REVISED AND UPDATED EDITION
The jaw once again emerges as the focus of intense disagreement. The jawbone is now replacing the jaw joint (TMJ) as a bone of contention in dentistry. Poor blood circulation in bone gradually causes bone to soften, eventually resulting in bone death (osteonecrosis); this process of deterioration creates hollowed-out spaces in the bone called cavitations.
An osteonecrosis creates cavitations. A cavitation is an expected outcome of osteonecrosis. An osteonecrosis is a disease of ischemia (impaired blood flow) and infarction of bone marrow microcirculation (insufficiency of blood). The term cavitation was first used by one of the most influential orthopedic disease investigators of the century, Phemister (1930) because of the unique ability to "hollow out" bone, producing air filled spaces or cavitations. 1 Recently, a more comprehensive, descriptive term has been applied to this phenomenon in the jawbone (alveolar bone), occurring in the absence of infection (aseptic) that is due to a deficient blood supply (avascular): NICO lesion (neuralgia-inducing cavitational osteonecrosis). 2
Diagnosis of osteonecrosis materializes in the office of the oral surgeon as an acknowledged medical entity. On the other hand, diagnosis of a cavitation appears in the dental office, more frequently in the office of a biological/holistic dentist, producing skepticism and dispute. Why is there so much confusion? Is this a semantic battle of diagnosis? Is this a political battle between mainstream dentistry and holistic dentistry? Does this conflict reflect a polarization between oral surgeons and dentists? The bottom line is simple: the patient is the one who suffers -- not only physically, but emotionally, mentally, and financially. As medical consumers, we have a right to information. As patients, we have a right to freedom of choice based on information that should be accessible.
What everyone should know when investigating the questionable diagnosis of 'cavitation' or the more acceptable diagnosis of 'osteonecrosis' seems to be a well-guarded secret. In essence, vital information is inaccessible to the patient. Furthermore, freedom of choice in dental health care is currently at risk in Arizona. Communicating with dentists in Washington and New Jersey and travelling to Nevada, California and Ohio has given me an all-too-clear panoramic picture of disorder and disagreement. Oral surgeons appear to be unaware of current research in their own field not to mention those dentists currently treating 'cavitations'. Nine months of research, travel, telephone calls, written communication, and utter frustration has finally produced current medical information that reaches far beyond the jawbone and dentistry.
Robert McMahon, DDS, the oral surgeon who is a primary catalyst behind current investigations in maxillofacial osteonecrosis, rises above the diagnostic dilemma ingrained in his profession for decades. Preliminary testing for this jawbone disorder should be threefold: 1)the evaluation for abnormal responses to local dental anesthesia; 2) very careful review of panographic and periapical dental x-rays; 3) careful palpation (feeling the tissues) of the jaws to search for small areas of tenderness. A more definitive test is a blood clotting test for coagulation disorders. Blood disorders are found in up to 80% of NICO patients. This information is based on a NICO research project headed by Dr. McMahon in coordination with Dr. Douglas Triplett (hematologist), Dr. Jerry Bouquot (oral pathologist) and Dr. Charles Glueck. Since 1989, Dr. McMahon has been the clinical investigator of the RIIB Project (Residual Infection in Bone) at Indiana University Medical Center as well as clinical investigator for the NICO Project (Neuralgia Inducing Cavitational Osteonecrosis) at the Cholesterol Center in Cincinnati, Ohio. Dr. Bouquot, who has done over 4,000 biopsy samples of NICO lesions at the Latvala Inflammatory Bone Registry of The Maxillofacial Center in Morgantown, West Viriginia, is coauthor of the bestselling textbook of Oral Pathology and is a reviewer for the New England Journal of Medicine and the Journal of the American Dental Association. Their research speaks for itself, underscoring current findings in hematology in genetic mutations of inherited blood disorders. Medical implications of these investigations not only affect dentistry but also cardiology, gynecology, and orthopedics.
