Evaluating the Potential of Herbal Extracts as Treatment in Immune Thrombocytopenia: A Review of Evidence and Limitations

Abstract

Immune thrombocytopenia, formerly idiopathic thrombocytopenia purpura (ITP), is an autoimmune disease characterized by the depletion of platelets below 100,000/µL when other causes of thrombocytopenia have been ruled out. It is associated with several infectious pathologies, disease states, and as a known side effect and complication of several drugs and chemotherapies. Standard treatment calls for glucocorticoid-mediated immunosuppression, intravenous immunoglobin transfusion, platelet stimulation, platelet transfusion, and splenectomy in instances of chronic and severe disease. While standard treatments are often effective, some cases prove resistant, and more commonly, some patients are unable to tolerate standard treatment protocols or opt out of surgical intervention. In addition, second-line therapies can be unfeasibly expensive and are associated with side effects themselves. Therefore, for a subset of patients afflicted by immune thrombocytopenia, the exploration of alternative treatment methods is needed in order to ease their burden of disease. Emerging evidence suggests that plant-derived extracts, traditionally used in regions such as Asia and Africa to manage acute thrombocytopenia, hold promise as alternative or adjunctive therapies for the mentioned subset of patients. These natural compounds may provide a cost-effective and less invasive option, potentially bridging gaps in current treatment regimens. We propose these extracts may play a role in fulfilling this deficiency in current treatment protocols. With this review, we aim to characterize and compile evidence that various organic extracts and compounds may be utilized to improve outcomes in these patients. By highlighting their clinical relevance and potential for integration into ITP treatment protocols, this manuscript underscores the importance of expanding the alternative therapies for ITP to improve patient outcomes and reduce treatment burdens.

1. Introduction

Immune thrombocytopenic purpura (ITP), also known as idiopathic thrombocytopenic purpura or immune thrombocytopenia, is an autoimmune syndrome characterized by IgG autoantibody-coated platelets that become sequestered in the spleen [1]. Though the pathogenesis is complex, the prevailing mechanistic pathway of thrombocytopenia arises from antibodies against the Ib/IIIa or Ib/IX platelet membrane glycoprotein complexes. These antibodies mark platelets for destruction in the spleen [2]. In a minority of cases such antibodies are not detected, suggesting a dysregulation in cellular immunity through participating cytotoxic and regulatory T lymphocytes [3]. The megakaryocytes that produce the body’s platelets are also targeted by these antibodies along with autoreactive T lymphocytes. Finally, ITP patients suffer from a decreased TPO level. This glycoprotein hormone, through binding megakaryocyte surface c-Mpl receptors, normally induces megakaryocyte proliferation and differentiation [2,4,5].

This confluence of mechanisms combines to decrease platelet numbers, manifesting symptoms such as fatigue, bruising, petechiae, and mucosal or excessive bleeding. When platelet counts are especially low (dropping below 10 × 10³/µL), these spontaneous bleeds may occur in the intracerebral or subarachnoid space and be life-threatening. ITP as a primary disease is a diagnosis of exclusion; therefore, the absence of infection, malignancy, and other autoimmune conditions should be ruled out in addition to the disease’s characteristic isolated thrombocytopenia [6,7].

ITP can be divided into the following two clinical subtypes: acute and chronic. The acute form presents as a sudden, idiopathic thrombocytopenia often following a viral infection in young children [8,9]. This form is self-limited and does not need long-term treatment as 85% of cases resolve within 3 to 5 months. In chronic ITP, symptoms last for over 12 months with no known identifiable trigger, mostly affecting women between the ages of 20 and 40 [8,9].

While the precise mechanism underlying the development of ITP remains unclear, it is believed that in 60–80% of cases, IgG antibodies against platelet phospholipid glycoproteins are produced in the spleen [9]. These autoantibodies then coat circulating platelets, rendering affected thrombocytes susceptible to opsonization and sequestration by macrophages into the spleen and liver. Additionally, it is hypothesized that impairment of thrombopoietin (TPO), a glycoprotein hormone involved in platelet production, can further decrease platelet count [9]. In response to thrombocytopenia, an increased number of megakaryocytes can be found upon bone examination, which may aid in diagnosis. This imbalance of increased platelet destruction and impaired thrombopoiesis eventually leads to symptomatic thrombocytopenia [9].

1.1. Current ITP Treatments

In patients requiring emergency treatment (i.e., hemodynamic compromise with platelet counts <20,000/μL, clinical presentation suggesting intracranial bleeds, or in preparation for surgery or other invasive procedures), a united management combining hemostatic control and combination therapy is recommended by the American Society of Hematology 2019 guidelines for ITP [10]. Combination therapy includes intravenous immunoglobulin (IVIG), platelet transfusions, and corticosteroids. Additionally, the healthcare team should recognize treatable underlying causes and consider taking patients off platelet-inhibiting medications (e.g., NSAIDs) [11].

1.1.1. IVIG

Intravenous immunoglobulin (IVIG) is a blood product derived from human plasma that contains a mixture of antibodies that competes as a decoy for Fc receptors of splenic macrophages, sparing the pathogenic platelet-bound immunoglobulin [12]. The competition of IVIG with the pathogenic autoantibodies is the therapeutic mechanism involving ITP, but there is an additional immunosuppressive effect [13]. There is evidence that IVIG neutralizes autoantibodies and complement directly by binding the variable region (antigen recognition site) and C3b/C4b fragments (and therefore the generation of C5 convertase), respectively [14]. The effect of immune system inhibition is short-lived and loses effect when all IVIG is consumed—due to this limited and non-curative nature, IVIG is used only in acute cases of severely low platelet counts (e.g., below 20,000/μL) with considerable risk of bleeds [15].

1.1.2. Platelet Transfusions

Due to the immediate benefit platelet transfusion provides in the management of ITP, it is often used in cases of acutely symptomatic, hospitalized patients [16]. By transfusing platelets to the patient, platelet numbers boost the hemostatic ability of forming clots, which can prevent dangerous bleeding complications [16]. This is especially useful to bridge the patient from a high-risk state until other treatments become active [17]. Goel et al. found that in a majority of hospitalized patients, platelet transfusion is not associated with improvement in clinical outcomes and most instances were not indicated by the current guidelines [18]. Furthermore, they found that blood transfusions are associated with higher odds of arterial thrombosis and mortality among other platelet disorders in thrombotic thrombocytopenic purpura (TTP) and heparin-induced thrombocytopenia (HIT) using four years of hospital admission data [18]. Similar to IVIG, platelet transfusion action is short-lived: platelets may still be rapidly destroyed under the same processes involved in ITP pathogenesis. This treatment modality does not address the autoantibodies targeting the platelets, so any therapeutic effect is rapid but transient and may require repeat transfusions.

