Plasma Replacement Therapy
Overview
Our Mission
We established the Young Blood Institute to advance new uses for well established blood plasma replacement therapies, historically used to naturally restore our body's immune system, which demonstrate potential to significantly mitigate or prevent many age-associated disease conditions as well as rejuvenate our body's stem cells. Our program only employs fully licensed physician sub-specialists (Transfusion Medicine and Immunology) and nurses. We administer therapies according to widely accepted evidenced based medicine guidelines established by the American Society For Apheresis (ASFA).
We established the Young Blood Institute to advance new uses for well established blood plasma replacement therapies, historically used to naturally restore our body's immune system, which demonstrate potential to significantly mitigate or prevent many age-associated disease conditions as well as rejuvenate our body's stem cells. Our program only employs fully licensed physician sub-specialists (Transfusion Medicine and Immunology) and nurses. We administer therapies according to widely accepted evidenced based medicine guidelines established by the American Society For Apheresis (ASFA).
Our Studies
Our studies of Heterochronic Plasma Exchange (HPE) – the replacement of aged plasma with young plasma components – began in 2018 and will continue over the next 2-3 years, or the first 1,000 patients, whichever comes first. Qualifying study subjects must be individuals 30 years or older and have 2 or more age-related conditions (senescence phenotypic factors) and/or an immunologic or inflammatory abnormality. We may exclude individuals with poor peripheral vascular access, diagnosis of malignancy, late stage Alzheimer’s disease, a positive pregnancy test in woman, and any medical condition that may deteriorate during plasma exchange procedures.
Our first treatment clinics will opened in Florida and California in the second half of 2018. In order to easily expand and diversify our study, we collaborate with existing clinics, age research facilities, wellness centers, hospitals, and institutes focused on age related disorders. We will also inclusively incorporate a broad cross-section of doctors and scientists with complimentary experience domestically and internationally. Please contact us if you have an interest in collaborating.
Basic Procedure
Heterochronic Plasma Exchange (HPE) follows proven, decades-old, well-established practices for Therapeutic Plasma Exchange (TPE), a U.S. FDA (and Internationally) approved procedure generally known as plasmapheresis. Considered an extracorporeal procedure because an apheresis machine circulates blood outside of the body in a continuous fashion, TPE filters and removes old plasma as well as pathogenic substances carried by the plasma in the blood. New plasma components, including albumin and immunoglobins, then replace the old plasma, which we discard.
Decades of medical experience, millions of procedures, and widely published scientific evidence in the field of immunology demonstrate that the removal of pathogenic substances in plasma plays a critical role in rejuvenating and restoring immune system function. Studies of aging populations evidence dysregulated immunity in the elderly due to the decline of the immune system, leading to increased morbidity. Dysregulated immunity in the elderly closely approximates the factors common in autoimmune diseases: autoimmunity, pro-inflammatory factors, and T-cell disorders. Inflammation, in particular, has been linked to sclerosis, dementia, cancer, cardiovascular disease, stroke, and Alzheimer's disease. Autoimmunity and dysregulated immunity, known as immune senescence, makes elderly populations three times more susceptible to infection than average. We have limited empirical data, primarily focused on Alzheimer's Disease, that removing inhibitory factors in age-associated disorders rejuvenates immune system function in subjects over 50 years old and/or prevents those conditions from developing; hence, the purpose of our study, which simply applies TPE to patients older than 50 years old. We call this evolution of traditional TPE practices Heterochronic, meaning different (from Greek héteros, meaning “different”) and age (from Greek khronikos meaning "time").
Our studies of Heterochronic Plasma Exchange (HPE) – the replacement of aged plasma with young plasma components – began in 2018 and will continue over the next 2-3 years, or the first 1,000 patients, whichever comes first. Qualifying study subjects must be individuals 30 years or older and have 2 or more age-related conditions (senescence phenotypic factors) and/or an immunologic or inflammatory abnormality. We may exclude individuals with poor peripheral vascular access, diagnosis of malignancy, late stage Alzheimer’s disease, a positive pregnancy test in woman, and any medical condition that may deteriorate during plasma exchange procedures.
Our first treatment clinics will opened in Florida and California in the second half of 2018. In order to easily expand and diversify our study, we collaborate with existing clinics, age research facilities, wellness centers, hospitals, and institutes focused on age related disorders. We will also inclusively incorporate a broad cross-section of doctors and scientists with complimentary experience domestically and internationally. Please contact us if you have an interest in collaborating.
