Efficacy and Safety of Tranexamic Acid (TXA) Used in Reduction of Pathological Blood Flow Present in Eye Disease and Eye Surgery

Abstract

Tranexamic acid (TXA) is an antifibrinolytic commonly used for hemostasis. TXA has been used extensively in medicine, although minimal reviews exist that assess its efficacy and safety in ophthalmologic use. The objective of this systematic review is therefore to effectively summarize the use of TXA within the context of ophthalmology. A literature review was conducted using electronic databases: PubMed Central, Google Scholar, and the University of Manitoba Library Database. Studies were collected through preset participant criteria and outcome measures. Comparisons were made based on derived similarity in goals and methods between studies. Twenty-seven studies in total were identified and used. A majority of studies with traumatic hyphema patients indicate a significant reduction of secondary hemorrhage rates (among the traumatic hyphema cohort studies, a range of 0 to 1.9% compared to 7.1 to 9.6% in control groups). TXA has been shown to significantly reduce central macular thickness in macular edema associated with retinal vein occlusion (8.3% reduction) but not in diabetic macular edema. However, no significant reduction of bleeding was demonstrated in post-vitrectomy patients nor during oculoplastic surgeries. In regards to ocular adverse effects, chromatopsia, central retinal vein occlusion, branch retinal artery occlusion, and ligneous conjunctivitis have been reported. TXA should be used with caution in patients with certain underlying conditions.

1. Introduction

Tranexamic acid (TXA) is an antifibrinolytic agent which has been used in medicine for bleeding control¹. TXA inhibits plasmin production, thereby maintaining blood clots and reducing bleeds¹. TXA was initially developed and released in 1962 to successfully treat heavy menstrual bleeding and its ability to effectively reduce bleeding has been further established in diverse cases, including various surgeries, parturition, hereditary bleeding disorders, and nosebleeds to name a few¹. TXA is found to be 6 to 10 times more potent than its other common antifibrinolytic, epsilon-aminocaproic acid (EACA)², and patients are less likely to experience the common side effects including nausea and diarrhea².

A literature search indicates a fair amount of research on the use of TXA and its effects in medicine, although minimal reviews exist that thoroughly assess its efficacy and safety in ophthalmologic use—only its use for traumatic hyphema has extensively been covered^3–7. The aim of this review is to report and interpret its historical use in current literature, while further directing its use towards a safer and more accurate use of TXA in ophthalmology. Thus, this review will effectively summarize the use of TXA within the context of ophthalmology firstly, by assessing its efficacy in ocular surgeries as well as treating ocular diseases involving pathological blood flow. Secondly, this review will aim to determine any ocular adverse effects to be cautious of from general TXA use.

Areas where TXA has been used in ophthalmology included traumatic hyphema, macular edema (ME), post-vitrectomy hemorrhage, and hemorrhage during and after oculoplastic surgery. It is also worth mentioning that Remifentanil and hydralazine—a synthetic opioid and a direct vasodilator, respectively—are drugs used for induced hypotension⁸ to reduce intraoperative blood loss and are considered safe but also more effective than TXA in this setting⁸. Bleeding control in these eye diseases and surgeries is necessary for the following reasons: Secondary hemorrhage in traumatic hyphema is generally associated with more serious complications than its first hemorrhage⁷. Macular edema is associated with progressive, irreversible loss of vision as it worsens and various invasive treatment modalities come with their own complication risks as well⁹. Overall, for eye diseases, pathological fluid flow should be kept within physiological conditions to prevent vision loss. Reduction of intraoperative blood loss is also desirable to reduce surgery time as well as the use of electrical cautery which can lead to scarring¹⁰.

In regards to ocular adverse effects, responses that may lead to serious damages to the eye were considered important. Left untreated, these particular eye diseases or adverse effects can lead to further damage, potentially degrading vision and eventually leading to blindness.

2. Materials and Methods

Search Strategy

A total of 23 primary studies (7 case studies, 11 cohort studies, and 5 RCTs) and 2 reviews were collected along with 2 follow-up articles obtained for supplementary information and 7 were excluded. Seven articles were requested for access by electronic delivery and the rest were able to be accessed online. Three search engines were used: PubMed Central (1980.1–2023.6), Google Scholar (1980.1–2023.6), and the University of Manitoba Library Database (1980.1–2023.6).

