Hyphema is defined as the presence of blood within the aqueous fluid of the anterior chamber. The most common cause of hyphema is trauma.
Postinjury accumulation of blood in the anterior chamber is one of the most challenging clinical problems encountered by the ophthalmologist. Even a small hyphema due to ocular injury can be a sign of major intraocular trauma with associated damage to vascular and other intraocular tissues.
Blunt trauma to the eye may result in injury to the conjunctiva, cornea, iris, pupillary sphincter, angle structures, lens, zonules, retina, vitreous, optic nerve, and other intraocular or intraorbital structures. Blunt trauma associated with a rapid, marked elevation in intraocular pressure with sudden distortion of intraocular structures produces the dynamic changes responsible for hyphema formation.
The lack of an ideal therapeutic program, the potential for secondary hemorrhage, and the secondary onset of glaucoma all threaten to turn an eye with an initially good visual prognosis into a complex therapeutic problem with a poor final visual result.
Classification and characteristics
Traumatic hyphema is encountered in both children and adults. Hyphema is usually the result of a projectile or deliberate blow that hits the exposed portion of the eye despite the protection of the bony orbital rim. Various missiles and objects have been incriminated, including balls, rocks, projectile toys, air gun pellets, BB gun pellets, automobile airbags, hockey pucks, champagne corks, bungee cords, paint balls, and the human fist. [1, 2, 3] More recently, air gun pellets and BB gun pellets have been made of plastic polymers. There have been cases involving objects larger than the orbit, such as soccer balls, and even durian fruit falling on the unlucky person napping beneath the durian tree. [4, 5] Slow-motion photography has demonstrated deformation of the soccer balls as impact occurs with the orbital rim, thereby imparting direct pressure to the globe, causing the hyphema. With the increase of child abuse, fists and belts have started to play a prominent role. Males are involved in 75% of traumatic hyphema cases. [6, 7]
Hyphema related to surgical procedures on the eye may occur intraoperatively or postoperatively. Surgical hyphema is a known complication of intraocular surgery and should be managed in a similar manner as traumatic hyphema.
Rarely, spontaneous hyphemas may occur and be confused with traumatic hyphemas. Spontaneous hyphemas are secondary to neovascularization (eg, diabetes mellitus, ischemia, cicatrix formation), ocular neoplasms (eg, retinoblastoma, iris melanomas, medulloepitheliomas,  uveitis, and vascular anomalies (eg, juvenile xanthogranuloma). Vascular tufts that exist at the pupillary border have been implicated in spontaneous hyphemas.  Spontaneous hyphemas due to iris chafing can be seen with anterior chamber intraocular lenses or poorly placed posterior chamber intraocular lenses.
The angular vessels first described by Arlt, as seen in Fuchs uveitis syndrome, produce a filiform angular hemorrhage and subsequent microhyphema when a diagnostic 30-gauge needle is placed through the limbus. This is known as Arlt’s sign.
Finally, an idiopathic hyphema of no known cause or recurrence may occur with spontaneous resolution. This is extremely rare.
When there is no layering of blood but blood cells are seen within the anterior chamber, the term microhyphema can be used and graded with the Standardization of Uveitis Nomenclature (SUN) criteria scale for grading anterior segment cells. The following clinical grading system for traumatic macrohyphemas is preferred:
Grade 1 - Layered blood occupying less than one third of the anterior chamber
Grade 2 - Blood filling one third to one half of the anterior chamber
Grade 3 - Layered blood filling one half to less than total of the anterior chamber
Grade 4 - Total clotted blood, often referred to as blackball or 8-ball hyphema
Most hyphemas fill less than one third of the anterior chamber. When hyphemas are divided into 4 groups according to the amount of filling of the anterior chamber, 58% involve less than one third of the anterior chamber, 20% involve one third to one half of the anterior chamber, 14% involve one half to less than total of the anterior chamber, and 8% are total hyphemas. Slightly fewer than one half of all hyphemas settle inferiorly to form a level; approximately 40% form a definite clot, usually adherent to the iris stroma; and 10% have a dark clot in contact with the endothelium. This last form may portend a poor outcome and corneal staining.
An alternative method of grading hyphemas involves measuring (in millimeters) the hyphema from the inferior 6-o'clock limbus. This method may help in monitoring the progress of resolution or the occurrence of rebleeding. Digital imaging analysis is also useful and objective but is available in only a few research or academic facilities.
The cause of an anterior chamber hemorrhage in contusion injuries is thought to be related to the posterior displacement of tissue or to the resultant fluid wave in the aqueous humor and the vitreous. This sudden dynamic shift stretches the limbal vessels and displaces the iris and the lens. This displacement may result in a tear at the iris or the ciliary body, usually at the angle structures.  A tear at the anterior aspect of the ciliary body is the most common site of bleeding and occurs in about 71% of cases.  The blood exits from the anterior chamber via the trabecular meshwork and the Schlemm canal or the juxtacanalicular tissue.
The usual duration of an uncomplicated hyphema is 5-6 days. The mean duration of elevated intraocular pressure, when it accompanies hyphema, is 6 days.
Hyphema describes the condition of the aqueous humor when red blood cells form a suspension in it.
The choroid and the iris contain a rich complex of vessels. The pupil is outlined and controlled by a complex set of iridial muscles, both sphincters and dilators. These muscles can be ruptured by sharp and/or blunt trauma. This is a frequent source of intraocular hemorrhage (hyphema). In addition, the iris root and/or the ciliary spur is a common location of bleeding from blunt trauma.
Surgical intervention into the eye for anterior segment procedures is accomplished routinely through various approaches. The most commonly used approaches in modern small incision surgery are via the limbus and/or the clear cornea. Clear cornea surgery markedly reduces the risk of bleeding from limbal vessels since the cornea in its healthy state is avascular. Scleral tunnel incision is subject to unpredictable hemorrhage, and the incision must be closed carefully with sutures.
