My Patient is Thrombocytopenic
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My patient is thrombocytopenic!Is (s)he? Why? And what shall I do?A practical approach to thrombocytopenia
L. Alberio
Department of Haematology and Central Haematology Laboratory, Inselspital, Bern University Hospital and Universityof Bern, Switzerland
KeywordsThrombocytopenia
SummarySolving the riddle of a thrombocytopenicpatient is a difficult and fascinating task. The
spectrum of possible aetiologies is wide,ranging from an in vitro artefact to severetreatment-resistant thrombocytopenic bleed-ing conditions, or even life-threatening pro-thrombotic states. Moreover, thrombocyto-penia by itself does not protect from throm-bosis and sometimes a patient with a lowplatelet count requires concomitant anti-thrombotic treatment as well. In order toidentify and treat the cause and the effects ofthe thrombocytopenia, you have to put to-gether several pieces of information, solving
a unique jig-jaw puzzle.The present work is not a textbook articleabout thrombocytopenia, rather a collectionof differential diagnostic thoughts, treatmentconcepts, and some basic knowledge, thatyou can retrieve when facing your nextthrombocytopenic patient. Enjoy reading it,but most importantly enjoy taking care of pa-tients with a low platelet count. I bet thepresent work will assist you in this challen-ging and rewarding clinical task.
SchlsselwrterThrombozytopenie
ZusammenfassungDas Rtsel eines thrombozytopenischenPatienten zu lsen, ist eine schwierige und
faszinierende Aufgabe. Das Spektrum dermglichen tiologien ist breit und reicht voneinem In-vitro-Artefakt bis zu behandlungs-resistenten thrombozytopenischen Blutun-gen oder sogar zu lebensbedrohlichen pro-thrombotischen Zustnden. Auerdemschtzt eine Thrombozytopenie an sich nichtvor Thrombosen und manchmal bedarf einPatient mit niedriger Plttchenzahl auch ei-ner begleitenden antithrombotischen Thera-pie. Um die Ursache und Effekte der Throm-bozytopenie zu identifizieren und zu behan-
deln, sind unterschiedliche Informationen zu-sammenzufgen, damit das einmalige Puzzledes Patienten gelst werden kann.Diese Arbeit ist kein Lehrbuchartikel berThrombozytopenie, eher eine Sammlung vondifferenzialdiagnostischen Gedanken, Be-handlungskonzepten und einigen Grundla-gen, die Sie abrufen knnen, wenn Sie dennchsten thrombozytopenischen Patientenbegegnen. Genieen Sie das Lesen und freu-en Sie sich vor allem, Patienten mit niedrigerPlttchenzahl zu betreuen. Ich wette, dassdiese Arbeit Sie bei der anspruchsvollen und
dankbaren klinischen Aufgabe untersttzt.
Correspondence to:
Lorenzo Alberio, M.D.Department of Haematology and Central HaematologyLaboratory, University Hospital Inselspital3010 Bern, SwitzerlandTel. +41/31/632 35 13, Fax+41/31/632 34 06E-mail:[email protected]
Mein(e) PatientIn hat eine Thrombozytopenie!
Ist es so? Warum? Und, was soll ich machen?
Hmostaseologie 2013; 33: 8394
DOI:10.5482/HAMO-13-01-0003
received: January 14, 2013accepted in revised form: March 13, 2013prepublished online: March 27, 2013
This article is intended to be used as a va-demecum when facing a thrombocyto-penic patient. You can read it and enjoy itsitting at your desk, but more usefully youcan open it on your tablet and jump fromone section to the other while evaluating
your patients condition. Section 1 will illustrate the clinical prob-
lem-solving approach I employ in myeveryday practice.
Section 2 will describe some peculiardifferential diagnostic thoughts.
Section 3 will briefly summarize themost relevant aspects of some aetiol-ogies of thrombocytopenia (highlightedby * in the text), listed in alphabeticalorder for better consultation.
Section 4 will handle some generalmanagement options.
Section 5 will offer you something tothink about.
Finally, I have tried to list useful referencesfor a more in depth reading, mostly includ-ing review articles and a few illustrativecase reports.
Section 1:Clinical problem solving
There are three key questions when ap-proaching a thrombocytopenic patient(14):1. Is there really thrombocytopenia?2. In case of true thrombocytopenia, what
is its underlying cause?3. Does this type of thrombocytopenia
require urgent treatment?