Basic Procedure
Heterochronic Plasma Exchange (HPE) follows proven, decades-old, well-established practices for Therapeutic Plasma Exchange (TPE), a U.S. FDA (and Internationally) approved procedure generally known as plasmapheresis. Considered an extracorporeal procedure because an apheresis machine circulates blood outside of the body in a continuous fashion, TPE filters and removes old plasma as well as pathogenic substances carried by the plasma in the blood. New plasma components, including albumin and immunoglobins, then replace the old plasma, which we discard.
Decades of medical experience, millions of procedures, and widely published scientific evidence in the field of immunology demonstrate that the removal of pathogenic substances in plasma plays a critical role in rejuvenating and restoring immune system function. Studies of aging populations evidence dysregulated immunity in the elderly due to the decline of the immune system, leading to increased morbidity. Dysregulated immunity in the elderly closely approximates the factors common in autoimmune diseases: autoimmunity, pro-inflammatory factors, and T-cell disorders. Inflammation, in particular, has been linked to sclerosis, dementia, cancer, cardiovascular disease, stroke, and Alzheimer's disease. Autoimmunity and dysregulated immunity, known as immune senescence, makes elderly populations three times more susceptible to infection than average. We have limited empirical data, primarily focused on Alzheimer's Disease, that removing inhibitory factors in age-associated disorders rejuvenates immune system function in subjects over 50 years old and/or prevents those conditions from developing; hence, the purpose of our study, which simply applies TPE to patients older than 50 years old. We call this evolution of traditional TPE practices Heterochronic, meaning different (from Greek héteros, meaning “different”) and age (from Greek khronikos meaning "time").
Source: K. Kaushansky, M.A. et al.: Hematology, 9th edition
Human plasma, which constitutes about 55% of total blood volume, cannot be completely replaced safely in one procedure; in HPE, we utilize typical TPE protocols, replacing around 60-70% a patient's plasma in one initial treatment. We then replace plasma with five successive treatments . Over 6 treatment sessions, we remove and replace plasma substances in an exponential fashion approaching 100% with each treatment.
Each procedure typically takes between 1-2 hours in an average size individual. HPE does not require medication or anesthesia. Patients remain awake in a comfortable reclined chair. We use only natural human albumin and immunoglobins, processed and distributed by regulated therapeutics manufacturers, making the entire procedure both safe and devoid of any drugs or man-made synthetic substances present in most medical therapies today.
Study Treatment Costs
Insurance companies do not yet reimburse costs of plasmapheresis as a preventative or prophylactic treatment modality for many age-related conditions or indications. While the cost of plasmapheresis pales in comparison to the consequences of many prospective age-related disorders such as Alzheimer's, Parkinson's, Type 2 diabetes, stroke, heart failure, et al., paying for the procedure itself might be considered expensive by many. So we depend on donations and direct contributions to conduct treatment therapies as a part of our clinical research study. Please contact us if you would like to contribute.
Study Treatment Costs
Insurance companies do not yet reimburse costs of plasmapheresis as a preventative or prophylactic treatment modality for many age-related conditions or indications. While the cost of plasmapheresis pales in comparison to the consequences of many prospective age-related disorders such as Alzheimer's, Parkinson's, Type 2 diabetes, stroke, heart failure, et al., paying for the procedure itself might be considered expensive by many. So we depend on donations and direct contributions to conduct treatment therapies as a part of our clinical research study. Please contact us if you would like to contribute.
The Studies
Note: this section may include more technical language; so we have added common English parenthetically as well as links to more in depth explanation as appropriate.
Intermittent Heterochronic Plasma Exchange as a Method for Mitigating Cellular Senescence
(periodic therapeutic plasma exchange to replace old plasma with young plasma components to minimize cellular aging)
Background
Advanced age is the main risk factor for most chronic diseases and functional deficit in humans. (1) Cellular senescence (cell aging) contributes to age related dysfunction by disrupting tissue structure and repair and the diminishing ability of the body to constrain the malignant proliferation of tumor cells. Senescent cells accumulate in various tissues and organs and secrete components which cause tissue damage and dysfunction.
Recent studies provide evidence that the systemic milieu (blood and its constituent elements) can inhibit or promote the cellular senescence process in mice. Heterochronic parabiotic models (shared circulatory systems) have demonstrated that exposure of aged progenitor and satellite cells to plasma of young mice restores the proliferation and regenerative capacity of these cells. Conversely, exposing a young mouse to an old systemic environment or plasma lead to impaired cellular and systemic function. (2,3,4,5) This process benefits the nervous system, liver function, heart muscle and stem cells.
