guideline

Guidelines on the diagnosis and management of

thrombotic thrombocytopenic purpura and other thrombotic
microangiopathies

Marie Scully,1 Beverley J. Hunt,2 Sylvia Benjamin,3 Ri Liesner,4 Peter Rose,5 Flora Peyvandi,6 Betty Cheung7 and Samuel J.
Machin8 on behalf of British Committee for Standards in Haematology
1
Department of Haematology, UCLH, London, 2Department of Haematology, King’s College and Guys &St Thomas’ NHS Trust, Lon-
don, 3Department of Haematology, NBSBT and Oxford University Hospitals (OUH) Trust, UK, 4Department of Haematology,
GOSH, London, 5Department of Haematology, University Hospitals Coventry &Warwickshire NHS trust, Coventry, UK, 6Department
of Haematology, IRCCS Maggiore Hospital Ca’ Granda Foundation, University of Milan, Milan, Italy, 7Department of Haematology,
Queen Elizabeth Hospital, SLHT, London and 8Department of Haematology, UCL, London, UK

Keywords: thrombotic thrombocytopenic purpura, the regional UK registry occurred within 24 h of presenta-
thrombotic microangiopathy, guidelines. tion, primarily in women (Scully et al, 2008).
In the last 15 years there has been a marked increase in
The guideline group was selected to be representative of UK- the understanding of the pathogenesis of TTP. It is now
based medical experts. MEDLINE and EMBASE were recognized that congenital and acute acquired TTP are due
searched systematically for publications in English, using the to a deficiency of von Willebrand factor (VWF) cleaving pro-
keywords: thrombotic thrombocytopenia purpura (TTP), AD- tein, also known as ADAMTS1, (a disintegrin and metallo-
AMTS13, plasma exchange (PEX) and relevant key words proteinase with a thrombospondin type 1 motif, member 13
related to the subsections of this guideline. The writing group – von Willebrand factor cleaving protein) (Fujikawa et al,
produced the draft guideline, which was subsequently revised 2001; Levy et al, 2001). In the absence of ADAMTS13, ultra
by consensus by members of the Haemostasis and Thrombo- large multimers of VWF (ULVWF) released from endothe-
sis Task Force of the BCSH. The guideline was then reviewed lium are not cleaved appropriately, and cause spontaneous
by a sounding board of British haematologists, the BCSH and platelet aggregates in conditions of high shear, such as in the
the British Society for Haematology Committee and com- microvasculature of the brain, heart and kidneys.
ments incorporated where appropriate. The ‘GRADE’ system Congenital TTP is due to an inherited deficiency of AD-
was used to quote levels and grades of evidence, details of AMTS13, but acquired immune TTP is due to the reduction
which can be found at http://www.bcshguidelines.com. of ADAMTS13 by autoantibodies directed against ADAM-
The objective of this guideline is to provide healthcare TS13 (Furlan et al, 1998a; Tsai & Lian, 1998). Other clinical
professionals with clear, up-to-date, and practical guidance forms of thrombotic microangiopathy (TMA) occur in the
on the management of TTP and related thrombotic microan- absence of severe deficiency.
giopathies, defined by thrombocytopenia, microangiopathic Diagnosis can be difficult, as there is clinical overlap with
haemolytic anaemia (MAHA) and small vessel thrombosis. haemolytic uraemic syndrome (HUS), autoimmune disease
and a spectrum of pregnancy-related problems.

Pathogenesis
Diagnosis of TTP
Thrombotic thrombocytopenic purpura (TTP) is rare, with a
reported incidence of six cases per million per year in the Thrombotic thrombocytopenic purpura was originally charac-
UK (Scully et al, 2008). It is an important diagnosis to make terized by a pentad of thrombocytopenia, MAHA, fluctuating
because the untreated mortality is 90%, which can be neurological signs, renal impairment and fever, often with
reduced with the prompt delivery of plasma exchange (PEX). insidious onset. However, TTP can present without the full
Early death still occurs: approximately half of the deaths in pentad; up to 35% of patients do not have neurological signs
at presentation and renal abnormalities and fever are not
prominent features. The revised diagnostic criteria state that
TTP must be considered in the presence of thrombocytopenia
Correspondence: Dr M Scully, BCSH Secretary, British Society for
and MAHA alone (Galbusera et al, 2006). This can result in an
Haematology, 100 White Lion Street, London N1 9PF, UK.
increased referral of other TMAs (Table I). TTP remains a
E-mail [email protected]

ª 2012 Blackwell Publishing Ltd First published online 25 May 2012

British Journal of Haematology, 2012, 158, 323–335 doi:10.1111/j.1365-2141.2012.09167.x
Guideline

