review the pathophysiology and various causes of hyphema
review management considerations for patients with hyphema
review the positive and negative predictive value
A 23 year old male presents to the emergency department after being assaulted 30 minutes previously. While under the influence of alcohol, he was in an altercation with another male on the street and suffered a blow to the left eye. He reports pain in around the left eye, as well as slightly decreased vision. There are no symptoms of diplopia, flashes, floaters, or visual field loss.
On exam, there is bruising of the left eyelid but no other apparent signs of trauma. Visual acuity is 20/20 and 20/50 corrected in the right and left eyes, respectively. Extraocular movements and confrontational visual fields are normal. Intraocular pressures are R 12 and L 16. Pupils are symmetric and both reactive to light, although the left appears more sluggish. There is no RAPD. Anterior segment exam is shown in the figure below of the left eye. The anterior chamber is deep with 2+ RBCs, 1+ WBC, 1+ pigment, 3+ flare, and wisps of fibrin near the pupillary margin. The lens and retina appear normal.
Which systemic condition would make this individual most prone to complications from his hyphema?
INCORRECT - although haemophilia should be considered in any patient with a spontaneous hyphema, it does not necessarily increase the risk of complications if managed appropriately.
• Sickle cell disease
CORRECT - sickle cell disease is a major risk factor for complications secondary to hyphema, and in fact it is recommended that all non-Caucasian individuals should have a sickle screen as a routine investigation.
• Sickle cell trait
INCORRECT - patients with sickle cell trait should be managed similar to those with sickle cell disease, although they are at significantly less risk of complications related to erythrocyte sickling.
• Idiopathic thrombocytopenia purpura (ITP)
INCORRECT - ITP is a condition characterized by a decrease in the number of platelets. Although a risk factor for hyphema, it does not increase the risk of complications to the degree that sickle cell disease does.
Hyphema is defined as blood within the anterior chamber and is caused by disruption of blood vessels within the iris or ciliary body.1 Most often, it occurs as a result of blunt or penetrating trauma to the eye, and is often found in association with other ocular injuries. It may also occur spontaneously, especially in the presence of a coagulopathy or vascular abnormality. In and of itself, it is generally a self-limiting condition causing no permanent vision loss. However, the related traumatic effects in the eye and orbit can be multiple.2
The mean annual incidence of hyphema is approximately 17 per 100,000 population per year,3 slightly more common in children and young adults.4 It has a male predominance of 3 to 1.5 Mostly the term hyphema refers to the visible (i.e. macroscopic) form of hyphema, but it should be noted that a small degree of hemorrhage may occur which is not visible to the naked eye- this is termed a microhyphema.
Any disruption of the fragile and vascular anterior uveal structures (i.e. iris and ciliary body) can cause bleeding into the anterior chamber. Both blunt and penetrating trauma may cause hyphema. In the setting of blunt ocular trauma, there is antero-posterior compression of the globe and simultaneous lateral globe expansion which induces stress on anterior chamber angle structures. In addition, there is posterior displacement of tissue and a resultant fluid wave in the aqueous and vitreous that stretches limbal vessels and displaces the iris and lens. The most common site of bleeding in such a scenario is the anterior aspect of the ciliary body, although any of the aforementioned structures may be injured. 6 On the other hand, penetrating injuries may cause hyphema by direct damage to blood vessels and this can be potentiated by hypotony.7
Approximately 40% of hyphemas are characterized by the formation of a clot which most frequently adheres to the iris. In the setting of an uncomplicated hyphema, the natural course is that of gradual absorption of blood over the course of about a week7 as red blood cells are drained via the trabecular meshwork and either the canal of Schlemm or juxtacanalicular tissue. Studies have shown that normal red blood cells are drained from the anterior chamber as relatively intact, undamaged cells.7
Again, the most common cause of hyphema is trauma. In urban centres, approximately 2/3 of traumatic cases are due to blunt trauma and 1/3 due to penetrating trauma.7 Overall, sports injuries account for about 60% of cases.8 In children, projectile injuries account for a fairly large proportion of hyphemas, while blows to the eye account for a large proportion in adults.7
Other causes of hyphema include:
· Surgery: hyphema may be an intraoperative, early postoperative or late postoperative complication of intraocular surery.9 Intraoperative bleeding has been reported with procedures such as peripheral iridectomy, cataract, and cyclodialysis surgery. Early postoperative bleeding is often due to a traumatized uveal vessel that was in spasm during surgery but dilates afterwards to cause hemorrhage, while late postoperative bleeding is often due to the formation of new blood vessels across a surgical wound that bleed when the wound is manipulated.7
· Laser treatments: anterior segment laser treatment such as SLT or ALT are occasionally complicated by hyphema.10 11