As a first step, it is therefore necessary toexclude a pre-analytic problem (e. g., amissmatch between tube and patient or in
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vitro platelet activation/aggregation due toinadequate anticoagulation of the bloodsample) and to exclude *pseudo-throm-bocytopenia by reviewing the blood smear.Inspection of blood cells morphology willalso reveal some important clues to the ori-
gin of the thrombocytopenia. Additionally,the clinical context in which thrombocy-topenia does occur, its timing and degree,and its clinical presentation will furthernarrow the differential diagnostic thinkingand allow you to proceed in a rational,cost-effective manner (Tab. 1).
Review the blood film
There are several clues to be looked for(Tab. 2).
Platelet aggregates and satellitism(platelets attaching to the surface of neut-rophils and monocytes) will indicate*pseudo-thrombocytopenia.
In the presence of platelet aggregates only,one should also consider the rare conditionof *von Willebrand disease type 2B (VWD
2B) and the even rarer *platelet-type VWD.Next, it is essential to assess platelet mor-phology:
small platelets will point to *Wiskott-Aldrich syndrome (WAS) and *X-linkedthrombocytopenia (XLT);
giant platelets with the size of red cellsor even larger are characteristic for*Bernard-Soulier syndrome (BSS) andthe family of *myosin heavy chain 9 re-lated diseases (MYH9-RD);
large platelets will suggest *immunethrombocytopenia (ITP);
pale gray platelets result from congenital(e.g., *gray platelet syndrome) or ac-quired (e. g., myelodysplastic syn-dromes, MDS) absence of alpha-gran-ules; in addition to being hypogranular
MDS-platelets may have highly variablesize and giant platelets may be seen.
Of note, automated platelet indices, such asmean platelet volume (MPV) and plateletsize deviation with (PDW), may providehelpful information in order to distinguishhyper-destructive from hypo-productivethrombocytopenias (5).
Red blood cell morphology will revealsome clinically relevant aetiologies:
The presence of micro-spherocytes ischaracteristic of autoimmune-mediatedhaemolytic anaemia which in combi-nation with (immune-mediated)
thrombocytopenia is diagnostic ofEvans syndrome. However, micro-spherocytes may be also present inthrombotic microangiopathies.
Red blood cell fragments (named frag-mentocytes or schistocytes) are pathog-nomic for a mechanical destruction,such as it occurs in micro-angiopathichaemolytic anaemias (MAHA) amongthem thrombotic-thrombocytopenicpurpura/haemolytic uremic syndrome(TTP/HUS) *disseminated intravas-
cular coagulation (DIC), dysfunctionalheart valves, hypertensive crises andothers.
Macrocytosis suggests vitamin B12/folate-deficiency or MDS.
Dacryocytes (teardrop-shaped redblood cells) are typical of myelofibrosis.
Intracellular organisms are diagnosticfor e. g. malaria (6) or babesiosis (7).
Finally, white blood cells shall be examin-ed.
In neutrophils,
light blue-violet cytoplasmic inclu-sions, 1 to 2 m in diameter (Dhle-like bodies) are typical for the *May-Hegglin anomaly and other*MYH9-RD;
hypolobulated neutrophils (pseudoPelger-Hut anomaly) are indicativeof MDS;
toxic granulation and bacteria inclu-sions, e. g. Capnocytophaga canimor-sus(8), reveal sepsis.
Intracellular morulae in granulocytes or
mononuclear phagocytes suggest ehrli-chiosis (9).
Atypical lymphocytes can point to aviral infection or a lymphoproliferativesyndrome as the underlying cause ofthrombocytopenia.
One also has to carefully look for blasts(MDS, acute leukaemia).
Tab. 1
Thrombocytopenia:stepwise approach
stepkey questions
review the blood film
consider the clinicalcontext
timing/degree ofthrombocytopenia
take a detailed history
examine the patient
ask for initiallaboratory tests
1. Is there really a thrombocytopenia?2. What is the underlying cause?3. Is urgent treatment required?
Tab. 2
Tab. 3
text
Tab. 4
skin: petechiae? telangiectasias? jaundice?erythema?
type of bleeding? (muco-cutaneous?soft tissues? joints?)
retinal bleeding? skin necrosis? limb ischaemia? thrombosis? organomegaly? (lymph nodes, spleen, liver) heart murmurs? syndromic features? (Tab. 5)
complete blood count, peripheral blood smear global coagulation assays, D-dimers serum creatinine, LDH, bilirubin, gamma-GT,
ALAT, ASAT
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Deviations from these expected patternsshould be recognized and prompt theevaluation of alternative aetiologies, in par-ticular
*HIT,
other *DITP,
sepsis, and
*DIC.
