Therapeutic Potential of Carica papaya Leaf against Thrombocytopenia

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Therapeutic Potential of Carica papaya Leaf against Thrombocytopenia

This entry is adapted from the peer-reviewed paper 10.3390/molecules27092760

Thrombocytopenia is a clinical manifestation that refers to the low platelet count, i.e., <150 × 10³/μL, of blood, resulting in imbalanced hemostasis, which leads to several fatal complications. The causative factors vary greatly, but, as a consequence, they interfere with platelet production and promote destruction, leading to death. Carica papaya leaf has unique therapeutic and medicinal characteristics against thrombocytopenia, and this is supported by scientific studies. Secondary metabolites and minerals in the leaf, such as carpaine and quercetin, promote platelet production, inhibit platelet destruction, and maintain platelet membrane through gene expression activity and the ceasing of viral proteases, respectively. Phytochemical profiles of C. papaya leaf revealed the presence of flavonoids, alkaloids, phenols, cardiac glycosides, tannins, terpenes, and saponins, which impart therapeutic potential to the leaf. The therapeutic benefits of the leaf include immunomodulatory, antiviral, antidiabetic, anticancer, antimalarial, antiangiogenic, antibacterial, and antioxidant activities. Several conducted scientific research studies have proved the efficacy of C. papaya leaf against thrombocytopenia, expanding the implication of natural sources to eradicate numerous ailments.

thrombocytopenia Carica papaya leaf phytochemicals gene expression activity therapeutic potential

1. Introduction

Thrombocytopenia is a hematological condition that is characterized by lower platelets count (< 150 × 10³ cells/μL of blood) and is often a multi-factorial disease ^[1]. Thrombocytes, commonly known as platelets, are blood cells (either nucleated or anucleated) produced in marrow with a normal range of (150–450 × 10³) cells/μL of blood ^[2]. The platelets play a significant role in the physiological system of the body, especially in vascular injury reactions. Platelets forestall the excessive blood loss after injury by forming a structural plug. The various receptors are present in the layers of plug for collagen, ADP, vessel divider von Willebrand factor, and fibrinogen ^[3]. The platelets have an average life span of 8–10 days, where two-thirds of the platelets are in blood and one-third is in the spleen. The major causes of thrombocytopenia include increased destruction, splenic sequestration, and decreased production of platelets by bone marrow ^[4]. The causative agents implicate a variety of types of thrombocytopenia, such as drug-induced thrombocytopenia, idiopathic thrombocytopenic purpura, HIV induced, dengue, liver cirrhosis, leukemia, chikungunya, hepatitis C virus, malaria, and various infections ^[2]^[5]. The incidence of thrombocytopenia in adults is 3.3/100,000 annually, with a prevalence factor of 9.5 per 100,000 adults ^[6].

Carica papaya is a herbaceous, non-woody, tree-resembling plant that belongs to the Caricaceae family ^[7]. The common name of this evergreen plant is papaya, which has spinally arranged broad leaves (50–70 cm) and bears fruit throughout the year ^[8]. C. papaya is a perennial plant that is native to Southern Mexico and is currently distributed throughout tropical areas worldwide. C. papaya fruit has been considered a quasi-drug, and the biological activities of its various parts, including leaves, fruits, shoots, roots, rinds or latex, and seeds, have been proved by several investigations ^[9]. C. papaya leaves have shown multiple therapeutic effects. Its leaves contain high amounts of fat-soluble vitamins (A, D, E, and K); vitamins B and C; and minerals such as iron, sodium, and magnesium ^[10]. In addition, potassium, nitrogen, and calcium are more absorbed during plant growth, and phosphorus is less extracted ^[11]. In a few Asian countries, the young C. papaya leaves are steamed to eat, similar to spinach, for health benefits. C. papaya leaf juice plays a role in liver repair and normalizes clotting by increasing the platelet and white-blood-cell count. Several studies have proved the potential of C. papaya leaves in preventing the complications of thrombocytopenia, due to its phytochemical profile ^[12].

