Hypercoagulation: Why The Importance for Gulf War Veterans

In reviewing obituaries and talking to several widows of Gulf War Veterans that suffered with unknown illnesses or had died of cardiac events or other causes the writer an ill gulf war veteran nurse having been a cardiovascular and critical care clinical specialist has alot of questions that are still to be answered.  What are the connecting points on our gulf war illness and the medical problems involving chronic fatigue that are not being addressed by the doctors at the Veterans Affairs and civilian doctors? 

Why are we having dental problems, vision problems, degenerative discs in the spinal cord? What testing is not being done that could help identify problems in our body?  What potential treatments might be important to consider? 

Why are we having early deaths for gulf war veterans?  What can be looked at to improve our quality of life?  What can be looked at to improve our health and increase our chances of surviving longer to meet our life goals? 

Can some of these answers in research be used now in clinical evaluation and care for us whether it be with the VA or civilian doctors?  What can I give the other veterans of the gulf war to help them stay alive?  What can I do to help the situation with information that could make the doctors and health care providers to pay closer attention and look for ways to help us?  What can I give researchers to pursue answers for us?

I can bring up concerns we are all having and keep digging and pushing for clues and potential answers.  I can provide the research articles that might need further evaluation not just by the researchers but our health care providers.  I can provide the information flow to veterans, researchers, health care providers to have them also review it and think and help make the connections and to discuss what they can do better.  I can open the door to the doctors and the researchers and veterans to keep asking informed questions for the goal of making a difference for each of us. 

I can share the research and push the VA and the doctors and researchers to make a difference in each of our lives.  I can look for other doctors and researchers that are willing to get involved and help.  I can encourage my fellow veterans that they can be a part of this also!  They can share the articles, they can push for communication to the doctors, they can push to have doctors and researchers and the veterans all sharing and communicating.

 I was there as a very educated and experienced nurse to care for my fellow troops, now veterans, my job, my duty as an officer and as a nurse remains to this day! I want answers not just for myself but for each of the hundreds of thousands of my fellow gulf war veterans who are all suffering.

Now why am I focused on the hypercoagulation problem?  Because I feel it is one piece of the situation that we all need to discuss.  How many gulf war veterans have hypercoagulation problems?  How many of the gulf war veterans with chronic fatigue and gulf war illness have even been tested for hypercoagulation?  If this is a problem, it is not helping our medical condition it is complicating it! 

In medicine, there is not just one thing we do to help treat any given condition.  In a complex medical situation there are usually several items we as health care providers are testing for or offering treatment to address or correct that can help the overall quality of life.

So I present the information that others in the Chronic Fatigue medical groups have in order to further the research sharing, the medical care possibilities, and hopefully make us better health wise and maybe even save some lives of our gulf war veterans!  This article below was a starting point for Dr Berg in his research into clinical lab findings that would help Chronic fatigue patients.  Others, doctors in treating Chronic fatigue patients have found it of value!

Hypercoagulation Disorders in Osteonecrosis
 
©The Maxillofacial Center for Diagnostics & Research 

The Maxillofacial Center, 165 Scott Avenue, Suite 100, Morgantown, WV 26508 USA
Phone: 304-292-4429   Fax: 304-291-5149    Email: [email protected]
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Brief Overview of Coagulation Disorders in Osteonecrosis

Ischemic osteonecrosis is not so much a disease in its own right as it is the natural consequence of a wide variety of systemic and local factors capable of compromising marrow blood flow.  Recent investigation has found that the more than 80% of persons with osteonecrosis of the hips, knees or jaws have a previously undiagnosed clotting disorders or “hypercoagulable state” (Table 1). These coagulopathies typically are not picked up on routine clotting tests but appear to provide a logical pathophysiological mechanism for marrow infarctions and clots, with subsequent inflammatory increase in intramedullary pressures and stagnation of blood.  Clots in capillaries and veins of the marrow are found in approximately 1 of every 7 biopsy samples of jawbone osteonecrosis and in only 1 of every 242 biopsy samples from routine bone infection of dental origin, i.e. periapical granulomas and inflamed periapical cysts.

Hypercoagulability is the increased risk of thrombosis or blood clot formation in blood vessels. The disorder comes in two forms, thrombophilia (increased tendency to form thrombi) and hypofibrinolysis (reduced ability to lyse thrombi once they form), both of which imply poor control of one or more aspects of the incredibly complicated coagulation homeostasis system. At least 6% of Western populations have an hypercoagulability state, usually as an autosomal dominant inherited defect or mutation. Hypercoagulability can also be caused by an ongoing environmental stimulus to thrombosis, such as a focal infection, medications (estrogen & corticosteroids), or autoimmune diseases ( lupus erythematosus). 

Moreover, the inherited disorders can be amplified by environmental factors.  Table 2 lists the specific hypercoagulation disorders found thus far in patients with osteonecrosis of the hips, knees and jaws.  Hypercoagulability should be suspected in persons with one or more of the following clinical features: thrombosis at a young age, family history of thrombosis, recurrent thrombosis, thrombosis in an unusual site, thrombosis for which no underlying mechanism can be identified, thrombosis in pregnancy, frequent spontaneous abortions, hip pain or replacement at an early age, stroke or myocardial infarction at an early age, osteonecrosis, Behçet’s disease, chronic fatigue syndrome, headache, fibromyalgia, idiopathic chronic facial pain, idiopathic death of tooth pulps.

Before the 1990s, the chances of identifying the underlying coagulation defect was extremely small, but ongoing research since then has established tests for more than 15 different disorders, most of them previously unknown to medicine (no test, no disease).

Treatment with the anticoagulants Coumadin, heparin and warfarin (targeted INR of 2.0-2.5), and with the anabolic-androgenic steroid Winstrol (6 mg daily) has normalized thrombophilia and hypofibrinolysis in osteonecrosis patients, with reversal or retardation of the osteonecrosis, although some patients with normalized fibrinolysis experienced no change in symptoms or in imaging features.