Hyphema can result from intraocular surgery, as follows:
Intraoperative bleeding: Ciliary body or iris injury may occur during a peripheral iridectomy, cataract extraction, cyclodialysis, canaloplasty,  and filtration procedure. It can also occur with laser peripheral iridectomy, more commonly with YAG laser than with argon laser, and argon laser trabeculoplasty (ALT). Hyphema is encountered during insertion of microstents with minimally invasive glaucoma surgeries (MIGS), which are becoming increasingly popular, as described by Hoeh et al with their experience with the CyPass Micro-Stent. 
Early postoperative bleeding: A traumatized uveal vessel that was in spasm and suddenly dilates or conjunctival bleeding that makes its way into the anterior chamber via a corneoscleral wound or sclerostomy
Late postoperative bleeding: New vessels growing across the corneoscleral wound that bleed when manipulated, a uveal wound that is reopened, or an intraocular lens (IOL) that causes chronic iris erosion (eg, uveitis-glaucoma-hyphema [UGH] syndrome)
In the United States, the incidence of hyphema is 17-20 per 100,000 people per year.
Herpes Zoster Uveitis 
Other problems to be considered
Iris microhemangiomas, iris varix, and pupillary microhemangiomas
Bleeding diatheses or clotting disturbances such as idiopathic thrombocytopenic purpura (ITP) or leukemias
Following laser trabeculoplasty  or iridotomy
Anticoagulation therapy, such as warfarin (Coumadin), clopidogrel bisulfate (Plavix), or aspirin
Elevated Intraocular Pressure
Increased intraocular pressures may accompany hyphemas of any size. Elevated intraocular pressures (>22 mm Hg) may be anticipated in approximately 32% of all patients with hyphemas at some time during their course.  Higher, more prolonged elevations of intraocular pressure are more commonly associated with near total or total hyphemas. Patients predisposed to glaucoma or with preexisting glaucoma and decreased facility of trabecular outflow are also more likely to develop glaucoma with a hyphema.
These highly elevated intraocular pressures occur during the acute phase of the hyphema and are separate from those related to angle recession.  In patients with pressure elevations, abnormal tonometric readings are frequently detected during the first 24 hours after injury. This initial period of elevated intraocular pressure is often followed by a period of normal or below normal pressure from the second day to the sixth day. Careful monitoring of the intraocular pressure is important and may determine the course of treatment. 
The early period of elevated intraocular pressure is probably the result of trabecular plugging by erythrocytes and fibrin. The following period of reduced pressure is most likely due to reduced aqueous production and uveitis, and it may actually increase the chance of secondary hemorrhage. This period of hypotony is commonly followed by a subsequent rise in intraocular pressure, probably coincidental with the recovery of the ciliary body.
Elevated intraocular pressure then subsides with recovery of the trabecular meshwork and disappearance of the hyphema.
Exceptions include patients with a hyphema occupying greater than 75% of the anterior chamber and those with a total hyphema, in whom pressure elevation frequently has its onset simultaneously with the initial hyphema and remains continually elevated until the hyphema has had considerable resolution. When large segments of the anterior chamber angle are irreparably damaged and/or when organization of the fibrin or clot produces extensive peripheral anterior synechiae, the intraocular hypertension continues, becoming intractable glaucoma.
Ghost cell glaucoma with hyphema and vitreous hemorrhage may cause elevated intraocular pressure 2 weeks to 3 months after the initial injury.  Gradual clearing of the hyphema occurs, with erythrocytes losing hemoglobin and becoming so-called ghost cells in the vitreous cavity. The ghost cells then circulate forward into the anterior chamber, with resultant trabecular blockage due to the distorted, bulky configuration of the crenated red blood cell. Considerable delayed elevation of intraocular pressure may occur with ghost cell glaucoma, particularly in patients with poor facility of outflow.
Secondary bleeding into the anterior chamber results in a markedly worse prognosis. Eventual visual recovery to a visual acuity of 20/50 (6/15) or better occurs in approximately 64% of patients with secondary hemorrhage as compared with 79.5% of patients in whom no rebleeding occurred. [6, 11] True secondary bleeding into the anterior chamber is indicated by an obvious increase in the amount of blood in the anterior chamber. Secondary hemorrhage occurs in approximately 25% (range, 7-38%) of all patients with hyphema. [6, 11] The incidence of secondary hemorrhage is higher in hyphemas classified as Grades 3 and 4. 
With near total to total hyphemas, in which the blood is dark and clotted, bright red blood often begins to appear at the periphery of the clot on the fourth day to the sixth day. This probably results from early dissolution of the clot and does not necessarily indicate a secondary hemorrhage. A large proportion (33%) of patients younger than 6 years has secondary hemorrhages; the likelihood of secondary hemorrhages decreases with age. Secondary hemorrhage usually occurs on the third day or the fourth day, but it may occur from the second day to the seventh day after trauma. [6, 19]
Secondary hemorrhage is probably due to lysis and retraction of the clot and fibrin aggregates that have occluded the initially traumatized vessel.  The secondary bleeding may result in increased intraocular pressure and corneal staining and is associated with a poorer visual prognosis. [20, 21]
Several studies have documented that secondary hemorrhage occurs more frequently in African American patients. In 1990, Spoor et al observed secondary hemorrhage in 24.2% of African American patients and in only 4.5% of white patients.  Two other studies demonstrated greater rates of secondary hemorrhage in African American patients that are highly significant (P < 0.05). [23, 24] In the initial systemic aminocaproic acid (ACA) study, African American patients comprised 66.2% of the population  ; 34% of African American patients in the placebo group developed secondary hemorrhage, and 20% of them had positive sickle cell trait by hemoglobin electrophoresis. There have also been studies showing a higher incidence of rebleeding in cases of hemophilia. 
