Hypercoagulation, Protein Accumulation, and Fibromyalgia

line Keith Berndtson, MD

Fibromyalgia and the Microcirculation of Blood and Lymph

Recent clinical experience suggests that pain, fatigue and other symptoms suffered by patients with fibromyalgia is related to an accumulation of proteins in the blood and lymph, and that this problem can respond well to treatments aimed at clearing protein debris.1,2 Though exact mechanisms are not well understood, accumulation of blood and lymph proteins appears to slow down blood flow in small arteries and lymph channels, creating conditions that, over time, result in widespread pain and chronic fatigue.

In the search for underlying causes of fibromyalgia, fibrin deposition on endothelial cell surfaces is a credible suspect. Endothelial cells line the inner walls of blood vessels, and they play an extraordinarily important role in controlling how blood circulates to our cells, and how our cells communicate with each other, especially at the level where our smallest arteries become capillaries. There is growing consensus among medical researchers that to fully understand cardiovascular disease, autoimmune disease, diabetes, cancer, and other chronic illnesses, we must understand the structure and function of endothelial cells.3 We can add fibromyalgia to the list.

According to the hypercoagulation theory, excess fibrin deposits disrupt endothelial cell membrane structures, exposing phospholipids and triggering an immune response. In an attempt to control the damage, cell adhesion molecules spring up to catch and hold the platelets, coagulation factors, and immune system cells being attracted to the vicinity. If the rate of protein accumulation exceeds the rate of breakdown, the microcirculation gets clogged and flow decreases.

The normal mechanism for counteracting this phenomenon, dilation of the blood vessels through nitric oxide synthesis and release,4 may be impaired in fibromyalgia. This interference with reflex vasodilation may occur through protein interactions with the enzymes that synthesize nitric oxide.5,6 These interactions may influence the availability of tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), or other mediators of the breakdown of fibrin.7

The uncompensated decrease in local perfusion pressure in turn reduces lymph flow, and the stasis of protein debris in the small lymphatics promotes fibrosis in muscle and other soft tissues. The whole process can evolve quickly, as with post-traumatic forms of fibromyalgia, or slowly, as with gradual-onset fibromyalgia. Either way, the result is widespread pain, chronic fatigue, and multiple other symptoms.

The clinical picture overlaps to some degree with anti-phospholipid antibody syndrome.8 This syndrome cause symptoms ranging from mild to severe. Serious problems include recurrent miscarriages, deep vein thrombosis, pulmonary embolus, heart attack, and stroke). In fibromyalgia, the clinical consequences of the hypercoagulable state are not directly life-threatening, but there are similarities, in that there appears to be some type of endothelial cell dysfunction.

What Triggers Excess Fibrin Deposition?

With severe or prolonged physical, mental, and/or emotional trauma, the body produces high levels of stress hormones and immune system mediators. In many patients with fibromyalgia, this hyperactivation of immune system function appears capable triggering an abnormal cascade of coagulation proteins, resulting in a hypercoagulable state, where excess fibrin deposition can occur. The trauma responsible for triggering a hypercoagulable state could be an accidental injury (such as a fall or a car accident), a flu-like illness, surgery, a gauntlet of stress, or literally any form of intense or sustained stress on one’s physical or mental health.

This tendency toward a hypercoagulable state may be stronger in some, compared to others, for genetic reasons. People can have genes causing them to produce too much of the raw material that will eventually turn into thrombin or fibrin (the “procoagulant” genetic type), while others have genes that result in lower amounts of the enzymes that clear fibrin away (the “hypofibrinolytic” genetic type). Some people can have both types of genes, predisposing to even more fibrin accumulation. Other genetic influences on coagulation or immune system function may also play a role.9

Potential triggers for immune system hyperactivation of coagulation in patients with fibromyalgia include food allergies, intestinal dysbiosis, leaky gut, sluggish liver, toxic metal burdens, and reactivation of stealth infections. The terms dysbiosis, leaky gut, and sluggish liver are typically used by natural and integrative medicine doctors, and rarely used by conventionally-trained doctors practicing in the mainstream. Yet these terms can easily be translated into scientific concepts understood by conventionally-trained physicians.

