Chapter 25: Bleeding disorders  /  281

Thrombocytopenia
Abnormal bleeding associated with thrombocytopenia or
abnormal platelet function is characterized by spontaneous
skin purpura (Fig. 25.3) and mucosal haemorrhage and pro-
longed bleeding after trauma (Table 25.1). The main causes of
thrombocytopenia are listed in Tables 25.3 and 25.4.

Failure of platelet production

This is the most common cause of thrombocytopenia and
is usually part of a generalized bone marrow failure (Table
All rights reserved. May not be reproduced in any form without permission from the publisher, except fair uses permitted under U.S. or applicable copyright law.

25.3). Selective megakaryocyte depression may result from

drug toxicity or viral infection. Rarely it is congenital as a
result of mutation of the c‐MPL thrombopoietin receptor
or of the RBM8A gene in association with absent radii. It is (a) (b)
also seen in the May–Hegglin anomaly with large inclusions
Figure 25.3  (a) Typical purpura; and (b) massive subcutaneous
haemorrhage in a patient with drug‐induced thrombocytopenia.

Table 25.3  Causes of thrombocytopenia. in granulocytes, or in Wiskott–Aldrich syndrome (WAS)

with eczema and immune deficiency (see Chapter 8). WAS
Failure of platelet production
is caused by mutation of the WASP gene, the protein being
Selective megakaryocyte depression
a regulator of signalling in haemopoietic cells. Diagnosis of
  rare congenital defects (see text)
  drugs, chemicals, viral infections
these causes of thrombocytopenia is made from the clini-
Part of general bone marrow failure cal history, peripheral blood count, the blood film and bone
  cytotoxic drugs marrow examination.
  radiotherapy
  aplastic anaemia
  leukaemia
  myelodysplastic syndromes
  myelofibrosis
 marrow infiltration (e.g. carcinoma, lymphoma, Gaucher’s
disease) Table 25.4  Thrombocytopenia as a result of drugs or toxins.
  multiple myeloma
Bone marrow suppression
  megaloblastic anaemia
Predictable (dose‐related)
  HIV infection
  ionizing radiation, cytotoxic drugs, ethanol
Increased consumption of platelets Occasional
Immune  chloramphenicol, co‐trimoxazole, idoxuridine, penicillamine,
  autoimmune organic arsenicals, benzene, etc.
  idiopathic
Immune mechanisms (proven or probable)
 associated with systemic lupus erythematosus, chronic
Analgesics, anti‐inflammatory drugs
lymphocytic leukaemia or lymphoma;
  gold salts
  infections: Helicobacter pylori, HIV, other viruses, malaria
Antimicrobials
  drug‐induced, e.g. heparin
 penicillins, rifamycin, sulphonamides, trimethoprim, para‐
  post‐transfusional purpura
aminosalicylate
  feto‐maternal alloimmune thrombocytopenia
Sedatives, anticonvulsants
Disseminated intravascular coagulation
  diazepam, sodium valproate, carbamazepine
Thrombotic thrombocytopenic purpura
Diuretics
Copyright 2016. Wiley-Blackwell.

Abnormal distribution of platelets   acetazolamide, chlorathiazides, furosemide

Splenomegaly (e.g. liver disease) Antidiabetics
  chlorpropamide, tolbutamide
Dilutional loss
Others
Massive transfusion of stored blood to bleeding patients
 digitoxin, heparin, methyldopa, oxyprenolol, quinine,
HIV, human immunodeficiency virus. quinidine

EBSCO Publishing : eBook Collection (EBSCOhost) - printed on 8/3/2021 8:49 PM via UNIVERSITY OF NEW SOUTH WALES
AN: 1072161 ; A. Victor Hoffbrand, Paul A. H. Moss.; Hoffbrand's Essential Haematology
Account: s9193785.main.ehost
 282  /  Chapter 25: Bleeding disorders