Table I. Differential diagnosis of thrombocytopenia and microangio- film, low haptoglobin levels and raised reticulocyte counts
pathic haemolytic anaemia. due to haemolysis. The direct Coombs test is negative. The
Autoimmune haemolysis/Evans syndrome combination of haemolysis and tissue ischaemia produces
Disseminated intravascular coagulation elevated lactate dehydrogenase (LDH) values.
Pregnancy-associated e.g. HELLP (haemolysis, elevated liver enzymes The clotting screen (prothrombin time, activated partial
and low platelets), eclampsia, haemolytic uraemic syndrome thromboplastin time and fibrinogen) is usually normal. A
Drugs eg quinine, simvastatin, interferon, Calcineurin inhibitors virology screen pre-treatment is necessary to exclude human
Malignant hypertension
immunodeficency virus (HIV) and other viral-associated
Infections, typically viral (cytomegalovirus, adenovirus, herpes
TTP, and as a baseline prior to plasma exposure. Troponin T
simplex virus) or severe bacterial (meningococcus, pneumococcus),
fungal
levels are raised in 50% of acute idiopathic TTP cases
Autoimmune disease (lupus nephritis, acute scleroderma) (Hughes et al, 2009), highlighting that cardiac involvement is
Vasculitis common. Raised troponin levels are a sinister finding, for
Haemolytic uraemic syndrome (diarrhoea positive/negative) coronary artery occlusion is a common mode of early death.
Malignancy The incidence of symptomatic heart failure is increased in
Catastrophic antiphospholipid syndrome patients who have been given a recent platelet transfusion
(Gami et al, 2005) (Table III).
Table II. Presenting clinical features and signs in acute TTP.
ADAMTS13 assays
Thrombocytopenia Epistaxis, bruising, petechiae, gingival
bleeding, haematuria, menorrhagia, Blood must be taken prior to treatment to assess baseline
gastrointestinal bleeding, retinal ADAMTS13 activity. Severely reduced ADAMTS13 activity
haemorrhage and haemoptysis (<5%) ± the presence of an inhibitor or IgG antibodies, con-
Central neurological – Confusion, headache, paresis, aphasia, firms the diagnosis (Peyvandi et al, 2004; Coppo et al, 2006;
often flitting and dysarthria, visual problems, Ferrari et al, 2007; Scully et al, 2007a). Decreased ADAMTS13
variable 70–80% encephalopathy, coma (10%) activity (<40% but >5%) has been reported in a wide variety of
Fever (>37·5°C)
non-TTP conditions such as uraemia, inflammatory states,
Non-specific symptoms Pallor, jaundice, fatigue, arthralgia or
post-operatively and during pregnancy (Loof et al, 2001;
myalgia
Mannucci et al, 2001; Moore et al, 2001). The specificity of
Jaundice Resulting from microangiopathic
haemolytic anaemia severe ADAMTS13 deficiency (<5%) in distinguishing acute
Renal Impairment Proteinuria, microhaematuria TTP from HUS is 90% (Bianchi et al, 2002; Zheng et al, 2004)
Cardiac Chest pain, heart failure, hypotension ADAMTS13 assays currently available include assays of
Gastro-intestinal tract Abdominal pain activity, antigen and neutralizing or non-neutralizing anti-
ADAMTS13 autoantibodies. Functional assays measuring
ADAMTS13 activity are based on the failure of the patient
diagnosis based on clinical history, examination of the patient
plasma to degrade VWF multimers or synthetic VWF pep-
and the blood film. ADAMTS 13 assays help to confirm the
tides. Inhibitory autoantibodies can be titrated in vitro using
diagnosis and monitor the course of the disease and possible
classical mixing studies and non-neutralizing antibodies can
need for additional treatments.
be detected by Western blotting or enzyme-linked immuno-
Presenting symptoms and signs are summarized in
sorbent assays (Peyvandi et al, 2010).
Table II and reflect widespread multi organ thromboses.
Neurological impairment has multiple presentations includ-
Recommendation
ing headache, altered personality, reduced cognition, tran-
sient ischaemic attacks, fits and fluctuating levels of 1 The diagnosis of TTP should be treated as a medical
consciousness including coma; the latter is a poor prognostic emergency (1A).
sign. Acute renal failure requiring haemodialysis is rare in 2 The initial diagnosis of TTP should be made on clinical
TTP and more indicative of HUS (Coppo et al, 2006; Scully history, examination and routine laboratory parameters
et al, 2008). Additional ischaemic complications may be seen, of the patient, including blood film review (1A).
such as abdominal pain due to intestinal ischaemia. 3 In view of the high risk of preventable, early deaths in
Consumption of platelets in platelet-rich thrombi results TTP, treatment with PEX should be initiated as soon as
in thrombocytopenia. The median platelet count is typically possible, preferably within 4–8 h, regardless of the time
10–30 9 109/l at presentation (Dervenoulas et al, 2000; of day at presentation, if a patient presents with a
Vesely et al, 2003; Coppo et al, 2006; Tuncer et al, 2007; MAHA and thrombocytopenia in the absence of any
Scully et al, 2008). Mechanical fragmentation of erythrocytes other identifiable clinical cause (1B).
during flow through partially occluded, high shear small 4 Serological tests for HIV, hepatitis B virus and hepatitis C
vessels causes a MAHA. Median haemoglobin levels on virus, autoantibody screen and when appropriate, a preg-
admission are typically 80–100 g/l, with schistocytes in the nancy test, should be performed at presentation (1A).