1.1.3. Corticosteroids

Corticosteroids can inhibit the pathophysiology of ITP through several mechanisms, such as decreasing the immune-mediated phagocytosis of platelets by human leukocytes and inhibiting the production of platelet-targeted autoantibodies [19,20,21]. These steroid hormones follow a release path through the hypothalamic–pituitary–adrenal (HPA) axis before eventually distributing into the blood and tissue where they have various physiological influences [22]. One of these involves suppressing the proliferation of T cells necessary for regulating the immune response and activating B cells that produce ITP-related antibodies. By inhibiting NF-kB and lowering the transcription of pro-inflammatory cytokines, corticosteroids further limit the recruitment of T cells and B cells and subsequently reduce the likelihood of autoimmune responses [23]. Accordingly, self-tolerance mechanisms involved in diseases such as ITP are modulated by corticosteroids. Corticosteroid toxicity is a broad and well-documented subject. More serious side effects of corticosteroid treatment include weight gain and Cushingoid appearance, osteoporosis, hyperglycemia, and psychiatric effects. Due to their immune-modulating properties, corticosteroid use may also exacerbate preexisting conditions and increase the risk of infection [23]. Other negative effects widely vary depending on the route of administration, dosage, and duration of treatment, and clinicians must be aware of these possibilities when prescribing these agents [24,25,26].

1.1.4. Rituximab

Rituximab is a chimeric human–mouse monoclonal antibody that targets and depletes the CD20+ B cells responsible for producing the anti-platelet autoantibodies. Rituximab does this through targeting the CD20 protein found on the surface of B cells, working by signaling induced cell death, complement-dependent cytotoxicity, and antibody-dependent cellular toxicity [27]. Stasi et al. conducted a study in which 14 of 30 chronic ITP patients displayed a durable response (>6 months) when treated with rituximab. Generally reserved for chronic ITP patients with failed response to corticosteroids, this four-week treatment can be combined with thrombopoietin receptor agonists to increase the chances of a durable platelet response [28]. A potential drawback of rituximab is its price. Since rituximab is a biological drug, which requires more complex research, development, production, and patenting compared to non-biologic alternatives, it is appreciably more expensive than other treatment alternatives [29]. A cycle of rituximab, which allows a sustained response for 5 years, is calculated to cost USD 30,896 [30]. Aside from immunosuppression increasing the risk of infection for those who take the drug, infusion reactions ascribed to anaphylaxis can be a possible reaction to rituximab administration [31].

1.1.5. Thrombopoietin Receptor Antagonists

Thrombopoietin receptor agonists (TPRAs) are a more recent pharmaceutical development for treating ITP, which stimulates the thrombopoietin receptors in the bone marrow to increase the generation of platelets. By mimicking the natural hormone thrombopoietin, which binds the c-Mpl on megakaryocytes, these platelet precursors are induced to replenish the decreased platelet counts of ITP. While there is ongoing clinical guidance on TPRA administration, unique indications for each approved TPRA (e.g., Romiplostim) must be considered in practice when used as a tool for ITP refractive to first-line therapy or those who cannot tolerate corticosteroids or splenectomy [32,33]. Although well-tolerated, these recombinant cytokines are not without adverse effects, as patients who receive the drug can experience non-specific symptoms such as headache, nausea, and fever [34]. Additionally, a six-month randomized study of Eltrombopag use found a mild increase in levels of alanine aminotransferase and bilirubin levels in 7% of treatment group participants [34]. A meta-analysis conducted by Tjepkema et al. found that in 11 studies there were no individual risk ratios of suffering from thromboembolic events that were statistically significant for patients who received TPRA therapy compared to a non-TPRA control group [35].

1.1.6. Splenectomy

Despite improvements in treating ITP over the past few decades, removal of the spleen remains a viable solution, especially in patients whose disease is refractory to the previously mentioned therapies [36]. Splenectomy targets two sites of ITP pathogenesis: removing both the primary site of platelet clearance and a primary supply of the body’s plasma cells, which produce anti-platelet antibodies. This procedure offers the highest rates of response (50–70%) when compared with other therapies but risks the morbidities associated with surgical intervention, as well as infection and cardiovascular complications due to the removal of a primary blood filter of the body [37]. Clinicians also avoid splenectomy within the first year of the patient’s ITP diagnosis to observe for spontaneous remission or meaningful response to other therapies. A 35-year monocentric study conducted by Palandri et al. found that nearly a fifth of ITP patients reviewed had undergone splenectomy as a third-line therapy and had the lowest rates of disease relapse [38].

1.1.7. Plant Extract

The proper use of herb-derived medicines is well-established, with their safety and efficacy recognized in the modern clinical setting. Patients may choose to utilize traditional medicine over, or alongside, allopathic medicine for various reasons. Some key motivations include alignment with cultural heritage, beliefs, and the perceived safety of using natural ingredients for their ailments—patients may find herbal remedies more trustworthy and familiar compared to synthetic ones. Personal or anecdotal experiences from others may strengthen these feelings. Additionally, herbal medicine may be more affordable and accessible than hospital care and pharmaceuticals, especially in lower-income groups or geographical areas with limited modern healthcare access. As the popularity of herbal alternatives or supplements to pharmacologic treatment develops, it is important to further research the mechanisms of these herbal therapies and grow clinical evidence. This public health issue is also recognized by the World Health Organization, which stresses the increasing importance of including herbal medicine in pharmacovigilance systems [39]. This way clinicians, practitioners, and patients can improve patient safety and health outcomes through the use of herbal medicines. However, side effects of herbal extracts treatment on thrombocytopenic patients must be mentioned. Each extract has their own side effect profiles and herb–drug interactions. C. papaya leaf extract, for example, reports mild gastroenteritis and some concern about hepatotoxicity and reproductive toxicity. It also has the potential to interact with hypoglycemic agents and some antibiotics, suggesting cytochrome P450 interaction [40]. Euphorbia species can cause ocular toxicity when used topically, or nausea and vomiting when ingested [41]. Finally, both I. batatas and A. sessilis extracts, when used in high enough dosages, can cause liver damage [42,43].

2. Herbal Extract and Efficacy on Thrombocytopenia Treatment

2.1. Carica Papaya

2.1.1. Extraction

Extraction of papain from C. papaya generally consists of conventional maceration, ultrasonic-assisted, or microwave-assisted extraction [44]. Conventional maceration is achieved through the soaking of dried leaf powder in ethanol or another solvent, filtering the ground leaf, then allowing for the solvent to evaporate [44]. Ultrasonic-assisted extraction can be accomplished through the utilization of ultrasound waves (200 W, 40 kHz) to disrupt plant cells and enhance solvent penetration, while microwave-assisted extraction applies rapid heating (60 °C, 800 W) to accelerate compound release. Samples can then be filtered and evaporated under reduced pressure [44].

