Platelet disorders
Dr. Klara Vezendi Szeged University Transfusiology Department
Hemorrhagic platelet disorders are caused by ! either quantitative deficiency of of circulated platelets (thrombocytopenia, thrombocytosis) ! a qualitative defect in platelet function or
combination of both. ! a combination Symptoms ! spontaneous cutaneous and mucosal bleeding and purpura ! prolonged bleeding follo"ing trauma and surgery.
Hemorrhagic platelet disorders are caused by ! either quantitative deficiency of of circulated platelets (thrombocytopenia, thrombocytosis) ! a qualitative defect in platelet function or
combination of both. ! a combination Symptoms ! spontaneous cutaneous and mucosal bleeding and purpura ! prolonged bleeding follo"ing trauma and surgery.
#. $uantative platelet disorders
%ormal platelet count &'(() '*( ! +*( , '( -l.
Thrombocytopenia is is defined as a platelet count is less than &'(() '*( , '( -l.
Thrombocytosis platelet platelet count is / +*( +*( , '(-l.
With normal platelet function, thrombocytopenia is rarely the cause of bleeding unless the count is less than 50 x 10 !l.
0auses of thrombocytopenia 1. •
1nsufficient platelet production –
2ultilineage bone marro" failure
–
Selective mega3aryocyte &2K) disruption
&leu3emia4 lymphoma4 myelofibrosis4 aplastic anemia4 carcinoma4 cytomegalovirus infection) &viral infections4 gold therapy4 alcohol into,ication4 amega3aryocytic thr.!penia)
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Hereditary thrombocytopenia &5ernard!Soulier4 6is3ott!#ldrich sy.)
•
Platelet se7uestration &hypersplenism due to portal hypertension or infiltrative disease)
0auses of thrombocytopenia 11. •
1ncreased peripheral platelet destruction –
#utoimmune 1TP4 S89
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#lloimmune post!transfusion purpura4 neonatal
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–
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Drug!induced heparin!induced
thrombocytopenia4 antibiotics
:ver consumption D104 TTP4 HUS4 e,tracorporal circulation
:ther –
Dilution &massive transfusion)
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#rtifactual &in vitro platelet clumping)
1mmune thrombocytopenic purpura &1TP) "athophysiology# formation of auto$ antibodies againts specific membrane glycoproteins &;P11a4 11b or 1b). The autoantibodies coated platelets are phagocytized by <9S. 1ncreased destruction of platelets combined "ith inade7uate compensation by the bone marro" results in thrombocytopenia.
%linical forms# ! acute 1TP often follo"s a viral illness4 mostly in children4 mild and self!limited and uncommonly re7uires specific therapy. ! chronic 1TP more commonly in adults4 moderate to severe thrombocytopenia "ith clinical findings that re7uire medical treatment.
&iagnosis# re7uires re7uires the e,clusion of other diseases associated "ith thrombocytopenia &e. g. leu3emia4 thrombotic thrombocytopenic purpura TTP4 drug reactions and myelodysplastic syndrome).
'aboratory# thrombocytopenia large4 immature platelets are often in peripheral blood smear 5one marro" 2K!s are present Platelet! associated 1g; antibodies in the serum test sensitivity =-!>>? negative negative result does not rule out the diagnosis.
%linical features# platelet!type &mucosal) bleeding4 @"et purpuraA and the absence of splenomegaly supports the diagnosis. leeding is often less pronounced than in cases of decreased production ith similar platelet counts.
Peripheral blood smear of a patient "ith 1TP decreased number of platelets and a large platelet in the middle.
5one marro" 2K!s are present.
1TP @"et purpuraA
*reatment# is necessary in the asymptomatic patient "ith platelet count B+( ,'(-l4 in the symptomatic patient +(!*( ,'(-l. 0orticosteroid prednisone prednisone &D '!C mg3gday)4 response rate *(!>(? -
Splenectomy if if steroid is ineffective after +!> months. 8aparoscopic mode4 C!+ "ee3s before operation Pneumococcal vaccination.