Increased destruction of platelets Pathogenesis

Autoimmune (idiopathic) thrombocytopenic purpura
Autoimmune (idiopathic) thrombocytopenic purpura (ITP)
may be divided into chronic and acute forms.
Chronic idiopathic thrombocytopenic purpura (ITP)
This is a relatively common disorder. The highest incidence has
been considered to be in women aged 15–50 years, although
some reports suggest an increasing incidence with age. It is the
most common cause of thrombocytopenia without anaemia or
neutropenia. It is usually idiopathic but may be seen in associa-
tion with other diseases such as systemic lupus erythematosus
(SLE), human immunodeficiency virus (HIV) infection, viral
hepatitis, Helicobacter pylori infection, chronic lymphocytic
leukaemia (CLL), Hodgkin lymphoma or autoimmune
haemolytic anaemia (Table 25.3).
Platelet autoantibodies, usually IgG, result in the premature
removal of platelets from the circulation by macrophages of the
reticuloendothelial system, especially the spleen (Fig. 25.4). In
many cases, the antibody is directed against the glycoprotein
(GP) IIb/IIIa or Ib complex. The normal lifespan of a platelet
is 10 days but in ITP this is reduced to a few hours. Total meg-
akaryocyte mass and platelet turnover are increased in parallel
to approximately five times normal.
Clinical features
The onset is often insidious with petechial haemorrhage, easy
bruising and, in women, menorrhagia. Mucosal bleeding (e.g.
epistaxes or gum bleeding) occurs in severe cases but fortu-
nately intracranial haemorrhage is rare. The severity of bleeding
in ITP is usually less than that seen in patients with compara-
ble degrees of thrombocytopenia from bone marrow failure;
this is attributed to the circulation of predominantly young,

TPO-RA pathway TPO pathway

Bone marrow

TPO- TPO- Liver

TPO TPO
RA RA
Megakaryocyte

Bloodstream Bloodstream

Protoplatelets
Platelets
Platelets

B lymphocyte

Antibodies

Macrophage

Platelet phagocytosis

Figure 25.4  The pathogenesis of thrombocytopenia in autoimmune thrombocytopenic purpura. Platelets coated by antibodies
are phagocytosed by macrophages. The actions of thrombopoietin (TPO) and thrombopoietin receptor agonists (TPO‐RA)
(thrombomimetics) are shown. These are orally active or given by injection and act to increase platelet production.

EBSCOhost - printed on 8/3/2021 8:49 PM via UNIVERSITY OF NEW SOUTH WALES. All use subject to https://www.ebsco.com/terms-of-use

functionally superior platelets in ITP. Chronic ITP tends to
relapse and remit spontaneously so the course may be diffi-
cult to predict. Many asymptomatic cases are discovered by a
routine blood count. The spleen is not palpable unless there is
an associated disease causing splenomegaly.
Diagnosis  on stopping the therapy.
  1 The platelet count is usually 10–100 × 109/L. The haemo-
globin concentration and white cell count are typically
normal unless there is iron deficiency anaemia because of
blood loss.
  2 The blood film shows reduced numbers of platelets, those
present often being large. There are no morphological ab-
normalities in the other cell lines.
  3 The bone marrow shows normal or increased numbers of
megakaryocytes.
  4 Sensitive tests are able to demonstrate specific anti‐glyco-
protein GPIIb/IIIa or GPIb antibodies on the platelet sur-
face or in the serum in most patients. Platelet‐associated
IgG assays are less specific. These tests are not usually used
in clinical practice.
Treatment
As this is a chronic disease the aim of treatment should be to
maintain a platelet count above the level at which spontaneous
bruising or bleeding occurs with the minimum of intervention.
In general, a platelet count above 20  ×  109/L without symp-
toms does not require treatment.
  1 Corticosteroids Eighty per cent of patients remit on high‐
dose corticosteroid therapy. Prednisolone 1 mg/kg/day is the
usual initial therapy in adults and the dosage is gradually
reduced after 10–14 days. In poor responders the dosage is
reduced more slowly but alternative immunosuppression or
splenectomy is considered.
  2 High‐dose intravenous immunoglobulin therapy is able
to produce a rapid rise in platelet count in the majority
of patients. A regimen of 400 mg/kg/day for 5 days or
1 g/kg/day for 2 days is used. It is particularly useful in
patients with life‐threatening haemorrhage, in steroid‐re-
fractory ITP, during pregnancy or prior to surgery. The
mechanism of action may be blockage of Fc receptors
on macrophages or modification of autoantibody
production.
  3 Monoclonal antibody Rituximab (anti‐CD20) produces
responses in approximately 50%, which are often durable
and it is now usually tried before splenectomy.
  4 Immunosuppressive drugs (e.g. vincristine, cyclophospha-
mide, azathioprine, mycophenolate mofetil or ciclosporin
alone or in combination) are usually reserved for those
patients who do not respond sufficiently to steroids or
rituximab.
  5 Thrombopoietin‐receptor agonists Romiplostim (subcu-
taneously) and eltrombopag (orally) are active non‐pep-
tide thrombopoietin‐receptor agonists (thrombomimetics)
EBSCOhost - printed on 8/3/2021 8:49 PM via UNIVERSITY OF NEW SOUTH WALES. All use subject to https://www.ebsco.com/terms-of-use
Chapter 25: Bleeding disorders  /  283
(Fig. 25.4). They stimulate thrombopoiesis (Fig. 25.5) and
are indicated for patients in whom steroids are contraindi-
cated or who are refractory to steroids. Trials of their use as
initial therapy in combination with corticosteroids are in
progress. Increased reticulin and fibrosis in the bone mar-
row may occur with prolonged treatment but are reversible
  6 Splenectomy With the increase in number of alternative
drugs, splenectomy is now performed less frequently for
ITP than previously. Good results occur in most patients
but in those with ITP refractory to steroids, immunoglob-
ulin or rituximab there may be little benefit. Splenunculi
must be removed otherwise subsequent relapse of ITP
can occur.
  7 Other treatments that may elicit a remission include dana-
zol (an androgen which may cause virilization in women)
and intravenous anti‐D immunoglobulin. It is often nec-
essary to combine two drugs (e.g. danazol and an immu-
nosuppressive agent). Helicobacter pylori infection should
be treated as there are some reports that this may improve
the platelet count, particularly in countries where the inci-
dence of the infection is common. Hepatitis C should also
be treated, if present.
  8 Platelet transfusions Platelet concentrates are beneficial in
patients with acute life‐threatening bleeding but their ben-
efit will only last for a few hours.
  9 Stem cell transplantation has cured some severe cases.
Acute idiopathic thrombocytopenic purpura
This is most common in children. In approximately 75%
of patients the episode follows vaccination or an infection
such as chickenpox or infectious mononucleosis. Most cases
are caused by non‐specific immune complex attachments to
platelets. Spontaneous remissions are usual but in 5–10%
of cases the disease becomes chronic, lasting more than 6
months. Fortunately, morbidity and mortality in acute ITP
is very low. The main risk is of cerebral haemorrhage, fortu-
nately rare. Most children do not have any bleeding even with
platelet counts <10 × 109/L but need to avoid trauma such as
contact sports.
The diagnosis is one of exclusion. If the platelet count is over
30 × 109/L no treatment is necessary unless the bleeding is severe.
Indeed many doctors do not treat even with platelet counts
<10 × 109/L if there is no haemorrhage. The main risk is of cer-
ebral haemorrhage. Treatment is with steroids and/or intravenous
immunoglobulin, especially if there is significant bleeding.
Infections
It seems likely that the thrombocytopenia associated with
many viral and protozoal infections is immune‐mediated. In
HIV infection, reduced platelet production is also involved
(see p. 328).
 284  /  Chapter 25: Bleeding disorders

