Heparin is an anticoagulant drug that may be useful to some ME patients. It is typically used in the prevention and treatment of both pulmonary embolism and deep vein thrombosis. It has been theorised that ME in some instances may be caused by a hypercoagulable state and thus heparin would treat this. I will; examine the heparin studies on ME patients, present the opinions of ME experts on heparin and detail which patients may benefit from either heparin or an alternative anticoagulation treatment.
The human body’s coagulation process is complicated. The ME-coagulation theory is doubly complex and a simplified theory describing it is as follows. Patients initially are struck down with an infection such as; HHV-6, EBV, CMV, chlamydia pneumonia, a tick borne disease or another pathogen. Research involving David Berg suggests that numerous infections can instigate the body’s blood clotting system. This may target those people with an acquired or genetic coagulation defect. After the clotting process is activated, the body creates ‘soluble fibrin monomers’ (SFM). These SFM are analogous to sheets that cover the blood vessels. The resultant impairment of blood circulation is then responsible for ME symptoms.
The first study by Berg et al. was published in 1998 and titled ‘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?’ The full paper can be found here. 20 CFS/Fibromyalgia patients were involved in this pilot study however there was no control group. The patients were tested for various coagulation measures. 90% had an abnormal ‘sonoclot rate’, 88% had abnormal ‘SFM’, 48% had abnormal ‘fibrinogen’ and 60% had abnormal ‘platelet activation’.
16 of the patients with positive ‘baseline studies’ were treated with placebo for a week followed by heparin. The heparin was administered subcutaneously twice a day and ranged from 5000 units to 8000 units. After one month, the subjects rated their subjective improvements. All 7 of the fibromyalgia patients improved. 1 patient noted some improvement, 3 had moderate improvement and 3 experienced significant improvement. All 9 of the CFS patients improved. 4 said they had moderate improvement whilst 5 had significant improvement. The paper continues on to state that most of the patients began to feel like their “old selves” within 2-4 days of commencing the heparin treatment.
The second study Berg et al. published was in 1999 and titled ‘Chronic Fatigue Syndrome (CFS) &/or Fibromyalgia (FM) as a Variation of Antiphospholipid Antibody Syndrome (APS): An Explanatory Model and Approach to Laboratory Diagnosis.’ The full paper can be found here. A blinded ‘prospective’ study is detailed within this paper. It contained 54 CFS/Fibromyalgia patients and 23 controls. Five specific coagulation tests were performed on all subjects and two positive tests were required to be classified as having coagulation problems. 94% of the CFS/Fibromyalgia patients were positive for hypercoagulation, in contrast to just 4% of the controls testing positive.
The Third paper by Berg et al. was titled ‘Low Level Activation of Coagulation with Coagulopathies in the Etiology of CFS / FM and Chronic Illnesses. An Explanatory Model.’ The full paper is behind a paywall but can be accessed here for free. This paper claims that in excess of 3000 patients with chronic illnesses have been tested for coagulation problems and over 80% of these patients have tested positive. The paper also mentions that genetic studies have found a 2-10 fold increase in coagulation protein defects among CFS/fibromyalgia patients and others with a chronic illness. The paper also alludes to ‘unpublished data’ that shows having SFM in the blood may cause very low sedimentation rates (in the 0-4 range).
The paper also refers to a retrospective study involving a cohort of 60 CFS/fibromyalgia patients. The subjects were given 5000 units subcutaneously of heparin, twice a day for an average of 8 months. The average improvement on a scale of 1-10 was 8.5, equivalent to an 85% improvement.
A Negative study has also been published by Kennedy et al. The 2006 study was titled ‘Is chronic fatigue syndrome associated with platelet activation?’ The full study can be found here. The study included 17 ‘CFS’ patients who fulfilled the contentious Fukuda criteria as well as 16 controls. The study found no coagulation abnormalities in the CFS patients studied.
What the ME Specialists Say
Dr. Teitelbaum has written “Using the blood thinner heparin has been able to help half of those who failed all other treatments.” He continues writing that “I find that about half of my patients with the most severe and refractory symptoms of CFS/FMS get better with this treatment.” Dr. Teitelbaum has found that almost every CFS patient he has tested to be positive for hypercoagulation. He does however stipulate that he hasn’t tested healthy controls to compare his results. Dr. Teitelbaum also warns about the dangers of heparin treatment and warns that it is a riskier drug than most of the other drugs he recommends. He tends to use it as a last resort. Dr. Teitelbam is also not 100% convinced in the hypercoagulation hypothesis. He speculates that another feature of heparin may be responsible for the positive effects on CFS patients such as its antiviral properties.
