Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura and haemolytic-uraemic syndrome are a couple of horrible problems which together with HELLP and MAHA fall into the spectrum of thrombotic microangiopathies. A good NEJM review article is available from 2004. TTP-HUS comes up remarkably often in the fellowship exam. Typically, its appearance in the SAQs is either accompanied by a pair of diseased-looking legs covered in pupura, or by a history of a young woman who has presented with thrombocytopenia and seizures.  It has been involved in the following past paper SAQs:

Characteristic features of TTP:

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

The classical literature describes a "pentad" of symptoms, consisting of thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, renal failure, and fever. Not all are required. If renal failure is the dominant feature, one might call it HUS; the boundaries between TTP and HUS are not completely clear.

Underlying pathophysiological process of TTP:

Low ADAMTS-13 levels are clearly implicated. One could really get carried away with the details of pathogenesis here. The college answer to Question 21 from the first paper of 2013 demonstrates the depth expected of the candidates:

"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."

So,  an excess of vWF leads to a systemic prothrombotic state, with microvascular thrombosis responsible for all the organ system damage.

TTP-like diseases

  • TTP
  • Eclampsia
  • HUS
  • Vasculitis
  • MAHA
  • DIC, meningococcaemia

Plasma exchange regimens for TTP

Plasma exchange in TTP aims to remove the ADAMTS-13 inhibitor 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. The college answers also mention the preferential use of cryodepleted plasma, which has less vWF than standard FFP.

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 haemofiltration 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 more detailed discussion of plasmapheresis is available in the over-long answer to Question 14 from the first CICM fellowship exam paper of 2010.

 

References

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.

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

Kakishita, Eizo. "Pathophysiology and treatment of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)."International journal of hematology 71.4 (2000): 320-327.

Noris, Marina, and Giuseppe Remuzzi. "Hemolytic uremic syndrome." Journal of the American Society of Nephrology 16.4 (2005): 1035-1050.

Kappler, Shane, Sarah Ronan-Bentle, and Autumn Graham. "Thrombotic Microangiopathies (TTP, HUS, HELLP)." Emergency Medicine Clinics of North America (2014).

Moake, Joel L.  http://www.danielyoung.net/articles/NEJM%20TTP-HUS%202002.pdf "Thrombotic microangiopathies." New England Journal of Medicine 347.8 (2002): 589-600.