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 Guideline

Table III. Testing and expected results for patients with a suspected 1 Neonates typically have severe neonatal jaundice. Blood
diagnosis of TTP Blood samples should be sent for investigation film examination may show schistocytes together with red
before first PEX.
cell anisocytosis. (Scully et al, 2006a).
For diagnosis 2 More frequently, the diagnosis is made later in infancy
Full blood count and blood film Anaemia, thrombocytopenia, or childhood (Schiff et al, 2004), typically with thrombocyto-
fragments on film penia, MAHA, jaundice and elevated LDH, although some
Reticulocyte count Raised
children may only have an isolated thrombocytopenia. Neu-
Haptoglobin Reduced
rological symptoms, such as hemiparesis, hemiplegia or sei-
Clotting screen including Normal
fibrinogen
zures, occur in 35% of cases (Loirat et al, 2006).
Urea and electrolytes Renal impairment 3 Patients may present in adulthood. In women, preg-
Troponin T/Troponin I For cardiac involvement nancy is a common precipitant and is associated with a sig-
Liver function tests Usually normal nificant neonatal morbidity and mortality (Fujimura et al,
Calcium May reduce with PEX 2009). Rarely ‘late-onset phenotype’ cases may not develop
Lactate dehydrogenase Raised due to haemolysis symptoms until their 50s and 60s with isolated cerebral
Urinalysis For protein events or renal disease ((Fujimura et al, 2011). Asymptom-
Direct antiglobulin test Negative atic male cases have been reported, usually detected because
Blood group and antibody To allow provision of blood they have affected siblings.
screen products
Patients with congenital TTP have persistently low levels
Hepatitis A/B/C and human Pre-blood products and to
of ADAMTS13, but they can be asymptomatic until a further
immunodeficiency virus testing exclude an underlying viral
precipitant
precipitating event results in a frank TTP episode. Events
Pregnancy test (in women of child-bearing age) include febrile episodes, infections, vaccinations, excess
ADAMTS 13 assay (activity/ Do not wait for result before alcohol intake and pregnancy (Furlan et al, 1997, 1998b;
antigen and inhibitor/antibody starting treatment in suspected Schneppenheim et al, 2003).
in specialized laboratory) TTP Congenital TTP has been missed in the past, because the
Electrocardiogram/Echocardiogram To document/monitor cardiac diagnosis has not been considered, or diagnosed as idiopathic
damage thrombocytopenic purpura or ‘atypical’ HUS (Veyradier
CT/MRI brain To determine neurological et al, 2003), illustrating the importance of consideration of
involvement* the diagnosis, review of the blood film and measurement of
For possible underlying cause
ADAMTS13 .
Thyroid function tests To exclude Graves Disease
The diagnosis of congenital TTP is dependent on detecting
Auto-antibody screen (ANA/RF/ Exclude associated autoimmune
LA/ACLA), including lupus disease
ADAMTS13 activity <5%, in the absence of antibodies to
anticoagulant ADAMTS13. In the last few years molecular diagnosis has
Stool culture For pathogenic Escherichia coli been used to confirm the diagnosis, and either a homozygous
(if diarrhoea) or compound heterozygote defect in ADAMTS13 is found.
CT Chest/abdomen/pelvis (if To look for underlying Testing of siblings and other first-degree relatives at risk
indicated) ± tumour markers malignancy should be considered.
PEX, plasma exchange; CT, computerized tomography; MRI, mag-
netic resonance imaging; ANA, antinuclear antibody; RF, rheumatoid Recommendations
factor; LA, lupus antibody; ACLA, anticardiolipin antibodies; TTP,
thrombotic thrombocytopenia purpura. 1 Congenital TTP should be considered in neonates pre-
*Brain scanning on admission should not interrupt PEX therapy. senting with severe jaundice. Presentation may also
occur in childhood or as an adult (1A).
5 Pre-treatment samples should be obtained to measure 2 The diagnosis of congenital TTP should be considered in
ADAMTS13 activity levels and to detect anti-ADAMTS13 children and adults with unexplained thrombocytopenia
antibodies. Measurement of ADAMTS 13 antigen levels (1B).
is also useful in congenital TTP cases (1B). 3 The diagnosis of congenital TTP is confirmed by ADAM-
TS13 activity <5%, absence of antibody and confirmation
of homozygous or compound heterozygous defects of the
Subgroups of TTP
ADAMTS13 gene (1A).
Congenital TTP
Acute idiopathic TTP
Congenital TTP is a rare disorder, with over 100 patients
described worldwide, but this is likely to be an underestimate. Acute idiopathic TTP is the most common form of TTP.
It has a varied phenotype and can present at any age. As a It is an autoimmune disease characterized by antibodies,
general rule, those with more severe phenotypes present early: usually IgG, directed against ADAMTS13. The incidence is