2. Thrombocytopenia Ameliorating Potential of C. papaya Leaf

The effectiveness of C. papaya leaf extract against thrombocytopenia is inevitable. Recent research has supported its antithrombocytopenia efficacy.

2.1. Drug-Induced Thrombocytopenia

The use of drugs has been vigorously increased during the last few decades, including those that affect platelet production and induce platelet destruction, leading to thrombocytopenia. Several drugs have been used for thrombocytopenia induction to determine the mitigating effects of CPL. Bleeding and clotting time were also evaluated, as these parameters are often prolonged during thrombocytopenia. Bleeding time is the time in which bleeding stops after the rupture, while clotting time is the time interval between the start of bleeding and the appearance of fibrin thread. In the following studies, the effect of CPL was investigated on thrombocytopenia, bleeding time, and clotting time.

2.1.1. Cyclophosphamide-Induced Thrombocytopenia

Nandini et al. performed an experimental study to evaluate the antithrombocytopenia effect of C. papaya leaf. Cyclophosmadide (Cyp) was injected subcutaneously (70 mg/kg BW) for six days to stabilize the thrombocytopenia (210.4 ± 14.2 × 10³ cells/μL) in a rat model. Sequential fractionation was used to identify the antithrombocytic phytochemicals in C. papaya leaf juice (CPLJ). CPLJ, along with identified fractions, were given to research participants at doses of 200 and 400 mg/kg BD for fourteen days in vivo. The levels of serum thrombopoietin and CD110/cmpl (thrombopoietin receptor on platelets) were measured by using ELISA and Western blotting, respectively. The platelet count was increased to 1073.50 ± 29.6 and 1189.80 ± 36.5 × 10³ cells/L, respectively, after CPLJ and butanol fraction administration. Leaf extracts were shown to reduce bleeding time, clotting time, and oxidative indicators. In comparison to the normal and treatment groups, the Cyp-treated group had a slight increase in thrombopoietin (TPO) levels. The expression of the CD110 receptor was found to be low in the Cyp-treated group, but the expression was increased in the CPLJ and butanol fraction treatment groups. The therapeutic efficacy of CPLJ and fractions in mitigating Cyp-induced thrombocytopenia in rat models was discovered by morphological evaluation of megakaryocytes in the bone marrow and histopathology of the liver and kidney ^[2].

In another study, the efficacy of CPLE on platelet augmentation in Cyp-induced thrombocytopenia rats was investigated. Blood samples from the retro-orbital plexus were taken on the 1st, 4th, 7th, 11th, and 41st days of the study for platelet count evaluation. The importance of CPLE against the envelope and NS1 proteins expression in DENV-infected THP-1 cells was determined by histopathology of the liver, kidney, and spleen on the 14th day and TPO, as well as IL-6 secretion. Erythrocyte damage and hydrogen peroxide–induced lipid peroxidation were reduced, whereas TPO and platelet count were significantly increased ^[13].

In a Cyp-induced thrombocytopenia animal model, researchers evaluated the effects of standardized aqueous CPLE on platelet count, extramedullary hematopoiesis (EMH), and immunomodulation. For myricetin, caffeic acid, trans-ferulic acid, and kaempferol, the extract was standardized by HPTLC after UPLC–qtof/MS fingerprinting for metabolite signature. The standardized CPLE were provided to Wistar rats (50 and 150 mg/kg) and albino rats (150 mg/kg) for 14 days to assess the effect on platelet and leukocyte proliferation response and immunomodulatory parameters, respectively. The standardized CPLE estimation by quantitative HPTLC exhibited the presence of myricetin, caffeic acid, trans-ferulic acid, and kaempferol, while UPLC–qtof/MS showed the identification of 24 metabolites. Standardized CPLE (150 mg/kg) oral administration exhibited a significant (p < 0.01) rise of thrombocytes in the Cyp-induced thrombocytopenia rat group. The results suggest the mediation of CPL in the release of platelets provides means to treat thrombocytopenia ^[5].