2.1.2. Mechanism of Action

Papain (papaya proteinase I) is a major cysteine proteinase enzyme isolated from C. papaya fruit latex. This endopeptidase has been observed to promote the proliferation of multipotent hematopoietic progenitor cells. An experiment by Aziz et al. found a dose-dependent increase of IL-6 synthesis in stem cells from human exfoliated deciduous teeth when treated with unripe papaya juice [45,46,47]. There are multiple proposed mechanisms for IL-6 effects on upregulating megakaryocytes. This is thought to be carried out directly, through soluble IL-6 receptor/IL-6 complexes that bind to glycoprotein (GP) 130 on CD34+ marrow progenitor cells. Indirect effects are implied too, suggested by IL-6-induced production of murine megakaryocytes being abolished by impeding biological TPO activity [45,46,47]. These effects are corroborated experimentally with A. Kaser’s work, which finds inflammatory thrombocytosis in IL-6-treated B57BL/10 mice, where up to a 46% increase in circulating platelet count was found. This increase is evidenced to be a TPO-dependent process, as injecting the mice with rabbit anti-TPO polyclonal antibody prior to IL-6 administration prevented the IL-6-induced increase of platelets and, in fact, caused a slight decrease in platelet levels compared to baseline [48].

2.2. Use of Papaya Leaf Extract for Thrombocytopenia in Humans

2.2.1. Carica papaya Leaf Extract in Chronic ITP

Hamplios et al. authored a case series wherein four patients received adjunctive C. papaya leaf extract (CPLE) alongside standard prednisone treatment for ITP [49]. The first, a 67-year-old man with a family history significant for ITP, experienced recurrent/chronic episodes of ITP spanning 14 years. During a remissive episode, with a platelet count (PC) of 5 × 10³/µL, his ITP was unresponsive to previously effective daily 100 mg prednisone. IVIG and 250 mg methyl prednisolone sodium succinate were added to the regiment, but his PC remained below 10 × 10³/µL. The patient, diagnosed with steroid refractory ITP, had his PC rise from 65 × 10³/µL three months after tapering off dual prednisone and CPLE therapy to 310 × 10³/µL (WNL) ten days after supplementing with 1200 mg CPLE capsule TID with 10 mg of prednisone [49].

The second case, a 21-year-old woman with a PC of 2 × 10³/µL, was treated with prednisone and IVIG with moderate response. She discontinued this protocol due to steroid side effects, and her PC remained between 10–15 × 10³/µL. A splenectomy was performed, resulting in a PC of 188 × 10³/µL, which deteriorated over the subsequent 4 months to 30–95 × 10³/µL. The patient then began 1000 mg CPLE TID, and 2 weeks later her PC was recorded at 156 × 10³/µL. At this time, the patient discontinued CPLE, and her PC was still WNL 1 week later [49].

The third, a 56-year-old man who was incidentally found to have a PC of 85 × 10³/µL. Over the course of several months, his PC dropped to 17 × 10³/µL and he was started on daily 60 mg prednisone, which improved his PC to 169 × 10³/µL. At that time his prednisone dose was lowered to 10 mg QOD for maintenance, but 3 months later his platelets once again dropped to 37 × 10³/µL. While awaiting a splenectomy, the patient began taking 1000 mg CPLE TID alongside 10 mg prednisone every other day. His PC increased the second month of starting medication (115 × 10³/µL) and remained adequate for the next serval months on the CPLE and prednisone. However, 2 months after discontinuing prednisone, his PC had dropped to 42 × 10³/µL and the patient was advised to undergo a splenectomy. He continued CPLE TID, but there was no improvement seen with his PC—37 × 10³/µL. He once again began taking prednisone with CPLE TID while waiting for surgery and his PC increased to 118 × 10³/µL [49].

The fourth and final case of Hampilios et al. describes a 60-year-old woman first diagnosed with ITP (PC: 30–40 × 10³/µL) as an incidental finding during a pre-work up for hysterectomy and oophorectomy. The patient was managed with 5–10 mg prednisone daily for 20 years. The patient was reportedly chronically thrombocytopenic during this time. At a PC of 98 × 10³/µL, she augmented her 5 mg daily prednisone with 1000 mg CPLE TID. Six days after the introduction of CPLE a PC of 109 × 10³/µL was recorded and CPLE treatment was deemed ineffective and discontinued. None of the patients reported adverse effects from CPLE alone or in combination with standard treatment [49].

2.2.2. C. papaya for Drug-Induced ITP

A recent review by Munir et al. looking at the therapeutic potential of C. papaya in the setting of ITP compiled instances of it being applied in numerous etiologies including, drug-induced thrombocytopenia (cyclophosphamide, busulfan, carboplatin, hydroxyurea, aspirin, gentamycin) in rat models—as well as in humans receiving chemotherapy—in decompensated cirrhosis, renal disease, acute febrile sickness, and in dengue fever [47]. Due to the nature of this review, we wish to emphasize the results of C. papaya in human-based studies and trials, but we will briefly address its application in drug induced thrombocytopenia in in vivo models in

Table 1. In vivo drug-induced thrombocytopenia rat models treated with CPLE.

Drug	Model	Tx	Dose (mg/kg)	Duration	PC0	PC1	Sig
CycP [50]	Wistar Rats	CPLE	150	14 days	408.5	1014.83	p < 0.001
Busulfan [51]	Sprague-Dawley Rats	CPLE	600	7 days	267	608 1	p < 0.00
Carboplatin [52]	Sprague-Dawley Rats	CPLE	400	21 days 2	241	973	-
Hydroxyurea [53]	Albino Rats	CPLE	3300	5 days	273	766	p < 0.001
Gentamycin [54]	Albino Rats	CPLE	100	21 days	481	720	p < 0.05

Abbreviations: Tx: treatment, PC0: baseline platelet count (units = × 10³/µL), PC1: post-treatment platelet count (units = × 10³/µL), Sig: significance, CycP: cyclophosphamide, CPLE: Carica papaya leaf extract, ¹ Measurement was taken on day 14, 1 week after discontinuation of treatment, ² Treatment was administered every other day.

below [47].

Table 1 shows the effects of Carica papaya leaf extract (CPLE) on platelet recovery in rat models of drug-induced thrombocytopenia. CPLE was tested at doses of 100–3300 mg/kg over 5–21 days across various drugs and rat models. Significant platelet count increases were observed in most cases (e.g., p < 0.001 for cyclophosphamide, busulfan, and hydroxyurea). The results highlight CPLE’s potential to improve thrombocytopenia caused by different drugs.

2.2.3. C. papaya in Chemotherapy-Induced ITP

Chemotherapy-induced thrombocytopenia (CIT) is a result of its broad, off-target effects leading to bone marrow suppression. Different drugs are known to have different mechanisms of inducing CIT, with alkylating agents suppressing pluripotent stem cells and cyclophosphamide-suppressing megakaryocytes. Sundarmurthy et al. aimed to promote megakaryopoiesis in patients undergoing various chemotherapies [55]. They randomly assigned 40 patients with CIT (PC: 30–100 × 10³/µL) to either an intervention (n = 20) or control group (n = 20). The intervention group received 1100 mg CPLE TID for 7 days, 1 week after receiving chemotherapy. Platelet levels were recorded on days 7, 10, 13, and 16 post chemotherapy as well as on day 28 to investigate potential adverse effects. They found a significant rise in the mean PC for every measurement after day 13.