Early postsurgical hyphemas can be caused by bleeding from the ciliary body, from cut ends of the Schlemm canal, from the iris or iris root, and from the corneoscleral wounds. Wounds located more posteriorly tend to bleed more.
Iris neovascularization can also result in a hyphema due to fragile iris vessels that can bleed from intraoperative manipulation.
Late-onset postcataract surgical hyphemas occur from the fine arborizing neovascular vessels that form in the inner aspect of the cataract incision site. These vessels are fragile and bleed spontaneously after minor trauma. Hyphemas in this setting may be caused by posterior chamber intraocular lens (PCIOL) haptics eroding the ciliary sulcus. Anterior chamber intraocular lens (ACIOL) haptics also may cause bleeding by chafing the iris surface.
Rubeosis, or iris neovascularization, can also be a source of late postoperative hyphema.
Uveitis-glaucoma-hyphema (UGH) syndrome related to intraocular lenses is seen weeks to months after surgery. Postoperative hyphema may also occur after laser procedures.
After ALT, bleeding may occur from an inadvertent laser treatment of the iris root vessel or from reflux of blood in the Schlemm canal.
After a laser iridotomy, bleeding may occur from an inadvertent laser treatment of the iris root vessel. The physician should apply pressure with the focusing lens to reduce the rate of bleeding and the size of hyphema formation if promptly recognized.
Complications of Hyphema
Complications of traumatic hyphema may be directly attributed to the retention of blood in the anterior chamber. The four most significant complications include posterior synechiae, peripheral anterior synechiae, corneal bloodstaining, and optic atrophy. [11, 26]
Posterior synechiae may form in patients with traumatic hyphema. This complication is secondary to iritis or iridocyclitis. However, they are relatively rare complications in patients who are medically treated. Posterior synechiae occur more frequently in patients who have had surgical evacuation of the hyphema.
Peripheral anterior synechiae
Peripheral anterior synechiae occur frequently in medically treated patients in whom the hyphema has remained in the anterior chamber for a prolonged period, typically 9 or more days. The pathogenesis of peripheral anterior synechiae may be due to a prolonged iritis associated with the initial trauma and/or chemical iritis resulting from blood in the anterior chamber. Alternately, the clot in the chamber angle may subsequently organize, producing trabecular meshwork fibrosis that closes the angle. Both mechanisms are likely to be involved. [6, 11]
Corneal bloodstaining primarily occurs in patients with a total hyphema and associated elevation of intraocular pressure. The following factors may increase the likelihood of corneal bloodstaining; all of these factors affect endothelial integrity:
Initial state of the corneal endothelium; decreased viability resulting from trauma or advanced age (eg, cornea guttata)
Surgical trauma to the endothelium
Large amount of formed clot in contact with the endothelium
Prolonged elevation of intraocular pressure
Corneal bloodstaining may occur with low or normal intraocular pressure; rarely, it may also occur in less than total hyphemas. However, these latter 2 instances probably can be anticipated only in eyes with a severely damaged or compromised endothelium. Corneal bloodstaining is more likely to occur in patients who have a total hyphema that remains for at least 6 days with concomitant, continuous intraocular pressures of greater than 25 mm Hg.  Clearing of the corneal bloodstains may require several or many months. Generally, the corneal bloodstains form centrally and then spread to the periphery of the corneal endothelium. During resolution, corneal bloodstaining clears peripherally and then centrally, reversing the sequence of the initial staining process.
Optic atrophy may result from either acute, transiently elevated intraocular pressure or chronically elevated intraocular pressure; each occurrence was studied in a series of patients with hyphema in an attempt to identify predisposing factors. [11, 27]
Nonglaucomatous optic atrophy in patients with hyphema may be due to either the initial trauma or the transient periods of markedly elevated intraocular pressure. Diffuse optic pallor (and not glaucomatous cupping) is the result of transient periods of markedly elevated intraocular pressure. Pallor occurs with constant pressure of 50 mm Hg or higher for 5 days or 35 mm Hg or higher for 7 days. [6, 11]
The authors have observed numerous patients with sickle cell trait who developed a nonglaucomatous optic atrophy with relatively low elevations of intraocular pressure of 35-39 mm Hg for 2-4 days.  In spite of maximum medical therapy, final visual acuity was less than 20/400 in all patients. The authors continue to observe optic atrophy in patients with sickle cell trait who are referred to their institution and who have not had vigorous control of intraocular pressure and/or delay in paracentesis. Other studies indicate that patients with sickle cell hemoglobinopathies and anterior chamber hyphemas have more sickled erythrocytes in their anterior chambers than in their circulating venous blood.  The sickled erythrocytes obstruct the trabecular meshwork more effectively than healthy cells, and a consequent elevation of intraocular pressure occurs with lesser amounts of hyphema.
Systemic hypotensive agents, such as acetazolamide and methazolamide, may not always be successful in reducing the intraocular pressure. In fact, they may be contraindicated in high or repeated dose regimens because of their possible contribution to intravascular hemoconcentration and increased microvascular sludging, both of which are detrimental in sickle cell hemoglobinopathy.
The increased intraocular pressure may not be tolerated well in these patients because of the increased susceptibility to impaired vascular perfusion within the optic nerve and the retina. Indeed, moderate elevation of intraocular pressure in patients with sickle cell hemoglobinopathy may produce rapid deterioration of visual function because of profound reduction of central retinal artery and posterior ciliary artery perfusion. [29, 30] For African American patients, the prevention of secondary hemorrhage is a critical factor.
Other complications associated with hyphema involve disruption of the posterior segment. These complications include, but are not limited to, choroidal rupture, macular scarring, retinal detachment, vitreous hemorrhage, and zonular dialysis. Even a case of sympathetic ophthalmia following hyphema has been reported. 