The majority of patients with osteonecrosis have one or more undiagnosed, inherited/acquired clotting disorders.3 In other words, a blood clot cannot properly dissolve, impairing healing by never allowing complete restoration of the microcirculation of the blood. This inherited/acquired hypercoagulable blood state predisposes patients to not only an osteonecrosis but more importantly to thrombosis. Symptoms may arise in the presence of triggering conditions such as dental trauma (extractions, root canals), surgery, immobilization, pregnancy, infection, menopause, exogenous estrogen, estrogen-containing oral contraceptives, alcoholism and glucocorticosteroids. A listing of some of the systemic blood disorders manifesting in an osteonecrosis of the jawbone is appropriate: elevated levels of antiphospholipid anitbodies (APS), the Leiden Factor V gene mutation, the Prothrombin (Factor II) gene mutation, homocysteinemia, fibrinogen deficiencies and fibrolyntic abnormalities, Protein S and Protein C deficiencies, activated protein C resistance, and antithrombin III deficiencies. The research is current: the Prothrombin (Factor II) gene mutation was only discovered in 1996.
The implications of this research are far-reaching. One ramification could affect approximately 6% of the female population: those women having a Leiden V Factor gene mutation who are given oral contraceptives or estrogen supplementation increase their risk for thrombosis 80 times that of the general population. Preventative measures for these thrombosis-prone women are clear: "...all women, prior to starting postmenopausal estrogen supplementation or oral contraceptives, patches or injections should have APCR/Factor V Leiden determinations. "4 Clinical, therapeutic, and pathologic experience point to this disease as a common basis for many facial pain syndromes such as temporomandibular joint disorder (TMJ), atypical facial neuralgia, trigeminal neuralgia and other craniomandibular disorders. The researchers hope that their hypotheses will stimulate research, discussion and additional interest in in-depth case-controlled investigations. 5
Carolyn Inabinet is a free-lance medical writer and is currently a patient of Dr. McMahon. She is author of The Cranial Connection, an introduction to cranial osteopathy. This publication has been endorsed by the American Academy of Osteopathy and has been used at Kirksville College of Osteopathic Medicine as an introductory text. She is the owner and principal instructor at Music Works Academy, Ltd. in Phoenix, AZ.
References:
Phemister, DB. Repair of bone in the presence of asceptic necrosis resulting from fractures, transplantations, and vascular obstruction. J. Bone Joint Surg 1930; 12:769-778.
This phenomenon popularly called 'cavitation' has been reported with a variety of names including Ratner bone cavity, alveolar cavitational osteopathosis, Roberts bone cavity, trigger point bone cavity, pathologic bone cavity and most recently NICO (neuralgia-inducing cavitational osteonecrosis).
Bouquot JE, McMahon,RE. Ischemic Osteonecrosis in Facial Pain Syndromes; A review of NICO (neuralgia-inducing cavitational osteonecrosis) based on experience with more than 2,000 patients. TM Diary 1996; 8:32-39.
Glueck CJ. McMahon RE, Bouquot JE, Rabinovich B. Thrombophilia, hyprfibrinolysis alveolar osteonecrosis of the jaws. Oral Surgery, Oral Medicine, Oral Pathology, 1996; 81:557-66.
Bouquot JE, McMahon,RE. Ischemic Osteonecrosis in Facial Pain Syndromes; A review of NICO (neuralgia-inducing cavitational osteonecrosis) based on experience with more than 2,000 patients. TM Diary 1996; 8:32-39.
Thrombophilia (increased tendency to develop thrombosis) and hypofibrinolysis (reduced ability to lyse thrombi) may be pathogenetic for osteonecrosis of the head of the femur (1-5, 10, 12-16) and jaw (6, 7) in adults and with osteonecrosis of the femur in children (Legg-Perthes disease) (8, 9, 11). In adults and children, thrombophilia or hypofibrinolysis may predispose to thrombotic venous occlusion in bone which leads to intramedullary hypertension, anoxia, and ischemic bone death characteristic of osteonecrosis.
Thrombophilia and hypofibrinolysis are transmitted as autosomal dominant traits, although their effects can be amplified by diseases and drugs (3,4,14,15). The major heritable thrombophilic and hypofibrinolytic disorders pathogenetic for osteonecrosis are as follows(1-16):
Thrombophilic Disorders:
Resistance to activated protein C:
Resistance to activated protein C is the most common currently recognized heritable thrombophilic factor, found in 3-7% of the general population and in 11% to 50% of patients with venous thrombosis (11). Heritable resistance to activated protein C is caused by a CGA-->CAA substitution at position 1691 of the Factor V Leiden gene which blocks binding of activated protein C to the prothrombotic Factor V, producing thrombophilia. Activated protein C resistance (APCR) can be amplified by exogenous estrogens (oral contraceptives, post-menopausal estrogen supplementation) (7).