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Guideline

four to six cases per million of the population per year in Drug-associated TTP
the United States (Miller et al, 2004; Terrell et al, 2005)
Drugs appear to be responsible for <15% of all TTP cases
and six cases per million per year in the UK (Scully et al,
(Vesely et al, 2003; Scully et al, 2008). Quinine can cause an
2008).
antibody-mediated idiosyncratic disorder, typically in
females. Thienopyridine-associated TTP is well recognized in
HIV-associated TTP association with ticlodipine with an incidence of one per
1600–5000 patients treated, but it has rarely been described
Thrombotic thrombocytopenia purpura may be the initial
with clopidogrel and there is uncertainty whether there is a
presenting feature of HIV disease or in those with low CD4
true association (Zakarija et al, 2009). Simvastatin (Koduri,
counts following non- compliance with antiviral treatment
1998; McCarthy et al, 1998; Vesely et al, 2003; Sundram
(Ucar et al, 1994; Gervasoni et al, 2002). Remission is depen-
et al, 2004; Scully et al, 2008), trimethoprim (Martin et al,
dent upon improving the immune status of the patient, for
2007) and peglyated interferon used to treat hepatitis C
stopping highly active anti retroviral therapy (HAART) can
(Deutsch et al, 2007; Serrano et al, 2007; Sallee et al, 2008)
result in acute TTP relapse (Miller et al, 2005), but contin-
have been anecdotally associated with antibody-positive TTP.
ued use of HAART usually prevents further relapses. TTP in
There are anecdotal reports of acquired TTP associated
HIV-positive individuals may be associated with the presence
with oestrogen-containing hormonal preparations such as the
of severe ADAMTS13 deficiency and anti-ADAMTS13 anti-
combined oral contraceptive pill (COCP) and hormone
bodies. Those with severe ADAMTS13 deficiency (<5%) have
replacement therapy (Scully et al, 2008). Some chemotherapy
fewer acquired immunodeficiency syndrome-related compli-
agents, such as gemcitabine, bleomycin and mitomycin–C
cations and higher CD4+ T cell counts, compared to HIV-
can cause HUS but not TTP.
TTP with ADAMTS13 levels >5%, who have an increased
mortality (Malak et al, 2008).
Recommendation
Pregnancy-associated TTP 1 Medications associated with precipitation of TTP include
quinine and oestrogen-containing medications, which
Pregnancy can be the initiating event for approximately 5–
should be avoided to prevent relapse in patients with a
25% of TTP cases (Ridolfi & Bell, 1981; Vesely et al, 2004;
previous episode of TTP (2C).
Scully et al, 2008), which are late onset adult congenital TTP
2 Women with previous TTP should be offered non-oestro-
or acute idiopathic TTP. Differentiating TTP from the more
gen containing contraception (1C).
common pregnancy-related TMAs, such as pre-eclampsia,
HELLP syndrome (haemolysis, elevated liver enzymes, low
platelets) and HUS is difficult, especially if TTP presents Transplant-associated microangiopathy
post-partum (Table IV). Thrombosis occurs in the placenta
Transplant-associated microangiopathy (TAM) is a MAHA
in untreated TTP pregnancies and results in fetal growth
and thrombocytopenia that occurs after bone marrow trans-
restriction, intrauterine fetal death and pre eclampsia. There
plantation. It may reflect endothelial toxicity associated with
is a continued risk of relapse during subsequent pregnancies.
chemotherapy, infections, immunosuppressives, such as ciclo-
Women with normal levels of ADAMTS13 pre-pregnancy
sporin A (CSA), and graft-versus-host disease (GVHD). TAM
have a lower risk of relapse (Ducloy-Bouthors et al, 2003;
has important differences from de novo TTP, namely, absence
Scully et al, 2006b).
of ADAMTS13 deficiency; rare neurological symptoms; a

Table IV. Typical features in pregnancy-associated microangiopathies.

Thrombo Coagulo Abdominal Renal Neurological

MAHA cytopenia pathy HBP symptoms Impairment symptoms

PET + + ± +++ ± ± ++
HELLP + ++ ± + +++ + ±
TTP ++ +++ ± + ++ +++
HUS + ++ ± ++ + +++ ±
AFLP ± + ++++ + +++ ++ +
SLE + + ± + ± ++ +
APLS + ++ ± ± ± ± ±

PET, pre-eclampsia; HELLP, haemolysis, elevated liver enzymes and low platelets; TTP, thrombotic thrombocytopenia purpura; HUS, haemolytic-
uraemic syndrome; AFLP: acute fatty liver of pregnancy; SLE, systemic lupus erythematosus; APLS, Antiphospholipid syndrome (catastrophic),
MAHA, microangiopathic haemolytic anaemia; HBP, hypertension.