Consider timing anddegree of the thrombocytopenia
After major surgery, platelet counts typi-cally decline quickly and reach their nadirwithin 1 to 4 days due to consumption anddilution (10), and immediately after mass-ive transfusion platelet counts may drop aslow as 50 G/l (11).
L. Alberio: A practical approach to thrombocytopenia
Consider the clinical context
The diagnostic thinking differs widely ac-cording to the clinical scenario (1, 3, 4)(Tab. 3).
Among ambulatory patients the mostfrequent causes are
*drug-induced thrombocytopenia(DITP) and
*ITP.
However, ITP is a diagnosed by exclusionand other options have to be considered aswell:
infections (e. g., HIV, HCV, CMV, EBV,Helicobacter pylorii);
connective tissue disorders (e.g., sys-temic lupus erythematodes, rheumatoidarthritis, antiphospholipid syndrome);
hypersplenism (e. g., following portalhypertension in liver cirrhosis or in caseof a splenic lymphoma);
primary marrow disorders;
*congenital thrombocytopenia;
common variable immunodeficiency.
Among acutely ill patients frequentaetiologies are
*DIC,
infection/sepsis,
*DITP,
*heparin-induced thrombocytopenia
(HIT), TTP/HUS, and
*post-transfusion purpura (PTP).
Frequent causes of thrombocytopeniaamong cardiac patients are
cardiac by-pass surgery,
*HIT,
*thrombocytopenia induced by glyco-protein (GP) IIb-IIIa inhibitors,
seldom TTP related to clopidogrel.
The differential diagnosis of a thrombo-cytopenic patient with thrombosis includes
*HIT, which is the most frequently en-countered diagnosis in this context,
anti-phospholipid syndrome (APS) and
paroxysmal nocturnal haemoglobinuria(PNH).
As for the differential diagnosis of throm-bocytopenia in intensive care patients,pregnant women and neonates the readeris referred toSection 2.
Tab. 2Thrombocytopenia:clues on the blood film
blood cells
platelets
redbloodcells
whitebloodcells
AIHA: autoimmune haemolytic anaemia; BSS: Bernard-Soulier syndrome;DIC: disseminated intravascular coagulation; ITP: immune thrombo-cytopenia; LPS: lymphoproliferative syndromes; MDS: myelodysplasticsyndromes; MYH9-RD: myosin heavy chain 9 related disorders;PMN: polymorphonuclear neutrophils; TTP: thrombotic thrombocyto-penic purpura; XLT: X-linked thrombocytopenia; VWD: von Willebranddisease
clue
aggregates
rosettes around PMN,
monocytessmall platelets
giant / large platelets
pale, gray platelets
micro-spherocytes
fragmentocytes
macrocytes
tear-drop shaped red bloodcells
nucleated red blood cells
inclusions
PMN
monocytes, inclusions(morulae)
atypical lymphocytes
blasts
blue-violet cyto-plasmic inclusions
hypolobulated nuclei
toxic granulations
inclusions (morulae)
aetiology
*pseudothrombocytopenia
*type 2B VWD, *platelet-type VWD
*pseudothrombocytopenia
*Wiskott-Aldrich syndrome,*XLT
*BSS, *MYH9-RD, *ITP,MDS
*Gray platelet syndrome,MDS
AIHA, thrombotic micro-angiopathies
thrombotic microangio-pathies, *DIC
Vit. B12/folate deficiency,MDS
myelofibrosis
haemolytic anaemia,myelofibrosis
malaria, babesiosis
*May-Hegglin anomaly,*MYH9-RD
MDS
sepsis
human granulocytotropicehrlichiosis
human monocytotropicehrlichiosis
viral infection, LPS
MDS, acute leukaemia
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In patients with *DITP the decrease of theplatelet count typically occurs within 13weeks after starting a new drug or within23 days (sometimes just a few hours) ofreceiving a drug that has been taken pre-viously (4). The thrombocytopenia is mod-erate to severe and it usually resolves in
510 days after drug withdrawal. Two pe-culiar cases of DITP are HIT and throm-bocytopenia induced by GPIIb-IIIa in-hibitors.
*HIT classically develops after exposureto heparin for 510 days and reaches a pla-telet count nadir at 70 G/l. Early-onset HIT,a few hours after the first administration ofheparin, may occur among patients with ahistory of heparin exposure in the priorthree months and is due to circulating anti-PF4/heparin antibodies (12). Finally, also a
delayed-onset form of HIT has been de-scribed, presenting 520 days after stop-ping heparin therapy and caused by hightitres of platelet activating HIT-antibodies(13, 14).