Prognosis and Treatment
Recognizing that the prognosis for visual recovery is directly related to the following 3 factors is important:
Amount of associated damage to other ocular structures (ie, choroidal rupture, macular scarring)
Whether secondary hemorrhage occurs
Whether complications of glaucoma, corneal bloodstaining, or optic atrophy occur
Treatment modalities should be directed at reducing both the incidence of secondary hemorrhage and the risk of corneal bloodstaining and optic atrophy.
The success of hyphema treatment, as judged by the recovery of visual acuity, is good in approximately 75% of patients. Approximately 80% of those with less than one third filling of the anterior chamber regain visual acuity of 20/40 (6/12) or better. Approximately 60% of those with a hyphema occupying greater than one half but less than total of the anterior chamber regain visual acuity of 20/40 (6/12) or better, while only approximately 35% of those with an initially total hyphema or a Grade 4 hyphema have good visual results. Approximately 60% of patients younger than 6 years have good visual results; older age groups have progressively higher percentages of good visual recovery.
The severity of the trauma is frequently related to the final visual outcome. Lens opacities, choroidal rupture, vitreous hemorrhage, angle-recession glaucoma, secondary macular edema, and retinal detachment are commonly associated with traumatic hyphema, compromising the final visual result. Hyphema related to any penetrating injury of the eye has a worse visual prognosis than hyphema associated with blunt trauma.
Of patients with hyphema, 14% have poor visual results from associated trauma, including such complications as glaucoma, vitreous hemorrhage, retinal detachment, choroidal rupture, or scleral rupture. Poor visual outcome in traumatic hyphema can be directly attributed to the hyphema in 11% of patients [27, 11] ; the poor visual outcome is usually the result of secondary hemorrhage associated with optic atrophy or corneal bloodstaining.
In African American patients, a sickle cell prep should be ordered if a hyphema is seen because the presence of a hyphema in patients with sickle cell trait or disease can produce significant ocular complications. Sickled red blood cells can more easily obstruct the trabecular meshwork and result in a high IOP, even in the presence of a relatively small hyphema. In addition, ischemic complications of the retina and the optic nerve are greater in patients with sickle cell trait and disease. A hemoglobin electrophoresis is also helpful. It helps distinguish sickle cell trait from disease once the sickle cell prep is positive.
In idiopathic hyphemas in patients with easy bruising, pallor, or complaints of fatigue, hematological evaluation should be considered.
Infrequently, a B-scan and/or a CT scan may be necessary to rule out an intraocular tumor or a foreign body if a thorough examination is not possible and the reasons for postoperative hyphema are not clear.
Rarely, an iris fluorescein angiogram may be needed if early iris neovascularization is suspected as an underlying cause of the hyphema.
Examination of the angle structures is critical to understanding the extent of the blunt trauma precipitating a hyphema. This can be delayed until after the critical 5-day, high-risk, re-bleed period, particularly dynamic gonioscopy. Angle abnormalities, synechiae, and recession may commonly be found. Rarely, a focus of bleeding can be photocoagulated with the argon laser on low-power settings, up to 300 mW with a 200-µm spot size. All patients with hyphema due to blunt trauma should undergo gonioscopy once the hyphema has cleared to rule out angle recession.
The customary treatment of patients with traumatic hyphema has included hospitalization, bed rest, bilateral patching, topical cycloplegics, topical steroids, systemic steroids, and sedation.  However, studies have not indicated that rigidly following this regimen is necessary to achieve acceptable therapeutic results. These studies provide evidence that no statistically significant difference exists in most areas of comparison between patients treated with bed rest, bilateral patches, and sedation and those treated with ambulation, a patch and shield on the injured eye only, and no sedation. [11, 33, 34, 35]
The authors recommend ambulation and a patch and shield for the injured eye. Sedation is recommended only in the extremely apprehensive individual. Hospitalization may be warranted in cases of severe trauma and rebleeding, when abuse is suspected, or when noncompliance to medical regimens or bed rest is a concern.
If analgesics are required for pain relief, acetaminophen (Tylenol) with or without codeine, depending on the severity of the pain, is preferred. The antiplatelet effect of aspirin tends to increase the incidence of rebleeding in patients with traumatic hyphema and should be strictly avoided.  Nonsteroidal anti-inflammatory drugs (NSAIDs) with analgesic activity, such as mefenamic acid (Ponstel) or naproxen (Aleve), share this deleterious antiplatelet effect.
In any therapeutic regimen, the injured globe requires adequate protection with a patch and shield.  Elevating the head of the bed 30-45° facilitates settling of the hyphema in the inferior anterior chamber and aids in classifying the hyphema. Inferior settling facilitates more rapid improvement of visual acuity, earlier evaluation of the posterior pole, and greater clearing of the anterior chamber angle. A better estimate of the decrease or increase in the amount of blood in the anterior chamber is also possible during subsequent biomicroscope examinations.
Various topical medications have been recommended for treating patients with traumatic hyphema, including cycloplegics for traumatic iridocyclitis and miotics to increase the surface area of the iris to enhance resorption of the hyphema. [21, 37, 38] Topical corticosteroids and estrogens [38, 39] have been recommended with contradictory results. 
Investigations conducted by the authors of patients with traumatic hyphema excluded the use of topical medications because of a lack of definite evidence of their advantages. [6, 27] One recommendation regarding topical medication is that the topical use of steroids after the third day or the fourth day of retained hyphema may be advantageous to decrease the associated iridocyclitis and to prevent or deter the development of peripheral anterior synechiae or posterior synechiae. Secondly, topical atropine (1%) is indicated in hyphemas occupying more than 50% of the anterior chamber to break the pupillary block.