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 Guideline

poor response to PEX and lack of evidence of systemic micro- The duration of PEX and the number of procedures
thrombi formation (Ruutu et al, 2007). required to achieve remission is highly variable, but is longer
in antibody-mediated TTP (Coppo et al, 2006).
An optimal regimen has not been determined. In the
Malignancy-associated thrombotic microangiopathy
Canadian apheresis trial, 1·59 plasma volume (PV) exchange
Thrombotic microangiopathy occurs in association with a was performed on the first 3 d followed by 1·0 PV exchange
variety of malignancies, especially adenocarcinomas, (Kwaan & thereafter (Rock et al, 1991). More intensive exchange, such
Gordon, 2001). Presentation may be either at an early stage of as twice daily PEX, may be required in resistant cases espe-
cancer or associated with disseminated disease. ADAMTS13 cially if there is new symptomatology, such as neurological
activity is not significantly reduced in these patients (Fontana or cardiac events. The benefit of an intensified PEX regimen
et al, 2001). has been difficult to document as other treatments are often
initiated or intensified simultaneously (Nguyen et al, 2008).
Daily exchanges should continue for a minimum of 2 d
Pancreatitis-associated TTP
after complete remission, defined as normal platelet count
Microangiopathic haemolytic anaemia has recently been (>1509 109/l). Tapering (reducing frequency and/or volume
reported in association with acute pancreatitis, sometimes a of PEX) has not been shown to reduce relapse rates
number of days after resolution of pancreatitis. ADAMTS13 (Bandarenko & Brecher, 1998).
activity was only moderately reduced and did not correlate Cryosupernatant is at least as efficacious as standard fresh
with the severity of TTP or pancreatitis. All patients were frozen plasma (FFP) (Rock et al, 1996; Brunskill et al, 2007).
successfully treated with PEX and corticosteroids (McDonald The UK Department of Health recommends the use of sol-
et al, 2009). vent/detergent-treated (S/D) plasma (O’Shaughnessy, 2006)
in TTP patients to reduce the risk of transfusion-transmitted
infection and adverse immune responses (Scully et al,
Haemolytic uraemic syndrome
2007b). S/D plasma contains reduced levels of protein S, but
Diarrhoeapositive (D+) HUS, associated typically with vero- an increased thrombotic rate has not been reported in cases
toxin-induced bloody diarrhoea, is treated with supportive where thromboprophylaxis with low molecular weight hepa-
care, which in some cases includes renal dialysis. Diarrhoea rin (LMWH) and low dose aspirin was used routinely once
negative (D ) HUS, not typically associated with bloody the platelet count was >50 9 109/l (Scully et al, 2007b).
diarrhoea, but may sometimes be associated with multisys- ADAMTS13 activity is present in normal amounts in FFP,
tem symptoms, similar to TTP, should be urgently treated S/D plasma, methylene blue-treated FFP (MB-FFP) and
with PEX (Kim et al, 2011). The primary differentiating fac- psoralen-treated FFP (Yarranton et al, 2005).
tor between HUS and TTP is the presence of oliguric/anuric In the UK, single donor MB-FFP is the recommended
renal impairment/failure in HUS. Increasingly, the role of plasma for use in all indications in those born after 1st Janu-
complement defects in D , atypical HUS is being defined ary 1996 to minimize the risk of prion transmission
(Kavanagh & Goodship, 2010) and use of the complement (O’Shaughnessy et al, 2004). However MB-FFP has been
inhibitor, eculizumab, appears successful in these cases (Al- associated with increased numbers of PEX and longer hospi-
Akash et al, 2011; Riedl et al, 2011), but may also have a role tal stay in TTP (de la Rubia et al, 2001; Rio-Garma et al,
in severe D+HUS (Lapeyraque et al, 2011). 2008). A prospective study using psoralen–FFP compared to
standard FFP showed equal efficacy and safety (Mintz et al,
2006).
Treatment of acute TTP
Plasma-related adverse events, such as allergic reactions,
A summary of the treatment protocol is shown in Fig 1. anaphylaxis and central venous catheter thrombosis,
appeared to be more frequent prior to the use of S/D plasma
(Scully et al, 2007b).
Plasma therapy
Daily PEX, preferably with spun apheresis, is the mainstay of
Recommendation
treatment and has reduced mortality rates, from over 90% to
10–20%. It allows removal of autoantibody, and repletes AD- 1 PEX should be started with 1·5 PV exchanges, using S/D
AMTS13. Delay in initiation of PEX leads to preventable plasma in all age groups and reassessed daily (1B).
early mortality (Pereira et al, 1995). Although PEX remains 2 The volume of exchange can be reduced to 1·0 PV when
the treatment of choice, large volume plasma infusions are the clinical condition and laboratory test results are sta-
indicated if there is to be a delay in arranging PEX. PEX has bilizing (2C).
been shown to be superior to plasma infusion at the end of 3 Intensification in frequency and or volume of PEX
the first treatment cycle and at 6 months (response rates procedures should be considered in life-threatening
47% and 78% vs. 25% and 49%) (Rock et al, 1991). cases (2B).

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Guideline

• Suspect TTP if patient has MAHA and thrombocytopenia in absence of other identifiable
cause
• Start treatment immediately if TTP is suspected and refer urgently for specialist advice and PEX
Suspected
• See Tables I, II and IV
TTP

• Take blood before starting PEX: FBC, blood film, reticulocytes, clotting, fibrinogen, U+E,
Troponin I/Troponin T, LFTs, Amylase, TFTs, calcium, LDH, pregnancy test, DAT, blood group
with antibody screen, ADAMTS13, Hepatitis A/B/C, HIV serology and autoantibody screen
Investigations • See Table III

• Other investigations should be performed promptly but can be delayed until after starting PEX:
urinalysis, stool culture (if diarrhoea), echocardiogram, CT brain (if neurological signs), and CT
Further chest/abdomen/pelvis to check for underlying malignancy (if indicated)
• See Table III
Investigations

• Request S/D FFP. If any delay in starting PEX then give FFP infusion (watch for fluid overload)
• Use standard FFP if S/D unavailable
Blood • Transfuse packed red cells when necessary to correct anaemia
• Platelet tranfusions are contraindicated unless bleeding is life-threatening
Products

• Start PEX with S/D FFP as soon as possible

• 1·5 plasma volumes 3, then 1 plasma volume/day with stabilization of condition
URGENT
treatment

• Give steroids; either IV methylprednisolone (1 g/day for 3 days) or oral prednisolone (e.g. 1
mg/kg/day) with an oral proton pump inhibitor
Start
• Give oral folic acid 5 mg OD
immediately
after PEX

• If HIV-positive, start HAART immediately

• If neurological or cardiac involvement, start rituximab
• See Section 3.7.2
Special cases

• When platelet count >50 109/l, start low molecular weight heparin thromboprophylaxis and
aspirin 75 mg OD
Prevent
thrombosis

• Continue daily PEX for a minimum of 2 d after platelet count has been >150 109/l, then stop
• If progressive symptoms, refractory disease or early relapse, then refer to Section 4
Treatment
Success?

Fig 1. Summary of treatment protocol for acute TTP. TTP, thrombotic thrombocytopenia purpura; MAHA, microangiopathic haemolytic
anaemia; PEX, plasma exchange; FBC, full blood count; U + E, urea and electrolytes test; LFTs, liver function tests; LDH, lactate dehydrogenase;
DAT, direct antiglobulin test; HIV, human immunodeficiency virus; CT, computerized tomography; S/D FFP, solvent/detergent-treated fresh
frozen plasma; IV, intravenously; OD, once daily; HAART, highly active anti retroviral therapy.