Severe thrombocytopenia, usually
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cases *BSS or *MYH9-RD, misdiagnosedas *ITP and unnecessarily treated accord-ingly, even with splenectomy: see (31, 32)and secondary citations listed in (33).
Investigating 35 patients with inheritedmacro-thrombocytopenias and 56 withITP at the same institution, Norris et al.confirmed the knowledge that platelet sizeis significantly larger in the former groupand conclude that combining microscope
evaluation of the mean platelet diameterwith the value of MPV obtained by an op-tical counter represents a powerful tool fordistinguishing inherited macro-throm-bocytopenias from ITP (33). From a practi-cal point of view they also show that bothimpedance and to a lesser extent (32) optical cell counters overestimate the de-gree of thrombocytopenia and underesti-mate the MPV, particularly in subjects withmacro-thrombocytopenias.
immunoassay for anti-PF4/heparinantibodies (30).
Finally, if the aetiology of the throm-bocytopenia is unclear or a bone mar-row disorder is suspected, a bone mar-row biopsy and aspirate should be per-formed (with additional sampling forflow cytometric analysis, cytogeneticsand/or microbiological investigations,as required).
Section 2: Some differen-tial-diagnostic challengesDistinguishing inherited macro-thrombocytopenias from ITP
This differential diagnosis is challengingand not without clinically relevant conse-quences. In fact, several publications reportthe recurrent observation of patients with a*congenital thrombocytopenia, in most
L. Alberio: A practical approach to thrombocytopenia
The presence of an ischaemic limb or skinnecrosis should raise suspicion of *HIT.During the physical examination oneshould also look for specific signs of anunderlying condition causing thrombo-cytopenia: e. g.,
skeletal abnormalities in syndromiccongenital thrombocytopenias(Tab. 5);
enlarged lymph nodes and spleen inlymphoma;
splenomegaly, telangiectasias, palmarerythema, jaundice and other stigmataof chronic liver disease in cirrhosis;
heart murmur in a dysfunctional aorticvalve.
Ask for laboratory tests
The initial laboratory assessment shouldinclude an automated complete bloodcount (other cytopenias?, lymphocytosis?)with inspection of the blood smear, globalcoagulation studies including D-dimers(*DIC?), serum creatinine, LDH, bilirubin(total and direct), gamma-GT, ALAT, andASAT (haemolysis?, hepatopathy?).According to the clinical context and thefirst laboratory results subsequent testingcould be more specific. For instance:
If haemolysis is suspected one should
ask for direct antiglobulin test (Coombstest), reticulocytes, haptoglobin,hydroxy-butyrate-dehydrogenase(HBDH), urinanalysis (where urobili-nogenuria would point to an extrava-scular haemolysis, while haemo-globinuria and/or haemosiderinuriawould indicate an intravascular one).
In case of suspected substrate deficien-cy, assess serum vitamin B12 and folatelevels.
When considering a viral aetiology, test
for HIV, hepatitis, CMV and EBV. Initial serologic testing for suspected
connective tissue disorders are ANAand anti-ds-DNA; with lupus antico-agulant, anti-cardiolipin and anti-2-glycoprotein I antibodies for APS.
In case of suspected immunodeficiencyassess quantitative immunoglobulin lev-els and T-cell subsets.
When considering *HIT one should de-fine its pre-test probability and combineit with the semi-quantitative result of an
Tab. 4Thrombocytopenia:history taking
questions to be asked
previous blood counts
bleeding history
family history of thrombo-cytopenia / bleeding
recurrent infections
cataracts, deafness,nephropathy
autoimmune disorders
previously diagnosedhaematologic diseases
recent live virus vaccination
recent new drug /medications
recent infection
recent travel
pregnancy
recent transfusion of bloodproducts
dietary habits
review hospital charts
CVID: common variable immunodeficiency (see: Salzer et al. Common vari-able immunodeficiency an update. Arthritis Res Ther 2012; 14: 223)
information
pre-existing versus acquired thrombo-cytopenia
congenital thrombocytopenia (Tab. 5)
syndromic thrombocytopenia (Tab. 5),CVID
syndromic thrombocytopenia(Tab. 5)
acquired thrombocytopenia, CVID
acquired thrombocytopenia
alloimmunization
alcohol?, quinine?, substrate deficiency?
drugs?, heparin?, antibiotics?, medicine-containing materials used in surgery?(e. g., vancomycine in joint replacementcement)
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Thrombocytopenia in the intensivecare unit
Thrombocytopenia is present in about1565% of patients at some point during
the stay in intensive care unit (10, 34, 35).Many potential aetiologies e. g., sepsis,*DIC, drugs, surgery, transfusions of bloodproducts, decreased platelet productiondue to pre-existing disorders are con-comitantly present in this setting and it isnot always possible to identify the real cul-prit.
