New patients often present with underlying, unseen risks to their health. During the examination, we make our best effort to detect both the obvious and the not-so-obvious. For example, just 1% to 2% of whites younger than 70 years of age have glaucoma; however, we spend a lot of time trying to detect glaucoma in our older patients.1-4 My point: Although a minority of patients actually develop glaucoma, routinely monitoring for it is never an afterthought in clinical practice.

But, many practitioners never consider the possibility of hypercoagulable states, when in fact they should––particularly in younger patients with histories of myocardial infarction, retinal thrombosis or neurologic symptoms consistent with transient ischemic attack (TIA).

Hereditary and acquired thrombophilias (hypercoagulable states) are relatively prevalent in the general population and may be associated with significant ocular and/or systemic morbidity. Deficiencies in the anticoagulation cascade or defective fibrinolysis may increase the risk of thrombosis.

The most common congenital hypercoagulable states that are known risk factors for venous or arterial thrombosis are include antithrombin (AT) deficiencies, protein C deficiency, protein S deficiency and activated protein C resistance (factor V Leiden).5

Acquired conditions include elevated antiphospholipid antibodies, hyperhomocysteinemia, and other risk factors that predispose an individual to thrombosis, such as hypertension, hyperlipidemia, hyperglycemia, carotid artery stenosis and smoking.6 Cumulatively, it is reasonable to estimate that at least 5% of whites may possess a hypercoagulable state.

Virchow’s triad states there are three main causes of thrombosis:7

• Changes in the blood vessel wall.
• Changes in blood flow.
• Changes in blood composition.

Blood flow and blood coagulation are at opposite ends of the spectrum. Defects in clot formation or over-reactive fibrinolysis can lead to hemorrhage. Predisposition to clotting occurs with increased blood cell counts, elevated immunoglobulins, dehydration, hypercholesterolemia, hyperglycemia, or genetic or acquired defects in clot inhibition. As a rule, inheritable hypercoagulabilities are autosomal dominant. Furthermore, traits seen in our patient population are heterozygous, because homozygous traits often manifest in spontaneous fetal abortion or death in early life.

Appropriate Tests for Hypercoagulable States
Patients suspected of having hypercoagulable states require several baseline tests, including:

• Physical evaluation
• Blood pressure/intraocular pressure
• Serology                                   
• CBC with differential
• Fasting blood glucose
• Lipid panel
• Activated protein C resistance (interpretive report)
• Protein C deficiency, antigenic assay (<70% of normal)
• Protein S deficiency, functional assay (<70% of normal)
• Protein S deficiency, antigenic assay (<70% of normal)
• Antithrombin deficiency, functional assay (<85% of normal)
• Antithrombin deficiency, antigenic assay (<25mg/dl)
• Homocysteine levels (high > 12umol/l)
• Antiphospholipid antibody (> 40IgG units)
• Lupus anticoagulant (prolonged PTT)
• Anticardiolipin antibody (> 5 GPLU) 

* Protein C, S, or antithrombin deficiencies are either type I or II. Type I (antigenic assays) deficiencies are quantitative and imply reduced amounts of protein C. Type II (functional assays) imply reduced protein activity. A functional assay should be performed first. If it is abnormal, perform an antigenic assay to determine if reduced amounts of protein C are responsible for function reduction. In either instance, values less than 70% of normal refer to a deficiency in the amount of the particular molecule (i.e., antithrombin) or in the activity level of the protein.

Hereditary States
• Activated protein C resistance (factor V Leiden). Activated protein C resistance is the most commonhereditary cause of venous thrombosis. First reported in 1993, the condition accounts for at least 20% of unselected patients with first-episode thrombosis and 50% of familial thrombosis.8,9 In these patients, activated protein C is unable to degrade factor V because of a point mutation that makes it resistant to degradation. More than 95% of cases are due to a point mutation at one of the arginine cleavage sites known as the factor V Leider mutation.8,9 The heterozygous state occurs in 2% to 5% of all whites (it is less common or exceedingly rare in other ethnic groups).8,10,11  Based on large-population studies, the potential risk for venous thrombosis is five to 10 times more likely for heterozygotes and 50 to 100 times more likely for homozygotes compared to persons with normal factor V.8,10 The risk of arterial thrombosis, however, is uncertain.