A key thing to understand is that in the wall of the small bowel resides roughly 40% of the human immune system. The surface area of a typical 20-foot length of small bowel would cover a tennis court. If the barrier function of the small bowel gets too stressed, the gut’s immune system will start reacting to greater numbers of gut-derived molecules that have no business in human metabolism. High rates of assimilation of these gut-derived toxins and antigens can quickly, or gradually, generate excessive stimulation of the immune system. The turnover of protein required to keep up with such an immune system workload can reach massive amounts. At a certain point, the accumulation of protein debris begins to exceed protein clearance, triggering sluggishness in the blood and lymph circulations, and in the liver’s ability to metabolize and detoxify the load.

The term “stealth infections” refers to viruses (Herpes Simplex, Human Herpesvirus-6, Epstein-Barr virus, Cytomegalovirus, Enterovirus, and others) that take up residence in particular cells of the body, remaining in a dormant state until conditions are ripe for reactivation. Upon reactivation, they begin to replicate inside of their host cells. These cells sense what is happening, and before they die, they send signals to the immune system to come and eliminate this enemy “pocket of resistance.”

As infection surveillance units arrive on the scene to contain the recently reactivated stealth enemy, incidental friendly fire damage to surrounding cells can occur. The patient feels achy and tired. The same process applies to small, intracellular bacteria, such as species of Mycoplasma and Chlamydia. It may apply to intracelluar fungal organisms as well. In people who are genetically predisposed, this process can trigger a hypercoagulable state.10

What are the Consequences of a Hypercoagulable State?

Fibrin is a stiff protein that functions as scaffolding for blood clots. In the case of fibromyalgia, large blood clots do not develop. Rather, the fibrin forms a meshwork, or screen, slowing down blood flow to the cells downstream, and interfering with cell functions and with cell-to-cell communications. This promotes the accumulation of additional forms of protein debris, all of which decreases the circulation’s ability to deliver oxygen and nutrients to the cells, and carry away the waste products from cellular metabolism. Over time, the result is chronic pain, fatigue, and a host of other symptoms and signs of a body that is not functioning normally. What kinds of things can go wrong?

Endothelial Cell Dysfunction

Endothelial cells at the level of these small arteries (called arterioles) contain mechanisms for gauging blood and tissue perfusion pressures.4 Fibrin deposition on arteriolar endothelial cell surfaces can interfere with the blood pressure feedback loop known as the neurovascular reflex arc, resulting in dysfunctional regulation circulating blood.

The symptoms and signs might include a chronically low blood pressure, unusual changes in heart rate or blood pressure, lightheadedness with changes in position, poor exercise tolerance, post-exertional malaise, prolonged recuperative time following exercise, and brain fog, many of which are reported by patients with fibromyalgia. Diagnoses that fall under the category of autonomic neuropathy include neurally-mediated hypotension, postural orthostatic tachycardia syndrome (POTS), and other specific forms of dysautonomia.11

Reactivation of Stealth Infections

A microcirculation jammed with protein is like a river backed up with deadfall – as the blood-swept proteins accumulate, flow stagnates, and conditions in the stream deteriorate, increasing the local acidity of the blood, lymph, and tissues. As the pH drops, so does the oxygen level, because oxygen release from hemoglobin is pH-dependent. As the oxygen tension in the blood and tissues decreases, it becomes harder for cells to control damaging free radicals. Key immune and antioxidant enzyme systems cannot function as well as they should. With a low oxygen tension, otherwise dormant intracellular viruses and bacteria experience more favorable conditions for replication. Research has shown that reactivation of stealth infections will launch immune reactions that, in turn, activate coagulation pathways.10,12,13

This helps explain why so many intracellular pathogens take up residence in endothelial cells and monocytes (a type of immune cell) – because these cells are more likely to witness a lower pH and oxygen tension due to protein accumulation in the blood and lymph. It is to their evolutionary advantage to lease space in cells that reside, or travel in, the murky backwaters of the human blood and lymph circulations.

Mitochondrial Dysfunction and Increased Oxidative Stress

In the cells most affected by the decreased flow of oxygen and nutrients, there exists an increase in free radical-induced oxidative stress. This impairs the cellular systems responsible for maintaining metabolic balance. Especially vulnerable are the cell’s energy-producing machines, called mitochondria. Impaired energy production, free radical control, and membrane fluidity may develop over time.

