Melissa Kaplan's
Chronic Neuroimmune Diseases
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Last updated January 1, 2014

A simplified introduction into hypercoagulable state...

Research conducted by Dr. David Berg and others at Hemex Laboratories¹ has found hypercoagulation to be a factor in many patients with chronic fatigue syndrome (CFS), fibromyalgia (FM), myofascial pain syndrome (MPS), and other disorders such as osteonecrosis (bone loss due to inadequate blood supply), and fetal loss.

Hypercoagulation (thickened blood) results from fibrin being deposited in small blood vessels. Fibrin is the body's natural bandaid: strands of fibrin form across a defect (wound, tear) in the walls of blood vessels, forming a mesh that holds platelets and blood cells. This beneficial clotting of cellular matter and fibrin strands plugs the leak, so to speak, holding things together until the body starts to repair itself.

Fibrin production is the last stage in a complex clotting process. The process itself starts off with the release of thrombin which in turn results in the production of soluble fibrin monomer (SFM), a sticky protein that increases blood viscosity. This leads to the deposit of fibrin on the endothelial cells that line the wall of the blood vessels. Under the normal conditions, it takes only a single burst of thrombin to generate a large amount of SFM which in turns produces sufficient amounts of fibrin to clot the defect. Testing of many patients diagnosed with CFS, FM, MPS shows that the thrombin-SFM-fibrin process is not working properly. Instead of a single burst of thrombin producing the amount of SFM needed, the thrombin keeps being produced at low levels. Instead of clots being formed, however, the result is that blood becomes increasingly thickened. The body's own ability to thin blood and break up clots is impaired because the fibrin smothering the endothelial cells prevents those cells from releasing heparans.

There are two different ways this scenario can be played out. The first is thrombinphilia, "thrombin loving", where the body keeps producing thrombin because the normal control that would prevent excessive or inappropriate thrombin generation fail, do not exist, or have somehow been overridden so the body keeps producing thrombin at low levels. The controller is anti-thrombin (AT). AT combines with thrombin to form thrombin/anti-thrombin (T/AT). Normally, when the endothelial cells release heparans, the release activates the AT, which acts slowly to reduce the thrombin. Not enough AT may be produced, or the amount may not be enough to keep up with the continuous thrombin production. Another possible cause is hypofibrinolysis, where too little heparans, the body's natural clot busters, is produced or circulated. So, in the (simplified) three part process (thrombin, antithrombin, heparans), one or more parts is dysregulated or rendered insufficient, leading to hypercoagulation.

Berg states that there are at least three possible causes for this thrombin malfunction:

• Viruses, bacteria and/or parasites can activate certain antibodies in the immune system, which in this case trigger the continual production of thrombin, generating excessive SFM and fibrin.
• Predispositional genetic defect in coagulation regulatory proteins (protein C, protein S, Factor VL, prothrombin gene mutation, PAI-1, Lp(a), or elevated homocysteine.
• Chemical exposure can result in changes that trigger the coagulation process.

The results of this thickened blood are widespread, due to the role blood plays as the major transport of nutrients and oxygen throughout the body:

• Thicker blood is harder to pump.
• Muscle, nerve, bone and organs function is impaired because of the inability of sufficient nutrients and oxygen to pass through the capillaries.
• The fibrin coating the vessel walls, the endothelial cells are no longer able to release heparans, the body's natural blood thinner.
• Hypercoagulation, by depriving the bowel of blood, may be a major factor in Irritable Bowel Disease.
• Viruses and bacteria may be hidden under the fibrin layer coating the vessel walls, essentially hiding them from antibiotic and antiviral treatments.

Some of the symptoms associated with hypercoagulation will surprise few with CFS and/or FM: brainfog, cognitive dysfunction, digestion problems, fatigue, and generalize malaise.

Because this hypercoagulability does not result in an immediate thrombosis (100% occlusion), but rather in fibrin deposition (50-95%), Berg, et al.² suggest that an appropriate name for this antiphospholipid antibody process would be Immune System Activation of Coagulation (ISAC) syndrome.