• Protein C and S deficiency. Protein C (sometimes called factor XIV) is a proteolytic enzyme produced in the liver that is vitamin K-dependent and fosters anticoagulant activity by inactivating previously activated factor V and factor VII in the clotting cascade. By inactivating factor V, protein C prevents the conversion of prothrombin to thrombin (this is similar to the action of warfarin).

Protein S is another vitamin K- dependent cofactor produced in the liver. It assists protein C action.

Insufficient amounts of protein C or S may result in a tendency for increased or recurrent thrombosis. Protein C deficiency may be congenital or acquired and is more essential than protein S, which acts as a cofactor to protein C. Being autosomal dominant, heterozygotes have protein C levels about half the normal range. Nearly one in 300 patients may possess either type of protein C deficiency.12 In heterozygotes, the first thrombotic event usually presents between age 10 and 50. (Homozygotes are symptomatic shortly after birth, and will suffer imminent death.) The risk of arterial thrombosis is uncertain.

Protein C or S deficiency also may be acquired. Some of the potential causes of acquired protein C or S deficiency include liver disease, pregnancy, oral contraceptive (OCP) use and HIV infection.13

• Antithrombin deficiency. Likely the least common inheritable cause of hypercoagulability, antithrombin (AT) deficiency is acquired as an autosomal dominant trait and is present in 0.17% of the population; however, rates of up to 1.5% have been reported.14,15 Because of its very high risk of venous thrombosis and its autosomal dominant inheritance, a positive family history of venous thrombosis before age 30 is common in AT deficiency. Again, homozygous individuals will die early in life.

There are two main types of AT deficiency. Type I is characterized by inadequate amounts of normal AT, which can be determined by immunologic assay. Type II deficiency is associated with normal levels of AT-III molecules; however, the AT-III molecules do not function properly. Pregnancy, surgery, trauma, or even OCP medications, may reduce AT-III levels 5% to 30%. Severe cases usually require life-long anticoagulant therapy.

• Hyperhomocysteinemia. An elevated homocysteine level has been a known risk factor for venous or arterial thrombosis and cardiovascular disease for at least 30 years.16 The exact mechanism is not known, but several pathways that increase the risk of thrombosis have been reported. Homocysteine is a naturally occurring amino acid that is converted to methionine or cysteine for further use in the body. Vitamins B6, B12 and folic acid are required in this conversion process. The pathway for conversion to cysteine requires vitamins B6, B12 and folate.

Hyperhomocysteinemia may be either genetic, as a result of a mutation in one of the metabolic enzymes in this pathway, or acquired as a result of B6, B12 or folate deficiency. Renal failure, hypothyroidism or certain medications may also cause hyperhomocysteinemia. The condition is relatively common and is found in 5% to 10% of the population.17,18

Elevated plasma homocysteine is more common in patients with pseudoexfoliative glaucoma, which may partially explain the increased risk of cardiovascular disease in patients with pseudoexfoliation syndrome.19,20

In one study, folic acid, B6 and B12 supplementation lowered homocysteine levels by 30%.21 Patients with exfoliation syndrome should be encouraged to have their serum homocysteine levels measured.

Ophthalmic Conditions Associated With Hypercoagulable States

• Protein C resistance: NAION, CRVO, BRVO, branch artery occlusion (BAO) and peripheral retinal neovascularization27,31,46,47 
• Antithrombin: BRVO35
• Protein S and C deficiency: CRVO and retinal vasculitis33,47
• Hyperhomocysteinemia: Pseudoexfoliative glaucoma, CRVO and BRVO19,20,23

• Antiphospholipid antibody: CRVO and BRVO36,38

Acquired States
• Antiphospholipid antibodies. Antiphospholipid antibodies (APA) are acquired antibodies that are directed against phospholipid protein complexes. They are associated with an increased risk of arterial or venous thrombosis. The two main types of APA are the lupus anticoagulant and anticardiolipin antibodies (ACA). Patients may possess one or both of these antibodies.

Anticardiolipin antibodies may be of the IgG, IgM or IgA type; however, IgG usually is associated with APA. The lupus anticoagulant (LA) is often present in patients with systemic lupus, but not always. Possession of the LA may increase the partial thromboplastin time (PTT) test in the laboratory because this antibody binds to phospholipid, which interferes with phospholipids’ ability to serve as an essential cofactor in the coagulation sequence. This explains why it was originally believed that this antibody predisposed affected patients to hemorrhage.