As the mitochondria struggle to perform, cellular energy-producing systems break down. As this happens, inorganic phosphate molecules start to back up in the affected cells. Interestingly, phosphate build-up is a key concept supporting another theory about the cause of fibromyalgia.14 This hypothesis proposes as a treatment for fibromyalgia the drug guafenisin, which, as long as its effects are not blocked by salicylates, increases the removal of inorganic phosphates via the kidneys. The guafenisin treatment protocol has produced varied success in fibromyalgia patients. From an integrative medicine perspective, guafenisin and anticoagulation therapies may simply be two different ways to treat the malfunctioning cellular machinery found in patients with fibromyalgia. One treatment does not substitute for another. Each treatment may complement the other.

Abnormal Thyroid Regulation and Thyroid Resistance Syndrome

Patients with subclinical hypothyroidism (abnormal labs without symptoms of hypothyroidism) are characterized by endothelial dysfunction resulting from a reduction in nitric oxide availability, a problem that can be reversed with thyroid therapy.15 This indicates that one of the earliest signs of abnormal thyroid regulation may occur at the level of the endothelial cell’s ability to regulate microcirculatory flow to the tissues of the body. This link between endothelial cell dysfunction and hypothyroidism raises some interesting questions about the presence of additional unforeseen mechanisms that can inhibit the effectiveness of the body’s thyroid hormone system. A recent, extraordinarily comprehensive scientific review of the thyroid hormone regulation system has outlined possible answers to these questions.16

Suspecting that 30 to 40% of all fibromyalgia patients suffer a syndrome of peripheral resistance to the T3 form of thyroid hormone, Lowe and colleagues performed a double-blind, placebo-controlled, crossover study which found that most of these patients “improved or recovered when permitted to use enough thyroid hormone as part of a more comprehensive regiment of metabolic rehabilitation.”17 As another example of a mechanism capable of producing resistance to thyroid hormone, estrogen dominant hormone stimulation may inhibit the conversion of T4 to T3 (the most active and potent cellular form of thyroid hormone), as evidenced by increased levels of reverse-T3 in the serum of women taking oral contraceptives.18 This is but one of several possible causes of thyroid resistance syndrome.16 (p. 295-338)

Anticoagulant and Protein Debris-Clearing Therapies in Fibromyalgia

Treating fibromyalgia with low dose anticoagulants, such as heparin or Coumadin®, can be helpful in selected case studies involving patients who appear to generate too much thrombin-related raw material.2 Treating with enzymes that help clear away fibrin, such as bromelain and Nattokinase®, is also proving helpful in selected case studies.2 Experience in Europe shows that the use of broad spectrum proteolytic enzyme blends can help clear protein debris from the blood and the lymph circulations.19,20 What follows is a brief summary of two series of cases, totaling 48 patients with fibromyalgia, treated with anticoagulants, or with enzymes, through Illinois Multi-Med.

Anti-coagulant Therapy (Heparin or Coumadin®)

The first case series involved 16 fibromyalgia patients (12 female, 4 male) placed on twice daily self-injections of heparin over a period of at least 12 weeks, two patients (female) experienced a dramatic decrease in pain and increase in energy. None of the remaining patients on heparin reported significant benefits, making the positive response rate in this small case series 12.5%. One patient who responded to the heparin protocol “stepped down” to oral Coumadin® once daily, with similar benefits. The other uses heparin intermittently for flare-ups of pain and fatigue.

Oral Fibrinolytic and Broad Spectrum Proteolytic Therapy

The second case series involved 32 fibromyalgia patients (24 female, 8 male) placed on oral Nattokinase® twice daily, with or without an additional broad spectrum proteolytic enzyme formula, 20 patients (17 female, 3 male) experienced a moderate to major decreases in pain and increases in energy. Other benefits noted included increased mental clarity, warmer hands and feet, and reduced dizziness. The positive response rate in this series was 62.5%, five times better than the response rate from heparin. The addition of a proteolytic enzyme blend to the fibrinolytic enzyme therapy increased the chance of self-reported moderate or major benefit by a factor of 2.3. Being on dessicated thyroid (a T3-T4 combination), as opposed to being on no thyroid medication, increased the chance of self-reported moderate to major benefit by a factor of 3.0.

In this series of cases, one patient (male) elected to discontinue the Nattokinase® due to symptoms of esophageal reflux. Two patients (female) complained of audible “gurgling” of the bowels (without pain). Alteration of dose timing did not succeed in changing this symptom for either patient, but each elected to continue therapy due to moderate decreases in pain and increases in energy.

Two cases in particular lead us to believe that in patients with fibromyalgia, Nattokinase® works to open up the blood microcirculation, whereas broad spectrum proteolytic enzyme formulas work appear to work in both the blood and the lymph.