2.1.2. Busulfan-Induced Thrombocytopenia

Busulfan-induced thrombocytopenia rats were investigated to observe the role of thrombopoietin (TPO) in the thrombocytosis effect of CPL. Aqueous and methanol extracts of CPL at 600 mg/kg were administered orally for 7 consecutive days. Intermittent determination of the serum platelet count at the end of the experiment revealed that aqueous and methanol extracts of CPL significantly increased platelet count compared to the control groups (x2 (2) = 25.373, p = 0.00). TPO levels were also increased as compared to controls ^[14].

2.1.3. Carboplatin-Induced Thrombocytopenia

In another study, an exploration of n-hexane, acetone, ethanol, and methanol extracts of CPLE obtained through Soxhlet apparatus, as well as distilled water extracts prepared by maceration for 8 h, was performed. Carboplatin-induced thrombocytopenia experimental animals were evaluated to observe an increase in platelet count. The findings revealed that thrombocytes rise with no adverse outcomes after hematological and histopathological studies ^[15].

2.1.4. Cotrimoxazole-Induced Thrombocytopenia

A researcher performed an in vivo study where five groups were formulated by dividing 30 male mice into negative control, positive control, ethanol 96% CPLE dose 0.5 g/kg BW, ethanol 96% CPLE dose 1 g/kg BW, and ethanol 96% CPLE dose 2 g/kg BW. Cotrimoxazole (249.6 mg/kg BW) for 8 days was used to induce thrombocytopenia. The trial results showed the fastest mean time for clotting (p < 0.0001), as well as the shortest bleeding time (2.74 ± 0.14), in the group with a CPLE dose of 2 g/kg BW (2.74 ± 0.14) ^[16].

2.1.5. Hydroxyurea-Induced Thrombocytopenia

Kumar et al. conducted a randomized study on albino rats, which were divided into eight groups (n = 6). Hydroxyurea (15 mg/kg) was given orally to induce thrombocytopenia. The first two groups served as saline and toxic control groups. The two different doses of commercial and fresh CPLE were orally given to six treatment groups for five days. The mean platelet count was raised on the 6th day in both low doses (2.06 to 4.93 lakh/mm³) and human equivalent dose (2.73 to 7.66 lakh/mm³) of commercial extract groups, as compared to the toxic control group (p < 0.05). A significant increase in mean platelet count was observed in the group with a human equivalent dose of fresh leaf extract (3.17 to 4.69 lakh/mm³), but the low dose of the fresh extract (3.28 to 3.76 lakh/mm³) did not show a significant rise. It was concluded that high doses of both fresh and commercial extracts enhance the platelet count, as well as RBC and WBC, with a decrease in bleeding and clotting time ^[17].

2.1.6. Aspirin-Induced Thrombocytopenia

Antithrombocytopenia efficacy of C. papaya fruit and leaf extracts on aspirin-induced thrombocytopenia was observed in male R. novergicus albino rats. The fifteen test subjects were separated into three blocks, each containing five rats as the control group, treatment group for fruit extract, and treatment group for leaf extract. The results showed no significant difference in the effect of leaf and fruit, but both enhanced the platelet count, along with the reduction in bleeding and clotting time ^[18].

2.1.7. Gentamicin-Induced Thrombocytopenia

The subcutaneous subjection of gentamicin (100 mg/kg) for 21 days resulted in an RBC, HGB, and PCV decrease, along with erythrocytic indices alteration, leukocytosis, granulocytosis, and thrombocytopenia. The oral administration of gentamicin and CPL (150 and 300 mg/kg) via a gastric tube for 21 days significantly hindered the drastic effects of gentamicin on the blood profile. The findings also depicted the improvement in erythrogram, leukogram, thrombocytes, EPO, and iron indices in a dose-dependent manner. Thus, CPLE has proved to be an appreciated hemostatic and nephroprotective agent of natural etiology that is good to attenuate blood disorders ^[19].