The structured search strategy used the following terms: “Tranexamic acid”, “tranexamic acid and ophthalmology”, “tranexamic acid and eye disease”, “tranexamic acid and ocular”, tranexamic acid and traumatic hyphema or hyphema”, “tranexamic acid and macular edema”, “tranexamic and and retinopathy”, and “tranexamic acid and oculoplastics”. For PubMed searches, MESH terms combined with Boolean operation “OR” and “AND” were used accordingly for tranexamic acid, ophthalmology, traumatic hyphema, macular edema, and retinopathy.

Figure 1. (A) PubMed Central literature searches (1980.1-2023.6). Studies (mainly primary studies) were collected based on review criteria. (B) Google Scholar literature searches (1980.1-2023.6). Studies (mainly primary studies) were collected based on review criteria. (C) Figure 3. University of Manitoba Library Database (access to both physical and digital content) literature searches (1980.1-2023.6). Studies (mainly primary studies) were collected based on review criteria.

Full text, peer-reviewed studies dating from January 1980 - June 2023 that were conducted in any geographical location, published in the English language or translated into English were included. Studies from journals that require subscription have been included—free access to these journals was possible through the University of Manitoba libraries.

Participants

Inclusion criteria are as follows: (i) human patients of all ages, sex/genders, and race; and (ii) undergoing or have undergone ophthalmologic TXA treatment for an eye disease or surgery (including oculoplastic surgery) or patients experiencing ocular adverse effects from the general use of TXA.

Exclusion criteria are as follows: (i) animal subjects; and (ii) patients undergoing or have undergone non-ocular TXA treatment or patients experiencing non-ocular adverse effects from TXA use.

Outcome measures

This review considered studies which used TXA systemically or topically to treat eye diseases and studies that investigated ocular adverse effects associated with general TXA use. The efficacy of TXA use was determined based on a statistically significant reduction of secondary hemorrhage (SH) for hyphemas, reduction of hemorrhage for diabetic post-vitrectomy, reduction of the central macular thickness (CMT) for ME, and reduction of surgical blood loss and SH for oculoplastics.

For ocular adverse effects, occurrences that may lead to serious damage to the eye or vision were considered important. This included chromatopsia, retinal vein and artery occlusions, and ligneous conjunctivitis.

Data extraction

Studies that met inclusion and exclusion criteria were gathered for full review, data collection, and critical appraisal. The following categories were used to extract data from collected articles: Author and publication year, type of study, study location, number of participants, age group and sex/gender, administration method: Oral/systemic or topical and dosage of TXA, frequency, administered length of time, the type of eye disease or surgery, study outcomes: Adverse effects and/or significant improvements of disease or surgery, and whether the study was peer-reviewed or not.

Age groups were defined as the following: Children = 1 to 12; Adolescents = 13 to 17; Adults = 18 to 64; Older Adults = 65+.

Articles were divided into their study designs for controlled examinations along with further extraction as in the following: Main focus, i.e. efficacy (and purpose of use) or ocular adverse effect, reported patients’ conditions prior, duration of study, and outcomes in detail.

Data extraction was performed using Google Sheets.

Data Analysis

The efficacy of TXA in eye disease and surgery was examined by dividing the topic further into individual eye diseases and surgeries. GraphPad PRISM was used to generate graphs (grouped graph¹¹; column graph¹²; statistical significance denoted by an asterisk symbol “*”).

Study comparisons

Comparisons were made among similar studies indicated in Table 1 and 2. to obtain congruent findings or rule out factors that may be associated with differing results. Whether studies were chosen to be grouped depended on the similarity in their goals and methodology.

The results of the data analysis will follow.

3. Results

3.1. Efficacy in eye disease and surgery 

Traumatic Hyphema / Hyphema        

An RCT conducted by Rahmani et al.¹³ indicates TXA to be a favorable agent in reducing SH while adjusting for other risk factors including the presence of optic nerve/retinal damage and pre-existing low vision. Patients in this trial were children and adolescents. Notably, results indicate that patients with low vision or elevated intraocular pressure (IOP) on admission have a greater chance of SH. Age, sex, and hyphema level differences were not significant between study groups.

