Plasmapheresis

Both Question 22 from the second paper of 2014 and the near-identical Question 14 from the first paper of 2010 discuss the principles, indications and complications of plasmapheresis. Question 21 from the first paper of 2013 mentions it in the context of TPP (we are invited to explain the difference between plasmafiltration and plasmapheresis). Question 5 from the first paper of 2005 takes a more reflective "critically evaluate" direction.  The college answers to these questions form an excellent concise overview of what is expected from the candidate. Most of the SAQs can be answered after reading Jeffrey L. Winters' 2012 article from Hematology. Additionally, our very own college examiners have put a whole chapter on this technique into Oh's Manual (Chapter 97, pp. 993).

In brief, the principles of plasmapheresis can be summarised as follows:

  • Plasmapheresis may refer to a variety of procedures, all involving the therapeutic separation of blood into components.
  • Separation of blood into cellular and fluid components offers the opportunity to discard or modify those components. 
  • This separation is usually accomplished by means of either a centrifuge or by the less frequently used method of porous membrane filtration.
  • Unlike dialysis or haemofiltration, there is no size barrier: plasmapheresis removes the whole plasma with molecules of all sizes.
  • Some blood components are then reinfused into the patient with or without modification, and the rest may be discarded or stored.
  • If plasma is being removed,  volume is replaced with 4% albumin or FFP
  • For plasmapheresis to be justified, the disease process must have a circulating factor involved in pathogenesis, which can be expected to persist in the circulation without sufficiently rapid endogenous clearance.

Modalities of plasmapheresis

The Greek word “ἀφαίρεσις”  means “to take away”  or “to separate", and crudely that is exactly what the plasmapheresis devices do. It is also a term in linguistics which describes the phonetic loss of a sound, for example the missing "k" in "knife".  Plasmapheresis might refer to several possible procedures, depending on which blood components are separated.

  • Plasma exchange, where whole plasma is removed in bulk and replaced with some sort of replacement fluid, usually 4% albumin.
  • LDL apheresis where triglycerides and cholesterol are removed from the plasma, and the plasma is then reinfused into the patient. There are actually a whole variety of different ways to do this, which includes exposing the blood to LDL antibodies, cellulose or polyacrylate beads, a low pH which precipitates the LDL particles, or a double filtration membrane.
  • RBC apheresis  where red cells are separated from donor blood for storage and later re-transfusion (i.e. this is how we get "packed" red cells).
  • RBC exchange where defective red cells are removed from a patient and "good" red cells are retransfused
  • Platelet apheresis where donated blood undergoes separation so that platelets can be stored for separate use; or, the less common application of removing platelets and discarding them, because the patient has severe thrombocytosis.
  • Leukopheresis, where leukocytes are separated from the blood - this could be either to remove defective cells (eg. to decrease their numbers in leukostasis) or to harvest the white cells for transfusion (eg. to collect granulocytes or haematopoietic stem cells).
  • Extracorporeal photopheresis  is a variety of leukopheresis where the white cells are exposed to UV light after being treated with psoralen (a weird mutagen which intercalates into DNA upon exposure to ultraviolet radiation). The mutant leukocytes are then reinfused into their original host so they might undergo apoptosis and trigger a variety of immunomodulatory effects. How this helps in GVHD and cutaneous T-cell lymphoma, nobody is completely sure.

Methods of blood separation by plasmapheresis apparatus

There are 2 techniques: 

  • Size-based separation using porous filters (less common)
  • Density-based separation using centrifuges (more common)

In the centrifuge method, blood separates into layers within a rapidly rotating cylinder, with the plasma staying in the centre of the cylinder, and cellular components moving to the periphery. The components of the blood separate into layers on the basis of density. The red cells end up being the densest and are at the extreme periphery of the blood column; next outermost are granulocytes, then the relatively lighter lymphocytes and finally the platelets. In the centre, plasma remains. 

This central plasma compartment is the siphoned off. Depending on what you want to dump and what you want to keep, the plasma may be discarded and the remaining cells mixed with a replacement fluid (albumin or FFP) and returned to the patient, or vice versa. There is some mixing of components at the interface between spinning layers (understandably they are not neatly arranged, as spinning fluid is prone to misbehaviour) so for example the plasma might contain some platelets. In short this means 

One measures the "dose" of plasma exchange by volume of replacement fluid as compared to the total plasma volume of the patient. If a patient has about 4L of plasma and 4L of replacement fluid is used in the course of plasma exchange, it is said to be a 1 plasma volume exchange.

The rate of removal is incomplete - one cannot remove the entire fluid volume by spinning the cells down to their "dry" weight. Thus, for every 1-1.5 plasma volumes exchanged, about 60-70% of the plasma substances are removed. For every subsequent volume exchanged, the absolute amount of the substances decreases but the proportion remains the same (60-70%). Thus, with increasing doses of plasma exchange, the efficiency diminishes. Generally speaking only 1-1.5 plasma volumes are exchanged in each session.

Indications for urgent plasma exchange

Having your plasma sucked out of your body, replaced with a foreign fluid and reinfused back into you is clearly a rather invasive process not without its adverse effects. It is therefore engaged upon only in such circumstances where there is no option other than to remove some component of the blood. There are two main characteristics for a disease process which make plasmapheresis a sensible decision:

  1. The disease has to be caused by some circulating factor, i.e. it has to be present in the blood
  2. That factor has to have a sufficiently long plasma half-life, such that "turning off" the process of its production will still result in significant amounts of it persisting in the bloodstream.