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Types of Thrombophilia (Increased Tendency to Form Clots)

Activated protein C resistance (APCR, RAPC). APCR is the most common heritable thrombophilic factor, found in 3-7% of the population. It 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. APCR can be amplified by exogenous estrogens and pregnancy. Increased risk of venous thrombosis, stroke and osteonecrosis; APCR is found in more than half of all patients with deep venous thrombosis, in 11-64% of persons with hypercoagulability, and in 18% of osteonecrosis patients.

Anticardiolipin antibodies and lupus anticoagulant (ACLA). These are antiphospholipid autoantibodies which are directed against negatively charged phospholipid antigens. They are prothrombotic via several mechanisms, including inhibition of prostacyclin synthesis, impairment of the thrombomodulin-protein C-protein S anticoagulant system, action as anti-endothelial cell antibodies, or interaction with platelet membrane phospholipids.

Associated with increased risk of venous thrombosis, arterial thrombosis, osteonecrosis, coronary artery disease.  Antiphospholipid antibody syndrome (APS). Persons with autoimmune or chronic “connective tissue” diseases, especially lupus erythematosus, chronic fatigue syndrome and myofascial pain syndrome, can develop antibodies directed against certain protective proteins (B2GP1 & Anagen V) in the walls of endothelial cells.

These patients have increased markers of coagulation activation and increased blood viscosity due to the generation of Soluble Fibrin Monomer (SFM). The immune attack is typically triggered by an infection, especially with CMV, HHV6, mycoplasma, chlamydia and pneumonia-related bacteria, with the pathogen-mediated immune response creating antibodies which cross react with the protective endothelial proteins and dislodge them from the cell surface. Additionally, cytokines released during the infection cause endothelial cells to down regulate antithrombotic activity (via Thrombomodulin & tPA) in favor of prothrombotic expression of Tissue Factor (TF). TF and PS presence allows binding of the coagulation tenase and prothrombinase complexes to endothelial cell surfaces, which then results in the generation of thrombin and SFM . SFM dimerizes easily, increasing blood viscosity and precipitating out on the surface of endothelial cells as fibrin deposits, creating local ischemia by blocking nutrient and oxygen delivery in the capillary beds. Initially, endothelial coating is all that is seen, but long-standing cases typically show complete blockage of vessels, i.e. infarction.

Three-fourths of all patients with APS have a hereditary defect in a coagulation regulatory protein, especially protein C, protein S, Factor V-Leiden, prothrombin gene mutation, PAI-1, Lp(a), and hyperhomocysteinemia. APS patients without a coagulation regulatory defect are much less symptomatic and may be completely asymptomatic. Many patients have mild thrombocytopenia. The syndrome should be suspected when an unexplained prolongation of the partial thromboplastin time (PTT) occurs. Testing is best performed in the absence of heparin or warfarin. Chronic illnesses due to a coagulation protein defect in APS patients include: infertility (recurrent fetal loss), transient ischemic attack (TIA), early myocardial infarction, early stroke, osteonecrosis, chronic fatigue syndrome, fibromyalgia (CFS/FM), Crohn’s disease, irritable bowel disease, multiple sclerosis, Sjögrens syndrome, Lyme disease.

Apolipoprotein E (ApoE) mutation. Persons homozygous for the ApoE-2 allele have an increased risk of familial type III hyperlipidemia, while those with the ApoE-4 allele are at increased risk of atherosclerosis vascular disease and increased levels of total cholesterol and ß-lipoprotein; risk for osteonecrosis is unknown. Evaluation for this mutation is indicated in all patients with combined total cholesterol greater than 260 mg/dl and triglycerides greater than 300 mg/dl, in order to identify type III hyperlipidemia.

Cystathionine ß-synthase (CBS) gene mutation. The CBS enzyme converts homocysteine to cystathionine. Mutation allows a build-up of homocysteine in the blood, i.e. hyperhomocysteinemia. Increased risk of coronary artery disease and stroke; risk of osteonecrosis is unknown. The most common mutations in the CBS gene are the G919A and T833C substitutions, resulting in a serine for glycine at amino acid residue 307 and a threonine for isoleucine at amino acid 278, respectively. Persons with the T833C mutation can respond to pyridoxine therapy but those with the G919A mutation do not respond.

Factor V (Leiden) mutation. Heterozygosity or, rarely, homozygosity for mutant Factor V gene (Leiden mutation) produces activated protein C resistance (APCR), which is the most common cause of venous thrombosis. A defect in the procoagulant protein, Factor V, does not allow binding by activated protein C, leading to unopposed procoagulant activity and increased risk of clot formation. APCR can be amplified by exogenous estrogens (oral contraceptives, post-menopausal estrogen supplementation). The mutation is an autosomal dominant change of guanine-1691-adenine (G1691A) on the Factor V gene. Found in at least 6%of Caucasians and 23% of NICO patients. Results in increased risk of coronary artery disease, stroke and ischemic osteonecrosis. For women who are heterozygous for the mutant allele, the risk of thrombosis is 80 times greater than normal when they use exogenous estrogen. It has been recommended, therefore that they not be given estrogens. Test: cDNAPCR assay.

Homocysteinemia (hyperhomocysteinemia). This amino acid abnormality is an independent and major risk factor for coronary artery disease, stroke and osteonecrosis, and a somewhat lesser risk factor for deep vein thrombosis and arterial thrombosis. Usual it is inherited  as an autosomal dominant trait but it can be acquired by a deficiency of vitamin B12 or folate, or renal insufficiency. It is suggested that plasma levels be measured, along witha fasting lipid profile and lipoprotein (a) levels, in all patients assesses for atherosclerosis risk.