4 Daily PEX should continue for a minimum of 2 d after intermediate purity factor VIII concentrate containing AD-
platelet count has been >150 3 109/l and then stopped AMTS13, such as 8Y (BPL; BioProducts Laboratory, Elstree,
(2B). Herts) (Allford et al, 2000), which has a small infusion vol-
ume and can be given in the outpatient or home setting. 15–
30 u/kg of 8Y has been used with reported success, although
Congenital TTP
there is no guaranteed constant quantity of ADAMTS13 in
Plasma-derived or recombinant concentrates of ADAMTS13 such concentrates. Antibodies to ADAMTS 13 have not been
are not yet available. Therefore current treatment consists of detected following the use of 8Y. Despite that ADAMTS13
plasma infusion/exchange or the use of a virally-inactivated has a half-life of only 2–3 d (Furlan et al, 1999; Suzuki et al,

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 Guideline

2004), the clinical effect of infusions of plasma (10–15 ml/kg) 2 Mothers with congenital TTP should attend a specialist
or BPL 8Y are such that infusions are required only every 10– centre and receive ADAMTS13 supplementation regularly
20 d, to achieve a normal platelet and haemoglobin level. throughout pregnancy and the post-partum period (1A).
Ultimately the frequency of treatment depends on the 3 Close liaison with an obstetrician with a special interest
patient’s phenotype. Some require regular ‘prophylactic’ ther- in feto-maternal medicine is required in mothers with
apy to keep the platelet count normal and avoid relapses at TTP (1A).
times of infection and other stress situations. The phenotypi- 4 In mothers with acquired TTP, ADAMTS13 activity
cally mildly affected, who have a normal platelet count most should be monitored throughout pregnancy to help pre-
of the time, only require occasional treatment. dict the need for adjuvant therapy and outcome (1B).
5 Pre-conceptual counselling is advised for subsequent
pregnancies and women of child bearing age should be
Recommendation
counselled about potential risks of pregnancy and COCP
1 S/D plasma infusion or intermediate purity Factor VIII (eg (2B).
BPL 8Y) should be used to treat congenital TTP (1C).
2 Treatment regimens for congenital TTP should be indi-
HIV–related TTP
vidualized according to the patient’s phenotype (1A).
In those with severe ADAMTS13 deficiency, there is normali-
zation in ADAMTS13 activity, as the CD4 count recovers
Treatment of TTP in pregnancy
and HIV viral load falls, after treatment with HAART and
Diagnosis of pregnancy-associated TTP is especially difficult PEX. Occasionally, further therapy is required, for example
if it develops postnatally. In any mother with a TMA, and with rituximab or steroids, which do not cause a significant
uncertainty as to the diagnosis (and recognizing that pre- increase in infectious complications (Hart et al, 2011).
eclampsia and HELLP can present in the postnatal period), Practically, HAART should be given immediately after
PEX should be considered. PEX to allow for maximal time for absorption.
If TTP develops in the first trimester, regular PEX may
allow continuation of pregnancy with delivery of a live infant
Recommendation
(Ambrose et al, 1985; Rozdzinski et al, 1992; Mokrzycki et al,
1995; Scully et al, 2006b). Delivery is the definitive treatment 1 If a patient with TTP is found to have HIV infection
of choice for pregnancy-associated TMA, although delivery then viral load should be measured and an HIV physi-
does not guarantee remission of TTP. cian should be closely involved in management (1A).
Pre-treatment ADAMTS13 assays will distinguish congeni- 2 TTP should be considered in an HIV-positive individual
tal and acquired TTP from other pregnancy-associated with a MAHA and thrombocytopenia (1A).
TMAs. In pre-eclampsia and HELLP syndrome ADAMTS13 3 PEX in conjunction with HAART (triple or quadruple
activity is reduced (median 31% range 12–43%) but antibod- therapy) should be started as soon as the diagnosis of
ies to ADAMTS13 are not found. HIV-associated TTP is made (1B).
Close liaison with an obstetrician with expertise in thrombo- 3 HAART should be given immediately after PEX therapy
sis and fetomaternal medicine is required. Serial fetal monitor- to maximize time for absorption (1A).
ing with uterine artery dopplers should be used to assess if there 4 HAART should be continued after remission to prevent
is adequate fetal growth and to assess placental blood flow. further relapse (1B).
Plasma infusions alone may be sufficient in mothers with 5 In resistant HIV-related TTP, rituximab could be consid-
congenital TTP. However, at delivery PEX may be required ered (2B).
to ensure adequate levels of ADAMTS13. The ideal frequency
of plasma replacement during pregnancy is unknown.
Bone marrow transplant-associated microangiopathy
In acquired TTP, it is difficult to predict future relapse in
pregnancy. A reduction in ADAMTS13 activity (<10%) at Management is difficult, as stopping CSA or switching to
the start of pregnancy may require elective therapy to pre- another immunosuppressive, such as tacrolimus, may worsen
vent microvascular thrombosis during pregnancy. Rituximab GVHD. No benefit has been shown with PEX; indeed in a ret-
has been used in pregnancy in autoimmune disorders and rospective review it was associated with an increased mortality
lymphoma (Chakravarty et al, 2011). (George et al, 2004). There is anecdotal experience of success-
ful use of defibrotide (Bayik et al, 1993; Pogliani et al, 2000).
Recommendation
Malignancy-associated thrombotic microangiopathy
1 If a TMA cannot be fully explained by a non-TTP preg-
nancy-related TMA, then the diagnosis of TTP must be Plasma exchange has no benefit (Werner et al, 2007). The
considered and PEX should be started (2B). treatment of the underlying cancer is the mainstay of therapy.