Eltrombopag 50 mg daily Post-therapy

240

200

Platelet count (x 109/L)

160

120

80

40

0
1 10 23 38 66 108 178 213 234
Study day

Figure 25.5  Response to eltrombopag in chronic immune thrombocytopenic purpura in a female aged 75 after failure of response to
prednisolone. Source: Courtesy of Professor A. Newland.

Drug‐induced immune thrombocytopenia
An immunological mechanism has been demonstrated as the
cause of many drug‐induced thrombocytopenias (Fig. 25.6).
Quinine (including that in tonic water), quinidine and heparin
are particularly common causes (Table 25.4).
The platelet count is often less than 10 × 109/L, and the
bone marrow shows normal or increased numbers of meg-
akaryocytes. Drug‐dependent antibodies against platelets
may be demonstrated in the sera of some patients. The
immediate treatment is to stop all suspected drugs but plate-
let concentrates should be given to patients with dangerous
bleeding.
Post‐transfusion purpura
This occurs as thrombocytopenia occurring approximately
10 days after a blood transfusion, and has been attributed to
antibodies in the recipient developing against human platelet
antigen‐1a (HPA‐1a) on the transfused platelets (see p. 342)

Antibody–drug–
Drug protein complex

Complement

Plasma
protein

B
cell

Antibody
C
Platelet

Platelet lysis

Figure 25.6  Usual type of platelet damage caused by drugs in which an antibody–drug–protein complex is deposited on the platelet
surface. If complement is attached and the sequence goes to completion, the platelet may be lysed directly. Otherwise it is removed by
reticuloendothelial cells because of opsonization with immunoglobulin and/or the C3 component of complement.

EBSCOhost - printed on 8/3/2021 8:49 PM via UNIVERSITY OF NEW SOUTH WALES. All use subject to https://www.ebsco.com/terms-of-use
 Chapter 25: Bleeding disorders  /  285

Thrombotic thrombocytopenic purpura (TTP)
and haemolytic uraemic syndrome (HUS)
Thrombotic thrombocytopenic purpura (TTP) occurs in famil-
ial or acquired forms. There is deficiency of the ADAMTS13
metalloprotease which breaks down ultra‐large von Willebrand
factor multimers (ULVWF) (Fig. 25.7). In the familial forms more
than 50 ADAMTS13 mutations have been reported whereas
the acquired forms follow the development of an inhibitory
IgG autoantibody, the presence of which may be stimulated by
infection, autoimmune/connective tissue disease, certain drugs,
stem cell transplantation or cardiac surgery. ULVWF multimeric
‘strings’ secreted from Weibel–Palade bodies are anchored to
the endothelial cells, and passing platelets adhere via their GPIb
receptors. Increasing platelet aggregation on to the ULVWF
multimeric strings has the potential to form large occlusive
platelet thrombi. These strings are capable of embolizing to
microvessels downstream and contributing to organ ischemia
(Fig. 25.8). In the closely related haemolytic uraemic syndrome
(HUS), ADAMTS13 levels are normal.