MTHFR (methylene tetrahydrofolate reductase) mutation/polymorphism. Homozygosity for this common polymorphism controls serum levels of homocysteine, a major thrombophilic risk factor. Homozygous persons have a 70% reduction in MTHFR activity and twice the normal level of homocysteine in their blood (i.e. hyperhomocysteinemia), resulting in thrombophilia. Inherited as an autosomal dominant mutation of cytosine-677-thymine (C677T).

Found in 65% of NICO patients. Increased risk of coronary artery disease, stroke and ischemic osteonecrosis. The C677T mutation responds to folic acid therapy.

Protein C deficiency. This vitamin K-dependent protein is synthesized in the liver and is activated by endothelial cell surface thrombin-thrombomodulin complex and, along with its co-factor protein S, inhibits the prothrombotic factors V and VIII. Protein C especially suppresses activity of factor Va and when it is diminished there is increased procoagulant activity. Increased risk of venous and arterial thrombosis, and osteonecrosis. The prothrombotic tendency of protein C deficiency is amplified by exogenous estrogens and pregnancy. This autosomal dominant hereditary deficiency is found in 0.3% of the general population and 2-5% of patients with deep vein thrombosis. Both heterozygotic and homozygotic mutations may produce hypercoagulability but the latter defect usually produces more severe disease, even a life-threatening hypercoagulopathy. Test: e.g., Rocket electroimmunoassay with rabbit anti-human protein C (Sigma), normal: 63-135%

Protein S deficiency. This vitamin K-dependent protein is synthesized in the liver and is a co-factor for protein C, helping to suppress factor Va activity. When deficient there is excessive factor Va activity and an increased risk of venous thrombosis, arterial thrombosis, coronary artery disease, and osteonecrosis. This autosomal dominant hereditary deficiency is found in 0.5% of the general population and in 5-9% of patients with deep vein thrombosis. Both heterozygotic and homozygotic mutations may produce hypercoagulability. Test: specific enzyme-linked immunoassay, e.g.  sserachrom free protein

S assay (Diagnostica Stago); normal value = 65-130%.

Prothrombin gene mutation/polymorphism. Prothrombin is the precursor of the serine protease thrombin. A G to A substitution at nucleotide position 20210 of the 3′-untranslated region (3’UT) of the prothrombin gene results in high levels of prothrombin and a thrombotic predisposition. Increased risk of deep vein thrombosis and stroke; risk of osteonecrosis is unknown. Carriers of the 20210A allele have almost a 3-fold increase in their risk of deep vein thrombosis. Test: cDNA PCR assay.

Additional thrombophilia or coagulation protein regulating defections. Decreased antithrombin, antithrombin III deficiency (found in 0.1% of the general population and in 0.5-4.9% of persons with hypercoagulability), Factor II gene mutation, decreased thrombomodulin, decreased heparin co-factor II, increased Factors II, VIII, IX, X, XI, XII.

One significant abnormality may contribute to a hypercoagulable state. Thrombophilia may be caused by more than one genetic abnormality in any of the proteins mentioned here.

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Hypofibrinolysis (Reduced Ability to Lyse Clots)

Decreased tissue plasminogen activator activity (tPA-Fx). tPA-Fx is the major stimulator of fibrinolysis. When it is not stimulated or is diminished the homeostatic process of thrombus lysis cannot begin or is considerably slowed, resulting in a prothrombotic or hypercoagulable state. Poorly stimulated tPA-Fx is often accompanied by high plasminogen activator inhibitor activity (PAI-Fx), the major inhibitor of fibrinolysis. High plasmatriglycerides and/or hyperinsulinemia can increase PAI-Fx and thereby decrease tPA-Fx. The PAI gene often shows 4G4G and 4G5G polymorphism, and the mutations can be tested with cDNA PCR.

Increased lipoprotein (a) [Lp(a)]. In marrow spaces high levels of Lp(a) appear to reduce fibrinolysis, especially in the presence of corticosteroid therapy.

Increased plasminogen activator inhibitor (PAI-1) gene polymorphism. PAI-1 is the main inhibitor of fibrinolysis and its increase leads to hypofibrinolysis, a hypercoagulable state.  A 4G allele of the common 4/5 guanine tract (4G/5G) polymorphism in the PAI-1 gene promoter region of chromosome 7 is associated with higher plasma PAI-1 activity. IncreasedPAI-1 activity results in a low level of stimulated tissue plasminogen activator activity (tPA-Fx), the major stimulator of fibrinolysis. Elevated plasma triglycerides and hyperinsulinemia increase PAI-Fx levels. Increased PAI-1 is found in 18% of NICO patients.

Significantly increased risk of coronary artery disease, deep vein thrombosis, stroke and osteonecrosis.

Additional hypofibrinolysis factors. Decreased levels of plasminogen, decreased urokinase, increased homocysteine,  increased Factor XI, positive TAFI. Two or more of these factors can interrelate and contribute to a hypercoagulable state.

Acquired inhibitors in coagulation homeostasis. Increased anticardiolipin antibody, lupus anticoagulant, antiphosphatidylSerine, B-2 glycoprotein I antibodies, annexin V antibodies.  Any of these antibody inhibitors may be seen as IgA or IgM, or both.

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References (Chronologic Order)

Nilsson IM, Krook H, Sternby HH, et al. Severe thrombotic disease in a young man with bone marrow and skeletal changes and with a high content of an inhibitor in the fibrinolytic system. Acta Med Scand 1961; 169:323-327.
Boettcher WG, Bonfiglio H, Hamilton HH, et al. Nontraumatic osteonecrosis of the femoral head. Part 1. Relation of altered hemostasis to etiology. J Bone Joint Surg 1970; 52A:312-321.

Utermann G, Hardewig A, Zimmer F. Apolipoprotein E phenotypes in patients with myocardial infarction. Hum Genet 1984; 65:237-241.

Degen SJF, Davies EW. Nucleotide sequence of the gene for human prothrombin. Biochemistry 1987; 26:6165-_____.

Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hha I. J Lipid Res 1990; 31:545-548.

Marinetti GV. Disorders of lipoprotein metabolism.. In:  Dyslipoproteinemias. Marinetti GV (ed). New York, Plenum Press, 1990.

Schneiderman J, Sawdey MS, Keeton MR, et al. Increase type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci USA 1992; 89:6998-7002.

Dawson SJ, Wiman B, Hamsten A, et al. The two allele sequences of a common polymorphism in the promotor of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268:10739-10745.

Glueck CJ, Glueck HI, Mieczkowski, et al. Familial high plasminogen activator inhibitor with hypofibrinolysis, a new pathophysiologic cause of osteonecrosis? Thromb Haemostas 1993; 69:460-465.

Koster T, Rosendaal FR, de Ronde H, et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342:1503-1506.

Van Veldhuizen PJ, Neff J, Murphey MD, et al. Decreased fibrinolytic potential in patients with idiopathic avascular necrosis and transient osteoporosis of the him. Am J Hematol 1993; 44:243-248.

Bertina RM, Koeleman BPC, Koster T, et al. Mutation in blood coagulation Factor V associated with resistance to activated protein C. Nature 1994; 369:64-67.

Glueck CJ, Glueck HI, Greenfield D, et al. Protein C deficiency, protein S deficiency, thrombophilia and hypofibrinolysis. Ped Res 1994; 35:383-388.

Glueck CJ, Glueck HI, Freiberg R, et al. High plasminogen activator inhibitor activity and hypofibrinolysis, a major cause of idiopathic osteonecrosis. Am J Hematol 1994; 45:156-166.

Glueck CJ, Glueck HI, Welch M, et al. Familial idiopathic osteonecrosis mediated by familial hypofibrinolysis with high levels of plasminogen activator inhibitor. Thromb Haemostas 1994; 71:195-198.

Kraus JP. Molecular basis of phenotype expression in homocysteinuria. J Inher Metab Dis 1994; 17:383-390.

Malinow MR. Plasma homocysteine and arterial occlusive diseases: A mini-review. Clin Chem 1994; 40:173-176.

Poort SR, Michiels JJ, Reitsma RH, Bertina RM. Homozygosity for a novel missense mutation in the prothrombin gene causing a severe bleeding disorder. Thromb Haemostas 1994; 72:819.

Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330:517-522.

Voorberg J, Roelse J, Koopman R, et al. Association of idiopathic venous thromboembolism with single point mutation at Arg-506 of Factor V. Lancet 1994; 343:1535.

Amundsen T, Ueland PM, Waage A. Plasma homocysteine levels in patients with deep venous thrombosis. Arterioscler Thromb Vasc Biol 1995; 15:1321-1323.

Bquer KA. Hypercoagulable states. In: Hoffman R, Benz EJ Jr, Shattil SJ, et al (eds). New York: Churchill Livingstone, 1995:1781-1795.

Bouquot J, McMahon R, Glueck C. Risk factors in ‘idiopathic’ osteonecrosis of the jaws: seven of ten NICO patients have hereditary clotting disorders. Proceedings of Annual Meeting, American Academy of Oral & Maxillofacial Pathology; Colorado Springs, Colorado; May, 1995.

Dahlback B. Resistance to activated protein C, the Arg-506 to Gln mutation in the Factor V gene, and venous thrombosis. Thromb Haemos 1995; 73:739-742.

Eriksson PB, Kallin FM, Van’t Hoffi, et al. Allele-specific increase in basal transcription of the plasminogen activator inhibitor-1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA 1995; 92:1851-1855.

Frosst P, Blom HJ, Milos R, et al. A candidate generic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995; 10:111-113.

Ginsberg JS, Wells PS, Brill-Edwards P, et al. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86:3685-3691.

Glueck CJ, Gruppo R, McMahon RE, Bouquot JE, Stroop D, Becker A, Tracy T, Wang P. Anticardiolipin antibodies and osteonecrosis of the jaws. J Invest Med 1995; 43 (suppl 3): 459A.

Glueck CJ, McMahon RE, Bouquot JE, Rabinovich B. Hypofibrinolysis and thrombophilia, pathophysiologic etiologies of osteonecrosis of the jaws and atypical facial neuralgia. J Orofacial Pain, 1995; 9:103.

Glueck CJ, McMahon RE, Bouquot JE, Stroop D, Tracy T, Freiberg R, Wang Y, Rabinovich B. The pathophysiology of idiopathic osteonecrosis of the jaws: thrombophilia and hypofibrinolysis. Proceedings of Annual Meeting, American Association of Physiology; May, 1995.

Glueck CJ, McMahon RE, Bouquot JE, Stroop D, Trent T, Freiberg R, Wang S. Resistance to activated protein C, estrogens, and osteonecrosis of the jaws. J Invest Med 1995; 43 (suppl): 234A.

Glueck CJ, Shaw P, Lang JE, et al. Evidence that homocysteine is an independent risk factor for atherosclerosis in hyperlipidemic patients. Amer J Card 1995; 75:132-136.

Gruppo R, Glueck C, McMahon R, Bouquot J. Anticardiolipin antibodies, thrombophilia and hypofibrinolysis in Neuralgia-Inducing Cavitational Osteonecrosis of jaw. J Oral Maxillofac Surg 1995; 53(suppl): 84-85.

Hellgren M, Svensson PJ, Dahlback B. Resistance to activated protein C as a basis for venous thromboembolism associated with pregnancy and oral contraceptives. Am J Obstet Gynecol 1995; 173:210-213.

Khamasta MA, Cuadrado MJ, Mujic F, et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332:992-997.

Kluijtman LA, et al. Molecular genetic analysis in mild hyperhomocysteinemia: A common mutation in the methylene tetrahydrofolate reductase gene is a risk factor for cardiovascular disease. Am J Human Genet 1995; 58:35-41.

