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Melissa Kaplan's
Herp Care Collection
Last updated January 1, 2014

Hypercoagulation

The CFS/FM/CMP Plot Thickens

Melissa Kaplan, The Carousel Network, 8(5), May 2001

 

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.

Diagnosis
(# Patients)

Significant
Improvement

Moderate
Improvement

Some
Improvement

FM (7)

3

3

1

CFS (9)

5

4

0

 

 

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

 1.

Hemex Laboratories, Inc.
2505 West Beryl Avenue
Phoenix, AZ 85021-1461
800-999-CLOT (2568)
Fax 602-997-4274

The cost of the ISAC test is $440; the test may be covered by Medicare and most insurance plans. Any physician can order the test kit and order forms directly from Hemex. The additional costs are the blood draw ($20-50, depending on lab). Since some of the tubes have to be frozen during shipping, patients may also be requested to furnish the dry ice.6 Because of the necessity to keep most of the blood samples frozen, they must be drawn and shipped Monday-Thursday, not on Friday.

Hypercoagulable state is discussed in much greater detail in documents available at the Hemex site.

 

2.

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 Coagulation and Fibrinolysis 1999: 10 435-438.

 

3.

Bromelain (500-1000 mg daily). Several journal articles suggest that bromelain, a natural substance found in pineapples, enhances fibrinolysis. It may thus be useful in patients having high Lp(a) or high PAI-1 values as these block fibrinolysis. Bromelain is available over the counter in various digestive aids and supplements. It may be as useful in such patients as such clot-busting drugs as tPA.

 

4.

Heparin Sodium 20 mu/ml. One month's supply (20 1 ml vials plus 60 insulin U-100 syringes) is around $75. Both are available, by prescription, from pharmacies. Dosing is weight-dependent, at either 4000 units or 5000 units, by subcutaneous injection, twice daily.

 

5.

Transfer Factor 560
Immunity Today
513A N Mur-Len
Olathe, KS 66062 USA
Ph. 1-888-217-2200; Fax 1-913-780-2317

The cost for three months (3 per day) is $450.

Animune holds the patent for transfer factor and has licensed two other companies to make and sell it. They are:

Source Naturals sells TF under the
Wellness Cell Response product name. It is available in health food stores and through online vitamin sellers such as Vitaminshoppe.com and BNatural.com

4Life Research, LC
9850 South 300 West
Sandy, Utah 84070
1-888-454-3374

4Life's prices are higher than Source Naturals's price

 

6.

Dry Ice: In Santa Rosa CA, the 4-5 pounds required for shipping can be purchased at West Coast Welders Supply Co., 1377 Cleveland Avenue, 707-546-6214; elsewhere, look for ice companies and welders in the phone book's yellow pages and call to inquire about the availability of dry ice. Pick it up on your way to your doctor's appointment. Bring a kitchen-sized plastic garbage bag and a cooler with you to transport it to your doctor's office. Standard re-freezable ice packs are not suitable for shipping these samples.

Update September 2001: Sonoma County residents can now take the HEMEX kit (picked up from their ordering physician) and make an appointment with Unilab to have blood drawn for the HEMEX tests. Unilab will then take care of packing the kit with dry ice, etc. To make an appointment, call Unilab at their 1111 Sonoma Avenue location, at 707-528-2828 and request an appointment, stating you have a kit to be drawn for. Appointments are scheduled for Tuesdays and Thursdays and are done only for kits and only at the 1111 Sonoma location.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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.

Hereditary Thromosis Risk Panel I

Test

Result

Norm

Antithrombin activity

84

75-125 %

Protein C activity

123

60-140 %

Protein S activity

53

65-150 %

APC Resistance

Negative

Negative

Factor II activity

125

60-120 %

Lp(a) - Lipoprotein (a)

7

0-30 mg/dl

Homocysteine

5.9

female: 0.0-9.0 µ mole/L
male: 0.0-13.0 µ mole/L
> 60 years 5.0-20.0 µ mole/L


Immune System Activation of Coagulation (ISAC) Panel

Fibrinogen

370

180-310 mg/dl

Prothrombin Fragment 1+2

1.4

0.4-1.1 nM F1+2

Thrombin/Antithrombin Complexes

1.4

1.0-4.1 ug/l

Soluble Fibrin Monomer

42

0-17 mg/L

Platelet Activation by Flow:

CD62P

49

0-27 %

CD62P + ADP

42

39-80%

Platelet Activation Index

Normal

Normal

 

 

 

 

 

 

 

 

 

 

 

 

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. Check out the price for Source Natural's Wellness Cell Response and see if Animue is selling it through their site.

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.

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.


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

Thrombophilia (Hypercoagulable States), Ward Reports, 1998

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

Hypercoagulable States, OHSU Div. of Oncology & Hematology, 1977

Hypercoagulable States, University of Florida

Hypercoagulable States/Thrombophilic States, The Thrombosis Interest Group of Canada

Antiphospholipid Syndrome Associated With Seizures, Southern Medical Journal 1996

Prethrombic or Hypercoagulable States, The Coagulation Center. A good basic discussion on how normal coagulation is supposed to work.

TEG® Tests vs Standard Coagulation Tests, Haemoscope Corporation

www.anapsid.org/aboutmk/xenoest/hypercoagulation

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