Interview with David Berg
David Berg is the Director and Cofounder, with Lois Hill Berg, of HEMEX Laboratories. Along with Dr. Harold Harrison and several clinical collaborators, they have developed the idea of the hypercoagulation/ immune system activation of coagulation theory in chronic diseases, a proposed cause of Chronic Fatigue Syndrome and Fibromyalgia, and have proposed an appropriate treatment that reduces many related symptoms. Mr. Berg has a M.S. degree in clinical pathology and laboratory medicine, and has been in practice for 35 years. HEMEX Laboratories offers testing and consultative services relating to the diagnosis, treatment, and monitoring of hematological, clotting and/or bleeding disorders.
We first became involved with research in chronic illnesses while we were performing re search regarding hypercoagulability – related infertility in women with one of the local infertility specialists here in Phoenix, AZ. We found that a hypercoagulable state, presumably due to a coagulation protein defect, existed in many women who were infertile and/or who had recurrent spontaneous abortions. Our colleague Dr. Couvaras observed that when he put women on low dose heparin in order to maintain pregnancy, some with CFS/FM-like symptoms, pelvic pain, and migraine-like headaches had amelioration of their symptoms. He asked us “Why?” As a result, we performed a retrospective study on 30 of these obstetric patients with chronic illness symptoms, and determined that all had coagulation system activation. As the hypercoagulability was decreased by heparin injections, the chronic illness symptoms diminished. This was the first clue to the connection between coagulation and chronic illnesses. These findings were published as a poster at the 1998 AACFS meeting in Cambridge, MA.
We subsequently refined our test panel for low level activation of coagulation to include Prothrombin fragment 1+2 (F1+2), thrombin/antithrombin complexes (T/AT) and Platelet Activation by Flow Cytometry assays. Thus, the ISAC or Immune System Activation of Coagulation panel consisting of fibrinogen (FIB), soluble fibrin monomer (SFM), F1+2, T/AT, and PA by Flow was born. With our partner and Medical Director, Dr. Harold Harrison and several clinical collaborators, we then designed and conducted a prospective, multi-center, blinded, case control, associative study of non-obstetric CFS/FM patients and controls, with centers in New York, Houston, and Phoenix. When the code was broken, identifying patients and controls, we were able to identify most of the CFS/FM patients based on having two or more positive test results out of the five assays in the ISAC panel. It was the first definitive evidence that, indeed, chronic illnesses have a demonstrable basis in the blood coagulation system. This study was published in the international journal Blood Coagulation & Fibrinolysis, 1999, 10:435-438. In another associative cohort study published in Blood Coagulation & Fibrinolysis, 2000, 11:673-678, we determined that Gulf War illness has similar findings of low level activation of coagulation.
In November, 1999, Dr. Joe Brewer (an Infectious Disease specialist in Kansas City) and I developed a model of pathogen activation of the immune and coagulation systems. The model proposes that the end result of such pathogenmediated activation is increased blood viscosity due to 1) an underlying coagulation regulatory protein defect, and 2) activation of the coagulation system by the pathogen. As the blood viscosity increases, the diminished blood flow creates hypoxia (lack of oxygen) and nutrient deprivation within various areas of the body. This is like trying to start your car in Wisconsin in the winter with 60- weight engine oil. This model explains the multi-organ symptomatology and also explains why the low dose heparin therapy is effective by increasing blood flow as the blood viscosity decreases. Thus, patients gain relief from their symptoms with this therapy.
The model states that coagulation activation generates thrombin, which converts fibrinogen to soluble fibrin monomer (SFM). Soluble fibrin becomes deposited in the micro-circulation (capillaries) as fibrin or fibrinoid-like deposition, blocking oxygen and nutrients transfer to parenchymal tissues. Many pathogens activate the immune system. These include viruses (such as EBV, CMV, HHV6 & others), bacteria (mycoplasma, chlamydia, borrelia, etc), fungi (such as candida), etc. These pathogens are anaerobes, i.e., they live and reproduce in an oxygen deprived cellular matrix or environment. That’s why fibrin deposition becomes important to the survival of the pathogens because it produces decreased oxygen in cells and tissues. One of the biggest challenges to a clinician is to figure out what pathogens are present in the patient, and therefore the most appropriate therapies against these pathogens. The average CFS/FM patient may have anywhere from one to seven pathogens that need eradication.
Positivity of two or more tests in the ISAC panel occurs in more than 80% of all patients tested. However, the longer a patient has been ill (many years), the less activation is needed by the pathogens for survival, and therefore fewer tests may be positive. Someone who has been ill for 10 years or more may only have one test positive in the panel. The ISAC panel also works very well for monitoring anticoagulant therapy between 4-6 weeks after therapy has started. It indicates whether or not there is enough heparin being given to the patient, the overall patient improvement and the reaction of the body to the pathogens, such as a Herxheimer-like reaction (relapse from infections or reactivation of pathogens).
In addition to the pathogens that can activate the immune system, metals (e.g. mercury, lead, aluminum), exogenous toxins, chemicals, allergens, physical trauma, vaccinations, and/or biological warfare agents can also activate the immune system. This may lead to secondary infections, which may also trigger coagulation activation. If the coagulation mechanism does not shut down properly, then there is continued thrombin generation and soluble fibrin formation, resulting in increased blood viscosity and decreased blood flow.