McMahon R, Glueck C, Bouquot J, Rabinovich B. Protein C disorders are risk factors for alveolar osteonecrosis and chronic facial pain. J Oral Maxillofac Surg 1995; 53(suppl): 169-170.

Sperandeo MP, Panico M, Pepe A, et al. Molecular analysis of patients affected by homocysteinuria due to cystathionine ß-synthase deficiency; report of a new mutation in exon 8 and a deletion in intron 11. J Inher Metal Dis 1995; 18:211-214.

Wiman B. Plasminogen activator inhibitor-1 (PAI-1) in plasma: its role in thrombotic disease. Thromb Haemostas 1995; 74:71-76.

deKnijff P, Havekes LM. Apolipoprotein E as a risk for coronary heart disease: a genetic and molecular biology approach. Cur Opinion in Lipid 1996; 7:593.

Glueck CJ, Crawford A, Roy D, et al. Association of antithrombotic factor deficiencies and hypofibrinolysis with Legg-Perthes disease. J Bone Jnt Surg 1996; 78A:3-13.

Gruppo R, Glueck CJ, McMahon RE, et al. The pathophysiology of osteonecrosis of the jaw: anticardiolipin antibodies, thrombophilia, and hypofibrinolysis. J Lab Clin Med 1996; 127:481-488.

Glueck CJ, McMahon RE, Bouquot JE, et al. Thrombophilia, hypofibrinolysis and osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol 1996; 81:557-566.

Glueck CJ, McMahon RE, Bouquot J, Tracy T, Seive-Smith L, Wang P. Treatment of thrombophilia and hypofibrinolysis ameliorates osteonecrosis of the jaws. J Investig Med 1996; 44:375.

Hammerschmidt DE. Thrombophilia: taking it on the jaw. J Lab Clin Med 1996; 127:411-412.

den Heijer MD, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Eng J Med 1996; 334:759-762.

Hu FL, Gu Z, Kozich V, et al. Molecular basis of cystathionine ß-synthase deficiency in pyridoxine responsive and nonresponsive homocysteinuria. Hum Molec Gen 1996; 2:1857-1860.

Lalouschek W, Suess E, Aull S, et al. Clinical and laboratory data in heterozygous Factor V Leiden mutation positive versus negative patients with TIA and minor stroke. Stroke 1996; 26:1963-64.

Nowak-Gottl U, Koch HG, Aschka I, et al. Resistance to activated protein C (APCR) in children with venous or arterial thromboembolism. Br J Haematol 1996; 92:992-998.

Poort SR, Rosendaal FR, Reitsma PH, Berdna RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996; 88:3698-3703.

Rosen R. Molecular genetics of methylenetetrahydrofolate reductase deficiency. J Inher Metal Dis 1996; 19:589-94.

Sperandeo MP, Candito M, Sebastio G, et al. Homocysteine response to methionine challenge in four obligate heterozygotes for homocysteinuria and relationship with cystathionine b-synthase mutations. J Inher Metab Dis 1996; 19:351-356.

Verhoef P, Stampger MJ, Buring JE, et al. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate. Amer J Epidem 1996; 143:845-859.

Glueck CJ, Brandt G, Gruppo R. Resistance to activated protein C and Legg-Perthes disease. Clinical Orthoped Rel Res 1997; 338:139-152.

Glueck CJ, Freiberg R, Gruppo R, et al. Thrombophilia and hypofibrinolysis: reversible pathogenetic etiologies of osteonecrosis in adults and in children (Legg-Perthes disease).

In; Urbaniak JR, Jones JP Jr (eds). Osteonecrosis: etiology, diagnosis, and treatment.  Rosemont, IL, Amer Acad Orthopedic Surgeons 1997:105-110.

Glueck CJ, Freiberg R, Tracy T, et al. Thrombophilia, hypofibrinolysis, and osteonecrosis. Clin Orthoped 1997; 334:43-56.

Glueck CJ, Fontaine RN, Gupta A, Alasmi M. Myocardial infarction in a 35 year old male with homocysteinemia, high plasminogen activator activity, and resistance to activated protein C. Metabolism 1997; ________.

Glueck CJ, McMahon RE, Bouquot JE. The treatment of thrombophilia and hypofibrinolysis ameliorates the pain of osteonecrosis of the jaws. J Orofacial Pain 1997; 11:180.

Glueck CJ, McMahon RE, Bouquot JE, et al. Heterozygosity for the Leiden mutation V gene, a common pathoetiology for osteonecrosis of the jaw with thrombophilia augmented by exogenous estrogens. J Lab Clin Med 1997; 130:540-543.

Glueck CJ, McMahon RE, Triplett DA, Bouquot JE, Wang P. The mutant Factor V Leiden gene and thrombophilic resistance to activated Protein C, a common (24%) significant (P = .001) pathoetiology of osteonecrosis of the jaws with chronic facial pain. J Orofacial Pain 1997; 11:179.

Hammerschmidt DE. Thrombophilic osteonecrosis: another chapter. J Lab Clin Med 1997; 130:451-452.

Harris JM, Abramson N. Evaluation of recurrent thrombosis and hypercoagulability. Amer Fam Physician 1997; 56:1591-1596.

Korompilias AV, Ortel TL, Gilkeson GS, et al. Hypercoagulability and osteonecrosis. In; Urbaniak JR, Jones JP Jr (eds). Osteonecrosis: etiology, diagnosis, and treament. Rosemont, IL, Amer Acad Orthopedic Surgeons 1997:111-116.

McMahon RE, Glueck CJ, Bouquot JE, Rabinovich B. Protein C Disorders are risk factors for  alveolar osteonecrosis and chronic facial pain. J Orofacial Pain 1997; 11:179.