2.2. Chemotherapy-Induced Thrombocytopenia

Cancer is the leading cause of death globally, and medical science emphasizes the use of chemotherapy to treat this emerging issue. Chemotherapy destroys the cancer cells, as well as the body’s cells, including platelets, thus leading to thrombocytopenia. Several types of research were performed to assess the effectiveness of C. papaya leaf in mitigating thrombocytopenia. In 2017, a human-based study was conducted in which forty patients with chemotherapy-induced thrombocytopenia (CIT) were randomly allocated to two groups. The intervention group (n = 20) received a 1100 mg dose of CPLE for 7 days after chemotherapy, whereas and no active treatment in the non-intervention group (n = 20) was used. The adverse outcomes were assessed by complete hemogram on days 7, 10, 13, 16 and follow up at 28 days after chemotherapy. The intervention group showed a rise in mean platelet count from 49.700 ± 12.649/mm³ to 55.350 ± 15.131/mm³ (p > 0.05), 147.540 ± 54.359/mm³ (p < 0.01), and 200.585 ± 51.893/mm³ (p < 0.01) on day 7, 10, 13 and 16, respectively. The non-intervention group showed a mean platelet count of 47.361 ± 13.110/mm³, 42.580 ± 12.108/mm³, 46.367 ± 14.776/mm³, and 54.238 ± 16.053/mm³ on respective days. White blood cell increase from baseline to day 7 were statistically significant (p < 0.001) as compared to control. Hence, it was concluded that CPLE statistically increased the platelet count by day 13 of post-chemotherapy along with other hematological parameters. Hence, CPLE could be a viable option for the treatment of CIT ^[20].

Management of CIT by C. papaya leaf was observed in another experiment in which the recruitment of thirty subjects as ‘case’ and thirty as ‘control’ was performed. The capsules (290 mg) of CP were given twice a day in ‘cases’ for 5 consecutive days or till normal platelet count. Platelet count increased from 101.93 ± 26.15 × 10³/μL to 173.75 ± 29.98 × 10³/μL (p = 1.37225 × 10⁻⁹) in “cases” and 99.36 ± 16.62 × 10³/μL to 101.75 ± 16.03 × 10³/μL (p = 0.11) in “controls”. Thus proving that CPL rises platelet count with no adverse effects ^[21].

A group of scientists after meeting the inclusion and exclusion criteria, assigned 250 patients randomly in a ratio of 1:1 to orally administer thrombobliss (5 mL syrup) twice a day and a placebo for five days. Daily monitoring of platelets showed the platelet elevation from the 2nd day and more evident after 72 h when both mean and median platelet count raised. The cancer patients undergoing chemotherapy elucidated a significantly raised platelet count (p < 0.05) by using thrombobliss (CPLE + Tinospora cordifolia leaf extract) with no adverse effects ^[4].

A single-centered retrospective study was directed at an Indian institute where 45 patients were selected with post 50 events of CIT. The malignancy-proven patients were given the standard doses of CPLE to assess therapeutic response. The results suggested that significant platelet count increment occurred in 54% of patients within 5 days, 16% of patients by 7 days, and 18% of patients after more than one week post CPLE administration. The remaining 12% of patients possessed deteriorating platelet counts even after CPLE intervention. Therefore, CIT can be recovered by CPLE therapy in most patients ^[22].

A prospective study including 40 subjects with CIT who were recruited as case and 20 as control was conducted to assess the responses to UPLAT^® and placebo, respectively. UPLAT^® (CPLE: 350 mg—2% flavonoids standardization + Tinospora cardifolia extract: 150 mg—3% bitters standardization) was given twice a day (2 units each) for 10 consecutive days to cases. The platelet count was significantly higher in the case group (93,990.00 ± 63,896.73) than in the control group (27,600.00 ± 29,758.42), with no side effects associated with treatment in post-chemotherapy cancer patients ^[23].

