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:

• Question 22.2 from the first paper of 2022 (HUS, rather than TTP)
• Question 7 from the first paper of 2022 (very quick notes on TTP)
• Question 17 from the second paper of 2019 (everything about TTP)
• Question 29 from the second paper of 2017 (HITTS vs. TTP-HUS)
• Question 22.3 from the second paper of 2016 (TTP and ADAMTS-13)
• Question 21 from the first paper of 2013 (TTP and plasmapheresis in great detail)
• Question 26.3 from the first paper of 2013 (TTP is one of the differentials)
• Question 15.2 from the second paper of 2012 (TTP is one of the differentials)
• Question 7.2  from the second paper of 2009 (image of purpura fulminans)
• Question 22.2 from the second paper of 2008 (identical to Question 15.2 from 2012-2)
• Question 30.2  from the first paper of 2008 (image of purpura fulminans again)
• Question 9 from the second paper of 2007 (identical to Question 15.2 from 2012-2)
• Question 8 from the first  paper of 2004 (TTP is one of the differentials)

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; and in fact Chiasakul & Cuker (2014) found that only 7% of patients present with the classic pentad.  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

Scully et al (2012) include this list of differentials in their guidelines statement.  In short, it is a list of thrombotic microangiopathies:

• Autoimmune haemolysis/Evans syndrome
• Disseminated intravascular coagulation
• Pregnancy‐associated e.g. HELLP (haemolysis, elevated liver enzymes and low  platelets), eclampsia
• Drugs eg quinine, simvastatin, interferon, Calcineurin inhibitors
• Malignant hypertension
• Infections, typically viral (cytomegalovirus, adenovirus, herpes simplex virus) or severe bacterial (meningococcus, pneumococcus), fungal
• Autoimmune disease (lupus nephritis, acute scleroderma)
• Vasculitis
• Haemolytic uraemic syndrome (diarrhoea positive/negative)
• Malignancy
• Catastrophic antiphospholipid syndrome

Haemolytic uraemic syndrome

Listed often alongside TTP (as TTP-HUS), this thrombotic microangiopathy is thought to form a part of the same spectrum of disease, except the ADAMTS-13 level is often normal. Like TTP, this is basically a non-autoimmune haemolytic anaemia with thrombocytopenia and acute renal failure. Karpman et al (2017) do a good job of writing it up, and the interested reader is redirected there if they want to know more than is necessary to answer Question 22.2 from the first paper of 2022, which only asked for the causes:

• Infectious agents
  • Shigatoxin producers:
    • Enterohaemorrhagic Escherichia coli (EHEC)
    • Shigella dysenteriae
    • Citrobacter freundii
  • Streptococcus pneumoniae
  • Pseudomonas aeruginosa
  • Enteroviruses (Coxsackie A and B, Echovirus)
  • HIV
  • CMV
• Complement dysregulation ("atypical" HUS)
  • Congenital mutations in regulatory complement proteins, eg. factor H, factor I, MCP, C3, factor B, clusterin, thrombomodulin, diacylglycerol kinase-e (DGKE)
  • Acquired, eg. antibody to Factor H
• Autoimmune
  • SLE
  • Antiphospholipid syndrome
  • Scleroderma
• Peripartum
  • HELLP and HUS are related
• Solid organ and bone marrow transplantation

Clinical features of TTP

Scully et al (2008) were able to relate ADAMTS13 activity with presenting symptoms to find the closest associations in TTP, among a cohort of Uk patients.

• Neurological abnormalities in 78% of cases:
  • Coma (10% require invasive ventilation)
  • Headache
  • Encephalopathy
  • Stroke, transient ischaemic attack
• Temperature greater than 37·5°CS
• Non‐specific symptoms: fatigue, arthralgia or myalgia
• Gastroenterological features
  • Diarrhoea
  • Jaundice
• Cardiac symptoms
  • Chest pain, shortness of breath, ECG changes
• Symptomatic thrombocytopenia (petechiae, bruising, haematuria, menorrhagia)
• Renal manifestations (oliguria, haematuria, fluid overload)

Diagnostic features

A measurement of ADAMTS13 activity which is less than 10% of population norms is generally viewed as diagnostic (Page et al, 2017). In addition to this, multiple additional abnormalities may coexist which are not TTP-specific but which support the diagnosis:

• MAHA- like blood film features: fragmented red cells and other evidence of haemolysis:
  • Negative Coombs test 
  • Elevated LDH
  • Low haptoglobin
  • High reticulocyte count
  • Elevated bilirubin with a low conjugated fraction
  • Free haemoglobin in the blood
• Thrombocytopenia (obviously) 
• Renal failure: raised urea and creatinine

The diagnostic workup should therefore include:

• ADAMTS13 activity
• Full blood count and blood film
• Renal function and liver function tests
• Troponin
• Coags and fibrinogen
• Haemolytic screen
  • Coombs test
  • Haptoglobin
  • Reticulocyte count
  • LDH
• Urinalysis for protein
• Pregnancy test
• Vasculitic (autoantibody) screen
• Stool culture (for enterohaemorrhagic E.coli)
• A CT of the chest and abdomen if malignancy is suspected

The Coombs direct antiglobulin test is supposed to be negative in TTP, as TTP is not an autoimmune haemolytic anaemia, i.e. the red cells are not getting attacked by antibodies. TTP does however get some microangiopathic haemolysis, where the fibrinous debris forming on the surfaces of denuded arterioles and capillaries have an abrasive effect on red cells, turning them into schistocytes. To be sure, you could have a Coombs-positive TTP, but if you did you could probably publish a case report about it (eg. Urahama et al, 2005)

Management of TTP

In a survey of Australian experience (Blombery et al, 2016):

• 94% had plasma exchange
• 13% had plasma infusion without plasmapheresis
• 71% had corticosteroids
• 39% ended up getting Rituximab

This spread might suggest that the management of TTP in Australia is some sort of lawless free-for-all, but in fact we are guided by the 2012 British guidelines (Scully et al, 2012). These guidelines are fairly prescriptive, and in fact there is an excellent flowchart of management which is reproduced below with no permission whatsoever:

In summary:

• Start plasma exchange: three daily sessions of .5 volumes, then 1 volume per day until resolution of clinical features.
• Continue plasma exchanges until 2 days after the platelet count is in excess of 150
• Immediately after plasma exchange, commence high dose steroids: 1g/day of methylprednisolone for 3 days, or oral prednisolone 1mg/kg/day
• Also:
  • give folic acid 5mg/day
  • Ensure PPI is added
• If there is neurological or cardiac involvement, commence Rituximab
• Don't transfuse any more platelets unless strongly indicated
• Once platelets increase to over 50, one may start s/c heparin and oral aspirin

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.