It should be noted that the patients had various solid tumors (colon, breast, lung, soft tissue or bone sarcoma or carcinoma, and epithelial), and as such, were undergoing different treatment regiments, to include first-line treatments for ITP in the form of corticosteroid. The authors reported the following: n = 2.5 in the intervention group and n = 5 in the control group taking chlorambucil with prednisolone, as well as n = 0 and n = 5 undergoing CHOP (cyclophosphamide, hydroxyl-daunorubicin, oncovin, prednisone) treatment in the intervention and control groups, respectively. They reported that overall, CPLE was well tolerated with few side effects, which were of mild to moderate severity and were comparable with the control group. The authors conclude that CPLE is a feasible and affordable treatment for CIT [55].

Similar to Sundarmurthy et al., Hussain et al. set out to investigate whether CIT could be ameliorated through the administration of 290 mg CPLE BID in a similar patient population (various cancers undergoing various treatment regiments) in intervals of 5 days [56]. They randomly assigned 60 people to either a treatment (n = 30) or control group (n = 30), none of which were receiving treatment for CIT/ITP. They reported mean PCs increased from 101.93 ± 26.15 × 10³/µL to 173.75 ± 29.98 × 10³/µL (p = 1.37225 × 10⁻⁹) in their treatment group, while recording mean PCs of 99.36 ± 16.62 × 10³/µL to 101.75 ± 16.03 × 10³/µL (p = 0.11) in their control. They reported no adverse effects experienced by the treatment group [56].

In 2017 Babu et al. set out to investigate the efficacy of “ThromboBliss”, a CPLE + Tinospora cordifolia leaf extract, in the treatment of CIT. They constructed a double-blind randomized controlled trial (n = 250) wherein the treatment group received 5 mL of the ThromboBliss syrup (375 mg Carica papaya and 125 mg Tinospora cardifolia extracts) BID and the control group receiving a placebo for five days [57]. It should be noted that their inclusion criteria consisted of patients with mean PCs between 20–150 × 10³/µL. They monitored PC daily and reported a significant result between the experimental and control groups. On day 15, they reported median PCs of 160 × 10³/µL and 120 × 10³/µL, respectively. They reported no adverse effects [57].

Tiwari et al. conducted a similar study to Babu et al., where a 350 mg CPLE + 150 mg T. cardifolia extract concoction called “UPLAT” was administered to 40 patients with CIT and compared to a placebo-receiving control group (n = 20) in a randomized placebo control study [58]. They report administering the UPLAT BID for 10 consecutive days. PCs were recorded on day 1 as a baseline and on day 15 upon completion of the study. They reported end-of-study mean PCs of 93,990.00 ± 63,896.73/µL for the intervention group and 27,600.00 ± 29,758.42/µL for the control. They reported no adverse events in the treatment group [58].

Panda et al. administered 1100 mg C. papaya + 500 mg T. cordifolia extracts BID in an attempt to correct thrombocytopenia in three patients with decompensated alcoholic liver cirrhosis [59]. They reported these three liver transplant candidates presented with ascites, jaundice, and six months of thrombocytopenia. One patient had a history of hepatic encephalopathy, and a separate patient reported varicose bleeding. Remarkably, Panda et al. reported recovery of the PC of all three individuals, all falling WNL after 90 days. PCs were collected at baseline and every 15 days once treatment began for three months. Each of the patients demonstrate linear PC improvement, from baselines of 60, 33, and 38 × 10³/µL to 155, 180, 167 × 10³/µL, respectively (

Table 2. Ninety-day platelet count in three decompensated alcoholic liver cirrhosis patients from Panda et al. [59].

Patient	Day 0	Day 15	Day 30	Day 60	Day 90
Patient #1	60	90	117	128	155
Patient #2	33	56	72	92	180
Patient #3	38	52	82	98	167

All platelet count units are × 10³/µL.

) [59].

Table 2 shows platelet count improvements over 90 days in three alcoholic liver cirrhosis patients treated with Carica papaya leaf extract. Counts increased steadily from Day 0 (e.g., 60 × 10³/µL) to Day 90 (e.g., 155 × 10³/µL). The data suggest sustained platelet recovery with treatment in these patients.

Sreelatha and Jose, 2020 conducted a retrospective study from July–December 2018 using data obtained from the Amrita Institute of Medical Sciences, Kochi, Kerala [60]. At this institution, administration of 1100 mg CPLE TID is standard protocol in all CIT patients until platelet recovery or up to a maximum of two weeks. PCs were generally collected every other day beginning the third day after initiating treatment with CPLE. They identified 50 patients with various cancers and undergoing various treatments (temozolomide, paclitaxel, docetaxel, gemcitabine, doxorubicin, cyclophosphamide, rituximab, vincristine, 5-fluorouracil, cisplatin, carboplatin, oxaliplatin, and capecitabine), but all sharing a diagnosis of CIT. The results suggested that improvement in PC 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. A total of 12% of patients showed no improvement in PC after CPLE administration. They reported a mean PC post chemotherapy of 61,260/µL. After CPLE treatment, the mean PC was 149,320/µL (p < 0.01). From this, the authors conclude that CPLE is a legitimate treatment for CIT. It should be noted that this study excluded patients with diagnoses of primary thrombocytopenia, hematological malignancies, or ITP [60].

2.3. Limitations and Areas for Improvement

2.3.1. CPLE in Chemotherapy Induced Thrombocytopenia

Sreelatha and Jose conducted a retrospective study to assess the effects of CPLE in patients with CIT, but several significant limitations undermine the robustness of their findings [60]. The study design lacked randomization and a control group, making it impossible to separate the effects of CPLE from natural platelet recovery or the influence of other interventions. Additionally, the retrospective nature introduces selection bias as only patients with delayed platelet recovery received CPLE, while those who recovered spontaneously were excluded. This selection bias may overstate the efficacy of the intervention. The study’s cohort included 50 episodes of CIT in 45 patients with a median age of 56.5 years (range: 19–75) [60]. A diverse range of malignancies were represented, including glioblastoma multiforme (GBM), colorectal cancer, gastric cancer, and breast cancer. Among these, GBM patients showed disproportionately poor responses to CPLE. For example, four of the nine patients (18%) who took longer than a week to recover were undergoing treatment for GBM, with three specifically on temozolomide, a highly myelosuppressive drug. Moreover, of the six patients (12%) whose platelet counts worsened, a notable proportion had GBM, indicating disease-specific resistance to CPLE. Temozolomide induces severe myelosuppression through stem cell depletion and immune-mediated destruction, mechanisms that CPLE may not effectively counteract.