Seven cohort studies^14–20 assessed TXA use in preventing SH among traumatic hyphema patients. The extractions are shown on Table 1. The older cohort studies (late 1900’s, except for Albiani et al.¹⁴) were most comparable to each other as they used the same route of drug administration, the same dosage of TXA, similar statistical analysis techniques, and largely inpatients receiving similar care. Apart from Vangsted & Nielsen’s study¹⁹, where neither the control nor the treatment group experienced SH at all, all other studies indicated overall that TXA significantly reduces SH rates (a range of 0 to 1.9% compared to 7.1 to 9.6% in control groups) and thus, is recommended as a treatment agent for traumatic hyphema among all age groups. Interestingly, Albiani’s study group indicates that the amount of microhyphema (grade 0; no visible blood inside the eye) cases in the TXA group were significantly higher than in the non-TXA group (p < 0.001). Clarke & Noël¹⁵ also investigated microscopic hyphema and found a significant reduction of SH with administration of TXA. However, ocular injuries associated with traumatic hyphema were more prevalent in this group when compared to other older studies that mainly assess higher grades of traumatic hyphema.

Table 1. Systematic extractions for comparison of 7 cohort studies examining TXA use in traumatic hyphema patients.

Abbreviations: TH, traumatic hyphema; S, significant; NS, not significant; Grp, group.

In one case study²¹,TXA was administered along with an antiviral and prednisolone to prevent SH after a total hyphema secondary to herpes zoster ophthalmicus. The hyphema was not resolved and surgery was performed, which cleared all residual blood clots. Continued drug administration without TXA led to improvements and the patient’s condition resolved thereafter.

Traumatic hyphema: Topical vs systemic administration

TXA can be administered orally or applied topically as eye drops. In the treatment of hyphema patients, Hosseini et al.²² demonstrated that topical administration is safe, tolerable by patients, and achieves effective therapeutic intraocular concentrations. Hosseini referenced Åstedt²³ to establish the sufficient concentration of TXA for acceptable inhibition of fibrinolysis as a minimum of 0.8 to 1 μg/mL in the aqueous humor. A single drop of topical 5% TXA reached higher than 1.5 μg/mL up to 160 minutes and decreased to an average of 1 μg/mL at 300 minutes and maintained for 9 hours. Compared to 5% TXA, using 10% TXA achieved up to an 82% increase in concentration. Demographics were not corrected for. None of the patients demonstrated ocular or systemic side effects from topical administration.

Hosseini ran another cohort study¹² to compare topical 5% TXA efficacy compared to oral administration in traumatic hyphema patients. While both orally and topically treated groups resulted in a statistically significant reduction of SH compared to the placebo group, the SH reduction rate between the oral and topical TXA groups was insignificant. There was no significant difference in age and sex/gender between the placebo and topical TXA groups. Between the oral and topical TXA groups, there was a significant difference in age, but no difference in sex/gender.

Figure 4. (A) SH rate comparison between the administration of topical TXA and oral placebo. Graph was generated using GraphPad PRISM with data obtained from Hosseini et al., 2014. (B) SH rate comparison between the administration of oral TXA (this group was historically used in Hosseini et al., 2009; hence abbreviated as “His ctrl”) and oral placebo. The asterisk symbol “*” denotes statistical significance.

Macular edema (ME)

One prospective cohort study¹¹ examined TXA given orally to patients with ME to examine its efficacy in decreasing central macular thickness (CMT)—an indicator of ME. Patients with ME in retinal vein occlusion (RVO) cases and diabetic ME (DME) cases were examined separately. Age, sex/gender, duration and type of ME were reported, but not statistically corrected for.

TXA was administered only for the first 2 weeks of the 6-week study period. Significant decreases in CMT were observed in the RVO group between baseline and 2 week measurements (8.3% reduction), but not 6 week measurements. DME cases did not show significant decreases between baseline and 2 week and 6 week measurements. It was concluded that TXA is effective in treating ME in RVO cases and continuing its use beyond the 2 weeks should prolong its effect. 

Figure 5. Mean CMT measurements of RVO and DME patients through the course of Takeyama et al.’s study¹¹. TXA was administered only for the first 2 weeks. The asterisk symbol “*” denotes statistical significance. The graph was generated using GraphPad PRISM with data obtained from Takeyama et al., 2018.

Diabetic Post-vitrectomy hemorrhage

Two RCTs^24,25 were conducted to determine TXA’s efficacy in preventing diabetic post-vitrectomy hemorrhage. Both studies controlled for their patients and methods and these factors were extracted into Table 3. Results were interpreted using the factors discussed.