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Guideline

apy. In a clinical trial of PEX with either steroids or CSA (2–

Recommendation
3 mg/kg twice daily), initial remission occurred in 89%, 14%
1 PEX is not indicated in the management of malignancy subsequently relapsed while on CSA and there was a 33%
and bone marrow transplant-associated TMA (1A). relapse after stopping 6 months of CSA treatment.
2 In cancer associated TMA, further treatment for the None of the eight CSA-treated patients suffered a relapse
underlying cancer should be considered (1A). in the first 30 d compared with 6/10 of the steroid-treated
patients. Overall 16/18 patients achieved a remission with an
increase in ADAMTS13 activity and decrease in antibodies to
Further treatments in acquired TTP
ADAMTS13 (Cataland et al, 2007a,b).
Corticosteroids. Steroids are widely used in combination In patients with renal impairment, tacrolimus is an alter-
with PEX in the initial treatment of acute immune TTP. native therapy, but side effects may preclude medium and
Higher dose pulsed steroids have shown to be associated with long-term use.
an improved patient outcome and usually have minimal side
effects (Balduini et al, 2010). However there is no random-
Recommendation
ized controlled trial addressing whether a combination of
PEX and corticosteroids is superior to PEX alone. CSA may be considered as second line therapy in patients
with acute or chronic relapsing acquired TTP (1C).
Recommendation
Other therapies. With the demonstrated utility and relative
Intravenous daily methylprednisolone (e.g. 1 g/d for three safety of rituximab, other drugs previously used for refrac-
consecutive days – adult dose) or high dose oral predniso- tory and remitting cases, such as vincristine and cyclophos-
lone (e.g. 1 mg/kg/d) should be considered (1B). phamide, whose use is associated with severe side effects, and
whose efficacy has been documented in small numbers of
Rituximab. Prospective studies have shown that rituximab is patients (Mazzei et al, 1998; Bohm et al, 2005), are not rec-
effective and safe in immune TTP, when patients failed to ommended except as part of a clinical trial.
respond to daily PEX and methylprednisolone and in
relapsed acute idiopathic TTP (Fakhouri et al, 2005; Scully Splenectomy. The mortality of open splenectomy in acute
et al, 2007a). Typically, 375 mg/m2 has been used weekly for TTP was reported to be approximately 40% (Rutkow, 1978).
4 weeks. Patients receiving rituximab showed reductions in In a retrospective case series of 33 patients splenectomized
anti-ADAMTS13 IgG antibody levels and increased ADAM- for acute refractory and relapsed disease, the 10-year relapse-
TS13 activity (Scully et al, 2007a). The risk of relapse appears free survival was 70% (Bohm et al, 2005; Kappers-Klunne
to be reduced with rituximab use (Heidel et al, 2007; Scully et al, 2005).
et al, 2011).
Ideally PEX should be withheld for at least 4 h after
Recommendation
completing a rituximab infusion (Hull & Eichbaum, 2006;
Scully et al, 2007a). Giving rituximab more frequently than Splenectomy may rarely be considered in the non-acute
weekly e.g. every 3–4 d, may overcome removal during PEX period of immune-mediated TTP but has limited proven
(McDonald et al, 2010). There is no evidence of increased benefit (2C).
infection risk with rituximab in TTP patients. A recent
Phase II UK study has shown benefit in using rituximab as
Antiplatelet agents
a first line therapy at presentation of TTP (Scully et al,
2011). The Italian Co-operative Group randomized 72 TTP patients
to PEX and steroids with and without aspirin and dipyrami-
dole (Bobbio-Pallavicini et al, 1997). There was no difference
Recommendation
in response rate or excessive haemorrhage and a non-signifi-
1 In acute idiopathic TTP with neurological/cardiac cant decreased rate of early death in the first 15 d in the an-
pathology, which are associated with a high mortality, tiplatelet-treated group (13·5% vs. 2·8%) (Bobbio-Pallavicini
rituximab should be considered on admission, in con- et al, 1997).
junction with PEX and steroids (1B).
2 Patients with refractory or relapsing immune-mediated
Recommendation
TTP should be offered rituximab (1B).
1 The clinical efficacy of antiplatelet agents in TTP is
Ciclosporin A and tacrolimus. Ciclosporin A was used suc- unproven but they are relatively safe (1B).
cessfully in one patient with relapsing TTP (Pasquale et al, 2 Low dose aspirin (75 mg OD) may be given during plate-
1998), but further relapses occurred after cessation of ther- let recovery (platelet count >50 3 109/l) (2B).