Chemotherapy heterogeneity further complicated the analysis [60]. Patients were treated with a wide array of regimens, such as cisplatin, docetaxel, gemcitabine, and paclitaxel, each with different thrombocytopenic profiles [60]. For instance, cisplatin often causes platelet suppression through direct bone marrow toxicity, while docetaxel-related thrombocytopenia is relatively mild and transient. The failure to stratify results by chemotherapy type limits the interpretability of the data, particularly when comparing outcomes across such varied mechanisms.

Statistically, while the mean platelet count improved significantly from 61,268/µL to 149,320/µL (p < 0.01), the lack of power in subgroup analyses makes conclusions for specific cancers like GBM unreliable. The study’s Wilcoxon signed-rank test revealed a weak correlation (R = 0.2189, p = 0.12) between pre- and post-treatment PCs, indicating variability in patient responses that undermines the generalizability of the findings [60]. Furthermore, adjuvant chemotherapy patients who received curative-intent treatment showed higher rates of thrombocytopenia compared to those on palliative therapy, likely due to more intense regimens. However, these baseline differences were not adequately adjusted for in the analysis.

2.3.2. Challenges in Evaluating CPLE Efficacy for Chronic ITP

Hampilos et al. explored CPLE’s role in chronic ITP through a case series of four patients. Due to the nature of case series, the individual cases lacked standardization in dosing. Patients received between 1000 mg/day and 3000 mg/day of CPLE, with treatment durations ranging from two weeks to several months with erratic and inconsistent dosing schedules. Such variability complicates the determination of an optimal dose or treatment duration. It should also be noted that these cases were patients with chronic ITP, and as such, may not represent the true efficiency of CPLE as a primary or adjunctive treatment of ITP. These patients were also receiving concurrent corticosteroid treatment, which confounds the true effectiveness of CPLE [49].

Babu et al. conducted a randomized trial on Thrombobliss (a combination of C. papaya and T. cordifolia), but their study was similarly limited in its applicability to CIT [57]. While the study included patients with microbial or chemotherapy-induced thrombocytopenia, it did not stratify results by cancer type. This omission is critical for understanding efficacy in heavily myelo-suppressed populations like GBM patients. For instance, GBM patients treated with temozolomide typically experience profound platelet depletion, necessitating more aggressive interventions [61]. Additionally, the short 5-day treatment window and 15-day follow-up leaves questions unanswered regarding the long-term efficacy and tolerance of CPLE in CIT patients [57].

The inclusion of heterogeneous malignancies and chemotherapy regimens introduces variability in thrombocytopenia severity and recovery dynamics. For example, gastric cancer patients undergoing intensive cisplatin-based therapy may have poorer marrow recovery compared to breast cancer patients on adjuvant regimens. Likewise, some of the CIT patients were undergoing treatment for their respective cancer that coincides with first-line therapy for ITP, namely, glucocorticoid steroids [49].

2.4. Euphorbia Hirta and Equisetum Hyemale

2.4.1. Mechanism of Action on Thrombocytopenia

Euphorbia hirta is a plant traditionally used in the Philippines to lessen and alleviate dengue-related bleeding symptoms [62]. Tayone et al. conducted an anti-dengue assay and plaque reduction neutralization test to investigate the anti-dengue activity of E. hirta. They found reduced plaque-forming capability when treated with E. hirta extracted with ethyl acetate and were able to identify six triterpenes and three flavonoid compounds [63]. This is suggestive that the E. hirta-mediated PC improvements in dengue patients are in part due to direct anti-dengue activity of the extract. In addition to its direct anti-dengue activity, E. hirta’s flavonoids have been demonstrated to be immunomodulators with anti-inflammatory and antioxidant action, mediating its effects through Nrf2 and NF-kB pathways [64].

Similar to E. hirta, Equisetum hyemale is reported to exhibit hemostatic effects by minimizing platelet aggregation and supporting overall clotting mechanisms through its antioxidant, nitrous oxide reducing, and anti-inflammatory properties [65,66]. This is attributed to the particular flavonoids, tannins, and polyphenols contained within the extract [65,66,67]. According to the following studies, these compounds promote pro-platelet formation during platelet maturation, stabilize mast cells, and thus are believed to enhance thrombopoiesis, while also mediating inflammatory reactions [68].

2.4.2. Current Research on Efficacy

Munazza Mir et al. evaluated the efficacy of E. hirta aqueous extract as a treatment for thrombocytopenia and flu-like symptoms in 125 dengue patients at Sir Ganga Ram Hospital, Lahore Pakistan [69]. Patients with a diagnosis of either dengue or dengue hemorrhagic fever, with PCs < 50 × 10³/µL were enrolled in the study. The patients were divided into two groups based on age: Group A—ages 30–55 (n = 54) and Group B—ages 14–25 (n = 71) [69]. The administration of E. hirta herbal water showed a significant increase in mean PC in Group A, from 29 ± 25 × 10³/µL to 41 ± 29 × 10³/µL 24 h after treatment was initiated (p < 0.05). In Group B, a cursory PC increase from 28 ± 1.5 × 10³/µL to 31 ± 23 × 10³/µL failed to reach statistical significance. In both Group A and B, changes in blood parameters were observed; total leukocyte count increased, and hematocrit levels decreased slightly. Over 70% of patients reported moderate recovery in platelet counts and improvement of flu-like symptoms.

The platelet-augmenting potential of E. hyemale and E. hirta in aspirin-induced thrombocytopenia was tested in Sprague-Dawley rats by Bangayan et al. [70]. Extracts were created by adding 4 g of the respective powdered plant to 250 mL of distilled water then reduced to 25 mL. They were then administered orally in single doses of either. PCs were collected at baseline, three days after administering aspirin, three days after initiation of treatment, and seven days after initiation of treatment. Treatment with 100% E. hirta (mean PC 301.4 to 842.4 × 10³/µL and 100% E. hyemale extract (mean PC 362.8 to 812 × 10³/µL) showed a similar increase as the steroid positive control (mean PC 400.8 to 839 × 10³/µL). Notably, a combination treatment of 50% E. hirta and 50% E. hyemale showed intermediate improvement (360.4 to 739.2 × 10³/µL). One-way ANOVA and Tukey’s Multiple Comparisons statistical analyses indicated significant differences (p < 0.01) between the treatments and the negative control (distilled water), but there were no significant differences between the extracts and the positive control [70].

2.4.3. Limitations and Areas for Improvement

Mir et al. did not describe the method used to create “herbal water of Tawa-tawa”, their E. hirta aqueous extract, nor did they include the doses administered to the patients. The authors did not mention—and for this review will be assumed—controlling for comorbidities or confounding by other medications taken by patients in the test groups. The study lacks both a control group and randomization, which precludes definitive attribution of the observed platelet recovery to E. hirta over the spontaneous recovery [69]. Furthermore, the observation period was limited to only 24 h, failing to capture long-term effects or sustainability of E. hirta-mediated platelet recovery.