· Rubeosis iridis: neovascularization of the iris (rubeosis iridis) is a relatively common cause of spontaneous hyphema. The differential diagnosis of rubeosis iridis includes proliferative diabetic retinopathy, ocular ischemic syndrome, retinal vein occlusions, chronic retinal detachments, and others (see figure 1). 7
· Vascular abnormalities
o Vascular iris tufts: vascular iris tufts are rare, benign idiopathic asymptomatic lesions that occasionally may cause a spontaneous hyphema.12 Most lesions can be watched conservatively, although occasionally laser photocoagulation may be considered if there is recurrent hemorrhage.13
o Juvenile Xanthogranuloma: juvenile xanthogranuloma (JXG) is a rare benign cutaneous disorder that presents predominantly with skin lesions during infancy.14 Ocular lesions are typically bilateral and most often involve diffuse or discrete iris nodules which can be vascular and bleed spontaneously to result in hyphema.14 Lesions may be present in other ocular structures including the ciliary body, anterior choroid, cornea, lids, and orbit.14
· Malignancies: a variety of malignancies may be associated with spontaneous hyphema. These include:
o Uveal melanoma
o Leukemia (ALL and AML)
o Histiocytosis X
o Metastatic tumors
o Others: Other tumors: lacrimal gland choristoma,16 microhemangioma17
· Uveitis: chronic uveitis, especially secondary to herpes zoster, may be associated with hyphema7
· Blood dyscrasias: underlying abnormalities in clotting or platelet function increase the risk of hyphema- such patients may suffer hyphema with minimal trauma or spontaneously. Disorders that have been reported to cause hyphema in the literature include haemophilia,18 von Willebrand disease, Glanzmann’s thrombasthenia,19 and immune thrombocytopenia purpura20
· Medications: both anticoagulants (e.g. warfarin) and antiplatelet agents (e.g. Plavix, Aspirin) increase risk of hyphema.7 A hyphema may occur spontaneously in a patient on warfarin, particularly with a supratherapeutic INR.21
· Child abuse: an important diagnosis to consider in children with hyphema without a clear cause (i.e. no evidence of ocular or systemic disease/medications).7
o Valsava maneuver: rarely, a hyphema has been reported to occur secondary to a valsava maneuver,22 the mechanism of which involves elevation of venous pressure in the head and neck and corresponding rise in intraocular venous pressure.22
o Iris nevus23
o Myotonic dystrophy
o Idiopathic: idiopathic hyphema has been reported but is extremely rare.
Additional causes of hyphema in infancy include persistent hyperplastic primary vitreous, retinopathy of prematurity, vascularized pupillary membrane, iris hemangioma, fetal distress syndrome, medulloepithelioma, leukemia, other blood dyscrasias, and metastatic tumors.14
Patients with hyphema typically present with vision loss, which is variable according to the degree of hyphema and presence of other injuries/underlying conditions. Patients with a microhyphema may have only slightly blurred vision, whereas patients with a full hyphema may present with complete blindness.2
As discussed in the pathophysiology section, the natural course of an uncomplicated hyphema is that of gradual resorption of blood over the course of about a week, during which patients will gradually regain vision. Unfortunately, a significant proportion of patients experience complications during this time that can negatively affect their prognosis. We will highlight the major complications below:
Rebleeding (also known as secondary hemorrhage) is the occurrence of a new hemorrhage after the initial trauma.2 It is manifested as an increase in size of the hyphema or appearance of a layer of fresh blood in the anterior chamber.7 Secondary hemorrhage typically occurs 3-5 days after the initial hemorrhage and is thought to be due to clot lysis and retraction within traumatized vessels.2 Studies suggest it is more common in African American individuals, occurring in approximately 25%.24 It should be noted that in patients with total or near total hyphemas, the edges of the clot often appear brighter due to clot dissolution and can mimic the appearance of secondary hemorrhage.6 Rebleeding also increases the risk of other complications including increased IOP, cornea bloodstaining, optic atrophy, and peripheral anterior synechiae.7 It also often signifies poor prognosis and substantially increases the likelihood of requiring surgical intervention.25 The relationship between size of initial hyphema and risk of rebleeding is unclear.
- Intraocular pressure elevation
Approximately 1/3 of all hyphema patients experience an increase in intraocular pressure.5 In the setting of traumatic hyphema, this may be due to occlusion of the trabecular meshwork (i.e. by clot, inflammatory cells, and erythrocytic debris), or pupillary block secondary to a collar button-shaped clot involving both the anterior and posterior chambers.7 In general, patients with larger hyphemas are more likely to experience elevation of intraocular pressure but this correlation is weak. Secondary hemorrhage is also a risk factor.7 The usual duration of IOP elevation is 5-6 days. Some patients may also have a pattern whereby IOP is initially elevated, then decreases for a few days before increasing again.
Intraocular pressure must be monitored closely in all patients with hyphema, preferably every day during the immediate follow-up. An IOP of 35 mmHg or more sustained for 5-7 days or more can cause irreversible optic nerve damage, while an IOP of 50 or more can do the same in 3-5 days.26 (this is called the “200 rule” for pressure concern- i.e. 3 days of 65, 4 days of 50, 5 days of 40, 6 days of 35, etc.)