Dr. Cheney mentions heparin in a talk given in the year 2000. He speaks of its ability to shift the immune system from Th2 dominant to Th1. This may potentially benefit ME patients with a Th2 shifted immune system. Dr. Cheney only recommends heparin if the patient tests positive to hypercoagulation. He has found approximately 50% of his patients testing positive.
Dr. Myhill is not an advocate of heparin in ME patients. She has trialled heparin usage in 4 of her patients with no success. She cites the aforementioned negative Kennedy et al. study as evidence against hypercoagulation being a factor in ME.
When it comes to hypercoagulation testing and ME, things can become complicated. It has been suggested by David Berg that any ME patient with cold hands and feet/Raynaud’s phenomenon and a low sedimentation rate be tested for hypercoagulation. Berg, who introduced the concept of specialised coagulation testing has found sedimentation rates “below 4 or 5” indicative of hypercoagulation in ME patients. Sedimentation testing is a standard blood test that is routinely done with most normal blood tests. Most ME patients will probably have this test on file and it is commonly listed as ‘ESR.’
The coagulation tests so far mentioned in the above studies and requested by the ME physicians have been specialised and done by the Hemex laboratory. They were taken over by Esoterix Laboratory Services who now do the coagulation tests and are based in the United States. This is considered the gold standard test in hypercoagulation.
Antiphospholipid antibody syndrome (APS), also sometimes referred to colloquially as Hughes’ Syndrome is an autoimmune disease that is characterised by blood coagulation. Standard laboratories around the world can test for APS. The studies and papers by Berg et al. above refer to their findings in ME patients as a “Variation of Antiphospholipid Antibody Syndrome.” The papers continue on to mention that “Antiphospholipid (APL) antibodies have been long associated with a hypercoagulable state, involving both procoagulant activity as well as inhibition of anticoagulant and fibrinolytic activity.” One of the APS antibodies that can be readily tested for is called ‘beta-2-glycoprotein.’ This according to Berg et al. can trigger the chain of clotting. The other subtests and their implication in APS are detailed here.
There exist several theories pertaining to the best methods of taking the heparin once hypercoagulation has been established in an ME patient.
Dr. Teielbaum does not mention what dosage of heparin he starts his patients on however if the patient doesn’t improve and the PTT blood test is still normal, he increases the dose to a maximum of 8000 units twice a day (a total of 16,000 units a day.) The heparin is administered by subcutaneous injection for the first six weeks. He switches them to nose spray heparin or sublingual heparin. Dr. Teitelbaum prophesizes that patients should start to feel better around the 10-14 day mark of treatment. He adds a 6-12 month course of either antibiotics such as doxycycline or antivirals depending on laboratory results. These are taken while the patient is still on heparin. Dr. Teitelbaum has his patients get a platelet count and PTT blood test every 3 days for the first 9 days after commencing heparin therapy and every week thereafter.
David Berg developed a protocol for treating ME patients for hypercoagulation and this can be found here. His system involves heparin being taken for 180 days. Transfer factor is taken from day 30-120 and antibiotics from day 30-90. If a patient has high Lp(a) or PAI-1 levels, he recommends bromelain be taken from day 1 to day 120.
Ken Lassesen has a model of ME that incorporates the hypercoagulation aspect. He has written about this here and here. He writes that the cause of the poor blood flow that is shown in many ME patients SPECT scan results may be due to hypercoagulation. He refers to a study in which the nootropic piracetam was taken concurrently with heparin. The accumulative effects of piracetam plus heparin were more beneficial to blood flow in the brain than the theoretical adding of piracetam and heparin. In other words, the piracetam and heparin complemented each other to combine to a greater efficacy.
