Here is an interesting article about how hyper-coagulation can be related to Fibro and CFS:
Besides heparin nattokinase and lumbrokinase help clear the blood of fibrin.
Low Level Activation of Coagulation with Coagulopathies in the Etiology of CFS / FM and Chronic Illnesses. An Explanatory Model Revisited1. DE BERG1, LH BERG1 and HH.HARRISON1,2; 1HEMEX Laboratories, Phoenix, Az, 2Univ AZ College of Medicine.
INTRODUCTION: Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) may be considered a Chronic Illnesses (CI). A MODEL of Low Level Activation of Coagulation in CFS / FM as a variant of Antiphospholipid Syndrome (APS) was first published in 19991.
The purpose of this presentation is to give additional supporting data to the 1999 hypothesis about the subthrombotic process termed ISAC (Immune System Activation of Coagulation) which results in low level activation of coagulation in CI patients, how the subthrombotic condition is effected by a coagulation protein defect and how this model of disease is involved on the cellular level in many different and seemingly unrelated disease processes.
MODEL: A pathogen (infection) plus a coagulation defect allows excess thrombin generation, converting fibrinogen to soluble fibrin. Soluble fibrin increases plasma viscosity and may decrease blood flow.
Soluble fibrin may be deposited on the capillary wall as fibrin deposition, slowing oxygen and nutrients transfer to the tissues and as well as waste products from reentering the blood stream.
DISCUSSION: In the initial cohort of 54 patients and 23 controls, 92% of the patients had a demonstrable hypercoagulable state or low level activation of coagulation. Subsequent cohorts have yielded from 78 - 92% coagulation activation as defined as two or more of the five ISAC (Immune System Activation of Coagulation) markers being positive.
After testing over 3000 patients with a variety of chronic illnesses, a coagulopathy (coagulation protein defect) has been found in over 80% of these patients. Genetic studies have shown a 2 to ~ 10 fold increase of coagulation protein defects over the general population rates in CFS/FM and chronic illnesses2.
A coagulation regulation protein defect allows accumulation of fibrin (fibrin deposition) on the blood capillary walls due to the lack of proper control of the clotting mechanism.
This may be due to either a thrombophilic defect (forms fibrin too easily) or a fibrinolytic defect (cannot clean up fibrin easily). These data allow for the discussion of a coagulation protein defect as being permissive and/or predispositional in chronic illnesses. Around 20% of patients tested have both a thrombophilic and fibrinolytic defect.
When a defect is present, a precipitating event (infection, trauma, etc) leads to coagulation activation. The inflammatory response and coagulation activation are the components of the host defense mechanism. If the body can wall off a pathogenic invader with fibrin, it can prevent a systemic infection.
Because of a regulatory protein inappropriate action at some point in the sequence of events to control the fibrin formation, thrombin generation continues at a low level which keeps the coagulation mechanism activated in this low level state.
This is the important paradigm shift from a thrombotic process (a blood clot) to an ongoing subthrombotic condition, as found in chronic illnesses. Supporting evidence comes from several sources. Pathogens, such as Epstein Barr virus (EBV), Cytomegalovirus (CMV), Human Herpes Virus 6 (HHV6), Mycoplasma (many species), Chlamydia pneumonia, tick borne disease (Borrelia [Lyme], Babesia, Bartonella, Ehrlichea), Human Herpes 1, 2 & 3, Staphylococcus, Streptococcus, parasites, and many more pathogens, have the capability of triggering the coagulation mechanism.
Many of these pathogens have amino acid sequences that induce cross reacting antibodies against the protective proteins on the blood vessel walls. B2GPI and Annexin V are two protective proteins on the inside of the capillary that keep coagulation proteins from binding to the endothelial cells (EC) and generating thrombin.
In 2000, CMV was shown to have two 19 amino acid sequences on its outer coat that induce anti-B2-GlycoProtein I (B2GPI) antibodies3. These findings suggest a mechanism of induction of autoimmune AntiPhosphoLipid antibodies after incidental exposure to viruses.
Since pathogens can induce the formation of these cross reacting antibodies, they can generate fibrin deposition over the ECs which are infected. Staph, Strep, CMV, EBV, HHV6 are just a few of these pathogens that have these capabilities4.
This gives support to the proposed 1999 model of CFS / FM being a variant of APS. Cross reacting antibodies strip the protective proteins that cover endothelial cells and allow binding of the coagulation cascade proteins and thrombin generation. Thrombin (IIa) generation results in the formation of Soluble Fibrin Monomers (SFM) from Fibrinogen (FI
5. Continuing low level thrombin generation converts SFM into Soluble Fibrin Protofibrils (SFP). [See photomicrographs]
When there is a burst of Thrombin (trauma), IIa activates Factor XIII which in turn cross-links SFPs into insoluble fibrin, i.e., a blood clot. Since SFPs are a method by which the body can wall off pathogens, SFPs have a protective mission in the blood [See diagram].
Soluble Fibrin deposited on EC can delay oxygen and nutrient delivery to tissues around capillaries as hypothesized in 1999.
