New studies have shown that in many Chronic Fatigue (CFS) / Fibromyalgia (FM) / Myofascial Pain (MFP) Syndrome, and Osteonecrosis patients, there exists a HYPERCOAGULABLE STATE [ICD9 289.8], evidenced by fibrin deposition in the small blood vessels.  This fibrin deposition, caused by excess thrombin generation, is detectable by new, sensitive coagulation assays. This hypercoagulable state is probably due to the immune system directly activating the CLOTTING CASCADE (Immune System Activation of Coagulation - ISAC theory) with or without PLATELET ACTIVATION (platelets can reinforce the clotting cascade). The hypercoagulable state may be due to a number of conditions, including a genetic predisposition to clotting which has not yet been diagnosed in the patient.

The coagulation CASCADE may be activated directly by an immunoglobulin (IgG antibody), which indicates a long-term inflammatory response from varied sources, such as, bacteria, viruses, trauma, etc.  An active clotting episode in the patient can be difficult to detect, but new markers (tests) for coagulation can show us when clotting, even on a small scale, is occurring.  The question which needs to be answered is: "What is the underlying process that is causing the thrombin generation?"  To help answer that question, a review of the coagulation process follows.

When the coagulation cascade is activated, clotting factors VII/Tissue Factor, Factors X, XI, IX, VIII, & V all combine in a sequential manner to convert Prothrombin (Factor II) to THROMBIN (Factor IIa). Prothrombin releases the activation peptide Prothrombin Fragment 1+2 (F1+2) when generating Thrombin.  Since thrombin has a half-life of 30 seconds, it cannot be directly measured in the blood. However, F1+2 can be measured since it has a half-life of 90 minutes.  An elevation of the marker F1+2 indicates there is direct thrombin generation in vivo (in the patient).

The natural defense mechanism in the body to the generation of excess or inappropriate thrombin  is an inhibitor called AntiThrombin (AT). AT combines with Thrombin to form Thrombin/Anti-Thrombin (T/AT) complexes and then T/AT complexes are removed from the blood. On endothelial cell surfaces are heparin like projections that naturally provide an anticoagulant environment to the blood stream. These heparans activate AT. AT is a slow inhibitor of thrombin, but in the presence of heparin, AT reacts 1000 times faster. This is the reason heparin is used as a drug in hospital settings when a patient has a blood clot. Heparin, as it is infused, combines with AntiThrombin, making the AT react with Thrombin much more rapidly, thus protecting the patient and reducing the risk of further clotting.  Therefore, when F1+2 increases, indicating thrombin generation, T/AT complexes should also be increased, resulting in the removal of thrombin from the blood stream.

When more thrombin is generated than can be removed by the T/AT system, THROMBIN (IIa) converts FIBRINOGEN (FIB) into an intermediate protein called SOLUBLE FIBRIN MONOMER (SFM). SFM increases blood viscosity, making the blood harder to pump. SFM is a sticky protein, so may be deposited on capillary wall Endothelial Cells (EC) forming "fibrin deposition" on these cell surfaces. This fibrin deposition also covers the EC heparans, down regulating the anticoagulant environment (blocking AT and Protein C activation)  and producing a procoagulant environment. This fibrin deposition may block the passage of nutrients through the capillary wall to surrounding tissues, such as nerve, muscle, bone or organ tissues. This is part of the explanation (pathology) of fetal demise and spontaneous abortions seen in recurrent miscarriages.

When there is excess thrombin (IIa) production, both SFM and insoluble FIBRIN (a blood clot) are formed. Thrombin also activates Protein C (APC), via Thrombomodulin (TM) on EC surfaces, which works to turn off thrombin production. Once fibrin deposition or blood clot formation occurs, it becomes necessary to dissolve the fibrin.  APC helps  activate the fibrinolytic system where tissue Plasminogen Activator (tPA - the clot buster drug) converts the protein Plasminogen into PLASMIN.  Plasmin is a very potent enzyme that digests fibrin, cells or clots and keeps the circulatory system of blood vessels open and clean.  If there is excessive fibrin deposition in a patient's blood stream, this process of cleaning up the vessels may take several weeks, if there is no new thrombin generation.

The other contributing factor in this thrombin formation is PLATELET ACTIVATION (PA) within the blood. Platelet activation reinforces the generation of thrombin by providing a surface for thrombin formation. Platelets may be directly activated by the immune system when IgG (immunoglobulins) activates finger like projections called glycoprotein receptors and causes  platelets to become "sticky". This sticky state can result in fibrin formation, vascular & endothelial cell changes and/or damage, and at times, platelet clumping. The migraine-like headaches often associated with CFS/FM may be due to the sticky platelets clumping together.   This Platelet Activation can be measured by a special laboratory procedure called flow cytometry. Aspirin may or may not normalize platelet activation.

The question "what caused this hypercoagulable state?" therefore may be answered in a number of different ways, including, microbiological (virus, bacteria, parasites), immune system activation or changes, chemical exposure, and/or genetic defects (including coagulation protein defects, such as Protein C, Protein S, APC Resistance, AntiThrombin, Factor II, etc.).

This hypercoagulable state, which results from activation of the coagulation system, may be treated with anticoagulant drug therapy: heparin (subcutaneous) and aspirin (if indicated), followed by low dose warfarin therapy.  Before starting any anticoagulant therapy, baseline levels of the markers of coagulation (F1+2, T/AT, SFM, FIB, and/or PA - ISAC Panel) should be ordered to confirm that the patient is indeed in a hypercoagulable state. If baseline laboratory tests are abnormal, hereditary risk factors should be tested also.  Once started, anticoagulant therapy should be monitored by SFM, FIB & PA tests [ICD9 964.2-anticoagulant monitoring] on a regular basis for 1-2 months.  After anticoagulation therapy has been determined to be successful, the physician may wish to discontinue the therapy, while still monitoring the appropriate markers.  If the symptoms recur, along with an elevation of the hypercoagulable state markers, long-term anticoagulation therapy should be considered.

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Updated April 1, 1999