Table 2. Systematic extractions for the comparison of two RCTs by Laatikainen et al.¹³ and Ramezani et al.¹², examining TXA use in patients for reducing post-vitrectomy hemorrhage.

Abbreviations: S, significant; NS, not significant

Both studies had similar routes of administration and statistical analysis techniques, but differing doses. Overall, neither showed significant differences in hemorrhage rates compared to control groups.

Oculoplastics

Intraoperative hemorrhage:

A cohort study²⁶ examined the reduction of intraoperative bleeding with preoperative TXA administration (subcutaneous injection) in patients with dermatochalasis undergoing upper eyelid blepharoplasty. The difference in intraoperative blood loss and the total time of cautery use between the TXA group and the placebo group was not statistically significant (p=0.602 and p=0.360, respectively).

An RCT²⁷ examined the surgical use of TXA in external dacryocystorhinostomy in patients with nasolacrimal duct obstruction. One dose of 1 g of TXA was administered intravenously 30 minutes prior to surgery to examine its effect in reducing intraoperative blood loss and whether nasal packing would be required postoperatively. Compared to the placebo group, the differences were insignificant (p=0.984 and p=0.471, respectively).

Another RCT⁸ examined the reduction of intraoperative bleeding with the surgical use of intravenous TXA (10 mg/kg; maximum dose of 1000 mg) in comparison to intravenous Remifentanil (0.1µ/kg), and Hydralazine (0.1 mg/kg) with patients diagnosed with chronic dacryocystitis undergoing dacryocystorhinostomy. All patients were operated in similar conditions. Results indicate that the mean blood loss volume with Remifentanil and Hydralazine was significantly lower than with TXA (p<0.05). Therefore, Remifentanil and Hydralazine were more effective than TXA in reducing bleeding. Age and sex/gender were not significant across study groups.

3.2. Ocular adverse effects

Retinal artery/vein occlusions

Wijetilleka, et al.²⁸ observed a two-day vision loss of a 30-year-old female who had developed central retinal artery occlusion and a relative afferent pupillary defect. The affected eye was not resolved after the discontinuation of TXA and remained permanently blind. On the other hand, Parsons, et al²⁹ showed that a 57-year-old developed a branch artery occlusion reported no issues following the discontinuation of TXA.

Al Shaharani & Al Ghamdi³⁰ observed a case of a central retinal vein occlusion in a 46-year-old female with a history of blurred vision along with flashes of light. The affected eye completely resolved after discontinuation of TXA and treatment with intravitreal ranibizumab. Kiser et al.³¹ also observed chromatopsia in a 7-year-old girl, suspecting a potential link to a central retinal vein occlusion, and the discontinuation of TXA resolved the issue as well.

Ligneous conjunctivitis

Song et al.³² observed a four-day severe eye pain in a 70-year-old female due to ligneous conjunctivitis. The pseudomembranes (characteristic of ligneous conjunctivitis) completely regressed after 6 weeks following the discontinuation of TXA with no recurrences after 30 weeks.

Diamond et al.³³ also observed a case of ligneous conjunctivitis in a 25-year-old female with a nine-month history of ocular irritation and sticky discharge. She received two separate bouts of TXA treatment, each resulting in ligneous conjunctivitis. Both discontinuations of TXA resolved the condition.

Overall interpretations of results and potential reasons for incongruent and inconclusive data will be noted in the discussion below. 

4. Discussion

The present review set out to descriptively summarize the efficacy of TXA and its ocular adverse effects. Results revealed that TXA is an effective agent in reducing hemorrhage and controlling undesirable, inappropriate, and pathological blood flow in traumatic hyphema and macular edema patients. However, there are studies that demonstrate insignificant benefits from using this drug. Within the current oculoplastic literature, TXA does not seem to be a good choice for reducing intraoperative bleeding, although more research is required and is being conducted³⁴ within this subspecialty.

Efficacy of TXA

In otherwise healthy individuals, TXA likely has high efficacy in traumatic hyphema and macular edema patients^{11,13,15–18,20}. Considering that many studies used TXA as the main treatment in a controlled environment, it seems safe to say that the reduction in hemorrhage and the reduction of macular thickness is associated with the antifibrinolytic effect of TXA.

