1999 Clinical and Scientific Meeting

D Berg [1], LH Berg [1], J Couvaras [2]

1 HEMEX Laboratories,
2 IVF Phoenix Introduction

Is CFS/FM Due to an Undefined Hypercoagulable State Brought on by Immune Activation of Coagulation? Does Adding Anticoagulant Therapy Improve CFS/FM Patient Symptoms?

In 1994, the question was asked "Are recurrent miscarriages a result of an underlying hypercoagulable state?" From the data of a patient study of 25 women, the conclusion was that there is a hypercoagulable (HC) state in a subset of recurrent miscarriage patients. This led to the definition and understanding of the HOPI (Hypercoagulation Of Pregnancy & Infertility) Syndrome [BLOOD:11/97] or Immune Activation of Coagulation (IAC). The treatment for these women is subcutaneous (sc) heparin before conception and throughout the pregnancy. To date, there have been more than 150 successful first time deliveries from three IVF practices in Phoenix.

Heparin reduces this hypercoagulable state and quiets some of the symptoms associated with an activated immune system. This treatment improves success rates from 25% to greater than 75%. Heparin also reduces some of the immune mediated symptoms, including headache, pelvic pain, and fatigue. This finding suggested that this therapy would be useful in chronic fatigue (CFS) and fibromyalgia (FM). A review of HOPI patients from one clinic indicated that a subgroup indeed clinically fit the diagnosis of CFS or FM. To validate this observation, this study was begun to answer two questions: A) Is there an underlying hypercoagulable state in CFS and FM , & B) if so, would heparin therapy relieve the symptoms and/or normalize the patient?

Methods

The Hypercoagulable Screen consists of four tests.

Fibrinogen: The Clauss method for fibrinogen measurement is the standard assay using the rate of fibrinogen convertion to fibrin in the presence of excess thrombin. The concentration is determined by using a reference curve prepared from the clotting times of reference plasma dilutions with known fibrinogen concentrations.

Soluble Fibrin Monomer (SFM): SFM is a chromogenic assay based on the fact that SFM considerably enhances the conversion of plasminogen to plasmin by tPA. The amount of SFM is determined by measuring the amidolytic activity of plasmin on the chromogenic substrate S-2390. The release of p-nitroaniline (pNA) is determined at 405 nm. The concentration of SFM is plotted against absorbance and is linear from 0 - 100 nmol/L in plasma.

Clotting Kinetics (Sonoclot): The Sonoclot is an ex-vivo analog tracing of a whole blood clotting time. The tracing displays four actions of the coagulation process, consisting of activation of the cascade (ONSET), fibrin monomer formation (RATE), platelet function (peak of tracing) and clot retraction and fibrinolytic activity. The Sonoclot represents the current status of the coagulation system of the patient.

Platelet Activation Score (PA Score): The PA Score is the amount of platelet activation in the patient. The assay is either: 1) a platelet aggregation procedure, using 2.5uM ADP agonist and measuring the area under the curve, or 2) platelet expression of glycoproteins on the platelet surface as indicators of activation, using PAC-1 antibody against GP IIb/IIIa, CD62 (P Selectin from alpha granules being incorporated into the platelet membrane) and 10 uM ADP.

Results

21 Female Patients: 9 CFS, 12 FM: See Table

Abnormal Patient Values:

1 test

1 patient

5%

2 tests

5 patients

24%

3 tests

12 patients

57%

4 tests

3 patients

14%

Abnormal Test Values:

Sonoclot Rate 19/21 90%
SFM 15/18 83%
PA Score 14/21 67%
Fibrinogen 11/21 52%

 

Improvement:
CFS
FM
None
0
0
Some
0
1
Moderate
4
7
Significant
5
4

 

See BD Lab Data as patient example of therapy and improvement.

Discussion

The hypothesis that a subgroup of CFS/FM patients have a hypercoagulable state is proven by demonstrating thrombin (IIa) generation in these patients. Additionally, two out of three patients have platelet activation (PA).

Platelet activation reinforces thrombin generation, worsening patients symptoms. Aspirin (ASA) does not completely reduce this activation, which creates the "sticky platelet" syndrome. Even 325 mg of ASA twice a day may not attenuate this stimulation. Only removing the source of the immune activation (IgG) will turn off platelet activation. Activated platelets produce IL-1 and TNFa which can induce an inflammatory response in the patient. [When using heparin or coumadin, 81 mg ASA per day is used as an antiplatelet drug.]

To shut off thrombin generation, anticoagulant therapy is necessary until the underlying cause of thrombin generation is determined and removed. Anticoagulants can stop thrombin production while giving the body time to recover and down regulate the immune activation. The standard method for anticoagulation is to begin with sc heparin and follow with low dose coumadin, both on a weight adjusted basis. The goal is to normalize the patient from the hypercoagulable state. This is a lower dose than therapeutic anticoagulant regimens.

Soluble Fibrin Monomer (SFM) deposition is like a teflon coating on endothelial cells lining the capillaries and blocking passage of nutrients through to muscles, organs, etc. Simply shutting off the thrombin generation will allow the body's fibrinolytic system time to dissolve and remove any fibrin deposition on capillary surfaces.

The disease process occurs over time causing patient symptoms and it will take time to reverse this process to dissolve the SFM. Patients may not be free of symptoms for 1-3 months. Most have moderate to excellent recovery and remain symptom-free. Only one patient out of these twenty-one had minimal improvement in symptoms. Two patients needed an additional week of heparin therapy after converting to coumadin during their treatment.

Conclusion

This pilot study has shown:

A long term, placebo controlled study is beginning at this time. Only patients with abnormal baseline coagulation test values will be treated with anticoagulants.

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