There is a growing body of evidence that telomere dysfunction can contribute to human aging. Telomere dysfunction inhibits the proliferation of B and T lymphocytes contributing to severe immune dysregulation. Changing the systemic environment of aging telomerase knockout (mTere-1-) mice restored normal T lymphopoisis.(5)
These studies strongly suggest that aged plasma contains inhibitory factors which contribute to cellular senescence. Some of these factors have been identified, others remain to be identified. It is also conceivable that young plasma contains stimulatory factors which contribute to healthy cell proliferation and function. (6,7,8,9)
Therapeutic Plasma Exchange (TPE) is a well-established therapy for a growing number of medical conditions. Its powerful immunomodulatory effect is well documented. TPE has the ability to remove pathogenic and proinflammatory factors. (10) In 1982 Kiprov, et al. first reported the effect of plasmapheresis on cellular immunity in patients with autoimmune disorders using monoclonal antibodies and flow cytometry. (11) They demonstrated that plasmapheresis leads to normalization of the CD4/CD8 ratio of these patients. Numerous studies have confirmed and expanded these observations. (12,13,14) More recent studies have shown that plasmapheresis affects the Th1/Th2 ratio and the production of cytokines (small proteins important in cell signaling) by these cells. (15) Repeated plasmapheresis leads to the increase of regulatory (CD4+CD25+ (high) Fox P3+) T-cells and clinical improvement in patients with SLE. (16)
Interesting observations have been made in plasma donors as well. Healthy HIV-positive plasma donors were studied over 2 years. Their CD4 cell count made substantial gains and tended towards stabilizing to normal. (17) In another study, healthy plasma donors showed an increase of serum testosterone levels. (Kiprov, Ivanova, personal communication)
Notably, recent studies revisiting blood exchange in mice provide evidence that heterochronic blood exchange between young and old mice, without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis (conjoining mice to share circulatory systems). When investigating muscle, liver and brain hippocampus under heterochronic blood exchange, in many cases, the inhibitory effects of old blood were more pronounced than the stimulatory effects of young blood. (24)
These recent studies with mice again comport with a growing and wide body of evidence in human studies documenting immune decline with aging blood (25) and molecular inflammation underpinning age-associated diseases (26).
Finally, recent studies conducted over the last 2+ years using Therapeutic Plasma Exchange on Alzheimer's patients have demonstrated positive results in slowing and stopping the progression of the disease, in some cases actually realizing improvements. (27)
Rationale for performing the Trial
These observations indicate that plasma exchange has the potential to positively affect the phenotype (observable physical properties of an organism) associated with aging and conceivably delay cellular senescence, including immunosenescence (the gradual deterioration of the immune system). In 2013, Dr. Kiprov published a hypothesis suggesting that intermittent heterochronic plasma exchange can be used as a modality for delaying cellular senescence. (18) This trial will attempt to measure in older people what has been measured in autoimmune patients, as well as rejuvenative effects in animal models on cellular behavior and new growth of cells in muscle, organ, and brain tissue.
Significance
Most chronic disease in humans, including many cancers, occur with advanced age, the result of declining immune function and chronic inflammation accumulated over time. These problems cause premature death as well as physical and mental dysfunction which require substantial medical care. Much of current medical care for our aging population includes a multitude of medications, many of which have unfavorable side effects and cross reactivity. The cumulative effect places an enormous financial burden on our medical system, families supporting aging parents, and enormous physical strain on patients themselves. Historically, we cited age itself as the primary cause of chronic disease. New evidence suggests the biological age of blood may indicate its potency to sustain and restore the body’s existing stem cell functions. If prophylactic (preventative) plasma exchange can delay cellular immunosenescence before it starts, HPE will have a significant beneficial impact on the systemic health of a rapidly increasing aging population, as well as markedly decrease the financial of medical care and human suffering.
Study Design and Plan
Subjects will undergo 6 plasma exchange procedures. They will be assessed and followed with general questionnaire, physical examination, a set of laboratory tests as well as cognition and quality of life tests.
Trial Design and Choice of Exchange Fluids
We conduct our study to gather human data on the potential for plasmapheresis to mitigate or reverse cellular and immune senescence. Few have previously considered the medical potential for plasmapheresis to mitigate or reverse cellular senescence, nor measured effects associated with aging, in spite of decades of TPE procedures. Thus, this treatment therapy has not been available to address age-associated immune dysregulation and cellular senescence until now.
Regarding the number and spacing of the plasma exchange procedures, and the exchange fluids to be used:
1) The majority of referenced studies in humans were performed as a treatment of autoimmune diseases; procedures were performed frequently over a short period of time. Our study protocol studies the effect of less frequent procedures in order to indicate whether age phenotype changes can be sustained over a longer period of time.