Taking these two principles, one can imagine the sort of disease-causing blood components one might want to extract. These might include the following undesirables:

  • Antibodies
  • Immune complexes
  • Abnormal plasma proteins, eg. myeloma light chains
  • Immunoglobulins
  • Protein-bound drugs
  • Monoclonal antibody drugs, eg. rituximab
  • Immune complexes
  • Cryoglobulins
  • Myeloma light chains
  • Bacterial endotoxin
  • High molecular weight toxins, eg. animal venom
  • Cholesterol-containing lipoproteins /triglycerides
  • Abnormal cells (eg. leukaemia blasts, excess RBCs or platelets)

The process of exchange is non-selective, and removes all plasma contents, good and bad. FFP replaces some of these, but not all. Albumin obviously only replaces albumin. Desirable molecules removed by plasma exchange and not replaced with standard replacement fluids include the following:

  • Antithrombin
  • Pseudocholinesterases and plasma esterases
  • Useful antibodies, including monoclonal biological agents
  • Useful medications
  • Nutrients, eg. glucose, amino acids, water-soluble vitamins
  • Diagnostically interesting antibodies (i.e. for serology)

Indications for urgent plasma exchange 

Russi and Marson have a 2011 article which presents a table with a few indications for urgent plasma exchange. The gospel list of all indications can be found in the ASFA guidelines statement from 2010. Their list is massive, spanning three pages of their ninety-five page statement. Highlights from this list (those indications which received Grade I recommendation) include the following:

Urgent plasma exchange:

  • TTP
  • Catastrophic antiphospholipid syndrome
  • Hyperviscosity syndrome (eg. myeloma)
  • Guillain-Barre syndrome
  • Myasthenia gravis
  • Acute fulminant hepatitis with encephalopathy
  • Amanita phalloides poisoning

Less urgent plasma exchange:

  • Erythrodermic cutaneous T-cell lymphoma
  • Wegeners granulomatosis
  • Goodpasture's syndrome
  • Eaton-Lambert syndrome
  • Babesiosis
  • Autoimmune haemolytic anaemia
  • Cryoglobulinaemia
  • Dermatomyositis/polymyositis
  • Hemolytic uremic syndrome
  • Familial hypercholesterolaemia
  • Focal segmental glomerulosclerosis
  • Paraproteinaemic polyneuropathy
  • Antibody-mediated renal transplant rejection
  • Fulminant Wilson's disease.

One should note that in their list of indications, the college noted some Grade II, III and IV recommendations, such as:

  • HELLP syndrome
  • Multiple sclerosis
  • HIV-related neuropathy
  • Pemphigus
  • Coagulation inhibitors
  • DIC
  • Overwhelming sepsis syndromes eg meningococcaemia
  • Reye’s syndrome
  • Paraquat poisoning

Complications of plasma exchange

The question specifically asks about complications unrelated to catheterisation. Catheterisation is classically something which produces an access point the characteristics of which are identical to what you might use for dialysis. Generally a standard vas cath is all that's required. 

Non-catheter-related complications include the following:

  • Due to the circuit exposure
    • Low fibrinogen and coagulopathy
    • Haemolysis and thrombocytopenia
    • Hypothermia
    • Complement activation
  • Due to anticoagulation
    • Paraesthesia due to hypocalcemia (due to regional citrate anticoagulation)
    • Bleeding complications
    • HITS
  • Due to the replacement fluid
    • Urticaria
    • Febrile reaction to blood products
    • Anaphylaxis
  • Due to the unavoidable removal of useful blood components
    • Loss of useful drugs
    • Immunesuppression
    • Anaphylaxis
    • Hypothermia
  • Due to volume loss
    • Hypotension
    • Vasovagal syncope
    • Nausea and vomiting

 

References

McLeod, Bruce C. "Therapeutic apheresis: use of human serum albumin, fresh frozen plasma and cryosupernatant plasma in therapeutic plasma exchange."Best Practice & Research Clinical Haematology 19.1 (2006): 157-167.

Reimann, P. M., and P. D. Mason. "Plasmapheresis: technique and complications." Intensive care medicine 16.1 (1990): 3-10.

Winters, Jeffrey L. "Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis guidelines." ASH Education Program Book 2012.1 (2012): 7-12.

Oh's Manual: Chapter 97 (pp. 993)  Therapeutic  plasma  exchange  and  intravenous  immunoglobulin  therapy  by Ian  Kerridge,  David  Collins  and  James  P  Isbister.

Szczepiorkowski, Zbigniew M., et al. "Guidelines on the use of therapeutic apheresis in clinical practice—Evidence‐based approach from the apheresis applications committee of the American Society for Apheresis." Journal of clinical apheresis 25.3 (2010): 83-177.

Russi, Gianpaolo, and Piero Marson. "Urgent plasma exchange: how, where and when." Blood Transfusion 9.4 (2011): 356.

Weinstein, Robert. "Basic principles of therapeutic blood exchange." Apheresis: principles and practice (2003): 295-320.