The study by Bangayan et al. was limited to an 11-day observation period, which leaves questions about the long-term efficacy of the extracts [70]. While the study demonstrated significant improvements in platelet counts, future studies could aim to elucidate and explore dose–response relationships or variations in treatment effectiveness over time. Additionally, the use of an aspirin-induced thrombocytopenia model in rats may not fully replicate the complex etiology of thrombocytopenia in human conditions such as dengue and ITP.

While Euphorbia hirta and Equisetum hyemale show potential in augmenting PCs and alleviating thrombocytopenia in both clinical and experimental settings, their therapeutic claims in humans are undermined by significant methodological and statistical limitations. The absence of control groups, small sample sizes, short observation periods, and lack of mechanistic validation restrict the reliability of findings. Future research should focus on randomized controlled trials with larger cohorts, extended follow-up periods, dose–response analyses, and molecular investigations to substantiate the efficacy and safety of these plant extracts.

2.5. Ipomoea batatas (L.) Lam (Sweet Potato)

2.5.1. Mechanism of Action on Thrombocytopenia

Figure 1 shows that the activation of JAK/STAT and NF-κB signaling pathways by flavonoids, such as quercetin and rutin.

Figure 1. General schematic of phytochemical’s anti-inflammatory activities in cytokine signaling, NF-kB and JAK-STAT pathway [71,72].

Figure 1. General schematic of phytochemical’s anti-inflammatory activities in cytokine signaling, NF-kB and JAK-STAT pathway [71,72].

The platelet-raising effects of sweet potato (Ipomoea batatas) leaf extract are attributed to its rich biochemical composition, which includes flavonoids, tannins, alkaloids, glycosides, saponins, and essential micronutrients such as iron, zinc, copper, manganese, folate, and vitamin B12 [73]. These compounds, particularly rich in purple-colored sweet potato, are believed to collectively enhance thrombopoiesis and stabilize platelets through direct and indirect mechanisms [72,73].

Flavonoids such as quercetin and rutin stimulate thrombopoiesis by modulating the transcriptional activity of GATA-1, a transcription factor essential for megakaryocyte lineage commitment [74]. These compounds also activate the JAK/STAT and NF-kB signaling pathways (Figure 1), which are critical for megakaryocyte proliferation, maturation, and differentiation into platelets [65,74]. Glycosides and saponins further amplify this process by promoting the release of hematopoietic growth factors such as thrombopoietin (TPO), which regulates platelet production in the bone marrow [75,76]. Additionally, the leaves’ high levels of folate and vitamin B12 support DNA synthesis in rapidly dividing hematopoietic cells, ensuring efficient cell proliferation and maturation [75,76].

The antioxidant properties of tannins and flavonoids play a critical role in reducing oxidative stress, which can damage megakaryocytes and platelets. By neutralizing reactive oxygen species (ROS), these compounds protect megakaryocytes from apoptosis and extend the lifespan of circulating platelets [77,78,79,80]. This effect preserves platelet integrity and supports the bone marrow microenvironment, optimizing conditions for thrombopoiesis [77,78,79,80]. Moreover, tannins enhance vascular integrity by promoting collagen synthesis, which strengthens blood vessel walls and reduces capillary fragility [81]. This could minimize platelet loss due to vascular leakage, particularly in conditions such as dengue-associated thrombocytopenia.

Sweet potato leaves also exhibit immunomodulatory effects that contribute to platelet preservation [82]. The bioactive compounds in the extract suppress pro-inflammatory cytokines such as TNF-α and IL-6, which are implicated in immune-mediated platelet destruction, as seen in ITP [8]. By attenuating inflammation, the extract reduces the rate of platelet clearance, enhancing overall PC. Furthermore, micronutrients like iron, zinc, and copper act as cofactors in enzymatic processes essential for hematopoiesis, further supporting the production and stability of blood cells [82]. Together, these multifaceted actions make sweet potato leaf extract a promising natural remedy for thrombocytopenia.

2.5.2. Current Research on Efficacy

Several studies have found evidence of the platelet-raising effects of sweet potato leaf extract. Hasan et al. conducted a dose–response study, administering aqueous I. batatas extract at doses of 100, 300, and 500 mg/kg body weight (BW) to rats over 14 days [83]. A dose-dependent increase in PC was observed: Group C (300 mg/kg BW) reached statistical significance (p < 0.05), and Group D (500 mg/kg BW) showed a highly significant rise from 225 ± 93 × 10³/µL to 760 ± 113 × 10³/µL (p < 0.01). Koffuor et al. investigated the hematologic effects of Ipomoea involucrata ethanolic extract in comparison to a negative control (saline) and a positive control (Feroglobin: Vitabiotics Ltd., London, UK; liquid tonic containing iron 0.2%, zinc 0.06%, copper 0.02%, manganese 0.025%, and vitamin B-Complex 0.039% in a blend of honey and malt) in New Zealand White Rabbits (n = 30). They administered 300 and 1000 mg/kg doses daily for 40 days; both doses increased platelets in a strongly significant manner (p < 0.01) after 20 days of treatment. The treatment groups were also comparable to their positive control [76]. Osime et al. demonstrated similar findings in a dose–response study in New Zealand White Rabbits. They reported a statistically significant increase in mean PC between their experimental and control groups, increasing from 156 × 10³/µL to 350 × 10³/µL after six weeks of extract administration (1–5 mL daily) [84]. These studies collectively suggest that sweet potato leaf extract enhances thrombopoiesis and platelet production, particularly at higher doses.

2.5.3. Limitations and Areas for Improvement

Despite promising findings, the studies have limitations, including small sample sizes (n = 8 for both Hasan et al. and Osime et al.) and a lack of human clinical trials, and none of the studies were conducted under conditions of thrombocytopenia. While the platelet-raising effects are dose-dependent, the mechanisms of action remain partially understood. Future research should include detailed biochemical and molecular investigations to identify specific pathways and active compounds responsible for thrombopoietic activity. Larger randomized controlled trials in both animals and humans are needed to validate efficacy and safety. Additionally, standardization of extract preparation and dosing protocols is essential to ensure consistency and reproducibility. The nutritional and phytochemical composition of sweet potato leaves highlights their potential as a cost-effective remedy for thrombocytopenia, but clinical trials comparing their efficacy to established treatments like TPO mimetics are necessary for broader therapeutic applications.

2.6. Alternanthera sessilis

2.6.1. Mechanism of Action on Thrombocytopenia

The platelet-raising potential of Alternanthera sessilis extract is attributed to its rich phytochemical composition, including oleanolic acid, saponins, tannins, flavonoids, and β-sitosterol [85,86,87]. These compounds collectively act on hematopoietic progenitor cells in the bone marrow to enhance thrombopoiesis. Oleanolic acid and saponins are known to stimulate TPO production, a cytokine critical for megakaryocyte proliferation and differentiation, thereby increasing platelet production [88]. Tannins and flavonoids exhibit strong antioxidant properties, reducing oxidative stress in megakaryocytes and preventing their apoptosis, which helps maintain a healthy bone marrow environment [89,90]. These compounds may also stabilize platelet membranes, mitigating premature destruction in circulation [91,92].