Several double-masked studies clearly establish the value of systemic aminocaproic acid (ACA, AMICAR) in the prevention of recurrent hemorrhages. [6, 40] If secondary hemorrhages are the result of lysis and retraction of a clot that has produced an occlusion of the traumatized vessel, then prevention of normally occurring clot lysis for 5-6 days should be advantageous to allow the injured blood vessel to more completely repair its integrity.  The antifibrinolytic activity of ACA given systemically has been demonstrated in other areas of the body to decrease the incidence of secondary hemorrhage.
ACA retards clot lysis by preventing plasmin from binding to the lysine in the fibrin clot. As a lysine analog, ACA competitively inactivates plasmin by occupying the site on plasmin that would normally bind to fibrin. In a similar manner, ACA binds to plasminogen, so that when activated to plasmin, it cannot attach to fibrin.
When ACA was administered orally in a dosage of 100 mg/kg every 4 hours for 5 days, a statistically significant reduction in the incidence of rebleeding of traumatic hyphemas was observed.  Systemic ACA should be used in hyphemas occupying 75% or less of the anterior chamber because the clot may persist in the anterior chamber for an increased period during administration of the drug. The continued retention of the clot in the anterior chamber could be a potential disadvantage with larger Grade 4 hyphemas.
In a prospective study by the authors, as well as 2 additional studies, patient groups treated with ACA and placebo were randomized and double-masked. [6, 23, 41, 40] In the ACA-treated group, the incidence of secondary hemorrhage was 3-4%. [6, 23, 41, 40] In the placebo-treated group, the incidence was 28-33%. ACA in a dosage of 50 mg/kg every 4 hours is equally as effective as 100 mg/kg every 4 hours, orally, for 5 days.  The total dosage of ACA should not exceed 30 grams per day.
Systemic ACA should not be used in patients who are pregnant or those with renal or hepatic insufficiency.
Since systemic ACA significantly reduces the incidence of secondary hemorrhage, a topical preparation could decrease the incidence of adverse effects. By concentrating the drug in the aqueous humor, a topical preparation would decrease the systemic concentration of ACA associated with many of the adverse effects.
For systemically administered ACA to be effective, it must penetrate into the anterior segment in sufficient concentration to retard fibrinolysis. To directly determine the concentration of ACA in the aqueous humor following systemic administration, using an animal model, the authors compared plasma and aqueous humor concentrations of ACA following intravenous (IV) administration of 50 mg/kg and 100 mg/kg, as well as after constant infusion of 25 mg/kg/h.  After IV administration, plasma levels were 10-fold higher than levels in the aqueous humor. Antifibrinolytic activity correlated directly with ACA concentration in plasma or the aqueous humor. The time to clot dissolution was greatest (2.5 times control) when the ACA concentration in the aqueous humor reached 30-35 mg/dL, which, thus, became the target concentration to achieve with topical therapy.
The authors' long-range goal is to improve the management of hyphema by decreasing the incidence of secondary hemorrhage using topical drug therapy that is more effective, less toxic, and better accepted by both patients and ophthalmologists than the currently available oral therapy with ACA.
Seven topical preparations containing ACA were studied to assess which could deliver the required amount of ACA into the aqueous humor.  The greatest ACA concentrations were obtained using either polyvinyl alcohol or carboxypolymethylene (CPM), 51 mg/dL and 58 mg/dL, respectively. The latter had a longer duration of action. Using an experimental model for hyphema, ACA in CPM was applied topically every 6 hours for 6 days or until a secondary hemorrhage occurred.  Compared to no treatment or the administration of a placebo (eg, vehicle without ACA), topical application of ACA significantly decreased the incidence of rebleeds from 33% to 10% (P < 0.05). No ocular adverse effects occurred after topical application of either formulation.
Additional studies have been performed to optimize the concentration of the vehicle and the drug.  The optimal combination is 30% ACA to 2% CPM. However, this combination did not lead to an increase in the duration of action using hyaluronic acid (Healon) or collagen shields as a depot.  The gel is administered in a glass syringe 4 times per day for 7 days. The gel is well tolerated by patients, including children.
Studies of 25% ACA have not seen a significant benefit in reducing rebleeding rates and increased the time to clot resolution.  However, a study concluded ACA was beneficial in treating patients with hyphema. 
The authors established a prospective, multicenter, double-masked, randomized clinical trial comparing oral and topical ACA. 
In the trial, 64 patients with traumatic hyphema treated with topical or systemic ACA were compared with 54 control patients with hyphema. Compared with the control group, topical and systemic ACA were statistically significant in preventing secondary hemorrhage. Only 3% (2/64) of the patients who received topical ACA (35 patients) or systemic ACA (29 patients) had secondary hemorrhage, compared with 22% (12/54) of the control group (P=0.002). Final visual acuity was 20/40 or better in 30 patients (86%) in the topical ACA group, compared with 23 patients (43%) in the control group (P=0.001). Final visual acuity was 20/40 or better in 20 patients (69%) in the systemic ACA group, compared with 23 patients (43%) in the control group (P=0.04). A final visual acuity of 20/40 or better was regained by 86% of patients in the topical ACA group, compared with 69% of patients in the systemic ACA group. 
Topical ACA appears to be a safe, effective treatment to prevent secondary hemorrhage in patients with traumatic hyphema. It is as effective as systemic ACA in reducing secondary hemorrhage, and no systemic adverse effects were observed with topical use. Topical ACA provides an effective outpatient treatment for traumatic hyphemas.