Type of Heparin and Dosage
There exists two types of injectable heparin used by ME patients. The first is unfractionated heparin (UFH). Most of the above studies used UFH and Dr. Teitelbaum used this type on his patients. Due to the short half-life of UFH, it requires subcutaneous injection twice a day. The dosage used varies but generally starts at around 4000-5000 units twice a day in a 0.2ml-1ml solution. Berg has stated that patients less than 68kg (150lbs) should start at 4000 units twice a day. In contrast, those over 68kg (150lbs) should begin their dose at 5000 units twice a day. Some specialists increase this up to a maximum of 8000 units twice a day if bloodwork remains normal. It is imperative to monitor UFH usage via blood tests. As mentioned earlier, Dr. Teitelbaum has his patients get a platelet count and PTT blood test every 3 days for the first 9 days of UFH treatment and every week thereafter. Dr. Teitelbaum instructs patients to use an insulin syringe to inject the UFH while others recommend using a tuberculin syringe.
The second type of subcutaneous, injectable heparin is known as low molecular weight heparin (LMWH). This variant is more predictable than UFH and is generally considered to be safer. The studies on ME patients and heparin usage are largely void, primarily due to LMWH more recently being introduced to the United States. Berg recommends patients under 68kg (150lbs) taking 30mg of LMWH in the morning. He encourages those over 68kg (150lbs) to take 30mg of LMWH in the morning and 15mg at night. Patients taking LMWH may require an anti-factor Xa activity blood test if they have other medical conditions such as renal impairment.
Sublingual UFH is another alternative for hypercoagulation. Ken Lassesen has written that this form can be of equitable effectiveness. It requires 2 minutes under the tongue before being spit out. After 6 weeks of UFH subcutaneous injection treatment, Dr. Teitelbaum has patients switch to either sublingual heparin or heparin in the form of a nasal spray.
Heparin-induced thrombocytopenia (HIT) is a potential side effect of heparin treatment. There is a lower likelihood of this occurring if the patient takes LMWH. Several studies have examined the risk of HIT with heparin usage and the chances of this occurring varies depending on the disease studied. The chance of LMWH causing HIT is fairly remote however there is a higher chance of UFH causing HIT. HIT causes a low platelet count and is most likely to occur 5-14 days after commencing heparin therapy. Vitamin D and calcium supplementation may reduce the chances of HIT occurring.
If Heparin is used for an extended period, a DEXA bone density scan should be performed. It is also imperative to have kidney and liver function tests prior to commencing heparin treatment. Those who have had a peptic ulcer should not take heparin. I should emphasise that heparin treatment is a riskier treatment than most other ME treatments. It is essential that a doctor monitors the progress of the treatment and is aware of the potential dangers.
The ME-hypercoagulation link, in some cases, can theoretically be treated without heparin and with supplements. Dr. Teitelbaum has written that the anticoagulation supplements his patients have tried have failed to yield any positive results. Despite this, there exists numerous accounts online of ME patients benefiting from anticoagulant supplements. Whether this is due to the supplements effects on coagulation or because of some other mechanism is not known. The supplements should not be taken with heparin due to the risk of excessive bleeding.
Nattokinase is an enzyme that is derived from the fermented soybeans called Nattō. Multiple studies have found it to have various anticoagulant properties. Numerous anecdotal reports litter the internet of non-ME patients replacing the prescription Warfarin with Nattokinase with degrees of success. Some ME patients have also found Nattokinase to be beneficial. The dosage should not exceed the maximum amount of 4000 fibrin units.
Lumbrokinase is an enzyme that is sourced from a type of earthworm. Some patients take it to break down the fibrin implicated in hypercoagulation. Several ME patients have noted an improvement in symptoms after taking Lumbrokinase. Serrapeptase is a similar enzyme to Lumbrokinase.
The ME-Hypercoagulation connection was a very promising theory until a small study with Fukuda criteria patients found no coagulation problems in CFS patients. The subsequent coagulation research in ME was then discontinued. Regardless of the validity of the hypercoagulation theory in ME, heparin has been an effective treatment for many patients. Those in the Berg studies experienced dramatic improvements and Dr. Teitelbaum’s comment that half of those ME patients with the most severe and difficult to treat symptoms “get better” with heparin provides hope. The double-edged sword with heparin is the potential side effects. This shifts the dynamics of the risk-reward ratio. If an ME patient is severely ill, with cold hands and feet and a low sedimentation rate, it may be worth getting subsequent and specialised coagulation testing done and discussing with their physician about whether heparin treatment is warranted.