Hyperoagulation Testing
As a part of Hemex's research, they have developed a test to determine if a patient has this hypercoagulation disorder. The Immune System Activation of Coagulation (ISAC) tests five substances; abnormal results on any two of the five is considered to be a positive indicator of hypercoagulation. Their results thus far have found 79-92 percent of the CFS and/or FM patients they tested have hypercoagulation. As with many of the more detailed blood tests developed in the past decade, the defects causing hypercoagulation are rarely or not at all detectable by the standard laboratory tests performed at general labs, such as Unilab, Quest Diagnostics, etc. The standard coagulation workup done by these labs assess only the risk of actual clotting, whereas the ISAC panel is 10-20 times more sensitive.

Treatment
In 1998, 16 patients started on taking heparin injections daily.

To improve the outcome, Berg now recommends testing for bacterial infections such as Mycoplasma and Chlamydia pneumonia, as well as for active virus infections, such as Humanherpes virus 6 (HHV6), Cytomegalyvirus (CMV), and Epstein-Barr virus (EBV). The heparin³ (two subcutaneous injections per day) is taken for six months. One month or so into the heparin, antibiotic and/or antiviral treatment is started to combat the bacteria and viruses exposed by the reduction in the fibrin coating the vessel walls; this treatment lasts three months. At this same time as the antibiotic/antiviral treatment is started, Transfer Factor⁴ is also started; it is continued for four months. For those who test high in lipoprotein (a) (Lp(a)) or high plasminogen activator inhibitor-1 (PAI-1), 500-1000 mg/day of bromelain⁵ is started at the same time as the heparin and is continued for four months. The heparin is continued after the antibiotic and transfer factor therapies have stopped to prevent any organisms remaining from starting the hypercoagulation process all over again.

Those who have had CFS/FM for more than 10 years may show only one abnormality - or none - on the ISAC test. However, a trial course of heparin, especially if done in conjunction with the antibiotic or transfer factor, may result in more abnormalities showing up in subsequent testing. Berg suspects that this is because the organisms buried beneath the fibrin sludge layer needn't be as active so they cease triggering the coagulation process. As the heparin starts clearing out the sludge and restores cell-to-cell communication, the organisms reactivate and step up their attack, once again triggering coagulation. Most patients, when re-tested one month into the heparin treatment, show more abnormalities on the ISAC test. This indicates progress is being made. This also means that, with the reactivation and the die-off of organisms that starts once antibiotic/antiviral treatment is started, patients may experience a herxheimer effect: feeling sicker before feeling better.

Meeting of the Minds
When Berg compared notes with the labs working on developing tests and protocols for HHV6 and Transfer Factor, he discovered they were all working in the same directions. Transfer factor contains specific IgG and IgM antibodies to HHV6 and CMV, and many people diagnosed with CFS who test positive for active HHV6 infections also test positive for hypercoagulation.

Resources and References

Related ICD-9 Codes:

289.8 Hypercoagulable State

964.2 Anticoagulant monitoring (post-diagnosis monitoring)

In researching this article, I relied extensively on the Hemex Laboratories, Inc. website.

On a personal note...
I started the heparin protocol in late April 2001 after having an abnormal ISAC. Results outside the norms are highlighted.

A month into the heparin shots, I got retested. The full results weren't back by the time of my follow-up appointment, but the fibrinogen was and it was even higher, indicating a need to increase my dose from 0.3 BID to 0.4 BID.

I was tested for HHV6 4+ years ago, with negative results. I was tested again six months ago, this time using ViraCor's HHV6 test. Unfortunately, the Th2 part of my immune system is so elevated that the test result came back with one word: hemotoxic. The antibodies killed their cell culture. Since this is not uncommon in cases of CFS with this type of Th2 imbalance (and in those who have been taking Transfer Factor), ViraCor developed a new test. My results on that, too, was negative. My physician feels that that may not be conclusive so has be taking Transfer Factor anyway, but a less expensive version of it. The one I am taking is sold through a multilevel marketing company, which doesn't thrill us, but the product is good. (Note: This is before I found out that the TF is patented by Animune.com and they have another authorized manufacturer selling it, for less, under the Source Natural Wellness Cell Response name. See footnote 5 above for more information.)