*DITP develops in up to 25% of acutely illpatients and should always be considered.
Potential offending drugs should be ident-ified, their causative likelihood estimatedand suspect drugs should be discontinuedor substituted based on individual clinical
risk/benefit assessment (36). In this regard,consider that antibiotics are a frequent aeti-ology (36) and that likelihood of *HITshould be assessed with the aid of a semi-quantitative immunoassay for anti-PF4/heparin antibodies (30). Finally, it is impor-tant to consider rare causes of thrombo-cytopenia, such as *PTP.
Differential diagnosis of maternalthrombocytopenia in pregnancy
During pregnancy the platelet countslightly decreases, resulting at term in levels
about 10% lower than pre-pregnant counts.This is thought to be the consequence ofdilution, accelerated platelet destruction inthe often damaged trophoblast surface ofthe placenta and because of increased invivo thrombin generation (37). Throm-bocytopenia is fairly common in pregnan-cy, occurring in 710% of pregnantwomen. Overall, cases are due to
gestational thrombocytopenia (75%),
1520% secondary to hypertensivedisorders,
Tab. 5 Congenital thrombocytopenias; adapted from (44, 48)
platelet size
large
normal
small
AD: autosomal dominant; AR: autosomal recessive; CYCS: somatic cytochrome c (gene); FLNA: filamin A (gene); GPIb: glycoprotein Ib; ITGA2: integrinalpha 2 (gene); ITGB3: integrin beta 3 (gene); MYH9-RD: myosin heavy chain 9 related disorders; THC: thrombocytopenia; TUBB1: beta1-tubulin (gene)
disease
*Bernard-Soulier syndrome
*MYH9-RD
dyserythropoietic anaemia withthrombocytopenia
X-linked thrombocytopenia withthalassemia
Paris-Trousseau thrombocytopenia,Jacobsen syndrome
*gray platelet syndrome
sitosterolaemia
*platelet-type von Willebrand disease
ITGA2/ITGB3-related thrombocytopenia
TUBB1-related macrothrombocytopenia
FLNA-related macrothrombocytopenia
*ANKRD26-RD (THC2)
congenital amegakaryocyticthrombocytopenia
congenital amegakaryocytic thrombo-cytopenia with radio-ulnar synostosis
familial platelet disorder and predisposi-tion to acute myelogenous leukaemia
thrombocytopenia with absent radii
CYCS-related thrombo-cytopenia (THC4)
*Wiskott-Aldrich syndrome
*X-linked thrombocytopenia
inheritance
AR AD
AD
X-linked
X-linked
AD
AR
AR
AD
AD
AD
X-linked
AD
AR
AD
AD
AR
AD
X-linked
X-linked
syndromic (and other) features
none
leukocytes inclusions, cataracts, nephropathy, deafness
anaemia from mild to severe, red blood cells anisopoikilocytosis;(reduced GPIb in large platelets)
haemolytic anaemia, unbalanced globin chain synthesis resemblingalpha-thalassemia; splenomegaly
cardiac and facial defects, developmental delay other defects
none; (pale platelets, myelofibrosis, splenomegaly, high serum vit. B12)
stomatocytosis, possible anaemia, tendon xanthomas, atherosclerosis
none
none
none
possible periventricular nodular heterotopia, bone dysplasia, mentalretardation other malformations
none; (risk of leukaemia?)
none; (reduced megakaryocytes, evolution into bone marrow aplasia)
radio-ulnar synostosis other defects; (reduced megakaryocytes,possible evolution into aplastic anaemia)
development of leukaemia or MDS in 40% of patients
bilateral radial aplasia other malformations; (platelet count tends torise and often normalizes in adult life, reduced megakaryocytes)
none
severe immunodeficiency, eczema
none or mild immunodeficiency
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89L. Alberio: A practical approach to thrombocytopenia
34% due to immune processes and
the remaining 12% made up constitu-tional thrombocytopenias, infectionsand malignancies (37).