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 Guideline

Supportive therapy Relapse

Red cell transfusion and folic acid supplementation are Relapse is defined as an episode of acute TTP more than
required during active haemolysis. It has been shown that 30 d after remission, and occurs in 20–50% of cases
transfusion in the critically ill is safe using a transfusion trig- (Shumak et al, 1995; Bandarenko & Brecher, 1998; Willis &
ger of 70 g/l. However this trigger was not applicable to Bandarenko, 2005). The Canadian Apheresis Group esti-
those with cardiac disease (Hebert et al, 1999) and, as car- mated that over a 10-year follow up, 36% of patients would
diac microvascular thrombosis is a feature of TTP, a higher relapse (Shumak et al, 1995).
haemoglobin level may be required in those with evidence of Patients with ADAMTS13 activity <10% or an anti-
cardiac involvement and acute haemolysis. ADAMTS13 antibody in remission had a 3-fold increase in
Due to the risk of precipitating further thrombotic events, relapse over 1 year (Peyvandi et al, 2008). In a further study,
platelet transfusions are contra-indicated unless there is life- if ADAMTS13 was <5% in remission, relapse occurred in
threatening haemorrhage. 38·5%, but if ADAMTS13 activity was >15%, only 5%
The risk of venous thromboembolism has never been for- relapsed (Ferrari et al, 2007).
mally quantified in acute TTP but is likely to be increased The use of rituximab in an acute epsiode reduces and
due to immobility and acute illness. Therefore routine delays the incidence of relapse (Scully et al, 2011). Prior to
LMWH thromboprophylaxis should be given once the plate- discharge all patients should be counselled regarding the risk
let count has recovered to >50 9 109/l (Yarranton et al, and the symptoms and signs of relapse. In patients who have
2003). Hepatitis B vaccination should be considered in TTP, had previous TTP episodes and where a reduction of AD-
once a platelet threshold of 50 9 109/l has been achieved, AMTS 13 activity from detectable levels to <5% is demon-
but studies of efficacy are required in the face of continued strated, elective rituximab therapy has been successfully used,
PEX and/or immunosuppression with rituximab. with normalization of ADAMTS 13 activity (Scully et al,
2007a; Bresin et al, 2009). Patients require long-term follow
up with ADAMTS 13 assay monitoring.
Recommendation
1 Red cell transfusion should be administered according to
Recommendation
clinical need especially if there is cardiac involvement (1A).
2 Folate supplementation is required during active haemol- 1 Increased PEX and/or rituximab therapy are the agents
ysis (1A). of choice in relapsing disease (1B).
3 Platelet transfusions are contra-indicated in TTP unless 2 Patients should be counselled about symptoms, signs
there is life-threatening haemorrhage (1A). and risk of relapse before discharge with verbal and
4 Thromboprophylaxis with LMWH is recommended once written information (1A).
platelet count has reached >50 3 109/l (1B).

Table V. Differential Diagnosis of haemolytic uraemic syndrome.

Refractory TTP
Infection Shiga & verocytoxin (Shiga-like
There is a subgroup of patients who present with TTP who (diarrhoea-positive) toxin)-producing bacteria
subsequently show a slow or incomplete response to
PEX ± corticosteroids. Refractory disease was previously Disorders of complement Genetic disorders of complement
arbitrarily defined as persistent thrombocytopenia or LDH regulation (diarrhoea- regulation e.g. Factor H, I, MCP
negative) (CD46), factor B (CFB), C3 (C3),
elevation after a total of seven daily PEX procedures. LDH is
thrombomodulin
not however, a reliable marker of disease activity. We have
Acquired disorders of complement
therefore redefined refractory disease as progression of clini- regulation e.g. anti-FH antibody
cal symptoms or persistent thrombocytopenia despite PEX. Other causes of Steptococcus pneumoniae
Intensification of PEX with the introduction of 12-hourly secondary HUS HIV
or double PV exchanges and the addition of further steroids Malignancy
have provided some benefit (Shumak et al, 1995; Bobbio-Pal- Defective cobalamin metabolism
lavicini et al, 1997; Bandarenko & Brecher, 1998; Kahwash & Drugs e.g. quinine, some chemotherapy
Lockwood, 2004; Nguyen et al, 2008). Rituximab is the cur- e.g. gemcitabine, bleomycin)
rent agent of choice in refractory disease (Scully et al, 2007a). Pregnancy
Other autoimmune diseases
e.g. SLE, APLS
Recommendation
HUS, haemolytic uraemic syndrome; HIV, human immunodeficiency
Increased frequency of PEX and addition of rituximab can virus; SLE, systemic lupus erythematosus; APLS, antiphospholipid
be considered in refractory TTP (1B). syndrome.

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Guideline

3 In patients with a documented reduction of ADAMTS 13 press, neither the authors, the British Society for Haematolo-
activity to <5%, elective therapy with rituximab can be gy nor the publishers accept any legal responsibility for the
considered (1B). content of these guidelines.

Haemolytic uraemic syndrome Guideline update

Haemolytic uraemic syndrome is characterized by MAHA, In 2003, the British Society for Haematology (BCSH) pub-
thrombocytopenia and acute renal failure. It maybe associated lished the first evidence-based guidelines for the diagnosis
with extensive multi-organ involvement, e.g. neurological, and management of thrombotic microangiopathies (Allford
hepatic complications, and cardiac problems and therefore et al, 2003). We have revised these based on new evidence
diagnostic overlap with TTP can occur. It is important to dif- available between 2003 and 2011.
ferentiate between D + HUS, atypical HUS and TTP because Separate guidelines for atypical haemolytic-uraemic syn-
the prognosis and management are different (Table V). The drome (HUS) (Taylor et al, 2010) and diarrhoea-positive
reader is referred to (Ariceta et al, 2009) and (Taylor et al, HUS (Ariceta et al, 2009) are now available, so these sections
2010) for further guidance in children and adults, respectively. have been reduced.

Conclusion Acknowledgements
TTP and other TMAs remain diagnostically difficult. The Dr Michael J Desborough, Academic Clinical Fellow, Oxford
current challenge is to ensure that haematologists, physicians, Deanery UK for review of Fig 1 and Ms Lucy MacKillop,
obstetricians and paediatricians are aware of the need to treat Obstetric Physician, Oxford Universities Hospital Trust for
acute TTP as a medical emergency to prevent unnecessary review of Table IV.
early mortality. The development of new drugs and recombi-
nant proteins, trialled in the developing networks should lead
Conflicts of interest
to better treatments in the future.
The Haemostasis Research unit, UCL has received an unre-
stricted educational grant from Octapharma, UK.
Disclaimer
While the advice and information in these guidelines is
believed to be true and accurate at the time of going to

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