Nemerson6 reported in the International Society Thrombosis & Hemostasis meeting (July, 2003, Birmingham, England) that 1 micron (1 Fm) of fibrin deposition changes the oxygen diffusion time, from RBC through the capillary wall to the local tissue, from 2 seconds (normal diffusion) to greater than 5 minutes. [See diagram]
This fibrin deposition not only creates local hypoxia, but also blocks nutrients and hormones from getting into the tissues easily as well as slowing down the process of waste removal from the tissues.
The fibrin deposition model explains the local tissue hypoxia found in many disease entities, including Fibromyalgia. Lindman, et al7, in 1995 showed swollen endothelial cells in muscle biopsies from trapezius muscles in myalgia patients.
They concluded that capillary derangements might be caused by disturbances in the muscle microcirculation, hypoxia or ischemia. “This might severely affect the microcirculation of the muscle by diminishing the exchange of gases and substrates between the capillaries and the surrounding tissues”. Park et al8 (1998), using P-31, detected metabolic abnormalities in muscles of patients with Fibromyalgia.
These metabolic abnormalities are consistent with weakness and fatigue in FM patients. This included significant decrease in ATP and ADP with increased AMP in patients over controls.
These findings were corroborated by several other similar studies. Park concluded that inadequate circulation and oxygenation leads to reduced tissue oxygenation, resulting in decreased ATP synthesis.
Jeschonneck, et al9, presented evidence in 2001 that Fibromyalgia is local hypoxia. They found chemical changes secondary to local hypoxia (ATP, ADP and [AMP), “moth-eaten fibers”, “disturbed” blood flow, higher RBC concentration, reduced RBC flow and increased RBC rouleau, decreased skin temperature, vasoconstriction of unknown pathophysiology, swollen endothelial cells and local muscle pain associated with local muscle hypoxia.
The end result is ischemia and pain. These findings could be easily explained by fibrin deposition proposed in the unifying coagulation activation model listed above. In addition to the build up of SFM and SFPs on the capillary walls, Soluble Fibrin may create another problem for the patient.
Increased SFM in the plasma may increase the plasma viscosity. Increased plasma viscosity decreases blood flow. Decreased blood flow may cause some end organ dysfunction. This may explain the Raynaud’s phenomenon of cold hands and/or cold feet.
Unpublished data indicate that increased SFM in the plasma may result in very low Sedimentation Rates, e.g., values between 0 - 4.
Thus, besides blocking oxygen and nutrients from entering the tissues and waste removal in a timely manner, blood flow is compromised by increased Soluble Fibrin. This may contribute to positive tilt table tests in CFS / FM patients.
Recent studies involving arthritis confirm the local and systemic activation of coagulation and fibrinolysis defects. So, et al10, (2003) showed that patients with arthritic joint disease have increased plasma and joint coagulation activation (F1+2, T/ATs, D-Dimers) as compared to healthy volunteers.
These activation markers were highest in RA patients. Increased fibrinolysis inhibitors (Thrombin Activated Fibrinolytic Inhibitor-TAFI) in the joints permits ongoing coagulation activation and blocks the removal of subsequent fibrin deposition.
The use of low dose heparin therapy may reverse the fibrin deposition and allow for potential treatment of pathogens. Clinical evidence of this subthrombotic pathophysiology as it relates to patient symptoms comes from the apparent efficacy of anticoagulant therapy in these patients.
In a retrospective study from one clinical practice11, a cohort of 60 CFS/FM patients was given 5000 units of sq heparin BID along with other therapies. The time on heparin ranged from 3 to 20 months with a average of 8 months of therapy. Each patient received a clinical assessment score before and after treatment as an outcomes evaluation. The average improvement (scale 1-10) was 8.5 (85%). The coagulation activation testing (ISAC panel) was positive in 78.3% of the patients at baseline and showed improvement on repeat testing.
Thus the ISAC panel is useful also for monitoring effectiveness of heparin therapy in CFS/FM patients.
SUMMARY: CFS, FM and other Chronic Illnesses may have a common etiology which is the subthrombotic process termed ISAC (Immune System Activation of Coagulation) which results in low level activation of coagulation. This has been described as a subset of AntiPhosphoLipid Antibody syndrome (APS).
A permissive or predispositional coagulation regulatory protein defect allows for ongoing thrombin generation from pathogen(s) activation.
Thrombin converts fibrinogen to soluble fibrin which may be deposited on capillary walls. Increased soluble fibrin increases plasma viscosity, decreasing blood flow throughout the body.
Fibrin deposition slows oxygen and nutrient delivery to local tissues, creating hypoxia, ischemia and decreasing ATP production within the cells.
The same process inhibits cellular metabolic wastes from reentering the blood stream for disposal.
Low dose heparin therapy (not warfarin) decreases thrombin generation and soluble fibrin production, improves blood flow, allows for fibrinolysis to clean up fibrin deposition, and allows the return of an anticoagulant environment (instead of a procoagulant environment) in the capillaries.
Other therapies may be indicated based on the hereditary coagulation defect(s) found in the patient.