To reduce SH in traumatic hyphema, topical steroids seem likely to have a similar or associated effect with TXA. A major difference between Albiani et al’s group¹⁴ from the older studies^15–20 is the application of topical steroids within the control group. Although Clarke & Noël¹⁵ did not have a control, systemic TXA and topical steroid-antibiotic ointment were applied to their treatment group, therefore allowing a stronger conclusion to be made about the efficacy of using both TXA and topical steroids for preventing SH. Through these studies it has been discovered that topical steroids seem to have a similar role in reducing SH in traumatic hyphema. Albiani et al.’s control group that received only topical steroids was compared to the TXA-treated group and was found to have a similarly low rate of SH cases (2.6%) while other cohort control groups had higher rates (7.1% to 9.6%). Topically applied steroids (glucocorticoids) act as vasoconstrictors³⁵ and this may be a potential reason for its similar effectiveness to TXA in reducing secondary hemorrhage.

A pattern exists where studies in this review show that in diabetic patients, TXA therapy is ineffective in managing hyphema, macular edema and post-vitrectomy hemorrhage^11,21,24,25. In Takeyama et al.’s¹¹ study, DME cases had no significant reduction in CMT and associated pathologies were generally worse than the RVO cases, indicating that in treating ME, diabetes likely affects the efficacy of TXA. Additionally, examining diabetic post-vitrectomy outcomes investigated by two study groups^24,25 showed diabetes to be a probable factor that has led to insignificant treatment results and Takeyama et al.’s study¹¹ supports the ineffectiveness in diabetic patients. In the case reported by Othman et al.²¹, several underlying conditions were present—diabetes, herpes zoster ophthalmicus, hypertension, and asthma—which all but asthma seem likely to affect TXA performance and may be associated with the insignificant outcome since patients without notable underlying conditions from other hyphema studies were able to achieve significant outcomes with TXA.

Henschen-Edman³⁶ indicates the possibility that the higher level of circulating glucose in diabetic individuals glycates lysine residues, offsetting the ability of lysine to bind tissue plasminogen activator (tPA) and plasminogen. Dunn et al.³⁷ also supports this hypothesis having observed a reduction in plasmin levels in diabetic individuals. It can be deduced that TXA, plasminogen or both may have undergone glycation, reducing their binding capacity and therefore reducing TXA’s intended effect.

Alam et al.²⁷ mentioned that a factor that may have led to insignificant reduction of intraoperative bleeding was the intermittent administration of TXA, whereas effective reduction of blood loss by TXA in major surgeries is achieved through continuous infusion³⁸. TXA in all studies examined in this review regarding surgery was administered either orally or by injection and therefore may have been a potential limiting factor for the efficacy of TXA. Nonetheless, for dacryocystorhinostomy at least, it is concluded that remifentanil and hydralazine are better-performing agents compared to TXA for reducing blood loss, according to Farsani et al.’s⁸ study. In other words, utilizing induced hypotension (IH) is more effective than the stabilization of blood clots.

Topical vs systemic administration

TXA can be administered orally, by injection (systemic), or as eye drops (topical) to treat traumatic hyphema. Topical administration as eye drops has been proven to be effective as it yields a significant reduction in SH in treating traumatic hyphema in both children and adults, similar to the effectiveness of oral administration. Moreover, topical administration also reduces the larger dosage required with systemic administration, thus, minimizing the common systemic side effects⁶ of antifibrinolytics. It is evident that the dose suggested for topical administration (one drop every 8 hours) is much lower than that of the standard oral route (25 mg/kg every 8 hours). Therefore, while achieving similar efficacy as systemic TXA, topical TXA would be more economical and better tolerable for patients.

Adverse Effects

Although exceedingly rare^30,32, the main ocular adverse effects are retinal vein or artery occlusions and ligneous conjunctivitis. Considering that in one case²⁸, the failure to resolve the adverse effect led to blindness in the affected eye, serious harm from TXA use is possible. However, it is worth mentioning that all adverse effects have been determined solely from case reports. No large-scale systematic studies were found that demonstrate significant ocular side effects.

Five out of the six cases show resolution of the adverse effect following the discontinuation of TXA^29–33 or have excluded other etiologies¹⁷, therefore the adverse effects can be associated with TXA. It seems that underlying conditions that intervene with the action¹ and metabolism³² of TXA, or conditions that interfere with coagulation pathways such as kidney dysfunction, hypoplasminogenemia, and Epstein’s syndrome may potentially lead to adverse effects, possibly due to excessive amounts in circulation and excess effect.