2) For exchange fluid, we use Human Serum Albumin (HSA), a primary plasma component, produced from healthy donor plasma by large plasma processing companies. 5% albumin is produced from donor sourced plasma, and the majority of blood donors in most countries are 18-44 years old. (21) HSA does not contain immunoglobulins and clotting factors. Via a standard intravenous (IV) infusion system, we replace aged plasma with 5% albumin -- the fluid of choice for TPE -- as an exchange fluid and finish the procedure with a small amount of intravenous gamma globulin (IVIG) infusion. 5% albumin has a very low reported incidence of adverse events during TPE at less than 4% (19), the least of any exchange fluid. HSA is well known for its capacity to bind a larger variety of molecules, including bilirubin, homocysteine and lipids. In addition, HSA may be the most abundant antioxidant in the body. (22) It is believed that its ability to bind free radicals is responsible for its antioxidant properties in addition to contribution to glutathione metabolism. Several large randomized clinical trials have demonstrated that mortality is lower in patients with sepsis who received albumin as a resuscitation fluid as opposed to crystalloids. It is believed that the multiple ligand-binding capacities and free-radical trapping properties of HSA are of paramount importance in the beneficial effect of HSA as they have been observed in the critical care as well as hematologic settings. (22) We postulate that HSA also binds molecules contributing to chronic inflammation and aging. Tests to determine such binding are a part of the study. Removing albumin with saturated binding sites and infusing fresh albumin with multiple unoccupied binding sites may have a beneficial effect in our study group. Since the half-life of HSA is about 20 days, we schedule PE treatments well within that window. IVIG will provide mainly IgG antibodies to a variety of infectious events. In addition, IVIG has been shown to modify cytokine production by slowing down the production of pro-inflammatory factors and enhancing the production of anti-inflammatory factors. (23)
Selection of Trial Population
This trial will include up to 1,000 subjects. Qualification includes individuals 50 years of age or older who have 2 or more of the senescence phenotypic factors and/or an immunologic or inflammatory abnormality.
These tests include C-reactive protein, sTNFI, sTNFII, TNFa, IL-10, IL-6, IL-1a, IL-1b, CD4, CD8, CD28, in peripheral blood, anti-nuclear antibodies, Rheumatoid factor, fibrinogen, anti-phospholipid antibodies. Clinical evidence for memory loss, cognitive deficiency or a diagnosis of a chronic inflammatory condition will also be qualifying criteria.
Tests will be conducted before, during, and after conclusion of HPE treatments; subjects will be monitored for 12 months after completing the HPE treatment therapy.
Exclusion Criteria
Criteria for Withdrawal
Concomitant Therapy
All participants will continue their current medications as prescribed by their physicians (if any). Non-prescription medications will be evaluated by the investigators and may or may not be discontinued for the period of the trial.
Initial Evaluation
All patients will undergo complete medical history and physical examination, including a chest X-ray, an electrocardiogram, and a pregnancy test for females who are not post-menopausal. The following laboratory tests will be performed (see Table 1 attached) 6 days prior to inclusion in the study and they will be asked to fill out a questionnaire (see Attachment 1).
Functional Testing
Data Confidentiality
Blood samples and any medical information obtained for the study will be stored using a patient ID number only. Study staff will “re-code” the samples with a new identification number prior to sending blood samples for testing. Test labs will only receive samples labeled with this new number. This serves to further protect the patient’s identity as well as to aid in interpretation of the study results. The study staff will keep the list linking personal information to the patient’s ID number and also the “re-code” list in a password-protected database on a secure server. Only the study staff of the Young Blood Institute will have access to patient identifying information.
Treatment Details
Plasma Exchange (PE) (one plasma volume) will be performed six times through peripheral veins access using the FDA approved blood cell separators, either the COBE Spectra Apheresis System or Terumo BCT Spectra Optia Apheresis System (Lakewood, CO).
Intravenous Immunoglobulin (IVIG) will be infused (2.0 gm) post each plasma exchange procedure.
TPE Procedure
Therapeutic Plasma Exchange (TPE) is an automated medical procedure performed with a sophisticated instrument called a blood cell separator. Whole blood is withdrawn from a patient’s vein (peripheral or central) into a cell separator in the presence of a citrate anticoagulant (ACD-A). Whole blood is separated into blood cells and plasma in a spinning belt based on the specific gravity of individual blood components. One plasma volume is removed and the plasma is discarded. The most frequently used replacement fluids are 5% Albumin and Fresh Frozen Plasma.