Patient A

Patient A had a history of fibromyalgia for six years. Seven months before starting therapy, she had lymph nodes removed from her right arm as part of a mastectomy for breast cancer. When she started Nattokinase®, she noted a decrease in pain and an increase in energy within two days, but on the third day her right arm began to swell from lymphedema. When she added a broad spectrum enzyme formula, the lymphedema subsided, and she found that she could continue to experience the benefits of fibrinolytic therapy without side effects.

We interpret this to suggest that a fibrinolytic enzyme can work to reduce pain and increase energy in this patient with fibromyalgia, but that the presumed relative increase in microcirculatory perfusion pressure resulted in lymphedema due to compromised lymphatic structures in her arm. By promoting the clearance of her lymphedema, the broad spectrum enzyme formula apparently help clear lymphatic protein debris, such that lymphatic drainage could occur even through a compromised lymphatic chain.

Patient B

Patient B had a history of fibromyalgia for five years. She did not report benefit from Nattokinase.® Within two days of staring the broad spectrum enzyme formula, her dizziness resolved. When she ran out, the dizziness returned. When she resumed broad spectrum enzyme therapy, the dizziness resolved again. We interpret this to suggest that the actions of broad spectrum enzyme formulas in the blood and/or lymph can address problems not addressed by a fibrinolytic enzyme alone.

Given these findings, for patients with fibromyalgia, we advise combination therapy with fibrinolytic and proteolytic enzymes, to help clear protein debris from both the blood and the lymph, and increase the chances of a favorable response. Monitoring for side effects is recommended. Thus far, most reported side effects described in case studies or on web-based message boards involve the digestive system (reflux, stomach pain, gas, bloating, frequent loose stools, and gurgling have all been reported). At present, there are no adequate data from which to assess the probabilities of adverse effects from these therapies. In our case series, both enzyme therapies were remarkably well tolerated.

The Future of Fibromyalgia Therapy

The biochemistry of human metabolism is extraordinarily complex. The molecular biology of endothelial cell function and coagulation are only now getting the attention they deserve for their roles in chronic illness. Our understanding of the links between the blood circulation and the lymph system is rudimentary, but advancing.21 The role of endothelial cell function in cardiovascular disease and other chronic diseases is being subject to increasingly creative analysis.22 This research should prove valuable to patients with fibromyalgia. As research progresses, we are likely to learn that endothelial cell function plays an important role in most, if not all, chronic illnesses, and that the specific type of endothelial cell dysfunction will vary somewhat from one illness to another. Of great interest is the apparent link between endothelial cell-mediated microcirculatory flow and thyroid hormone regulation of metabolism.

There are multiple laboratory tests available to help identify the presence of coagulation abnormalities and pro-inflammatory states; making proper clinical sense of these tests is a challenge, given our incomplete understanding of molecular and cellular biology. There are also multiple ways to evaluate hypometabolic, clinically hypothyroid states. The best use of these tests in fibromyalgia awaits further investigation.

There is also much to learn about which types of stress or trauma, combined with which type of genetic picture, result in which type of hypercoagulable/pro-inflammatory state, let alone which forms of treatment work best for which pattern of abnormality. Early reports of success using anticoagulants, fibrinolytic enzymes, and proteolytic enzymes are promising. Most of the research pertaining to oral enzyme combinations currently emanates from Europe and Asia, where they are used more routinely in patients with inflammatory diseases, trauma (surgical and accidental), infections, and cancer.23

As we learn more about the uses of thyroid hormone preparations, and the special properties of individual enzymes and of enzyme combinations, we will be able to use them more intelligently. Currently, we know that thyroid hormones do more to regulate human metabolism than just about any other molecules in all of biology.16 We also know that individual enzymes and enzyme combinations have fibrinolytic, hemorheologic, anti-edematous, anti-inflammatory, and immunomodulatory properties; they can activate macrophages and natural killer cells, and they can influence the actions of cytokine, immune complexes, and cell adhesion molecules.24

It will take time for well-designed clinical studies to answer these questions, but enough is already known about safety to proceed with trials of therapy using enzymes to control the hypercoagulable, lymph-congested states that may exist in the majority of patients with fibromyalgia.

Illinois Multi-Med is committed to making available the latest, most promising methods for the evaluation and treatment of fibromyalgia.

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