The first key initial assessment is a blood
film to confirm genuine thrombocytopeniaand exclude the presence of microangio-pathy, which would point to an obstetricemergency (e. g., HELLP syndrome, pre-eclampsia, TTP/HUS).
Gestational thrombocytopenia causesmild thrombocytopenia, usually >70G/l, occurs in the latter half of pregnan-cy, from mid-second or third trimester,is not associated with maternal bleed-ing, and spontaneously resolves shortlyafter delivery, usually very quickly and
within 12 months in all cases. *ITP can occur at any time during preg-
nancy, is the most frequent cause of alow platelet count in the first and sec-ond trimester, frequently reaches pla-telet counts
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Drug-induced thrombocytopenia
The basic pathophysiological mechanismof drug-induced thrombocytopenia(DITP) is accelerated platelet destructioncaused by drug-dependent antibodies. At
least two mechanisms are responsible forthe formation of pathogenic antibodies:
Reversible drug binding to surface GP(most commonly GPIb-V-IX or GPIIb-IIIa) induces the exposure of immuno-genic new epitopes.
The drug itself becomes an integral partof the new epitope (4, 27).
DITP can be confirmed by the demonstra-tion of drug-dependent platelet antibodiesin vitro (52). This requires the continual
presence of the suspected drug duringreaction, because drug association withplatelets is mediated by noncovalent bind-ing and the drugs are easily dissociated byin vitro washing procedures.
Glycoprotein IIb-IIIa inhibitors
Severe thrombocytopenia is observed in0.12% of patients after exposure to GPIIb-IIIa inhibitors (abciximab, eptifibatide, ti-rofiban). This phenomenon is thought tobe caused by naturally occurring anti-
bodies directed against ligand-induced epi-topes on the fibrinogen receptor (15, 16,53).
Gray platelet syndrome
This is an autosomal dominant thrombo-cytopenia associated with enlarged pla-telets, mild bleeding due to absent orgreatly reduced alpha-granules, and earlyonset of myelofibrosis (47).
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia (HIT)is a prothrombotic and potentially fatalside effect of heparin-treatment unfrac-tionated and low molecular weight hepa-rins, and possibly fondaparinux as well (54) mediated by platelet-activating anti-bodies directed against multi-molecularcomplexes of platelet factor 4 (PF4) and he-parin. Management involves cessation ofany heparin, initiation of an alternative
anticoagulant (e. g., danaparoid, argatro-ban), and avoidance of vitamin-K antago-nists in the acute phase, because of the highrisk of inducing coumarin necrosis (alsonamed: venous limb gangrene) (55).
Immune thrombocytopenic purpura
Primary immune thrombocytopenic pur-pura (ITP) is an acquired immune-me-diated disorder characterized by isolatedthrombocytopenia and absence of anyidentifiable causes of thrombocytopenia.Treatment is rarely required in asympto-matic patients with a platelet count >2030G/l. When treatment is necessary, initialimmunosuppressive management is by glu-cocorticoids, with the administration of
tranexamic acid and/or intravenousimmunoglobulins in order to controlbleeding. For glucosteroid-resistant pa-tients there are several second-line options,including rituximab, thrombopoietin(TPO) receptor agonists (eltrombopag,romiplostim), and splenectomy (38, 56).
Myosin heavy chain 9 relateddiseases
Myosin heavy chain 9 related diseases(MYH9-RD) are the autosomal dominant
syndromic macro-thrombocytopenias de-riving from mutations in the gene for theheavy chain of the non-muscle myosin IIA.The term MYH9-RD encompasses fourthrombocytopenias, previously describedas distinct entities:
May-Heggelin anomaly,
Sebastian platelet syndrome,
Fechtner syndrome, and
Epstein syndrome.
The clinical phenotype is characterized by
congenital macro-thrombocytopenia, oftenDhle-like inclusions in neutrophils, anda variable risk of developing proteinuricnephropathy, sensorineural deafness and/or cataract (44).
Neonatal alloimmunethrombocytopenia
Neonatal alloimmune thrombocytopenia(NAIT) is the most common cause of se-vere thrombocytopenia and intracerebral
haemorrhage (ICH) in term neonates.NAIT results from trans-placental passageof maternal antibodies directed against apaternally derived fetal platelet antigen. Incontrast to haemolytic disease of the new-born, NAIT can present in a first pregnan-
cy, and subsequent ones are usually moreseverely affected. Clinical presentationvaries from asymptomatic thrombocytope-nia to disabling ICH (41).