McMahon RE, Glueck CJ, Bouquot JE, Triplett. The prevalence of factor V Leiden and methylene-tetrahydrofolate reductase (MTHFR) gene mutations in 87 patients with osteonecrosis of the jaw  and chronic facial pain. J Orofacial Pain 1997; 11:179-180.

Mont MA, Glueck CJ, Wang P, et al. Risk factors for progression to osteonecrosis in patients with systemic lupus erythematosus. J Rheumatol 1997; 24:654-662.

Pierre-Jacques H, Glueck CJ, Mont MA, Hungerford DS. Familial heterozygous protein S deficiency in a patient who had multifocal osteonecrosis. J Bone Jnt Surg 1997; 79-A:1079-1084.

Brandt G, Gruppo R, Glueck CJ, et al. Sensitivity, specificity, and predictive value of modified  assays for activated protein C resistance in children. Thrombosis Haemostasis 1998; 79:567-570.

Eldridge JC, Dilley A, Dorris J, et al. Thrombophilia due to protein C deficiency, protein S deficiency or resistance to activated protein C as a cause of Legg-Perthes disease. Pediatrics 1998; 102:14A.

Falanga A. Mechanisms of hypercoagulation in malignancy and during chemotherapy. Haemostasis 1998; 28 (suppl 3):50-60.

Freedman P, Reich M, Steinlauf. NICO and anticoagulation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 86:3-5.

Glueck CJ. NICO and anticoagulation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 86:5-7.

Glueck CJ, Freiberg R, Crawford A, et al. Second hand smoke, hypofibrinolysis, and childhood osteonecrosis of the hip, Legg-Perthes disease. Clin Orthoped 1998; 352-159-167.

Gruppo R, Glueck CJ, Wall E, et al. Legg-Perthes disease in three siblings, 2 heterozygous and 1 homozygous for the Factor V Leiden mutation. J Pediatrics 1998; 132:885-888.

Glueck CJ, McMahon R, Bouquot J, et al. A preliminary pilot study of treatment of thrombophilia and hypofibrinolysis and amelioration of the pain of osteonecrosis of the jaws. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998; 85:64-73.

Glueck CJ, McMahon RE, Bouquot JE, Triplett D. Exogenous estrogens may exacerbate thrombophilia, impair bone healing and contribute to development of chronic facial pain. J Craniomand Pract 1998; 16:143-153.

Mira Y, Vaya A, Martinez M, et al. Hemorhealogical alterations and hypercoagulable state in deep vein thrombosis. Clin Hemorheal Microcirc 1998; 19:265-270.

Sulaiman-Shoab S. Activated protein C resistance: the commonest hereditary hypercoagulation disorder. Br J Surg 1998; 85:1161.

Wiener-Megnagi Z, Ben-Shlomo I, et al. Resistance to activated protein C and the leiden mutation: high prevalence in patients with abruptio placentae. Am J Obstet Gynecol 1998; 179:1565-1567.

Arruda VR, Belangero WD, Oxelo MC, et al. Inherited risk factors for thrombophilia among children with Legg-Calve’-Perthes disease. J Ped Orthop 1999; 19:84-87.

Berg D, Berg LH, Couvaras J, Harrison H. Chronic fatigue syndrome &/or fibromyalgia as a variation of antiphospholipid antibody syndrome (APS): An explanatory model and approach to laboratory diagnosis. Blood Coag Fibrinolysis 1999; 10:435-438.

Bouquot JE, LaMarche MG. Ischemic osteonecrosis under fixed partial denture pontics: radiographic and microscopic features in 38 patients with chronic pain. J Pros Dent 1999; 81:148-158.

de Boer AW, Levi M, Reddingius RE, et al. Intraperitoneal hypercoagulation and hypofibrinolysis is present in childhood peritonitis. Pediatr Nephrol 1999; 13:284-287.

Park KJ, Kim HJ, Hwang SC, et al. The imbalance between coagulation and fibrinolysis is related to the severity of the illness and the prognosis in sepsis. Korean J Intern Med 1999; 14:72-77.

Schorge JO, Goldhaber SZ, Duska LR, et al. Clinically significant venous thromboembolism after gynecologic surgery. J Reprod Med 1999; 44:669-673.

Bouquot JE, McMahon RE. Neuropathic pain in maxillofacial osteonecrosis (NICO). J Oral Maxillofac Surg 2000; 58: in press.

Kupfermine MJ, Yair D, Bornstein NM, et al. Transient focal neurological deficits during pregnancy in carriers of inherited thrombophilia. Stroke 2000; 31:892-895.

Spina V, Aleandri V, Morini F. The impact of the factor V Leiden mutation on pregnancy. Hum Reprod Update 2000; 6:301-306.

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Tables

Hypercoagulation States in Osteonecrosis Patients & the Normal Population

Table 1: Coagulation disorders found in patients with ischemic osteonecrosis of the hips, knees and jaws, compared to the proportions found in patients with deep vein thrombosis of soft tissues and with the normal population. Thrombophilia = increased tendency to develop thrombi; hypofibrinolysis = reduced ability to lyse thrombi.

Coagulation Defect Normal
Population Deep Vein
Thrombosis
Osteonecrosis
Thrombophilia, hereditary types* 2-5% 5-9% 50-70%
Thrombophilia, acquired types 3-7% 20-50% 33%
Hypofibrinolysis, hereditary types * <1% 5-15% 18-22%
Hypofibrinolysis, acquired types <1% 20-25% 50%
Total (includes multiple coagulopathies) 2-7% 20-50% 65-87%

                   * usually autosomal dominant

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Hypercoagulable States in Ischemic Osteonecrosis

Table 2: Hypercoagulation states or disorders found in patients with ischemic osteonecrosis (IO) of the hips, knees and jaws, listed by test needed and coagulation type.