Optic atrophy is a complication that may develop in patients with hyphema from either traumatic optic neuropathy relating to the original injury, or glaucomatous damage secondary to increased IOP. Glaucoma occurs in 0-20% of patients with a history of traumatic hyphema and may arise from damage to the trabecular meshwork (often with angle recession), descemetization and fibrosis of the trabecular meshwork, siderosis of the trabecular endothelium, or peripheral anterior synechiae formation leading to secondary angle closure glaucoma.27 Ghost cell glaucoma may also occur months after the initial injury- this occurs when red blood cells lose haemoglobin to become transparent (“ghost cells”), migrate to the vitreous, and circulate back towards the anterior chamber to block the trabecular meshwork.
Corneal bloodstaining refers to corneal discoloration due to extra and intracellular haemoglobin particles as well as intracellular hemosiderin within the cornea. It occurs in 2-11% of patients (higher with total hyphema),6 and is a major cause of visual impairment with the condition. In children, it may even cause amblyopia.28 It almost always requires an elevated IOP, although case reports have described patients without elevated IOP. Apart from intraocular pressure, risk factors include large hyphema, rebleeding, prolonged clot duration, and corneal endothelial cell dysfunction. 7
The pathophysiology of corneal bloodstaining has been studied extensively and thought to involve a multi-step process. First, haemoglobin is released from red blood cells in the anterior chamber and diffuses across Descemet’s membrane to form aggregates within the membrane as well as the stromal lamellae.29 Second, keratocytes in the stroma phagocytise and metabolize the haemoglobin particles to produce intracellular hemosiderin.29 This intracellular hemosiderin, if excessive, can induce keratocyte necrosis, possibly due to cytotoxic oxygen species being exposed to light.29, 30 Histologically, the result is a decrease in cellularity of the posterior stroma.29 The released hemosiderin is then phagocytised by keratocytes in the anterior stroma.29 On microscopy a gradient of haemoglobin degradation can be seen from posterior to anterior corneal stroma with hemosiderin-laden keratocytes predominating anteriorly.29, 30
The first sign of corneal bloodstaining is usually a straw yellow discoloration of the deep stroma, especially centrally. This precedes gross staining by 24-36 hours.7 After resolution of the hyphema, bloodstaining usually slowly improves, clearing from the periphery towards the centre. This improvement often takes months and sometimes even years.7 31 Clearing of the blood staining occurs due to a combination of phagocytic action of keratocytes, epithelial cell shedding, and diffusion of haemoglobin breakdown products into the conjunctival circulation. 32 31
Both posterior and peripheral anterior synechiae (PAS) may occur with hyphema, the latter (i.e. PAS) are more common and occur due to inflammation or clot organization. Patients with hyphema present for more than one week are at greatest risk.7 Posterior synechiae usually form secondary to concurrent iritis/iridocyclitis.
Sickle cell trait/disease
Sickle-cell disease is an autosomal recessive genetic blood disorder characterized by red blood cells that assume an abnormal, rigid, “sickle” shape. It occurs secondary to a point mutation in the gene encoding the B-globin chain of haemoglobin, creating the haemoglobin variant Hb S.33 Individuals homozygous for this mutant B-globin are said to have sickle cell disease (sickle cell anemia, HbSS), while individuals with only one mutant copy are said to have sickle cell trait (HbAS). Approximately 1/3 of people in sub-Saharan Africa are thought to be carriers of the condition (i.e. sickle cell trait), presumably because of a fitness advantage with respect to malaria infection.33 Approximately 1 in 12 African Americans are carriers.
In low-oxygen or stressful environments such as acidosis or dehydration, red blood cells in affected individuals “sickle” to assume an inelastic, irregular shaped cell that is unable to deform passing through narrow capillaries, resulting in vessel occlusion and ischemia. Hemolysis may also occur secondary to destruction of the sickled cells within the spleen and resultant anemia (“haemolytic crisis”). Other major complications include a vaso-occlusive crisis, splenic sequestration, aplastic crisis, and stroke. Individuals with sickle trait are rarely symptomatic from a systemic standpoint.
Sickle cell disease/trait is of special relevance in the management of hyphema. The anterior chamber is a relatively hypoxic and acidotic environment and tends to induce sickling of red blood cells.2 Studies have shown erythrocyte sickling to be greater in aqueous than in blood.33 When such sickling occurs, the normal drainage of red blood cells through the trabecular meshwork is impaired and the cells cause resistance to aqueous outflow, increasing risk of IOP elevation.34 With increased IOP, aqueous perfusion and oxygenation is further decreased to further potentiate sickling, causing a positive feedback loop.33
Patients with both sickle cell disease and trait are at risk of such sickling in the setting of hyphema. They are also at higher risk of other complications such as optic nerve atrophy and secondary hemorrhage, and have a poorer prognosis overall.35 Elevated intraocular pressure also tends to be poorly tolerated in patients with sickle cell disease- especially with IOP >40 mmHg, central retinal artery occlusion (CRAO) may develop.36 It should be noted that patients with sickle cell disease may have profound elevation of IOP with even a small hyphema.7