Each bottle of Transfer Factor from 4Life (item #24010) contains 90 200 mg capsules and costs $37.95 each ($379.50 for ten bottles - ask about their 12 bottles for the price of 10 offer if you will need to buy that many or want to share an order with someone). Taxes and shipping costs are added to the product price. The company also makes a Transfer Factor Plus product (60 300 mg capsules, $53.95/bottle). I asked my doctor about using TF Plus rather than the regular TF; he said that many patients seem to have an adverser reaction to it so he recommends using the regular TF. Dosing starts at one capsule, once a day, gradually increasing to one capsule three times a day. (Note that prices and product availability change over time, and new products and protocols emerge as ongoing research changes our understanding of the disease and treatment process.)

Even though my Lp(a) was within normal ranges, because of its apparent assistance in busting clots, my doctor has me taking 200-500 mg of bromelain daily, along with the Transfer Factor and heparin.

For information on the labs doing the CFS immune panel and other testing useful in diagnosing the scope of problems in those with CFS and/or FM, see my Testing Laboratories page.

May 2003 Update:
I have been on high doses of doxycycline (200 mg TID for four months) as part of my treatment for Lyme disease. During the latter part of the third month, I noticed that I was bleeding more when scratched, cut, and after needle sticks (blood draws and IVs). I then realized that my bleeding wasn't excessive--it was normal. What had been abnormal was how little I bled over the past couple of years subsequent to hypercoagulation setting in. My horrendously thick and prolonged periods were also getting better. It is possible that the high dose doxy is having some effect on some other organisms that have been hiding in my body, or that Borrelia burgdorferi, the spirochete that causes Lyme disease, was somehow culpable in the triggering of the hypercoagulation.

September 2003 Update:
Well, I was wrong. It's not the doxy that has affected the change in my bleeding and periods. I told my doctor about the changes in bleeding, and so we decided to do the ISAC test again to see what it looked like. But first, my doc put me on three weeks or sublingual heparin (0.5 ml 2 x d). The ISAC test results did show a change from the last one two years ago: it was worse!

When musing about this with some friends knowledgeable about herbs, one reminded me that artemesinin, a factor found in the plant Artemesia (wormwood), has anti-thrombin factors, resulting in thinning the blood. I have been taking artemesinin to help combat babesiosis, an infection caused by the Babesia organism, frequently found in people who have been infected by Borrelia, the organism that causes Lyme disease (neuroborreliosis). So, without affecting the underlying cause(s) of this hypercoagulation disorder, the artemesinin is thus far the only thing I have tried that is at least superficially thinning my blood.

Warning: Artemesia can cause serious heart/cardiac problems, including cardiac arrest, in people who are sensitive to it, so taking it should be done only after discussing it with your doctor and being monitored. Also, start out with very low dose to see how it affects you, ramping up slowly, especially if you tend to be hypersensitive to 'normal' doses of drugs, herbs and supplements.

I recently came across nattokinase, a naturally occurring fibrolytic enzyme found in soy. I won't be taking it as it is far more expensive than artemesia, but if you are one of that small group who did not respond to the heparin/transfer factor/antibiotic/bromelain protocol for hypercoagulation, you might want to look into nattokinase as a work-around to the continuing hypercoagulation.

In closing...
For those severely ill with any of the many disorders being found extensively in those with CFS and FM, "fixing" the hypercoagulation may not be a cure-all, but when it works it can improve function and quality of life.

My doctor, who has done the testing and prescribed this protocol for a number of patients, is finding that a few get worse on the heparain, even at lower than the recommended 0.3-0.4 cc/day, and about one third experience no improvement at all. He is going to try to figure out if there is anything in the HEMEX or other tests that may be used to help predict which patients may fall into the worse or no-change treatment response categories.

Since the time I was doing the heparin protocol, the treatment for hypercoagulable state has evolved, with many patients doing better on higher doses of heparin given sublingually, rather than injected. In discussing the more normal bleeding with my doctor, we decided that I will try heparin again, this time orally. As of this date, I have started the new heparin protocol. I will take the HEMEX test again in three weeks to see if there is any improvement over my last panel.

Related Articles
Note: these articles/units discuss hypercoagulable state in general, not necessarily as it pertains to CFS.

Hypercoagulation and Borreliosis (Lyme disease)

Evaluation of the hypercoagulable state: Whom to screen, how to test and treat, Postgraduate Medicine, 2000

Hypercoagulable States, MedlinePlus (NIH)

Hypercoagulable States, University of Florida

TEG® Tests vs Standard Coagulation Tests, Haemoscope Corporation

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