Clotting Factor
 Change in Hypercoag. States
 % in IO
 Inher-
ited?
 Test
 Comment
 
Factor V Leiden mutation
 Present, Thrombophilia
 30%
 Yes
 PCR
 Causes thrombophilia through resistance to protein C; heterozygotic or homozygotic (rarely). In 6% of Caucasians. Risk of coronary disease and stroke, especially with estrogen. Thrombophilia increases 100-fold by exogenous estrogen, SERMS, pregnancy.
 
Prothrombin gene mutation
 Present,
Thrombophilia
 20%
 Yes
 PCR
 Causes high levels of prothrombin, i.e. thrombophilia, and an increased risk of deep vein thrombosis and stroke. Thrombophilia increased 100-fold by exogenous estrogen, SERMS, pregnancy.
 
Methylenetetrahydrofolate reductase (MTHFR) mutation
 Present,
Thrombophilia
 30%
 Yes
 PCR
 Patients homozygous for this mutation usually have high fasting serum homocysteine and respond to folic acid (5 mg), vitamin B6 (100 mg) & vitamin B12 (2000 mcg) daily. Increased risk of stroke & coronary artery disease.
 
Plasminogen activator inhibitor (PAI-1) gene
 Present, Hypofibrinolysis
 18%
 Yes
 PCR
 Produces excess PAI, the major inhibitor of fibrinolysis, hence, results in hypofibrinolysis. Made worse by elevated triglycerides and hyperinsulinemia.
 
Anticardiolipin antibody
 Increased, Thrombophilia
 33%
 Maybe
 Serology
 An antiphospholipid autoantibody which causes thrombophilia by damaging endothelial cells and platelets. Often found in lupus erythematosus; increases with age. Increased risk of venous & arterial clots. May be acquired.
 
Lupus anticoagulant
 Increased, Thrombophilia
 33%
 No
 Serology
 Another antiphospholipid antibody originally found in patients with systemic lupus (SLE) but very common in patients without SLE.
 
Homocysteinemia (hyperhomocysteinemia)
 Present,
Thrombophilia
 30%
 Usually
 Serology
 Causes thrombophilia; can be acquired through vitamin B12 or folate deficiency, or renal insufficiency. Major risk for coronary artery disease, stroke, and deep vein or arterial thrombosis.
 
Resistance to activated
protein C
 Increased, Thrombophilia
 18%
 Yes
 Serology
 Produces thrombophilia; related to Factor V Leiden mutation. Increased risk of deep vein thrombosis & stroke . Thrombophilia increased by exogenous estrogen, SERMS.
 
Protein C
 Decreased, Thrombophilia
 3%
 Yes
 Serology
 Causes thrombophilia. Decreased additionally by local or systemic infection and exogenous estrogen.
 
Protein S, total & free
 Decreased, Thrombophilia
 5%
 Yes
 Serology
 Causes thrombophilia. Decreased additionally by local or systemic infection and excess estrogen.
 
Factor VIII
 Increased Thrombophilia
 ?
 Yes
 Serology
 Greater risk of thrombosis than heterozygous factor V Leiden
 
Lipoprotein (a)
 Increased,
Hypofibrinolysis
 36%
 Yes
 Serology
 A strongly atherogenic and hypofibrinolytic lipoprotein. Made worse by corticosteroid therapy.
 
Plasminogen activator inhibitor activity
 Increased,
Hypofibrinolysis
 18%
 Yes
 Serology
 The major inhibitor of fibrinolysis. Made worse by elevated triglycerides and hyperinsulinemia.
 
Total:
 81%
   Includes patients with multiple coagulopathies
 
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Table 3: Web Sites with Additional Information about Hypercoagulation And/or Osteonecrosis & Painful Jawbone Osteonecrosis (NICO)

Institution Name Website

Affinity Labeling Corp., Lexington, Kentucky http://www.altcorp.com
 Information about neurotoxicity in jawbone osteonecrosis tissue samples using affinity labeling assays. Drs. Boyd Haley & Kurt Pendergrass, Directors.  Affiliated with Univ. of Kentucky Cholesterol Center, Jewish Hospital, Cincinnati, Ohio http://blues.fd1.uc.edu 
 Detailed information about hypercoagulation. Dr. Charles Glueck, Director; sign up for research studies

Facial Pain Center, Columbus, Ohio http://www.drshankland.com
  Information about facial pain & NICO. Dr. Wes Shankland, Director
 
Hemex Laboratories, Phoenix, Arizona http://www.hemex.com 
 Detailed information about hypercoagulation.  Dr. David Berg, Director

The Maxillofacial Center, Morgantown, West Virginia http://www.maxillofacialcenter.com
 Information about jawbone osteonecrosis, all features.  Dr. Jerry Bouquot, Director of Research

Midwest Hemostasis and Thrombosis Laboratories http://www.midwestcoag.com  Information about hypercoagulation.  Dr. Douglas Triplett, Director

Molecular Diagnostic Laboratories, Cincinnati, Ohio http://www.mdl-labs.com
 Information about hereditary hypercoagulation. 

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Table 4: Suggested laboratories and centers for hypercoagulation testing or profiling.
Institution/Lab Name & Address Contact
Number(s) Director of the Lab/Comments
Cholesterol Center, Jewish Hospital,  ABC, 3200 Burnett Avenue, Cincinnati, Ohio 513-585-7800
fax: 513-585-7950
[email protected] Dr. Charles Glueck, Director. Affiliated with the University of Cincinnati.