Many of videos about the TPE procedure and therapeutic apheresis can be found on YouTube. Here we provide a few helpful links to save time: Plasma Exchange-Mayo Clinic, Plasmapheresis, Principles & Applications of Therapeutic Plasma Exchange, the Alzheimer's Management By Amyloid Removal (AMBAR) study. A more lengthy review of apheresis generally can be found at Therapeutic Apheresis: Common Indications, Better Disease Understanding.
Notes
In this study blood will be withdrawn and returned from peripheral veins. These are most commonly the antecubital veins in both arms; however other peripheral veins may be used.
Anticoagulation
The anticoagulant used in TPE (and extracorporeal blood processing generally) with currently available blood cell separators is Anticoagulant Citrate Dextrose Solution, Solution A, USP (2.13% free citrate ion) or ACD-A, a sterile, non-pyrogenic (will not cause fever or inflammatory responses) citrate based anticoagulant to prevent blood clotting. Citrate binds calcium ions and blocks the calcium dependent pathway of the coagulation system. It is short acting and it is infused in the machine rather than directly into the circulation. And although it may cause hypocalcemia (low calcium levels), it is usually mild and short lasting. In order to diminish the side effects of ACD-A (hypocalcemia), the patients receive a continuous I.V. infusion of calcium gluconate throughout the procedure.
Adverse Reactions associated with Therapeutic Plasma Exchange (TPE)
TPE involves the following possible risks and/or discomforts:
Vital signs are taken prior to each procedure. During the procedure blood pressure and pulse are taken every 15 minutes. Vital signs are repeated at the end of the procedure. Manual pressure is applied at the puncture sites after the removal of the intravenous catheters until any bleeding stops. Afterwards pressure dressings are applied at both needle sites and subjects are instructed not to remove the dressings for at least 2 hours. Blood pressure is repeated after 20-30 minutes after discontinuation of the procedure and if blood pressure is normal and the subject has no complaints, they are discharged. The consent form provides a phone number for the subjects to call if they experience any discomfort. Delayed adverse reactions from TPE are extremely rare.
Intermittent Heterochronic Plasma Exchange as a Method for Mitigating Cellular Senescence
(periodic therapeutic plasma exchange to replace old plasma with young plasma components to minimize cellular aging)
Background
Advanced age is the main risk factor for most chronic diseases and functional deficit in humans. (1) Cellular senescence (cell aging) contributes to age related dysfunction by disrupting tissue structure and repair and the diminishing ability of the body to constrain the malignant proliferation of tumor cells. Senescent cells accumulate in various tissues and organs and secrete components which cause tissue damage and dysfunction.
Recent studies provide evidence that the systemic milieu (blood and its constituent elements) can inhibit or promote the cellular senescence process in mice. Heterochronic parabiotic models (shared circulatory systems) have demonstrated that exposure of aged progenitor and satellite cells to plasma of young mice restores the proliferation and regenerative capacity of these cells. Conversely, exposing a young mouse to an old systemic environment or plasma lead to impaired cellular and systemic function. (2,3,4,5) This process benefits the nervous system, liver function, heart muscle and stem cells.
There is a growing body of evidence that telomere dysfunction can contribute to human aging. Telomere dysfunction inhibits the proliferation of B and T lymphocytes contributing to severe immune dysregulation. Changing the systemic environment of aging telomerase knockout (mTere-1-) mice restored normal T lymphopoisis.(5)
These studies strongly suggest that aged plasma contains inhibitory factors which contribute to cellular senescence. Some of these factors have been identified, others remain to be identified. It is also conceivable that young plasma contains stimulatory factors which contribute to healthy cell proliferation and function. (6,7,8,9)
Therapeutic Plasma Exchange (TPE) is a well-established therapy for a growing number of medical conditions. Its powerful immunomodulatory effect is well documented. TPE has the ability to remove pathogenic and proinflammatory factors. (10) In 1982 Kiprov, et al. first reported the effect of plasmapheresis on cellular immunity in patients with autoimmune disorders using monoclonal antibodies and flow cytometry. (11) They demonstrated that plasmapheresis leads to normalization of the CD4/CD8 ratio of these patients. Numerous studies have confirmed and expanded these observations. (12,13,14) More recent studies have shown that plasmapheresis affects the Th1/Th2 ratio and the production of cytokines (small proteins important in cell signaling) by these cells. (15) Repeated plasmapheresis leads to the increase of regulatory (CD4+CD25+ (high) Fox P3+) T-cells and clinical improvement in patients with SLE. (16)
Interesting observations have been made in plasma donors as well. Healthy HIV-positive plasma donors were studied over 2 years. Their CD4 cell count made substantial gains and tended towards stabilizing to normal. (17) In another study, healthy plasma donors showed an increase of serum testosterone levels. (Kiprov, Ivanova, personal communication)
Notably, recent studies revisiting blood exchange in mice provide evidence that heterochronic blood exchange between young and old mice, without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis (conjoining mice to share circulatory systems). When investigating muscle, liver and brain hippocampus under heterochronic blood exchange, in many cases, the inhibitory effects of old blood were more pronounced than the stimulatory effects of young blood. (24)
These recent studies with mice again comport with a growing and wide body of evidence in human studies documenting immune decline with aging blood (25) and molecular inflammation underpinning age-associated diseases (26).