Protein C deficiency:
When protein C is deficient, factor Va is inadequately suppressed, leading to increased procoagulant activity and increased risk of venous thrombosis. The thrombotic tendency in protein C deficiency can be amplified by exogenous estrogens and by pregnancy.
Protein S deficiency:
Protein S is a cofactor for protein C. When protein S is deficient, factor Va is not adequately suppressed, leading to increased procoagulant activity and increased risk of venous and arterial thrombosis.
Protein C and S deficiency have been found in 2-5% and 5-9% of patients with venous thrombosis. Protein C is activated by an endothelial cell surface thrombin-thrombomodulin complex, and along with its cofactor protein S inhibits the prothrombotic factors V and VIII; hence deficiency in protein C and/or S leads to thrombophilia.
Anticardiolipin Antibodies:
Anticardiolipin antibodies (ACLA) belong to a family of antiphospholipid autoantibodies which are directed against negatively charged phospholipid antigens. Anticardiolipin antibodies are prothrombotic by a variety of mechanisms including inhibition of prostacyclin synthesis, impairment of the thrombomodulin-protein C-protein S anticoagulant system, acting as anti- endothelial cell antibodies, or interacting with platelet membrane phospholipids. ACLA are associated with both venous and arterial thrombi.
Hypofibrinolysis:
Low stimulated tissue plasminogen activator activity (tPA-Fx) often accompanied by high plasminogen activator inhibitor activity (PAI-Fx):
There is an excess of the major inhibitor of fibrinolysis, PAI-Fx, so that the major stimulator of fibrinolysis, tPA-Fx, cannot be activated; the process of lysis of thrombi cannot begin, or is slowed. High plasma triglycerides can increase PAI-Fx, causing a decrease in tPA-Fx.
High lipoprotein (a) [Lp(a)]: In the closed space of bone, we believe that high Lp(a) may reduce fibrinolysis. The apparent hypofibrinolytic action of Lp(a) in bone appears to be augmented by corticosteroid therapy.
Thrombophilia and/or hypofibrinolysis have been found in 76% of 289 patients with osteonecrosis (17). In studies of osteonecrosis of the hip, provided that therapy is begun prior to irreversible segmental collapse of the head of the femur (5, 17), treatment of thrombophilia and hypofibrinolysis can reverse or retard the progression of osteonecrosis. Two adults with early, potentially reversible osteonecrosis of the hip (Ficat stages I, II) had thrombophilia (resistance to activated protein C, protein C deficiency) and were treated respectively with Coumadin (targeted INR of 2-2.5) and with Winstrol (an anabolic-androgenic steroid) 6 mg/day (6,7,11). On therapy, thrombophilia was normalized, severe hip pain resolved, and the progression of their osteonecrosis was reversed/retarded, as shown by MRI/X-ray. Two adults with osteonecrosis of the hip (Ficat stages I, II) had hypofibrinolysis (high PAI-1, high Lp[a]). Winstrol (6 mg/day) normalized fibrinolytic activity, resolved their severe hip pain, and reversed/retarded their osteonecrosis, as shown by MRI and X-ray. In 4 hypofibrinolytic adults (high PAI-1, high Lp[a]) with more advanced osteonecrosis (segmental collapse of the head of the femur-Ficat stages III, IV), Winstrol (6 mg/day) normalized fibrinolysis but had no effect on hip pain, MRI, or X-ray.
DISCUSSION
Our studies in 289 adults and children with osteonecrosis of the hip, knee, or jaw have begun to illuminate the pathogenetics of osteonecrosis (1-17). The majority (about 80%) of patients with osteonecrosis have heritable thrombophilia (increased likelihood of thrombosis) and/or hypofibrinolysis (reduced ability to lyse thrombi).
References:
Glueck, CJ, Glueck HI, Mieczkowski L, Tracy T, Speirs J, Stroop D. Familial high plasminogen activator inhibitor with hypofibrinolysis, a new pathophysiologic cause of osteonecrosis? Thrombosis Haemostasis 1993;69:460-465.
Glueck CJ, Glueck HI, Welch M, Freiberg R, Stroop D, Hamer T, Tracy T. Familial idiopathic osteonecrosis mediated by familial hypofibrinolysis with high levels of plasminogen activator inhibitor. Thrombosis Haemostasis. 1994; 71:195-198.
