammation which re- den on the kidneys in long term that causes chronic endothelial
sults with hypercoagulability, endothelial dysfunction, and an ac- damage [84]. With prolonged weight excess, there are increased
celerated atherosclerosis [72]. Beside terminating with cirrhosis, urinary protein excretion, loss of nephron function, and exacer-
NAFLD is associated with higher overall mortality rates as well bated HT. With the development of dyslipidemia and DM in cases
as increased prevalences of cardiovascular diseases [73]. Authors with excess weight, CRD progresses much more easily [83]. On
reported independent associations between NAFLD and impaired the other hand, the systemic inflammatory effects of smoking on
flow-mediated vasodilation and increased mean carotid artery in- endothelial cells may also be important in the CRD [85]. Although
tima-media thickness (CIMT) [74]. NAFLD may be considered as some authors reported that alcohol was not related with the CRD
one of the hepatic consequences of the metabolic syndrome and [85], various metabolites of alcohol circulate even in the blood
SCD [75]. Probably smoking also takes role in the inflammatory vessels of the kidneys and give harm to the renal vascular endothe-
process of the capillary endothelium in liver, since the systemic in- lium. Chronic inflammatory or infectious processes may also ter-
flammatory effects of smoking on endothelial cells is well-known minate with the accelerated atherosclerosis in the renal vascula-
with Buerger’s disease and COPD [76]. Increased oxidative stress, ture [77]. Although CRD is due to the atherosclerotic process of
inactivation of antiproteases, and release of proinflammatory me- the renal vasculature, there are close relationships between CRD
diators may terminate with the systemic atherosclerosis in smok- and other atherosclerotic consequences of the metabolic syndrome
ers. The atherosclerotic effects of alcohol is much more prominent including CHD, COPD, PAD, cirrhosis, and stroke [86, 87]. For
in hepatic endothelium probably due to the highest concentrations example, the most common cause of death was the cardiovascular
of its metabolites there. Chronic infectious or inflammatory pro- diseases in the CRD again [88]. The hardened RBC-induced cap-
cesses and cancers may also terminate with an accelerated ather- illary endothelial damage in the renal vasculature may be the main
osclerosis in whole body [77]. For example, chronic hepatitis C cause of CRD in the SCD. In another definition, CRD may just be
virus (HCV) infection raised CIMT, and normalization of hepatic one of the several atherosclerotic consequences of the metabolic
function with HCV clearance may be secondary to reversal of fa- syndrome and SCD, again [89].
vourable lipids observed with the chronic infection [77, 78]. As a Stroke is an important cause of death, and develops as an acute
result, cirrhosis may also be another atherosclerotic consequence thromboembolic event on the chronic atherosclerotic background
of the SCD. in most of the cases. Aging, male gender, smoking, alcohol, and
The increased frequency of CRD can also be explained by aging excess weight may be the major underlying causes. Stroke is also
of the human being, and increased prevalence of excess weight all a common complication of the SCD [90, 91]. Similar to the leg ul-
over the world [79, 80]. Aging, physical inactivity, sedentary life- cers, stroke is particularly higher in the SCA and cases with higher
style, animal-rich diet, excess weight, smoking, alcohol, inflamma- WBCs counts [92]. Sickling induced capillary endothelial damage,
tory or infectious processes, and cancers may be the major causes activations of WBCs, PLTs, and coagulation system, and hemol-
of the renal endothelial inflammation. The inflammatory process ysis may terminate with chronic capillary endothelial inflamma-
is enhanced by release of various chemicals by lymphocytes to tion, edema, and fibrosis [93]. Probably, stroke may not have a
repair the damaged endothelial cells of the renal arteriols. Due to macrovascular origin in the SCD, and diffuse capillary endothelial
the continuous irritation of the vascular endothelial cells, promi- inflammation, edema, and fibrosis may be much more important.
nent changes develop in the architecture of the renal tissues with Infections, inflammations, medical or surgical emergencies, and

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Volume 13 Issue 12 -2024 Research Article

emotional stress may precipitate stroke by increasing basal meta- 12. Mankad VN, Williams JP, Harpen MD, Manci E, Longenecker G,
bolic rate and sickling. A significant reduction of stroke with hy- Moore RB, et al. Magnetic resonance imaging of bone marrow in
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As a conclusion, the hardened RBC-induced capillary endothelial
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