Hemex Laboratories, Phoenix,  Arizona.  800-999-CLOT (2568) Dr. David Berg, Director. 
Midwest Hemostasis and Thrombosis Laboratories,
2001 West 86th Street, Indianapolis, Indiana 46260 317-803-0390
fax: 317-803-0433
[email protected]
 [email protected] Dr. Douglas Triplett, Director.  Affiliated with the Indiana University
Molecular Diagnostics Laboratory, 3130 Highland Avenue, Suite 3315, Cincinnati, Ohio 45219

513-475-6631
fax: 513-221-1891
[email protected] Dr. Robert Fontaine, Director. Affiliated with the University of Cincinnati
  
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Townsend Letter, Nov, 2009 by Jule Klotter
 ..Ken Lassesen, MS, developed chronic fatigue immune deficiency syndrome (CFIDS) in 1999. He considers himself lucky because he worked for Microsoft and, therefore, had health insurance that put little restriction on testing. He also had a family-practice doctor who “believed that CFS was very real.” She didn’t know how to treat it, but she was willing to learn from peer-reviewed research. Lassesen found a study by David Berg et al. that linked chronic fatigue syndrome (CFS) to antiphospholipid antibody syndrome (APS) (aka Hughes syndrome), a hypercoagulable condition. The characteristic “sticky” blood impedes the delivery of oxygen and nutrients throughout the body and removal of cellular waste and toxins.

In their October 1999 paper for Blood Coagulation & Fibrinolysis, David Berg and colleagues describe their blinded prospective study for testing the hypothesis that most people with CFS or fibromyalgia (FM) have antiphospholipid syndrome. (CFS and fibromyalgia share many physiological characteristics and symptoms.) Fifty-four people diagnosed with CFS or fibromyalgia and 23 controls were given five tests to evaluate their blood: fibrinogen (FIB), prothrombin fragment 1 2 (F1 2), thrombin/antithrombin complexes (T/AT), soluble fibrin monomer (SFM), and platelet activation by flow cytometry (PA) using CD62P and ADP.

The object was to differentiate the controls from the patients simply by looking at the test results. People with two or more assays that indicated hypercoagulability were labeled patients. The researchers correctly identified 22 of the 23 controls and 50 of the 54 patients: “One control was positive in two assays for a false positivity rate of 4%. Of the 54 patients, 4 had normal values, for a false negative rate of only 7.4%. This shows that 92 % of CFS and/or FM patients had a demonstrable hypercoagulable state.” In previous, unpublished research, Berg et al. found that “three out of four CFS &/or FM patients have a genetic deficiency [for thrombophilia or hypofibrinolysis]”–which may promote “sticky” blood.

 They also report that “[c]ertain pathogens induce the immune system generation of  APL antibodies and can be a triggering mechanism for APS.” Several pathogens have been linked to the onset of CFS and FM. In an editorial for Annals of Rheumatic Diseases, Y. Shoenfeld and colleagues “suggest that molecular mimicry mechanism between the pathogen andthe [[beta]2-glycoprotein l] molecule may be the cause of [antiphospholipid antibody syndrome].”
 
Chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) are no longer viewed as psychosomatic diseases where sufferers must dysfunction quietly without complaint. whilst still poorly understood, they are very real conditions that primarily affect young and middle aged Caucasian women (CFS is 1½ times more prevalent in women than in men).

Increasing evidence shows that both CFS and FMS may be the compounding result of a group of several syndromes that simply begin to overwhelm the body’s immune system, for example an undetected viral infection, chemical or food allergy, candida infection, excessive stress etc.
There is presently no agreement within the medical or naturopathic communities as to the primary cause of these conditions but candida, hypercoagulation, Epstein-Barr virus, cytomegalovirus, brucella, human herpes virus-6, chemical toxicity, nutritional deficiencies and imbalanced stress hormones are all thought to be possible contributors. 

Constant fatigue, muscle pain and weakness (not relieved by bed rest) are prevalent symptoms in these complex syndromes which can exacerbate a vast array of disorders such as allergies, multiple chemical sensitivity, joint pain, anxiety, depression and impaired concentration and memory. Put simplistically, the differential diagnosis for fibromyalgia is the existence of chronic widespread pain with palpable pain in 11 out of 18 specific points.

The debilitating nature of these conditions often brings negative feelings, low self esteem and hopelessness. Dr B Sahley, of the Pain & Stress Centre in San Antonio, Texas stated that “many chronic pain patients tell me that they perceive themselves as a burden to their families and feel unable to communicate. yet communication is the key to improvement and moving forward in your life. you must never stop believing you will get better.”

There is hope and there is help Treatment by a good cranial osteopath, healthy nutrition, adequate exercise and rest and plenty of clean fresh water are paramount, but there are also herbal and nutritional supplements that may assist with management of these syndromes.
 

Radiance® FibroMalic
Radiance® FibroMalic is a formula based on the synergistic blend of natural nutrients researched and successfully clinically trialled by Dr Billie Sahley PhD.,  at the Pain & Stress Centre in San Antonio, for reduction of symptoms associated with fibromyalgia, chronic fatigue and chronic pain. The formula includes malic acid, standardised boswellia extract, magnesium, vitamin C, vitamin B6 and chromium. This formula is designed to help remove toxins, relieve inflammation, reduce muscular tension and improve energy production in order to help relieve the symptoms associated to fibromyalgia and chronic fatigue.  

Radiance® Magnesium Complex
Magnesium is the “anti-stress” mineral as it functions to relax skeletal muscles as well as the smooth muscles of blood vessels and the gastrointestinal tract (while calcium stimulates muscle contraction, magnesium relaxes them). Magnesium deficiency has become increasingly common and is considered to be a contributing factor not only to muscular tension, cramps and pain, but cardiovascular disease and heart attack. Multiple studies have now confirmed that patients with chronic fatigue and fibromyalgia have improved energy levels, better emotional state and less pain when the diet is supplemented with magnesium. Radiance® Magnesium Complex supplies 266mg magnesium with synergistic calcium, zinc and vitamin D to boost magnesium levels where signs of deficiency including poor sleep and muscular discomfort are present.

B J Sahley, Ph.D., C.N.C., K M Birkner, C.R.N.A., Ph.D., Malic Acid and Magnesium for Fibromyalgia and Chronic Pain Syndrome, Pain & Stress Publications, Texas, 2002

(Originally published in Health & Herbal News Magazine Volume 18, Issue 1)