2.3. Disease-Induced Thrombocytopenia

Several diseases of vital organs, such as decompensated cirrhosis and kidney diseases, also lead to thrombocytopenia. The CPLE and T. cordifolia extract potential impact against alcoholic decompensate cirrhosis was investigated by using Cariden (Phytoextracts of CP 1100 mg and T. cordifolia 500 mg). The enhancement in platelet count within 15 days was observed by this product, with a normalization period of 90 days in all cases ^[24].

Another research investigated the preventative impact of CPLE capsules in patients with acute febrile sickness and thrombocytopenia. The patients were randomly assigned to one of two groups (control or intervention) (n = 40), with the latter receiving the two capsules thrice a day. The results demonstrated a substantial rise in platelet count and maintenance of normal hematocrit when CPLE capsules were used ^[25].

Additionally, methanol and acetone aqueous extracts were found to be effective in increasing platelets. The purpose of this research was to determine the extracts’ active involvement in platelet count and bleeding time in rats, while the decocted leaf powder was supplied therapeutically to patients with a low platelet count. Methanol and acetone aqueous extracts and the positive control (heparin) group demonstrated a 68, 56, and 72% reduction in platelet aggregation, respectively. The research found that the C. papaya leaf may have the ability to boost platelet count by inhibiting platelet aggregation ^[26].

Neonates suffering from thrombocytopenia may undergo serious complications, such as intraventricular hemorrhage. Therefore, the CPLE incorporation was performed in the thrombocytopenic neonate. A pre-term newborn with low birth weight was diagnosed with persistent thrombocytopenia and was not responding to any kind of medical treatment. CPLE was administered to the baby thrice a day for 7 days, at a dose of 20 mg/kg. The results showed a normal platelet count without any type of side effects. The well-being of the baby was confirmed by regular follow-ups up to the age of 18 months ^[27].

In a prospective experimental study, thrombocytopenic children (1–12 years) with dengue hemorrhagic fever grades I and II were included to assess CPLE efficacy. The intervention group consisted of 147 subjects who were given the CPLE syrup with standard therapy, while the control group (n = 147) received only the standard therapy for 5 days. The increase in the platelet count was significant in the carpill-treated (CPLE syrup) group in comparison to the control group (p < 0.05). The mean-platelet-count increase in the intervention group was 89,739.31, p = 0.030, by day 3, and then it was raised to 168,922.75, (p = 0.023), by day 5, which is a safe tolerance level ^[28].

2.4. Dengue-Induced Thrombocytopenia

Dengue is a global epidemic which is still a threat to human life. Dengue fever drastically destroys the platelets, leading to thrombocytopenia. In Asian countries, to treat this type of thrombocytopenia, C. papaya leaves are used as traditional medicine. In an open study, a total of 500 patients suffering from thrombocytopenia that is associated with dengue fever were divided into study and control groups. CPLE 1100 mg thrice a day for five days consecutively in a week, along with supportive and symptomatic treatment, was provided to the study group, while the control group received only symptomatic and supportive treatment. An increase in the platelet count was observed earlier in the treated group as compared to the controlled group. The average hospitalization time was 5.42 ± 0.98 days and 7.2 ± 0.97 days in the study and control group, respectively ^[29]. A study was aimed to evaluate the effect of C. papaya leaf extract on the count of platelet in patients with dengue fever by including 100 cases. The study group received CPLE 500 mg thrice a day for five days, and at the same frequency, placebo capsules were received by the control group. The study group showed a significant increase (p < 0.01) in platelet count compared to the control group; moreover, the study group showed less incidences of complication ^[30]. CPLE’s role in improving this type of thrombocytopenia was assessed by observing 100 patients divided into two groups. CPLE at 10 mL three times a day was given to the patients, along with kiwi fruit and without any other supportive treatment. The mean platelet count of the study group significantly increased from 212,210 ± 72,257 cells/cumm to 275,282 ± 78,969 cells/cumm (p-value = 0.000). The WBC count in the study group also increased compared to the control group after CPLE treatment ^[31]. Hemorrhagic fever, a complication of dengue, often leads to thrombocytopenia. Another study which had six randomized clinical trials and contained 988 subjects showed an increase in the platelet count in dengue patients after using the C. papaya leaf extract. Pooled assessments showed a significant increase in platelet count on day 3 (MD = 12.18; CI 10.28–14.08), day 4 (MD = 31.30; CI 27.77–34.83), and day 5 (MD = 13.23; CI 9.90–16.55). The random-effects model on day 5 also showed a significant increase in platelet count. Furthermore, the studies based on frequency, route of administration, and dosage showed a noteworthy rise in platelet count ^[32].