Glueck CJ, Freiberg R, Glueck HI, et al: Hypofibrinolysis: A common, major cause of osteonecrosis. Am. J. Hematology 1994;45:156-166.
Glueck CJ, Freiberg R, Tracy T, Stroop D, Wang P: Thrombophilia, hypofibrinolysis, and osteonecrosis. Clinical Orthopedics, (ARCO Symposium Issue),1997;334:43-56.
Glueck CJ, Freiberg R, Glueck HI, Tracy T, Stroop D, Hamer T: Idiopathic osteonecrosis, hypofibrinolysis, high plasminogen activator inhibitor, high Lp(a), and therapy with Stanozolol. Am. J. Hematology 1995;48:213- 220.
Gruppo R, Glueck CJ, McMahon RE, Bouquot J, Becker A, Tracy T, Wang P: Anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. Pathophysiology of osteonecrosis of the jaw. J Lab Clin. Med. 1996;127(5):481-488.
Glueck CJ, McMahon RE, Bouquot J, Stroop D, Tracy T, Wang P: Pathophysiology of osteonecrosis of the jaw: Thrombophilia and hypofibrinolysis. Oral Surgery, Oral Medicine, Oral Pathology 1996;81(5):557-566.
Glueck CJ, Glueck HI, Greenfield D, et al: Protein C and S deficiency, thrombophilia, and hypofibrinolysis: Pathophysiologic Causes of Legg- Perthes Disease. Pediatric Research 1994;35:383-388.
Glueck CJ, Crawford A, Roy D, Freiberg R, Glueck HI, Stroop D: Association of antithrombotic factor deficiency and hypofibrinolysis with Legg Perthes disease. Journal of Bone and Joint Surgery 1996;78-A: 3-13.
Glueck CJ, Glueck HI, Tracy T, Speirs J, McCray C, Stroop D: Relationships between lipoprotein (a), lipids, apolipoproteins, basal and stimulated fibrinolytic regulators, and D-Dimer. Metabolism 1993;42:236-246.
Glueck CJ, Brandt G, Gruppo R, Crawford A, et al. Resistance to activated protein C and Legg-Perthes disease. Clinical Orthopedics and Rel. Res. 1997; 338:139-52.
Glueck CJ, Fontaine RN, Gupta, A, Tracy T, Wang P. A major gene for plasminogen activator inhibitor activity.J. Invest. Med. 1997;314A.
Glueck CJ, Fontaine, RN, Gupta, A, Tracy T, Wang P. 4G/4G and 4G/5G polymorphisms in the plasminogen-activator inhibitor gene promotor: associations with plasminogen activator inhibitor activity, insulin, and triglycerides. J. Invest. Med. 1997; 330A.
Glueck CJ, Fontaine, RN, Gupta A, Tracy T, Wang P. Familial 4G/4G/ homozygosity in the plasminogen-activator inhibitor gene promotor, hyperinsulinemia, thrombosis, and osteonecrosis. J. Invest. Med. 1997; 331A
THROMBOPHILIA AND HYPOFIBRINOLYSIS: PATHOGENETIC ETIOLOGIES OF OSTEONECROSIS. CJ Glueck, R Freiberg, R Gruppo, A Crawford. Jewish Hosp, Cincinnati, Ohio., In Press, Thrombosis and Haemostasis, 1997
Thrombophilia and hypofibrinolysis may be pathogenetic for osteonecrosis (ON) of the femur in adults and children, causing thrombotic venous occlusion in bone, intramedullary hypertension, and ischemic bone death. Thrombophilia and hypofibrinolysis were assessed in 291 patients with ON, 103 adults in 3 cohorts with ON of the hip (n=30,31,42), 64children with ON of the hip, and 124 adults with ON of the jaw in 2 cohorts (n=49, n=55). Of the 291 patients, 75% had familial thrombophilia /hypofibrinolysis. Only 14 of 64 (22%) children with ON had normal coagulation measures. In 64 children with ON, the mutant Factor V gene was found in 13% vs 4% of healthy normal children (p=.02), low protein C in 28% vs 3% (p=.005), and low stimulated tissue plasminogen activator activity (tPA-Fx) in 36% vs 14% (p=.05). In 3 cohorts comprising 103 adults with ON of the hip, only 13%, 26%, and 33% respectively had normal coagulation measures. In these 103 patients, low tPA-Fx (usually with high plasminogen activator inhibitor activity [PAI-Fx]) was found in 28% vs 6% of normal controls (p=.02), and high Lp(a) in 40% vs 22% (p=.001). In the 42 patients where anticardiolipin antibodies (ACLA) were measured, 22% had high IgG vs 5% of controls (p=.02), 22% had high IgA vs 3% of controls (p=.008). Of 124 patients with ON of the jaw, only 27% had normal coagulation measures. The mutantFactor V gene was found in 22% of patients vs 0% of controls (p=.001), low protein C in 14% vs 0% (.02), and high PAI-Fx in 18% vs 8% (p=.03). Most (75%) children and adults with ON have heritable thrombophilia and/or hypofibrinolysis which, we postulate, facilitate thrombotic blockage of venous drainage of bone, subsequent increase in bone venous pressure, reduced arterial perfusion, anoxia, and subsequent ischemic bone death (osteonecrosis).