Finally, recent studies conducted over the last 2+ years using Therapeutic Plasma Exchange on Alzheimer's patients have demonstrated positive results in slowing and stopping the progression of the disease, in some cases actually realizing improvements. (27)
Rationale for performing the Trial
These observations indicate that plasma exchange has the potential to positively affect the phenotype (observable physical properties of an organism) associated with aging and conceivably delay cellular senescence, including immunosenescence (the gradual deterioration of the immune system). In 2013, Dr. Kiprov published a hypothesis suggesting that intermittent heterochronic plasma exchange can be used as a modality for delaying cellular senescence. (18) This trial will attempt to measure in older people what has been measured in autoimmune patients, as well as rejuvenative effects in animal models on cellular behavior and new growth of cells in muscle, organ, and brain tissue.
Significance
Most chronic disease in humans, including many cancers, occur with advanced age, the result of declining immune function and chronic inflammation accumulated over time. These problems cause premature death as well as physical and mental dysfunction which require substantial medical care. Much of current medical care for our aging population includes a multitude of medications, many of which have unfavorable side effects and cross reactivity. The cumulative effect places an enormous financial burden on our medical system, families supporting aging parents, and enormous physical strain on patients themselves. Historically, we cited age itself as the primary cause of chronic disease. New evidence suggests the biological age of blood may indicate its potency to sustain and restore the body’s existing stem cell functions. If prophylactic (preventative) plasma exchange can delay cellular immunosenescence before it starts, HPE will have a significant beneficial impact on the systemic health of a rapidly increasing aging population, as well as markedly decrease the financial of medical care and human suffering.
Study Design and Plan
Subjects will undergo 6 plasma exchange procedures. They will be assessed and followed with general questionnaire, physical examination, a set of laboratory tests as well as cognition and quality of life tests.
Trial Design and Choice of Exchange Fluids
We conduct our study to gather human data on the potential for plasmapheresis to mitigate or reverse cellular and immune senescence. Few have previously considered the medical potential for plasmapheresis to mitigate or reverse cellular senescence, nor measured effects associated with aging, in spite of decades of TPE procedures. Thus, this treatment therapy has not been available to address age-associated immune dysregulation and cellular senescence until now.
Regarding the number and spacing of the plasma exchange procedures, and the exchange fluids to be used:
1) The majority of referenced studies in humans were performed as a treatment of autoimmune diseases; procedures were performed frequently over a short period of time. Our study protocol studies the effect of less frequent procedures in order to indicate whether age phenotype changes can be sustained over a longer period of time.
2) For exchange fluid, we use Human Serum Albumin (HSA), a primary plasma component, produced from healthy donor plasma by large plasma processing companies. 5% albumin is produced from donor sourced plasma, and the majority of blood donors in most countries are 18-44 years old. (21) HSA does not contain immunoglobulins and clotting factors. Via a standard intravenous (IV) infusion system, we replace aged plasma with 5% albumin -- the fluid of choice for TPE -- as an exchange fluid and finish the procedure with a small amount of intravenous gamma globulin (IVIG) infusion. 5% albumin has a very low reported incidence of adverse events during TPE at less than 4% (19), the least of any exchange fluid. HSA is well known for its capacity to bind a larger variety of molecules, including bilirubin, homocysteine and lipids. In addition, HSA may be the most abundant antioxidant in the body. (22) It is believed that its ability to bind free radicals is responsible for its antioxidant properties in addition to contribution to glutathione metabolism. Several large randomized clinical trials have demonstrated that mortality is lower in patients with sepsis who received albumin as a resuscitation fluid as opposed to crystalloids. It is believed that the multiple ligand-binding capacities and free-radical trapping properties of HSA are of paramount importance in the beneficial effect of HSA as they have been observed in the critical care as well as hematologic settings. (22) We postulate that HSA also binds molecules contributing to chronic inflammation and aging. Tests to determine such binding are a part of the study. Removing albumin with saturated binding sites and infusing fresh albumin with multiple unoccupied binding sites may have a beneficial effect in our study group. Since the half-life of HSA is about 20 days, we schedule PE treatments well within that window. IVIG will provide mainly IgG antibodies to a variety of infectious events. In addition, IVIG has been shown to modify cytokine production by slowing down the production of pro-inflammatory factors and enhancing the production of anti-inflammatory factors. (23)
Selection of Trial Population
This trial will include up to 1,000 subjects. Qualification includes individuals 50 years of age or older who have 2 or more of the senescence phenotypic factors and/or an immunologic or inflammatory abnormality.