Although not approved for ophthalmic use in the United States, another lysine analog, tranexamic acid, also has antifibrinolytic properties. In a series of children treated with tranexamic acid (25 mg/kg/d), the incidence of secondary hemorrhage was significantly reduced.  Like ACA, tranexamic acid has been associated with nausea, vomiting, and hypotension. Unlike ACA, tranexamic acid is associated with visual abnormalities, which could complicate the ophthalmologic evaluation of the patient. In addition, some patients in this study were treated with other drugs, including topical steroids. One study found that tranexamic acid was better than oral steroids in preventing rebleeding rates.  A meta-analysis of hyphema literature determined antifibrinolytics had a significant impact on hyphema rebleeding.  The authors suggested antifibrinolytics use in patients at high risk for associated hyphema complications.
A 2013 Cochrane review concluded that the antifibrinolytics ACA (both topical and systemic), tranexamic acid, and aminomethylbenzoic acid all reduced the rate of secondary hemorrhage.  Until a commercial option becomes readily available, topical ACA can be ordered through Leiter's Pharmacy.
Other investigators have suggested that systemic steroids decrease the incidence of secondary hemorrhage. Initial studies supporting this claim were neither randomized nor double-masked. [37, 53] In 1980, a randomized, double-masked, prospective study by Spoor and associates observed a secondary hemorrhage rate of 20% in controls and 13% in treated patients, which was not statistically significant.  In 1991, Farber and colleagues compared treatment with oral ACA with oral prednisone in a well-controlled trial.  Their study suggested that both drugs decrease the incidence of secondary hemorrhage by a similar amount, albeit by different mechanisms. Because of the small number of rebleeds, the confidence limits were large and may have masked a real difference.
The previously mentioned 2013 Cochrane review noted that the evidence for the use of corticosteroids in traumatic hyphema is limited owing to studies with small sample sizes and low rates of complications. However, conflicting data continue to emerge.  A 2014 retrospective analysis that examined visual outcomes, incidence of rebleeding, and intraocular pressures in 98 eyes treated with corticosteroid therapy (as well as bed rest, elevation of head of bed, and hydration) and in 108 eyes treated with supportive therapy alone identified no difference between the visual outcomes or incidence of rebleeding. The intraocular pressure was significantly lower in the supportive therapy group. 
Other studies have recommended oral steroids combined with traditional treatments to reduce rebleeding rates. [51, 36] A randomized, comparative study of ACA versus oral steroids found no significant difference in the outcomes between the 2 treatments.  Despite conflicting data, many practitioners still tend to prescribe topical corticosteroids at least anecdotally for the potential benefits of avoiding complications due to intraocular inflammation.
The major difficulty with this study was that controls were not used. The lack of a true control population is unfortunate in comparing the 2 groups. In addition, the study excluded all patients with sickle cell trait. These patients are one group that should be considered for systemic ACA or systemic corticosteroid treatment. In addition, patients with gastric ulcer or diabetes mellitus and those who were intoxicated or had bleeding were excluded. The mode of action of prednisone is unclear and may be related to an anti-inflammatory influence on traumatized blood vessels with reduced engorgement and a propensity for rebleeding. Additional randomized studies with controls would be extremely helpful in determining whether or not a significant reduction of secondary hemorrhage occurs with systemic prednisone in comparison with systemic ACA.
Some studies have investigated the application of intracameral tissue plasminogen activator (t-PA) in the management of traumatic hyphema.  However, these studies have been neither large nor randomized. A potential problem with t-PA is the associated risk of rebleeding of the initial wound.
Application of t-PA has been considered in resolving hyphemas that either fail to clear spontaneously or are associated with malignant intraocular pressure,  although the actual timing of t-PA administration from the initial injury has yet to be determined.
Topical antiglaucomatous medications usually lower intraocular pressure. With the advent of newer glaucoma modalities, initiating therapy incrementally with brimonidine tartrate (Alphagan, Allergan), followed by latanoprost (Xalatan, Pharmacia) and timolol maleate (Timoptic-XE, Merck), is recommended. If intraocular pressure is still elevated, a topical carbonic anhydrase inhibitor should be added. In patients with sickle cell trait or sickle cell disease, methazolamide and topical beta-blockers should be substituted. [10, 58]
If intraocular pressure is still uncontrolled, systemic medication should be given during the acute phase of the hyphema. Acetazolamide (20 mg/kg/d) may be administered in 4 divided doses for intraocular pressure of greater than 22 mm Hg. However, acetazolamide can increase the concentration of anterior chamber ascorbate, lower the pH of human plasma, and exacerbate sickling of erythrocytes. Therefore, methazolamide (10 mg/kg/d), administered in 4 divided doses, is preferred in pediatric patients with sickle cell trait or sickle cell disease. [6, 28]
Osmotic agents (preferably mannitol) should be considered for intraocular pressure above 35 mm Hg in spite of topical medications. Orally administered glycerol is effective; however, nausea and vomiting are often associated with its administration in patients with elevated intraocular pressure. Mannitol is administered intravenously, 1.5 g/kg (usually in a 10% solution), over a period of approximately 45 minutes. This agent may be given 2 times a day (or every 8 hours in patients with extremely high pressure) in attempt to keep the intraocular pressure below 35 mm Hg. Renal output, blood urea nitrogen, and electrolyte values should be monitored in all patients in whom such therapy is continued for several days.
Outpatient Versus Hospitalization
With increasing emphasis on cost containment, outpatient management of hyphema has become more popular in recent years. Several studies have demonstrated no significant difference in final visual acuities in patients with smaller hyphemas treated at home or those treated in hospitals. [59, 46, 60, 61, 40, 62]
Microhyphemas can be treated on an outpatient basis, unless secondary hemorrhage occurs or elevated intraocular pressure is uncontrolled. Patients with traumatic hyphema occupying less than one third of the anterior chamber can be treated on an outpatient basis with systemic or topical ACA. If the hyphema occupies more than one third of the anterior chamber, intraocular pressure is elevated beyond 30 mm Hg, or both, hospitalization is recommended. The decision to hospitalize also depends on the cooperation of the patient, family members, and the extent of ocular injury. For outpatients, daily ocular examinations, including an evaluation of the amount of hyphema and intraocular pressure, should be performed. Daily ophthalmic sketches are helpful in estimating the amount and the rate of resolution or rebleeding. Applanation tonometry must be performed at least once daily and twice daily in patients with elevated intraocular pressures.