This commonality can be seen in the four out of the six case studies that observed the adverse effects: The patient’s lab work in Kiser et al’s³¹ report revealed low a platelet count, elevated international normalized ratio (INR), and elevated activated partial thromboplastin (PT); in Parson et al’s²⁹ report, the patient’s platelet count was as low as 62,000 cells/mm³ (the normal count in adults ranges from 150,000 to 450,000 cells/mm³, according to a report by Rokkam et al.³⁹); in Song et al.’s³² report, the patient had chronic renal failure and revealed low plasma plasminogen activity (<25%) compared to the normal range of 73-94%; and in Diamond et al.’s³³ report, the patient was previously diagnosed with Epstein’s syndrome which is marked by reduced platelet count and plasminogen deficiency.

In fact, retinal vein and artery occlusions typically occur due to thrombosis⁴⁰ or embolism⁴¹, respectively, and a major factor leading to the development of ligneous conjunctivitis is low plasmin activity⁴². The function of TXA in inhibiting plasminogen and promoting blood clotting would therefore add to their development. Therefore, physicians should be cautious with the dosage of TXA when dealing with patients with the mentioned underlying conditions.

Clinical Relevance

Based on the potential for adverse effects presented by certain case studies as well as the limited proven benefits of the drug, a question can be posed regarding the effectiveness of TXA within ophthalmology. TXA should be administered or prescribed with caution specifically in patients with the following conditions: Diabetes mellitus, blood or bone marrow cancer, kidney dysfunction, renal problems, and conditions that are linked to changes in blood platelet counts. Notably, Epstein’s syndrome constitutes both platelet disfiguration and renal problems (macrothrombocytopenia and renal failure).

TXA dosage should also be carefully administered or prescribed and modified for women. Currently presented case studies regarding adverse effects of TXA use are 100% female, where 5 out of 6 were adults. Adverse effects from TXA were most common in those with preexisting blood, thrombotic, and metabolic pathologies, likely having disrupted the mechanism of action¹ and metabolism³² of TXA. Disregarding conditions that affect these pathways may potentially result in adverse effects when prescribing TXA.

Limitations

Takeyama et al.’s study¹¹ had a small sample size (14 eyes; 6 RVO & 7 DME) and found heterogeneity among participants. Results may have been quite clear, but due to this limitation, the conclusion should be considered with caution.

Numerous studies^{11,15–17,19,20,22,25} did not statistically correct for demographics and in several studies^14,24,25, age and/or sex/gender were significantly different. Thus, results may not accurately represent the general population.

Additionally, treatment plans and control groups in the cohort studies examining traumatic hyphema were not identical between compared studies, thus, the significance of each result would have been obtained from different baseline levels and controls. The overall conclusion for the efficacy of TXA in traumatic hyphema based on those cohort studies is not absolute and is merely an association.

Also, although this study covers a large area of ophthalmology, some parts of this review may not have been as thoroughly investigated as other parts. For example, more background information and supplementary research have been done for traumatic hyphema than ME, which is partly due to the degree of available evidence. As such, a few areas in this research may be lacking in depth and more research should be conducted in order to completely establish the relationships between TXA and eye diseases and surgeries.

Future directions

Moving forwards, If one were to pursue this area of research, further investigation and trials are suggested for the following: (i) further application of topical TXA to grow its sample size; (ii) individual topical steroid use or in combination with TXA in treating hyphema; (iii) potential differences in pathologies of microhyphema compared to higher grades of hyphema; and (iv) male and female differences in pharmacodynamics and pharmacokinetics with TXA since the reported adverse effects were seen in 100% females. These findings will contribute to a better understanding of where TXA treatment is most efficacious while also determining safer dosages and contraindications to treatment.

5. Conclusion

TXA has shown to be effective in treating traumatic hyphema and ME. TXA treatment has not shown to be effective in the reduction of intraoperative blood loss during oculoplastic surgery or in patients with diabetes. Caution should be taken in patients with diabetes, blood or bone marrow cancer, kidney dysfunction, renal problems, and conditions that are linked to changes in blood platelet counts or changes. Ocular complications such as retinal artery/vein occlusions and ligneous conjunctivitis have been reported.

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