Post-transfusion purpura
Post-transfusion purpura (PTP) is a raretransfusion reaction occurring in patientssensitized by previous pregnancies ortransfusions (male to female ratio about1 : 25) after administration of platelet-con-
taining blood products, such as red cells,platelets, or granulocyte concentrates (17,57). Thrombocytopenia in PTP is me-diated by patients alloantibodies directedagainst specific antigens of transfused pla-telets, most frequently HPA-1a (HPA-1b,HPA-5/5b and other platelet antigens aremuch less common). Despite the fact thatthe patients platelets do not display the tar-get antigen, they are destroyed as innocentbystander by a poorly understood mech-anism; current hypotheses:
The patients platelets adsorb immune
complexes and are destroyed. An autoantibody is elaborated in re-
sponse to the foreign protein.
The antigen is passively acquired fromdonor plasma.
The diagnosis of PTP is confirmed byshowing that the patient has a circulatingalloantibody to a common platelet antigen,most often against HPA-1a, and that thepatients own platelets lack this antigen.Thrombocytopenia in PTP is severe,
usually
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91L. Alberio: A practical approach to thrombocytopenia
and/or transfusion of HPA-1a negative pla-telets. Of note, some case reports describePTP induced by transfused alloantibodiesdirected against patients antigens, thesecases are best reported as passive alloimunethrombocytopenia (59, 60).
Platelet-type VWD
Platelet-type VWD is characterized bygain-of-function mutations of the genescoding for GPIb-V-IX, leading to increasedinteractions with plasmatic VWF. Theclinical phenotype (mild bleeding, largeplatelets, thrombocytopenia sponta-neous/under stress, reduction of high mo-lecular weight VWF multimers) is similarto type 2B VWD (47).
Pseudo-thrombocytopenia
This is a laboratory artefact caused by invitro platelet aggregation due to naturallyoccurring antibodies directed against epi-topes on GPIIb-IIIa (1, 61). Such epitopesare normally hidden but become expressedupon calcium chelation by EDTA and de-creasing blood sample temperature. In onestudy, 15.3% of ambulatory patients withisolated thrombocytopenia had pseudo-thrombocytopenia (62). A saw-teeth ap-
pearance of the platelet volume curve on thegraphical output from automated haematol-ogy analyzers suggests this condition, whichcan be confirmed by visual inspection of theblood smear and by measuring the plateletcount in a citrated blood sample (61).
VWD type 2B
VWD 2B is characterized by mutationswithin the VWF-gene leading to an in-creased binding with GPIb-V-IX-complex
on the platelet surface. The clinical pheno-type (mild bleeding, large platelets, throm-bocytopenia spontaneous/under stress,reduction of high molecular weight VWFmultimers) is similar to platelet-type VWD(47).
Wiskott-Aldrich syndrome andX-linked thrombocytopenia
Wiskott-Aldrich syndrome (WAS), aX-linked recessive disease, combines
thrombocytopenia and small platelets witheczema, recurrent infections due to im-mune deficiency and an increased risk forautoimmunity and malignancy.
A milder form without the immuneproblems is known as hereditary X-linked
thrombocytopenia (XLT). Both WAS andXLT are mediated by mutations in theWAS gene, which encodes WASp, a signal-ing protein involved in cytoskeleton func-tions (47).
Section 4: Generalmanagement options
In this section I will describe some generaltreatment concepts. For the specific man-
agement of a given thrombocytopenic dis-order the reader is referred to the publi-cations listed in the bibliography. Note thatthe degree of thrombocytopenia by itselfdoes not predict bleeding and young pla-telets in hyper-regenerative thrombocyto-penic states, such as ITP or bone marrowregeneration after intensive chemotherapy,are considered haemostatically more effi-cient than platelets in hypo-regenerativestates.
Tranexamic acidTranexamic acid (TXA) is a synthetic ana-logue of the amino acid lysine, which pre-vents dissolution of the fibrin clot. It acts asan antifibrinolytic by two mechanisms:
TXA forms a reversible complex withplasminogen, displacing it from fibrinand thus decreasing its activation byt-PA (tissue plasminogen activator).
TXA also blocks the proteolytic activityof plasmin.
TXA is widely used to stabilize clotting invarious bleeding disorders and traumaticbleeding (63, 64). We successfully employTXA to prevent bleeding, particularlymuco-cutaneous bleeding, in thrombo-cytopenic disorders as well. A rationale forthis use is the initial antifibrinolytic actionof platelets in the forming fibrin clot (65)and the observation that fibrin-boundplasminogen inhibits the binding of leuko-cytes and platelets on the clot surface (66).TXA would substitute for the missing in-
itial anti-fibrinolytic action of platelets and,by preventing plasminogen binding to fi-brin, it would enhance platelet-mediatedstabilization and growth of the formingclot.