Abstract and Articles in press:
16. AMELIORATION OF OSTEONECROSIS BY TREATMENT OF THROMBOPHILIA AND HYPOFIBRINOLYSIS. R Freiberg, CJ Glueck. Jewish Hospital, Cincinnati, Ohio, USA. In Press. Thrombosis and Haemostasis, 1997.
Thrombophilia and hypofibrinolysis may be pathogenetic for osteonecrosis of the femur, causing thrombotic venous occlusion in bone, intramedullary hypertension, anoxia, and ischemic bone death (osteonecrosis [ON]). We assessed whether treatment of thrombophilia /hypofibrinolysis would ameliorate ON. Familial thrombophilia or hypofibrinolysis in 9 adults with osteonecrosis were treated with Coumadin (target INR 2.5) or Winstrol (6 mg/day) (anabolic-andro genicsteroid), with follow-up of thrombophilia/ hypofibrinolysis for about 1 year on therapy. Two adults with early ON of the hip (Ficat stages I, II) had familial thrombophilia (resistance to activated protein C, protein C deficiency). On Coumadin and Winstrol, respectively, thrombophilia was normalized, severe hip pain resolved with resumption of usual activities, and was reversed/retarded, as shown by MRI/X-ray. Three adults with early ON (Ficat stages I, II) had hypofibrinolysis (high plasminogen activator inhibitor activity [PAI-Fx], high Lp[a]). Winstrol normalized fibrinolytic activity, completely resolved severe hip pain with resumption of usual activity, and reversed/retarded ON, by MRI/X-ray. In 4 hypofibrinolytic adults (high PAI-Fx, high Lp[a]) with more advanced ON (segmental collapse of the head of the femur (Ficat III, IV), Winstrol normalized fibrinolysis without improving hip pain, activity restriction, or MRI/X-ray progression of ON. If therapy to normalize thrombophilia/ hypofibrinolysis is begun early in ON, before irreversible collapse of the head of the femur, progression of ON can be stopped and often reversed. Normalization of thrombophilia/hypofibrinolysis cannot improve ON, if started after collapse of the head of the femur. Most patients with osteonecrosis have thrombophilia and/or hypofibrinolysis as a major underlying pathoetiology. When assessing a patient with osteonecrosis one should measure the major determinants of thrombophilia: resistance to activated protein C (and, if abnormal, do the PCR assay for the Mutant Factor V Leiden gene), protein C, protein S, anticardiolipin antibodies IgG and IgM, and the lupus anticoagulant. Also, one should measure the major determinants of hypofibrinolysis: plasminogen activator inhibitor 1 and stimulated tissue plasminogen activator activity, and lp(a). With these measures in hand, the underlying coagulation defect can be treated and if the osteonecrosis is Ficat I or II, it can be reversed by treatment of the coagulation defect.
17. Glueck CJ, Freiberg R, Gruppo R et al. Thrombophilia and hypofibrinolysis: Reversible pathogenetic etiologies of osteonecrosis in adults and children. In Urbaniak JR, Jones, TP Jr(eds). Osteonecrosis: etiology, diagnosis, and treatment. Rosemony, IL. Amer. Acad. Orthopedic surgeons. 1997;pp105-110.
Recent progress in amelioration of osteonecrosis by treatment of thrombophilia and hypofibrinolysis.