In vivo, however, the opposite is true. PTT-based lupus assays are now designed to have a low concentration of phospholipid to enhance sensitivity of the test when assessing clotting studies––thus an extended PPT is not a false positive.

In the body, LA and ACA increase coaguability. These antibodies may be associated with thrombocytopenia as well as recurrent miscarriages. Any patients with a history of recurrent miscarriage and thrombotic event should be assessed for APAs.

APAs occur in 3% to 5% of the general population. In a recent study, the rate of thrombosis was 1% per year in individuals with no history of thrombosis; 4% per year in patients with systemic lupus erythematosus; 5% per year in individuals with any history of thrombotic event; and 6% per year in individuals with a high IgG titer for ACA (>40).22

• Other causes. Other factors that predispose patients to thrombosis include postoperative state (particularly with a low perioperative hematocrit), trauma, pregnancy, OCP use, obesity, immobility, malignancy, polycythemia, diabetes or systemic hypertension. Primary open-angle glaucoma also may predispose an individual to intraocular thrombosis.

Patient History & Presentation
Thrombotic events in the eye are more common in older age. Younger patients (less than 56 years old) who present with retinal thrombosis or nonarteritic anterior ischemic optic neuropathy (NAION) require special consideration to determine if a hypercoagulable state exists. You must document any reports of previous peripheral or coronary artery disease, or other vascular or occlusive events, as well as any family history of thrombotic disease. Blood glucose, blood pressure and complete blood count with differential are required. A poor diet––particularly a vitamin B-deficient diet––must be determined as well. Finally, be sure to ask whether the patient is pregnant or may be pregnant.

Patients less than 56 years of age with hypercoagulable states often present with central retinal vein occlusion (CRVO) or branch retinal vein occlusion (BRVO). Additionally, numerous studies have analyzed the relationship between accelerated atherosclerosis, venous occlusive disease and pseudoexfoliative glaucoma secondary to hyperhomocysteinemia.19,20,23-28 And, homocysteine has been associated with macular degeneration and dementia (both Alzheimer’s and non-Alzheimer’s).27,28

Venous occlusive disease may be associated with protein C resistance, protein C or S deficiency, antithrombin deficiency or antiphospholipid antibodies.12,29-38 So, always question the patient about any incidents that could initiate TIAs. Recurrent miscarriages, pulmonary embolism or deep vein thrombosis (DVT) are also indicative of a hypercoagulable state.39

It is critical to determine whether a patient has a congenital or acquired hypercoagulable state, because it will help guide treatment decisions and/or lifestyle modifications. DVT, myocardial infarction or accelerated atherosclerosis are all potential difficulties that young patients with a hypercoagulable state may experience.39-43 The use of lifetime anticoagulant therapy and/or supplemental B complex may be required to prevent future thrombotic events. As mentioned previously, B6, B12 and folate supplementation have been shown to reduce homocysteine levels in patients with hyperhomocysteinemia.17,21,44 Specific supplementation recommendations are still under investigation.

• Anticoagulation therapy. Any patient with a thrombophilic state who suffers a venous clot will receive anticoagulation therapy. This can be accomplished with several different medications, such as warfarin, heparin or low molecular weight heparin. Keep in mind that the long-term use of anticoagulation therapy has some risks. Most notably, 3% of patients experience a major hemorrhage––20% of which are fatal.45

For patients with APA, immunosuppressant medications are not likely protective. Instead, aspirin or oral anticoagulants are required.

In addition to vitamin B6, B12 and folate supplementation, patients with hyperhomocysteinemia will likely require anticoagulation therapy. Remember, the use of warfarin is contraindicated during pregnancy.

• Modifiable risk factors. Patients can reduce their chances of thromboembolism by eliminating several risk factors. Well-documented modifiable risk factors include hypertension, hyperlipidemia, hyperglycemia, sickle cell disease, asymptomatic carotid stenosis, atrial fibrillation and smoking. Less well-documented risk factors include obesity, physical inactivity, poor diet/nutrition, alcohol abuse and drug use.46 Any evaluation of a patient with thromboembolic disease and/or associated symptoms requires a comprehensive review of systems to rule out these potential risk factors.

Hypercoagulable states are more common than many of the primary disorders we routinely screen for during a conventional ophthalmic exam. Any younger patient with past or present evidence of arterial or venous occlusion should be examined for one of the many hypercoagulable states in order to begin treatment or prevent future ischemic events.

Dr. Banyas is in private practice and provides skilled nursing services in Pittsburgh.

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