Plasma Endothelial cell

No platelet VWF multimers
aggregation

Protease cleaves
between tyrosine (842) VWF dimers
and methionine (843)
of monomeric substrate
VWF monomers
(a) NORMAL

Platelet VWF multimers

aggregation

Ultra-large
VWF multimers

Protease VWF dimers

Antibody

VWF monomers
(b) ACQUIRED TTP

VWF multimers
Platelet
aggregation

Ultra-large
VWF multimers

VWF dimers
Protease absent
or defective
VWF monomers
(c) FAMILIAL TTP

Figure 25.7  Proposed pathogenesis of thrombotic thrombocytopenic purpura (TTP). Von Willebrand factor (VWF) consists of a series
of VWF multimers each of molecular weight (MW) 250 kDa which are covalently linked. (a) Under physiological circumstances a
metalloprotease ADAMTS13 cleaves high molecular weight multimers at a Tyr‐842–Met‐843 bond and the resulting VWF has an
MW of 500–20 000 kDa. (b) In non‐familial TTP, an antibody develops to the metalloprotease and so blocks cleavage of VWF multimers.
(c) In congenital forms of TTP, the protease appears to be absent. In both cases, the resultant ultra‐large VWF multimers can
bind platelets under high shear stress conditions and lead to platelet aggregation.

EBSCOhost - printed on 8/3/2021 8:49 PM via UNIVERSITY OF NEW SOUTH WALES. All use subject to https://www.ebsco.com/terms-of-use
 286  /  Chapter 25: Bleeding disorders

TTP has traditionally been described as a pentad of

(a)
(b)
Figure 25.8  Thrombotic thrombocytopenic purpura. (a) Platelet
thrombus in a small cardiac vessel with minor endothelial and
inflammatory reaction. Source: Courtesy of Dr J.E. McLaughlin.
(b) Peripheral blood film showing red cell fragmentation.
thrombocytopenia, microangiopathic haemolytic anaemia,
neurological abnormalities, renal failure and fever. The
microvascular thrombosis causes variable degrees of tissue
ischaemia and infarction and is responsible for the micro-
angiopathic haemolytic anaemia and thrombocytopenia
(Fig. 25.8). Thrombocytopenia, schistocytes in the blood film
and an impressively elevated serum lactate dehydrogenase
(LDH) value are sufficient to suggest the diagnosis. The serum
LDH is derived both from ischaemic or necrotic tissue cells
and lysed red cells. Coagulation tests are normal in contrast to
the findings in DIC (see Fig. 26.9). ADAMTS13 is absent or
severely reduced in plasma.
Treatment is with plasma exchange, using fresh frozen
plasma (FFP) or cryosupernatant. This removes the large molec-
ular weight VWF multimers and the antibody and provides
ADAMTS13. The platelet count and serum LDH are useful for
monitoring the response to treatment. Rituximab (anti‐CD20)
is also effective, used in conjunction with plasma infusions or
with plasma exchange, and subsequently for reducing the risk
of relapse. In refractory cases and chronic relapsing cases, high‐
dose corticosteroids, vincristine, intravenous immunoglobulin,
rituximab and immunosuppressive therapy with azathioprine
or cyclophosphamide have been used. In untreated cases mor-
tality may approach 90%. Relapses are frequent.
HUS in children has many common features but organ
damage is limited to the kidneys. There is also usually diar-
rhoea and epileptic seizures may occur. Many cases are asso-
ciated with Escherichia coli infection with the verotoxin 0157
strain or with other organisms, especially Shigella. Supportive
renal dialysis and control of hypertension are the mainstays of
treatment. Platelet transfusions are contraindicated in HUS
and TTP. For atypical HUS, treatment is as for renal failure
but eculizumab (see p. 247) may be added to inhibit comple-
ment activation.

Splenic pool
30% 60%

90%

Circulating platelets
70% 10–40%

Figure 25.9  The platelet distribution between the circulation and spleen in normal individuals (left), and in patients with moderate or
massive splenomegaly (right).

EBSCOhost - printed on 8/3/2021 8:49 PM via UNIVERSITY OF NEW SOUTH WALES. All use subject to https://www.ebsco.com/terms-of-use