AMELIORATION OF OSTEONECROSIS BY TREATMENT OF THROMBOPHILIA AND HYPOFIBRINOLYSIS. CJ Glueck, RA Freiberg, R Gruppo, P Kirk, RN Fontaine, A Gupta, T Tracy, P Wang. Cholesterol Center, Jewish Hospital, Cincinnati, Ohio. J Invest Med 1998;46:227A
Fifteen patients with Ficat stage I or II osteonecrosis (ON), 5 with thrombophilia, and 10 with hypofibrinolysis, were treated to determine the effect of therapy (Rx) on the symptomatic and radiographic progression of ON. To assess symptomatic relief, pain was rated daily by 5 numeric scores. MRI scans were done initially and at 6-8 months on Rx. Of the 5 thrombophilic patients, 2 had homocysteinemia, 1 was heterozygous for the mutant Factor V Leiden gene, 1 had high anticardiolipin antibody (IgG). They were treated for 26 weeks (range 6-42) with folic acid/B6 (n=2), or coumadin (n=2), or low molecular weight heparin (n=1). Twenty-two of 25 (88%) pain scores were improved on Rx (p<.001). On Rx, 4 of 5 patients became pain free. MRIs in 3 improved after 30, 38, and 39 weeks on Rx. Of the 10 hypofibrinolytic patients, 7 had high plasminogen activator inhibitor activity (PAI-Fx), 4 were homozygous and 3 heterozygous for the mutant PAI-1 gene, 4 had high Lp(a). They were treated with the anabolic-androgenic steroid, Winstrol (6 mg/day) for 11 weeks (range 3-31). Sixteen of 46 (35%) of pain scores were improved on Rx (p<.001), 23 (50%) were unchanged, and 7 (15%) worsened. On Rx, 1 of 10 patients became pain free; MRIs in 4 patients were unchanged after 4, 10, 12, and 31 weeks on Rx. Rx for thrombophilia was more successful than for hypofibrinolysis with 100% improvement in overall pain score vs 40%, p=.04, and 100% vs 33% improvement in mood score, p=.028. After covariance adjusting for severity of pain before Rx, pain relief in the thrombophilic group was greater than in the hypofibrinolytic group (p=.02). Rx of thrombophilia and hypofibrinolysis ON before segmental collapse of the head of the femur shows promise in amelioration of ON.
HERITABLE THROMBOPHILIA AND HYPOFIBRINOLYSIS: COMMON PATHOETIOLOGIES OF RETINAL VEIN THROMBOSIS. L Vadlamani, CJ Glueck, H Bell, A Gupta, RN Fontaine, P Wang, T Tracy, R Gruppo, D Stroop. Cholesterol Center, Jewish Hospital, Cincinnati, Ohio
In 17 patients, our specific aim was to determine whether heritable thrombophilias and hypofibrinolyses were pathoetiologic risk factors for retinal vein thrombosis (RVT). Coagulation measures in 17 patients with RVT were compared to those in healthy normal controls. Three of 17 patients (18%) were heterozygous for the thrombophilic Factor V Leiden G1691A mutation versus 7 of 233 controls (3%), p=.023. Two of 17 (12%) patients had normal alleles (5G/5G) for the plasminogen activator inhibitor (PAI) gene promoter; 88% were heterozygous or homozygous for the 4G polymorphism. Of 234 controls, 85 (36%) had 5G/5G; 149 (64%) were either heterozygous or homozygous for the 4G polymorphism, p=.03. Of 14 RVT patients with measures of dilute Russel's viper venom time, a thrombophilic antiphospholipid antibody, 6 (43%) were abnormal (>38.8 sec) vs 1/30 (3.3%) controls p=.002. Patients were more likely (8/16, 50%) to have high levels of hypofibrinolytic Lp(a) (>35 mg/dl) than controls (5/40, 13%), X2=9, p=.003. Patients were more likely to have high levels of the major determinant of hypofibrinolysis, plasminogen activator inhibitor activity (PAI-Fx). PAI-Fx was high (>22 U/L) in 6/16 patients (38%) vs 1/40 controls (2.5%), X2=12.8, p=.001. Hypofibrinolytic disorders often occurred in clusters. Median Lp(a) in patients with the 4G/4G genotype was 62 mg/dL vs 5.3 in 4G/4G controls (p=.048). Patients with retinal vein thrombosis commonly have both thrombophilia and hypofibrinolysis, opening avenues to protection of the contralateral eye by anticoagulant therapy, and to prevention of thrombosis in other venous and arterial beds.