These tests include C-reactive protein, sTNFI, sTNFII, TNFa, IL-10, IL-6, IL-1a, IL-1b, CD4, CD8, CD28, in peripheral blood, anti-nuclear antibodies, Rheumatoid factor, fibrinogen, anti-phospholipid antibodies. Clinical evidence for memory loss, cognitive deficiency or a diagnosis of a chronic inflammatory condition will also be qualifying criteria.
Tests will be conducted before, during, and after conclusion of HPE treatments; subjects will be monitored for 12 months after completing the HPE treatment therapy.
Exclusion Criteria
- Poor peripheral vascular access
- Diagnosis of malignancy
- Late stage Alzheimer’s disease
- Positive pregnancy test in woman who are not post-menopausal
- Any medical conditions which may deteriorate because of plasma exchange procedures. These include but are not limited to symptomatic coronary artery disease, congestive heart failure and restrictive pulmonary diseases (COPD, pulmonary fibrosis). Low fibrinogen levels or other coagulation abnormalities that may predispose the subject to bleeding. Note: Although the use of ACE (angiotensin-converting-enzyme) inhibitors, a pharmaceutical drug used primarily for the treatment of hypertension and congestive heart failure, is not an exclusion criteria, subjects who are on ACE inhibitors will be requested to discontinue the drug at least 48 hours prior to TPE procedure and be placed on another anti-hypertension drug if necessary as determined by their prescribing physician.
- Subjects who are unable to understand and sign the consent form and need a legally authorized representative will be excluded from the study.
Criteria for Withdrawal
- Subjects may be withdrawn from the protocol if it is determined that their peripheral veins do not provide adequate blood flow for proper plasma exchange procedure.
- Subjects may be withdrawn if they exhibit adverse reactions considered to be more than mild (reaction which requires discontinuation of the procedure).
Concomitant Therapy
All participants will continue their current medications as prescribed by their physicians (if any). Non-prescription medications will be evaluated by the investigators and may or may not be discontinued for the period of the trial.
Initial Evaluation
All patients will undergo complete medical history and physical examination, including a chest X-ray, an electrocardiogram, and a pregnancy test for females who are not post-menopausal. The following laboratory tests will be performed (see Table 1 attached) 6 days prior to inclusion in the study and they will be asked to fill out a questionnaire (see Attachment 1).
Functional Testing
- Cognitive ability/memory testing
- Physical strength, Up and Go
- Age-specific quality of life scale
Data Confidentiality
Blood samples and any medical information obtained for the study will be stored using a patient ID number only. Study staff will “re-code” the samples with a new identification number prior to sending blood samples for testing. Test labs will only receive samples labeled with this new number. This serves to further protect the patient’s identity as well as to aid in interpretation of the study results. The study staff will keep the list linking personal information to the patient’s ID number and also the “re-code” list in a password-protected database on a secure server. Only the study staff of the Young Blood Institute will have access to patient identifying information.
Treatment Details
Plasma Exchange (PE) (one plasma volume) will be performed six times through peripheral veins access using the FDA approved blood cell separators, either the COBE Spectra Apheresis System or Terumo BCT Spectra Optia Apheresis System (Lakewood, CO).
Intravenous Immunoglobulin (IVIG) will be infused (2.0 gm) post each plasma exchange procedure.
TPE Procedure
Therapeutic Plasma Exchange (TPE) is an automated medical procedure performed with a sophisticated instrument called a blood cell separator. Whole blood is withdrawn from a patient’s vein (peripheral or central) into a cell separator in the presence of a citrate anticoagulant (ACD-A). Whole blood is separated into blood cells and plasma in a spinning belt based on the specific gravity of individual blood components. One plasma volume is removed and the plasma is discarded. The most frequently used replacement fluids are 5% Albumin and Fresh Frozen Plasma.