When you look for a genetic basis in this model, one can test for seven different regulatory proteins of the coagulation mechanism plus homocysteine in a panel we call the HTRP (Hereditary Thrombosis Risk Panel). In July 2001, at the International Society of Thrombosis and Hemostasis meeting in Paris, we presented data from a retrospective study of over 400 chronically ill patients, 83% had one or more demonstrable coagulation protein defects. Forty percent of the patients had a thrombophilia defect (decreased protein C, decreased protein S, decreased anti-thrombin, APC resistance/factor V Leiden positivity, or increased prothrombin/prothrombin gene mutation positivity). 39% of the patients have defects in the fibrinolytic system (hypofibrinolysis due to elevated lipoprotein (a) – Lp(a) and/or PAI1-plasminogen activator inhibitor-1. 21% of these patients had a defect in both the thrombophilia and hypofibrinolysis marker groups. This means that not only do they form fibrin easily, but also they are compromised in the ability to clean up the fibrin deposition.
Let’s put this in plain English. When a pathogen(s) gains a foothold, especially in the endothelial cells in the blood vessels (as well as other cells), the bug(s) can be protected by the coagulation mechanism of fibrin deposition on top of the infected cells. Half of the patients form fibrin very fast, becoming fibrin(oid) deposition. Half of the patients have an inability to clean up the fibrin, and therefore continue to have oxygen and nutrient starvation of tissues for a long time. For example, if the fibrin deposition occurs in a muscle, it says “ouch,” and you have a tender point as in Fibromyalgia. If it is in the placenta, the placenta is compromised by fibrin deposition and the baby aborts. As blood viscosity increases and blood flow is reduced throughout the body, the patient becomes hypo-this and hypo-that, such as hypothyroid, hypo-HPAaxis, hypo-estrogen, etc. The use of low dose heparin restores blood flow throughout the body and hormones from the endocrine system tend to normalize. Thus, the blood flow issue becomes one of the most important issues of chronic illnesses. Unfortunately there is no easy test to measure blood flow, only the effects of blood flow.
If you consider the movie “Braveheart” (1000 AD) and you went to battle and were wounded, you probably would have bled to death unless you clotted fast. By clotting fast, you saved your own life and passed on this new trait to your children. This hypothesis may explain how these coagulation defects were genetically selected during the last 2000 years in Europe. Life expectancy back then was only 30-40 years. With our life expectancy now of 80+ years, these traits are no longer beneficial, but rather deleterious to our health. It was the Spanish, French, British, Germans, Italians, Scandinavians, etc. (Europeans) that colonized the Americas. This explains why most of the chronically ill patients are white people of European decent. Therefore we have a genetic basis in the coagulation system for chronic illnesses that is very straightforward.
The model of reduced blood flow from increased blood viscosity due to activation of coagulation accompanied by a coagulation protein defect gives a scientific basis for a contribution to the pathophysiology of chronic illness. It also gives a measurable or quantifiable, objective aspect to testing the blood of patients with these diseases. It is no longer “all in your head”, but rather in your “blood.” It’s not rocket science, but a simple, logical explanation for what’s going on in many chronically ill patients.
HEMEX Laboratories provides testing services and consultative interpretations to clinicians and physicians throughout the United States. For more information, technical reprints, and/or patient information, please see their website at www. hemex.com
The following is a brief summary of the work of David Berg of Hemex Laboratory in Phoenix, Arizona, linking an immune activated hypercoagulation mechanism to a wide range of chronic conditions.
Immune System Activation of Coagulation ( I S A C ) :Chronic Illnesses Due to a Coagulation Protein Defect
Infertility (Recurrent Fetal Loss), TIA, Osteonecrosis of the Jaw, Chronic Fatigue Syndrome/Fibromyalgia (CFS/FM), Crohn’s Disease, IBD, Multiple Sclerosis, Sjogren’s Syndrome, Lyme Disease.
The Model – A Paradigm Shift
The model proposes that a majority of individuals diagnosed with chronic illnesses, based on clinical criteria, may be potentially classified as “Anti Phospholipid Antibody Syndrome” (APS) with the endothelial cell (EC) as the disease target. These patients have a hypercoagulable state demonstrated by increased markers of coagulation activation and increased blood viscosity due to the generation of Soluble Fibrin Monomer (SFM). The CFS/FM process may be triggered by a variety of pathogens (CMV, HHV6, Mycoplasma, Ch1, pneumonia, etc.), resulting in pathogen-mediated immune activation that induces antibodies which cross-react with BC protective proteins B2GP1 & Annexin V. These antibodies dislodge the protective proteins from EC surfaces, exposing PhosphatidylSerine (PS) on the EC surfaces in capillary beds. Pathogens induce inflammatory responses which include cytokine modulation of EC to down-regulate the antithrombotic environment (Thrombomodulin, tPA) in favor of prothrombotic expression of Tissue Factor (TF). TF and PS exposure allows binding of the coagulation tenase and prothrombinase complexes to EC surfaces.
This results in thrombin generation leading to SFM formation. SFM dimerizes easily, increasing blood viscosity and precipitating out on EC surfaces as fibrin(old) deposition, creating local ischemia and pathology, blocking nutrient and oxygen delivery in the microcirculation. A hereditary defect in a coagulation regulatory protein, such as protein C, protein S, Factor VL, prothrombin gene mutation, PAI-1, Lp(a), or elevated homocysteine is predispositional in greater than 755 of patients. Because this hypercoaguability does not result in an immediate thrombosis (100% occlusion), but rather in fibrin deposition (50-95%), we suggest that an appropriate name for this antiphospholipid antibody process to be Immune System Activation of Coagulation (ISAX) syndrome. This model provides an explanation for the therapeutic benefits reported with low dose anticoagulant therapy (heparin or warfarin) in the majority of chronically ill patients.
People are not chronically ill unless there is a coagulation regulatory protein defect as seen in Thrombophilia or Hypofibrinolysis.