Additionally, TXA counteracts the later
onset of platelet profibrinolytic effects onthe growing thrombus (65). The use ofTXA in thrombocytopenic patients is safe(67) and published clinical evidence existsfor the management of menorrhagia, gen-erally and in chemotherapy-inducedthrombocytopenia (68, 69); for Quebecplatelet disorder (70); and hereditaryhaemorrhagic teleangiectasia (71).
Desmopressin
Desmopressin (1-deamino-8-D-argininevasopressin, DDAVP) is a synthetic ana-logue of vasopressin, which exerts an anti-diuretic action and is employed for treat-ment of diabetes insipidus and nocturia.Because of its ability to promote release ofVWF (and t-PA) from Weibel-Paladebodies of endothelial cells DDAVP is alsoemployed, at a dose of 0.3 g/kg bodyweight, for treating VWD type 1, mildhaemophilia A and platelet disorders (72).
Recombinant activated humanfactor VII
Recombinant activated human factor VII(rFVIIa) is licensed for treating bleeding inhaemophilia patients with inhibitors and inpatients with Glanzmann thrombasthenia(73). rFVIIa binds to tissue factor (TF) ex-posed at sites of injury and promotesthrombin generation independently fromfactor VIII and IX. At high concentrationsrFVIIa also binds to activated platelets.There is evidence that rFVIIa is able to
control bleeding in platelet function defects(73, 74) and we have shown that rFVIIa, ata low dose of 60 g/kg body weight, is effi-cacious and safe in controlling massivebleeding, even in thrombocytopenic pa-tients (75). We have successfully employedrFVIIa in severe cases of treatment-refrac-tory *ITP as well (unpublished). It appearsthat low doses of rFVIIa do not signifi-cantly increase the thrombotic risk (75, 76).
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92 L. Alberio: A practical approach to thrombocytopenia
Platelet transfusion
Most of the evidence for platelet trans-fusion therapy derives from studies con-ducted in patients with chemotherapy-in-duced thrombocytopenia (2). In these pa-
tients the platelet trigger for prophylacticplatelet transfusion is generally set at aplatelet count of 10 G/l (77). At our institu-tion, the transfusion policy is even morerestrictive with a threshold set at
5 G/l in patients without fever or bleed-ing,
10 G/l in patients with fever, and
20 G/l in those with bleeding signs (78).
High-quality evidence is lacking to guideplatelet transfusion practice in non-oncol-
ogy patients. Published guidelines indicatea transfusion trigger of 50 G/l for patientswho have overt bleeding or who require aninvasive procedure (2).
Antithrombotic treatment
A low platelet count does not protectagainst thrombosis and is generally not areason to withhold antithrombotic therapy.Based on published experience Arnold andLim propose that anticoagulation is likelyto be safe for most patients with platelet
counts above 30 G/l (2). At our institutionwe have the following platelet countthresholds:
20 G/l for anticoagulation of in-hospitalpatients with chemotherapy-inducedthrombocytopenia,
2030 G/l for anticoagulation in out-patients,
30 G/l for single-agent anti-platelettreatment,
50 G/l for double anti-platelet treat-ment.
If necessary and based on an individualizedrisk/benefit assessment, platelet count canbe raised with TPO receptor agonists(eltrombopag, romiplostim), as in the caseof patients with hepatitis C in order toallow treatment with interferon and riba-virin (79).
Section 5: For your thinking
Why do we have so many platelets whenin fact 510% of the normal number aresufficient for adequate haemostasis (4)?
Is this just redundancy in the bodys
haemostatic system or do platelets haveother physiological roles?
If the question intrigues you, read for in-stance following publications (8083). Youwill discover that platelets play a relevantrole e. g. in pulmonary vascular physio-pathology (80), angiogenesis (81), inflam-mation and immune response (82), and inmediating viral clearance (83).
ConclusionEvaluating a thrombocytopenic patient is adifficult and fascinating task, like solving aunique jig-jaw puzzle. History taking, clini-cal examination skills, asking for and inter-preting laboratory tests, your knowledge,clinical experience and way of thinking areall required to make a good diagnosis andimplement the optimal management. Thiswork shall assist you in this challengingand rewarding clinical task.
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