A comparative study was carried out in dengue-affected children aged 1 to 16 years with platelets ≤1.5 × 10⁵ per μL and ≥50 × 10³/μL. Thirty children were allotted to the study group, as well as to the control group. A 1100 mg tablet prepared with C. papaya leaf extract formulated for children above 12 years and syrup at 10 mL for 6-to-12-year-old children and 5 mL for ages below 6 years was given three times a day for 5 days to the study group, and routine symptomatic treatment was given to control group. The platelets count of both groups was monitored and compared. The results indicated that, out of thirty patients, twenty-one were male. The mean platelet count of the study group was 143,270 per μL, while for the control group, it was 148,200 per μL and thus comparable (p = 0.76). Meanwhile, on day 5, the mean platelet count was 162,933 per μL and 197,333 per μL in the study and control group, respectively, which showed no significant difference (p = 0.15). It was concluded that the extract of C. papaya leaf helped increase the platelets in dengue patients as compared to the control group, with no side effects ^[33].

A longitudinal study was conducted including 200 participants who were randomized into two groups. The study group was given CPLE, while the other group had routine supportive treatment. Follow-up from the day of admission to discharge from the hospital revealed a notable difference in mean RBC levels (p = 0.045). Moreover, the increase in platelet count in the study group as compared to the placebo group was observed. On the third day, there was a great difference between the study and placebo groups (p = 0.002), and the discharge rate was earlier in the test group than in the control group ^[34].

The platelet-count increase was assessed via the administration of C. papaya leaf in dengue patients. Eleven patients were provided with fruits such as C. papaya, apples, guava in crumbs, and a spoonful of powdered C. papaya leaves with 8 h gape. Patients were also receiving the symptomatic treatment for dengue. A platelet count rise, as well as a decrease in dengue hemorrhagic fever and dengue shock syndrome incidences, was observed ^[35]. Indian scientists evaluated the efficacy of CPLE and CPLE safety in severe thrombocytopenia management in dengue infection. Adult dengue patients (n = 51) with platelet counts 30,000/L were randomly assigned to the treatment group (n = 26) or the placebo group (n = 24). On day 3, patients treated with CPLE had a significant (p = 0.007) increase in platelet counts (482% ± 284) compared to the placebo (331% ± 370) group. Patients in the treatment group required fewer platelet transfusions (1/26 vs. 2/24), and their median time to reach 50,000/L was 2 days (IQR 2–3), compared to 3 days (IQR 2–4) in the placebo group. CPLE was a safe and well-tolerated procedure that did not result in a substantial reduction in mean hospitalization time. Plasma cytokine profiling revealed that the study group faced a lower rise in TNF and IFN levels than the placebo group ^[36].

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Rana Muhammad Aadil

Przemysław Kowalczewski

zhiwei liu

Tayyaba Tariq

Roshina Rabail

Jacek Lewandowicz

Andrzej Blecharczyk

Muhammad Inam-Ur-Raheem

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Update Date: 24 May 2022

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