β-Sitosterol, a phytosterol, is thought to suppress pro-inflammatory cytokines such as TNF-α and IL-6, implicated in autoimmune platelet destruction, contributing factors in conditions like ITP [93,94]. Additionally, the anti-inflammatory properties of A. sessilis may contribute to reducing immune-mediated platelet destruction viral infections [95,96]. While these proposed mechanisms provide a theoretical basis for the hematologic effects of A. sessilis, direct evidence validating these pathways remains sparse, necessitating further molecular and biochemical studies.

2.6.2. Trials and Evidence of Efficacy

Nayana et al. investigated the hematopoietic ability of A. sessilis in albino rats with cyclophosphamide-induced thrombocytopenia. They administered aqueous extracts at doses of 200 mg/kg (n = 6) and 400 mg/kg (n = 6) for 15 days and compared a saline receiving control [97]. Both treatment groups demonstrated significant increases in PCs compared to controls by day 4 (p < 0.05), and highly significant (p < 0.001) by day 11.

Similarly, Arollado et al. evaluated A. sessilis in Sprague-Dawley rats with anagrelide-induced thrombocytopenia [86]. Treatment with the plant extract led to a 93.18% increase in platelet counts (p = 0.0001). While this effect was significant, it was lower than that observed for other plants, such as C. papaya (125.87%) and Ipomoea batatas (green: 107.88%; violet: 106.07%). These results suggest that while A. sessilis exhibits hematologic properties, its efficacy may be slightly inferior to some alternative plant-based treatments. Both studies indicate that A. sessilis could potentially stabilize platelet membranes and enhance thrombopoiesis; however, the lack of corroborative studies in larger animal models or humans limits the clinical relevance of these findings.

2.6.3. Weaknesses, Questionable Validity, and Areas for Improvement

The absence of a dose-dependent effect in the Nayana et al. study raises questions about the biological plausibility of the observed platelet augmentation [97]. This lack of dose-responsiveness suggests either confounding factors or a plateau effect in the plant’s activity that requires further investigation.

Mechanistic validation is another critical shortcoming. While hypotheses regarding TPO stimulation, antioxidant activity, and membrane stabilization are proposed, these remain speculative without direct biochemical or molecular evidence. The reliance on animal models without human trials is a significant limitation. Differences in pharmacokinetics, pharmacodynamics, and potential adverse effects between species highlight the need for clinical studies to establish safety and efficacy in humans. Additionally, long-term safety data are lacking, which is particularly relevant for plant-based therapies given their potential for variable bioactive component concentrations.

To enhance the credibility and applicability of these findings, future research must address these limitations. Larger sample sizes and well-designed dose–response studies are essential to determine optimal therapeutic dosages. Mechanistic studies should elucidate the molecular pathways involved in platelet augmentation, providing a clearer understanding of how A. sessilis affects thrombopoiesis. Incorporating advanced imaging and molecular tagging techniques could further clarify the interaction of active compounds with biological targets. Randomized controlled trials in humans with thrombocytopenic conditions would provide the necessary evidence to translate preclinical findings into clinical practice. Until such data are available, the therapeutic potential of A. sessilis remains speculative, requiring rigorous validation. Moreover, comparative effectiveness studies against standard therapies would position A. sessilis within the current therapeutic landscape, informing clinical decisions and potential adoption.

2.7. Momordica charantia L. (Bitter Melon)

2.7.1. Mechanism of Action on Thrombocytopenia

The antithrombocytopenic effects of Momordica charantia L. (bitter melon) may be due to its bioactive metabolites’ antioxidant, anti-inflammatory, and hematinic properties [98,99,100]. According to several studies, phytochemicals such as momorcharin, charartine, and cucurbitanes have been isolated from M. Charantia, and these phenolics and flavonoids are known to have antioxidant properties [101,102,103,104,105]. These may prevent apoptosis, promote platelet production, and stabilize platelet membranes, reducing premature destruction [106].

2.7.2. Trials and Evidence of Efficacy

In the same study conducted by Arollano et al. on anagrelide-induced thrombocytopenia in Sprague-Dawley Rats, M. charantia extract failed to show significant platelet-increasing activity (p = 0.1014) [86]. In a study exploring the antithrombocytopenic activity of M. charantia, Ahamad et al. used a busulfan-induced thrombocytopenic rat model to assess the efficacy of hydroalcoholic extract (mother extract) and its fractions (DCM, hexane, n-butanol, and aqueous) [107]. The DCM fraction demonstrated the most significant effect, increasing platelet counts from 2800/µL in the toxic control to near-normal levels of 9200/µL over 20 days (p < 0.05). The mother extract also improved platelet counts but to a slightly lesser extent.

Hematological parameters such as hemoglobin levels, total leukocyte count (TLC), and packed cell volume (PCV) also improved. For instance, hemoglobin levels, which dropped to 9.7 g/dL in the toxic control group, were restored to 15.9 g/dL with DCM fraction treatment. Similarly, leukocyte counts, significantly reduced in the toxic group, recovered substantially in the treated rats.

A study by Ume Kalsoom Dar et al. evaluated the effects of Momordica charantia crude extract on platelet counts in rabbits [5]. A significant increase in platelet levels at a low dose (10 mg) was found, with counts rising to 827 × 10⁹/µL from a baseline of 357 × 10⁹/µL in 90 days. The crude extract also stabilized electrolyte levels and increased hemoglobin levels. These results show the potential of M. charantia in treating thrombocytopenia, warranting further investigation to identify its exact mechanism of action.

In another study by Zhang et al., the effects of M. charantia exosomes (MCEs) were examined on platelet function [108]. Platelets isolated from healthy human volunteers were treated with MCEs at concentrations of 0.1, 40, and 200 μg/mL. At 200 μg/mL, MCEs significantly inhibited platelet activation markers, reducing PAC-1 expression to 40.64% and CD62P to 44.39%, compared to ADP-treated controls (76.28% and 71%, respectively, p < 0.001). MCEs also showed a dose-dependent reduction in platelet adhesion, with inhibition rates of up to 36.67% at higher concentrations.

In vivo efficacy was demonstrated using a middle cerebral artery occlusion (MCAO) rat model, where MCEs reduced platelet aggregation and thrombus formation. At 200 μg/kg, platelet aggregation rates decreased by 31.46%, and maximum thrombus agglutination intensity dropped by 19.81% (p < 0.01). Additionally, MCEs significantly inhibited platelet-mediated migration of HCT116 tumor cells, reducing migration rates by 84.52% at 200 μg/mL (p < 0.01), highlighting their potential role in mitigating tumor metastasis.

Together, these studies demonstrate the dual benefits of M. charantia and its derivatives in enhancing platelet counts and modulating platelet function, offering promise for managing thrombocytopenia and related thrombotic conditions.