Minimal bloodstaining is often difficult to detect against a background of blood in the anterior chamber. Under such circumstances, the cornea often assumes a yellowish cast, which is reflected from the yellowish fibrinous coagulum in the anterior chamber. The most typical early sign of corneal bloodstaining is the presence of tiny yellowish granules that initially appear in the posterior third of the corneal stroma. An additional finding is a lack of definition or a blurred appearance of the ordinarily sharply defined fibrillar structure of the involved corneal stroma. The latter is independent of the yellowish color transmitted to the stroma by the contents of the anterior chamber.
The authors have found this sign to be useful in recognizing the very early stages of corneal bloodstaining. These biomicroscopic signs of corneal bloodstaining usually precede gross staining by only 24-36 hours. Surgical treatment in this early stage may prevent gross staining, and the cornea may clear in 4-6 months. However, once grossly visible staining develops, many months may elapse before clearing is complete.
Generally, medical management seems to produce the best visual results for patients with less than total hyphemas. Certainly, other causes of inflammation or bleeding should be ruled out, particularly when the history of trauma is questionable. 
For several reasons, surgical management is fraught with complication.  First, surgery is chosen for the most severe presentations of hyphema, thus selecting out the most difficult cases. Surgical intervention is rarely indicated for hyphemas that occupy less than one half of the anterior chamber; these lesser hyphemas (either primary or secondary) usually resolve spontaneously under any medical regimen and require no surgical intervention.
In 2 prospective series totaling 196 patients, no corneal bloodstaining or optic atrophy was noted in hyphemas of 50% or less. [6, 11] Corneal bloodstaining, with rare exceptions, only occurs in patients with hyphemas that are total at some time during their course. The results of surgical evacuation to improve secondary glaucoma in small hyphemas (75% or less) are disappointing. The ocular hypertension in these instances results more frequently from damage to the trabecular structures than from plugging by red cells and fibrin. Surgical evacuation in these instances may produce only temporary postsurgical hypotony, with a rapid return to preoperative intraocular pressure.
The authors believe that most hyphemas, including total hyphemas, should be medically treated for the first 4 days. Spontaneous resolution of the hyphema occurs quite rapidly during this period, and these cases have the best prognosis. In one series of 20 eyes with total hyphemas, 4 of these 20 eyes (20%) cleared sufficiently by day 4 to rule out surgery.  An additional 4 eyes resolved spontaneously on medical treatment over a longer period.
Four days after onset of total hyphema
Microscopic corneal bloodstaining (at any time)
Total hyphema with intraocular pressures of 50 mm Hg or more for 4 days (to prevent optic atrophy)
Total hyphemas or hyphemas filling greater than 75% of the anterior chamber present for 6 days with pressures of 25 mm Hg or more (to prevent corneal bloodstaining)
Hyphemas filling greater than 50% of the anterior chamber retained longer than 8-9 days (to prevent peripheral anterior synechiae)
In patients with sickle cell trait or sickle cell disease who have hyphemas of any size that are associated with intraocular pressures of greater than 35 mm Hg for more than 24 hours
If intraocular pressure remains elevated at 50 mm Hg or more for 4 days, surgery should not be delayed. One study noted optic atrophy in 50% of patients with total hyphemas when surgery was delayed. Corneal bloodstaining occurred in 43% of patients.  A 2013 study of 138 pediatric traumatic hyphemas found an increased likelihood of required surgical intervention if patients presented with increased intraocular pressure. 
Patients with sickle cell hemoglobinopathies and even those with sickle cell trait require surgical intervention if intraocular pressure is not controlled within 24 hours. [6, 28] An interesting study of hyphema in rabbits measured partial oxygen pressure in the aqueous humor after injection of blood from a patient with sickle cell versus injection of an air or oxygen bubble with the blood from the patient. After 10 hours, the partial pressure of oxygen was 123.35 mm Hg in the blood plus air bubble group and 306.47 mm Hg in the blood plus oxygen group, compared to 78.45 mm Hg and 73.97 mm Hg for the placebo (no injection) and blood only injection groups, respectively. The authors recommended leaving an air or oxygen bubble in the anterior chamber after a washout in patients with sickle cell disease or trait. 
MomPremier et al described a two-needle, office-based technique for performing an air-fluid exchange (see image below) in several patients without sickle cell.  The authors of this article have not attempted this technique.
Surgery for patients with hyphema should be cautiously approached. In 2 series involving 196 patients, surgery was performed in only 14 patients (7.1%). [6, 11] Risks of surgery include damage to the corneal endothelium, the lens, and/or the iris; prolapse of the intraocular contents; rebleeding; and increased synechiae formation. With the exception of patients with sickle cell trait, no patients in these series required surgery if the hyphema occupied less than 50% of the anterior chamber. Total hyphema evacuation by vitrectomy instrumentation, peripheral iridectomy, and trabeculectomy has been recommended.