Many of videos about the TPE procedure and therapeutic apheresis can be found on YouTube. Here we provide a few helpful links to save time: Plasma Exchange-Mayo Clinic, Plasmapheresis, Principles & Applications of Therapeutic Plasma Exchange, the Alzheimer's Management By Amyloid Removal (AMBAR) study. A more lengthy review of apheresis generally can be found at Therapeutic Apheresis: Common Indications, Better Disease Understanding.
Notes
In this study blood will be withdrawn and returned from peripheral veins. These are most commonly the antecubital veins in both arms; however other peripheral veins may be used.
Anticoagulation
The anticoagulant used in TPE (and extracorporeal blood processing generally) with currently available blood cell separators is Anticoagulant Citrate Dextrose Solution, Solution A, USP (2.13% free citrate ion) or ACD-A, a sterile, non-pyrogenic (will not cause fever or inflammatory responses) citrate based anticoagulant to prevent blood clotting. Citrate binds calcium ions and blocks the calcium dependent pathway of the coagulation system. It is short acting and it is infused in the machine rather than directly into the circulation. And although it may cause hypocalcemia (low calcium levels), it is usually mild and short lasting. In order to diminish the side effects of ACD-A (hypocalcemia), the patients receive a continuous I.V. infusion of calcium gluconate throughout the procedure.
Adverse Reactions associated with Therapeutic Plasma Exchange (TPE)
TPE involves the following possible risks and/or discomforts:
- Hematoma (bruising) or infection at the site of the needle insertion. Discomfort at the site of the needle, which will be in place for several hours, may occur.
- The anticoagulant may cause tingling sensations around the mouth, hands, and body. Muscle cramps, nausea, vomiting may occur, but this does not happen often (<4% of the time). There is a very small risk that the anticoagulant will lead to bleeding.
- Rarely, blood pressure may fall and lightheadedness or fainting may occur. Shock, irregular heartbeats and death have been reported, but are rare and usually due to illness rather than the therapeutic apheresis procedure. Air embolism (large amounts of air entering the circulation) is an extremely rare complication of apheresis that may cause death.
- Allergic reactions, rarely fatal, to albumin have occurred but are extremely rare. Less severe reactions such as fevers, hives, and wheezing can occur and may require treatment.
- Although all the blood products are tested for infectious diseases, there is a minimal risk that albumin could transmit infections, such as HIV or Hepatitis.
Vital signs are taken prior to each procedure. During the procedure blood pressure and pulse are taken every 15 minutes. Vital signs are repeated at the end of the procedure. Manual pressure is applied at the puncture sites after the removal of the intravenous catheters until any bleeding stops. Afterwards pressure dressings are applied at both needle sites and subjects are instructed not to remove the dressings for at least 2 hours. Blood pressure is repeated after 20-30 minutes after discontinuation of the procedure and if blood pressure is normal and the subject has no complaints, they are discharged. The consent form provides a phone number for the subjects to call if they experience any discomfort. Delayed adverse reactions from TPE are extremely rare.
Summary
Therapeutic Plasma Exchange (in patients over 30 years of age, we call this Heterochronic Plasma Exchange) removes circulating substances that cause disease or contribute to disease states, as well as pro-inflammatory factors (fibrinogen, IL-6, TNF alpha etc.), positively affecting the cellular immune system. Albumin is a powerful antioxidant, providing a binding site for free radicals, and contains beneficial proteins. IV introduced immunoglobulins replace (old) antibodies and serve as a powerful immunomodulator. In addition to measuring known medical effects of plasmapheresis in older subjects, which allow the body's immune system to function at peak performance, we will measure newly hypothesized scientific effects of cellular rejuvenation, including revival of the body's own capable but dormant stem cells when exposed to a new intracorporeal environment.
Therapeutic Plasma Exchange (in patients over 30 years of age, we call this Heterochronic Plasma Exchange) removes circulating substances that cause disease or contribute to disease states, as well as pro-inflammatory factors (fibrinogen, IL-6, TNF alpha etc.), positively affecting the cellular immune system. Albumin is a powerful antioxidant, providing a binding site for free radicals, and contains beneficial proteins. IV introduced immunoglobulins replace (old) antibodies and serve as a powerful immunomodulator. In addition to measuring known medical effects of plasmapheresis in older subjects, which allow the body's immune system to function at peak performance, we will measure newly hypothesized scientific effects of cellular rejuvenation, including revival of the body's own capable but dormant stem cells when exposed to a new intracorporeal environment.