2.7.3. Limitations

As mentioned above, M. charantia extract failed to improve PC in a statistically significant fashion in anagrelide-induced thrombocytopenia. Further investigation into the relationship between M. charantia and drug-induced thrombocytopenia could help elucidate the extracts MOA regarding hematopoiesis and paint a picture of when its application as a treatment of thrombocytopenia is appropriate. The studies on M. charantia extracts and exosomes demonstrate promising antithrombocytopenic and antiplatelet effects but suffer from critical limitations, primarily due to small sample sizes, which undermine statistical robustness. Ahamad et al. used only six rats per group to assess the efficacy of different fractions of M. charantia extract [107]. This limited number lacks the statistical power needed to detect significant differences, increasing the risk of Type I and Type II errors. Biological variability in response to herbal interventions further compounds the problem, limiting the generalizability of the findings.

Similarly, Zhang et al.’s study on M. charantia exosomes tested platelet activity using blood from only five healthy donors, failing to account for interindividual variability in platelet function due to factors such as age, sex, or health status [108]. The MCAO rat model employed in the same study included just seven rats per treatment group, restricting the ability to identify dose-dependent effects or variability within treatment responses.

Another major gap is the absence of dose–response analyses in either study [108]. Although various concentrations of M. charantia fractions and exosomes were tested, the lack of systematic exploration of dose–response relationships prevents the determination of optimal therapeutic doses or the identification of potential toxic thresholds.

Mechanistically, both studies rely on hypotheses such as reduced PAC-1 and CD62P expression, cytokine modulation, and oxidative stress reduction to explain observed effects [108]. However, no direct measurements of these pathways, such as cytokine profiles or thrombopoietin levels, were conducted. This lack of molecular evidence limits the biological plausibility of the proposed mechanisms.

Additionally, neither study benchmarks M. charantia derivatives against standard treatments like thrombopoietin receptor agonists or antiplatelet drugs (e.g., aspirin or clopidogrel). Without such comparisons, it is unclear whether M. charantia offers advantages in efficacy, safety, or reduced side effects. To truly assess the clinical relevance of these findings, future research should aim to incorporate larger, more diverse study populations and include direct comparative trials with established therapies. These steps are critical to validate the use of M. charantia in clinical settings and to fully understand its therapeutic potential and limitations.

3. Conclusions

Table 3. Overview of human and animal studies on herbal extracts for thrombocytopenia by country.

Herbal Extract	Study/Reference	Trial Type	Sample Size	Key Findings	Country
Carica papaya L.	Hamplios et al. [49]	Case series (Chronic ITP)	4 patients	Significant platelet increase in steroid-refractory ITP patients	USA
-	Sundarmurthy et al. [55]	Randomized controlled trial (CIT)	40 patients	Significant platelet increase post-chemo in intervention group	India
-	Hussain et al. [56]	Randomized controlled trial (CIT)	60 patients	Significant platelet increase; no adverse effects reported	Pakistan
-	Babu et al. [57]	RCT (ThromboBliss, CPLE + T. cordifolia)	250 patients	Significant platelet recovery; improved outcomes	India
-	Tiwari et al. [58]	RCT (UPLAT, CPLE + T. cordifolia)	40 patients	Significant platelet increase in intervention group	India
-	Panda et al. [59]	Case series (Liver cirrhosis)	3 patients	Sustained platelet recovery over 90 days	India
-	Sreelatha and Jose [60]	Retrospective study (CIT)	50 patients	Platelet improvement in 88% of patients	India
-	Kumar et al. [53]	In vivo (Hydroxyurea-induced)	Albino rats	Significant platelet recovery post treatment	India
Euphorbia hirta L.	Mir et al. [69]	Clinical study (Dengue)	125 patients	Platelet increase and improvement in flu-like symptoms	Pakistan
-	Bangayan et al. [70]	In vivo (Aspirin-induced thrombocytopenia)	Sprague-Dawley rats	Significant platelet increase comparable to steroids	Philippines
Equisetum hyemale L.	Bangayan et al. [70]	In vivo (Aspirin-induced thrombocytopenia)	Sprague-Dawley rats	Significant platelet recovery similar to Euphorbia hirta	Philippines
Ipomoea batatas (L.) Lam	Hasan et al. [83]	In vivo (Dose–response)	Rats	Dose-dependent significant platelet increase	Bangladesh
-	Koffuor et al. [76]	In vivo (Hematopoiesis study)	Rabbits	Significant platelet increase comparable to positive control	Ghana
-	Osime et al. [84]	In vivo (Dose–response)	Rabbits	Significant platelet increase at higher doses	Nigeria
Alternanthera sessilis (L.)	Nayana et al. [97]	In vivo (Cyclophosphamide-induced)	Albino rats	Significant platelet increase by day 11	India
-	Arollado et al. [86]	In vivo (Anagrelide-induced)	Sprague-Dawley rats	Platelet increase observed but lower than Carica papaya	Philippines
Momordica charantia L.	Dar et al. [5]	In vivo (Rabbit study)	Rabbits	Significant platelet increase at low doses	Pakistan
-	Ahmad et al. [107]	In vivo (Busulfan-induced thrombocytopenia)	Rats	DCM fraction significantly restored platelet count	India
-	Zhang et al. [108]	In vitro/In vivo (Platelet function)	Platelets/Rats	Reduced platelet activation and thrombus formation	China

provides a comprehensive overview of both human and animal studies on herbal extracts for thrombocytopenia, highlighting the study type, platelet recovery outcomes, and the countries where the research was conducted, including India, the Philippines, Pakistan, Ghana, and China.

Herbal extracts such as Carica papaya, Euphorbia hirta, Equisetum hyemale, Ipomoea batatas, A. sessilis, and Momordica charantia L. (see Table 3) have shown promising potential in managing thrombocytopenia by enhancing thrombopoiesis, reducing oxidative stress, and stabilizing platelets. Their ability to increase platelet counts in conditions like chemotherapy-induced thrombocytopenia and dengue were suggested through multiple preclinical studies and limited clinical trials. Despite its limited trials, a natural and potentially cost-effective alternative offered by the herbal extracts to conventional treatments may sound beneficial. However, the therapeutic promise and cost effectiveness of these extracts is undermined by significant limitations in the available evidence, including small sample sizes, lack of randomization, and short observation periods. Most importantly, direct mechanistic validation is lacking, such as cytokine profiling or assessments of thrombopoietin activity, and limits the understanding of their biological pathways and efficacy. Furthermore, clinical relevance of the findings via trials are weak due to variability in treatment responses, lack of standardized dosing, and insufficient comparisons with established therapies. Despite these gaps, the potential cost savings, lower risk of severe side effects, and broader accessibility make these herbal extracts an attractive area for further research. Rigorous randomized controlled trials with larger cohorts, longer follow-up periods, and clear dose–response studies are essential to confirm their efficacy and establish their role in managing thrombocytopenia in clinical practice.