With respect to thrombotic thrombocytopaenic purpura (TTP):

  • List the classical clinical features of TTP.
  • Describe the underlying pathophysiological process
  • Plasma exchange has been used to treat TTP and Guillain Barre syndrome. Outline the important differences between the plasma exchange treatment regimens used for each condition
  • Explain the difference between plasmafiltration and plasmapheresis
  • Steroids and rituximab are two drug therapies commonly recommended as adjunctive therapy in TTP. Outline the mechanism of action for each in treating TTP

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College Answer

a)

Thrombocytopaenia, Microangiopathic haemolytic anaemia, fever, neurological symptoms, renal failure.

b)

A trigger such as infection, surgery, pancreatitis, pregnancy, produces endothelial activation. ADAMTS 13 is a von Willebrand factor cleaving protein. When endothelial activation occurs and ADAMTS 13 activity is low (often due to an autoantibody inhibitor), large vWF multimers accumulate causing microvascular thrombosis and haemolysis

c)

In TTP daily exchanges of 1.5 plasma volumes are used until remission has occurs (platelet count > 150). Replacement with cryodepleted plasma has been recommended as it has less vWF than standard FFP and adequate amounts of ADAMTS 13, but there is no clearly demonstrated clinical advantage over replacement with standard FFP. Replacement with 4% albumin would be inappropriate.

In Guillain Barre Syndrome a course of treatment is given, typically 1.5 plasma volumes every second day for a total of 5 exchanges. The treatment is NOT continued until remission. Replacement with albumin has a lower complication rate than with FFP, and so is preferred.

d)

With plasmafiltration, the patient’s blood is pumped through a circuit similar to a renal replacement therapy circuit. The membrane used filters plasma off. The filtered plasma is replaced with a colloid such as 4% albumin or FFP.

With plasmapheresis, the patient’s blood drains into a reservoir where it is centrifuged into its compents. The non-plasma components are returned to the patient. The discarded plasma is replaced with a colloid such as 4% albumin or FFP

e)

Steroids such as methylprednisolone or prednisolone bind to steroid receptors in the cytoplasm, and are then translocated into the nucleus where they interaction with specific DNA sequences to either enhance or suppress gene transcription. This causes widespread effects on both innate and acquired immunity, suppressing the immune response.

Rituximab is an antibody against CD20 receptors on B cells, resulting killing of these cells, and hence suppressing the immune response.

Discussion

With such succinct college answers it is difficult to find room for improvement. References for further reading will have to suffice.

A good NEJM review article is available from 2004, and within it one may be able to find the majority of the answers to the first parts of the question.

Characteristic features of TTP:

  • Anaemia
  • Thrombocytopenia
  • Microangiopathic haemolytic anaemia
  • Schistocytosis
  • Neuorological symptoms
  • Fever and renal failure are actually uncommon

Underlying pathophysiological process of TTP:

Low ADAMTS-13 levels are clearly implicated. One could really get carried away with the details of pathogenesis here. A brief explanation would have to be limited to the statement that a loss of ADAMTS-13-mediated vWF destruction leads to an exccess of vWF and thus to a systemic prothrombotic state, with microvascular thrombosis responsile for all the organ system damage.

Plasma exchange regimens for TTP and for Guillain-Barre syndrome

Plasma exchange in TTP aims to remove the ADAMTS-13 inhbitor while replacing the missing ADAMTS-13 protein, and thus the replacement fluid needs to be FFP (as a pure albumin solution would have no ADAMTS-13 in it). One is obliged to continue the treatments until the microvascular thrombosis and thrombocytopenia are no longer posing a problem.

Plasma exchange for Guillain-Barre syndrome aims to clear the aetiological autoantibody from the bloodstream. In essence, we say "we have no idea which antibody is causing the demyelination, so we will get rid of all of them". The evidence seems to support a 5-treatment regimen; it seems that six treatments are no better than four. Because there is no missing proteins to replace, the exchanged plasma can be FFP or albumin - it does not seem to matter to the resolution of disease. However, because FFP has a slightly higher risk of transfusion reactions, so in general albumin is the recommended replacement solution, unless there are specific reasons to replace blood proteins.

The technique of plasmapheresis is discussed in a frustrating article of which only view the first two pages are available to the subscriptionless reader. It is at a basic level the centrifugal separation of blood components.

In contrast, a decent quality plasma filtration article is available to the pennyless public. It describes the process as being virtually identical to the hemofiltration of renal replacement therapy, with the main difference being the size of the membrane pores (they need to be large enough to allow the extrusion of all non-cellular blood components).

A good review of the immunosuppressant mechanism of corticosteroid therapy was published in 2011 in Molecular and Cellular Endocrinology. Its 35 pages are a wild excess of detail for the time-poor exam candidate. For a workmanlike understanding of the mechanism, the CICM answer will suffice.

As for Rituximab, the monoclonal CD20 antibody- one can avail oneself of the Roche propaganda pamphlet, or read about the mechanism of its effect in the 2010 article from the Seminars in Hematology. The pragmatic exam candidate will probably limit themselves to the understanding that an attack on the CD20 receptor results in a complement-mediated B cell holocaust.

References

References

Batlle, Daniel C., et al. "The use of the urinary anion gap in the diagnosis of hyperchloremic metabolic acidosis." New England Journal of Medicine 318.10 (1988): 594-599.

George, James N. "Thrombotic thrombocytopenic purpura." New England Journal of Medicine 354.18 (2006): 1927-1935.

Peyvandi, Flora, et al. "von Willebrand factor cleaving protease (ADAMTS‐13) and ADAMTS‐13 neutralizing autoantibodies in 100 patients with thrombotic thrombocytopenic purpura." British journal of haematology 127.4 (2004): 433-439.

Tsai, Han-Mou. "Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura." Journal of the American Society of Nephrology 14.4 (2003): 1072-1081.

Zheng, X. Long, et al. "Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura." Blood103.11 (2004): 4043-4049.

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.

Raphael, J. C., et al. "Plasma exchange for Guillain-Barré syndrome." Cochrane Database Syst Rev 2.2 (2002).

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

Coutinho, Agnes E., and Karen E. Chapman. "The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights." Molecular and cellular endocrinology 335.1 (2011): 2-13.