Generally, the authors recommend the type of surgical intervention with which the surgeon is most familiar. Hyphema surgery should be preceded by intravenous acetazolamide and mannitol if the intraocular pressure is elevated. The operation should be performed under general anesthesia in all patients. The operating microscope should be used in all instances. Presently, the 4 major approaches include the following:
Hyphema evacuation with closed vitrectomy instrumentation
Irrigation and aspiration through a small incision
Clot irrigation with trabeculectomy
Currently, the preferred technique is evacuation of the hyphema with vitrectomy instrumentation. The initial clear corneal incision is made with a diamond blade. To avoid both the iris and the lens, the blade is oriented and pushed into the anterior chamber in such a manner that it is parallel to the plane of the iris. A 20-gauge Ocutome or similar guillotine instrument, attached to an infusion line of balanced salt solution plus (BSS-Plus), is gently placed into the anterior chamber. The bottle of BSS-Plus should be 30-40 cm above the eye to maintain normal intraocular pressure. With the Ocutome cutting port half open and the infusion line in place, irrigating and aspirating free blood from the formed clot are possible. The suction mode is initially set at 4, and the cutting speed is set at 150 for the procedure. An anterior chamber maintainer can help stabilize fluctuations in intraocular pressure during clot evacuation. 
Extreme care is required to avoid any contact with the iris, the lens, or the corneal endothelium. Directing the guillotine port anteriorly and keeping the port in view at all times generally avoids intraoperative uveal tissue injury. This operative procedure is used to remove the central portion of the clot. Removing the entire clot in the periphery of the anterior chamber is not necessary.
If a secondary hemorrhage occurs during the operative procedure, the authors recommend tamponade of the bleeding by elevation of the infusion bottle to approximately 70 cm above the eye for several minutes. If the bleeding continues, filling the anterior chamber with an air bubble after evacuating the clot is helpful. If bleeding persists, bimanual bipolar diathermy is extremely helpful when the bleeding site is visible.  At the end of the surgical procedure, filling the anterior chamber with an air bubble is helpful. This also helps to control any secondary bleeding. The corneal incision is closed with two 10-0 nylon sutures. The response in lowering intraocular pressure with the Ocutome instrumentation has been quite successful. Each eye operated on with this technique has shown an initial decrease in intraocular pressure associated with the surgery.
Paracentesis causes little surgical trauma and relieves the elevated intraocular pressure. Paracentesis is especially beneficial in patients with sickle cell trait or sickle cell disease. However, the decrease in intraocular pressure may be transient, and appreciable reduction may not occur in the amount of the formed clot.
Irrigation by a single or double needle technique has the advantage of a small incision. The authors prefer using a diamond blade and entering at the 1-o'clock position in the right eye and at the 11-o'clock position in the left eye. The entry should be through clear cornea. The irrigating needle should extend just through the corneal endothelium, and a slow push-pull maneuver with the single needle technique washes out the erythrocytes from the anterior chamber clot, often leaving the fibrin matrix. To reduce the likelihood of rebleeding during the operative procedure, care should be undertaken not to produce violent alterations in the anterior chamber pressure. If rebleeding does occur, an air bubble can be effectively introduced for tamponade. After a 5-minute wait, irrigation maneuvers can be resumed. Using the single or double needle technique, the surgeon must be particularly careful to have direct visualization of the anterior chamber.
This technique has some disadvantages. Sometimes, maintaining the position of the needle tip in the anterior chamber during the procedure is difficult. A hazardous situation is created when the collar-button type of formed clot occupies both the anterior and posterior chambers. This produces pupillary block with anterior displacement of the iris-lens diaphragm.
Generally, trabeculectomy is not used in smaller hyphemas. However, in patients with total hyphema, trabeculectomy with peripheral iridectomy should be considered. Trabeculectomy is performed with gentle irrigation of the anterior chamber hyphema. This surgery is relatively safe and should be performed early for patients with total hyphema unless the elevated intraocular pressure is medically controlled and resolution of the hyphema is clearly imminent.
The authors currently perform trabeculectomy on patients with total hyphema persisting to day 4 and find it superior to clot evacuation. Several patients referred to the authors' institution have had attempts at clot evacuation. One patient sustained complete iridodialysis related to attempted clot evacuation. In addition, the authors have treated other patients who have been referred after optic atrophy developed with total hyphemas.
When trabeculectomy is performed, the authors use a partial-thickness lamellar technique. Superficial episcleral vessels are coagulated with the bipolar cautery. A superficial lamellar flap is developed through one-third scleral thickness, creating a 3 X 3-mm trap door hinged at the limbal area. A 1 X 4-mm window through the scleral root and the trabecular meshwork into the anterior chamber is fashioned with a diamond knife. Peripheral iridectomy is performed, followed by gentle irrigation of the clot in the area of the trabeculectomy site. Two 10-0 nylon scleral flap sutures are used to close the trabeculectomy site. First the Tenon capsule and then the conjunctiva are closed with a running 8-0 or 9-0 Vicryl suture in a layered, anatomical fashion. Once the conjunctiva has healed, the nylon scleral suture(s) can be lasered to open up the trabeculectomy site (when necessary). This technique has been invaluable in difficult total hyphema cases.
Topically applied mitomycin-C may be a useful adjunct in the prevention of long-term trabeculectomy failure, particularly in patients with trauma and, therefore, a predisposition to inflammation.
Because each of these surgical procedures has its own set of complications, the surgeon should approach each patient with caution and individualize the surgical strategy. Postoperative care should include meticulous control of nausea and emesis to avoid significant fluctuations in intraocular pressure.
Postoperative hyphemas may be seen at the time of surgery or within the first 2-3 days after surgery. If bleeding is identified intraoperatively, it must be identified and coagulated if it does not cease on its own. The surgeon can reduce postsurgical hyphemas by creating internal sclerostomy as anteriorly as possible to reduce bleeding during filtration surgery. In uveitis-glaucoma-hyphema (UGH) syndrome associated with archaic design anterior chamber IOLs and sulcus posterior chamber IOLs, the treatment may require removal of the lens that is causing the problem and replacing it with another lens.
A chaffing lens haptic can be diagnosed with ultrasound biomicroscopy (UBM)  or the video feature of endoscopic cyclophotocoagulation (ECP). ECP may also serve a role in treating areas of chaffing, potentially resolving UGH.