> ? -
High dose iv. gammaglobuline &1V1;) ' g3gday for C to + days -
-
alloimmune Post!transfusion purpura alloimmune !'( days after platelet transfusion severe thrombocytopenia. "athophysiology# "latelet$specific antibodies in the recipient+s serum F most fre7uently against HP#!'a antigen. Patients become sensitized to platelet antigen from prior transfusion of platelet!containing products or from pregnancy. This e,plains the much higher incidence among "omen. *reatment# 1V1; &=(( &=(( mg3gday for * days or ' g3gday for C days)4 plasmapheresis #dditional platelet transfusions can "orsen the thrombocytopeniaG urther transfusions should be "ashed or HP#!'a antigenFnegative.
%eonatal alloimmune thrombocytopenia &%#1T) a potentially severe disease caused by fetomaternal incompatibility for platelet specific antigens. "athogenesis# it it is due to the presence of fetal platelet!specific antigens &HP#! 'a) that are not e,pressed on maternal platelets. #s a result of fetomaternal bleeds4 fetal platelets entry into the maternal circulation alloantibodies alloantibodies are produced by the mother. These antibodies cross the placenta and destroy fetal platelets thrombocytopenia4 ris3 of intracranial hemorrhage. *reatment# in utero transfusion of HP#!'a !negative platelets. etal scalp vein platelet count estimations at the time of delivery to determine the mode of delivery &cesarean sectionI).
Heparin!induced thrombocytopenia &H1T) Type 1 "ithin the first days after e,posure to heparin4 is a non$immune disorder4 and it occurs "ith the direct effect heparin &platelet agglutination). %o clinical conse7uences. #bout '( ? of patients receiving heparin.
of
Type 11 -$10 days after heparin treatment4 is is an immune$mediated disorder. "athophysiology# antibody formation against the heparin! platelet factor = comple,. The antibodies bind to the surface of platelets and induce their activation and activate endothelial cells thrombosis &is usually venous DVT4 P94 rarely arterial stro3e4 21)
%o bleeding. The mortality rate is appro,imately C(?. ncidence# (4+!+?4 most commonly "ith unfractionated heparin4 has no relation to the heparin dose.
&iagnosis of /* *ype # mostly clinical. &e,pensive4 high 8aboratory serotonin serotonin release assay &e,pensive4 sensitivity and specificity)4
heparin!induced platelet aggregation test lo" sensitivity4 high specificity) H1P# lo"
*reatment# $ stop heparin ! use alternative anticoagulants direct thrombin inhibitors &argatroban4 hirudin) anti Ja drugs &danaparoid) oral anticoagulants
Drug induced purpuras &Vancomycin)
Thrombotic microangiopathies microangiopathies TTP4 HUS #cute4 fulminant disorders characterized by thrombocytopenia and microangiopathic hemolytic anemia. Pathophysiology is the same4 clinical picture is different.
Thrombotic thrombocytopenic purpura &TTP4 2oschco"itz syndrome) 1. •
pentad of signs# signs# –
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thrombocytopenia microangiopathic hemolytic anemia
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fever
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renal dysfunction
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neurologic signs.
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clinical triad# –
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thrombocytopenia red cell fragments &schistocytes) increased lactate dehydrogenase &8DH)
Thrombotic thrombocytopenic purpura &TTP4 2oschco"itz syndrome) 11. %auses# recently lin3ed to the inhibition of the $ 1diopathic is recently the enzyme #D#2TS'+ by antibodies & autoimmune disease). #D#2TS'+ is a metalloprotease responsible responsible for the brea3do"n of v6 . Very large v6 molecules are more prone to lead to coagulation .
! Secundary =( ? of all cases of TTP 0ancer4 bone marro" transplantation4 pregnancy4 H1V! infection4 drugs &7uinine4 platelet aggregation inhibitors ticlopidine4 clopidogrel4 immunosuppressants).
*reatment# plasma e,change &=(!>( ml3gday) immunosuppressive drugs &glucocorticoids4 vincristine4 cyclophosphamide)
Hemolytic uremic syndrome &HUS4 ;asser disease) 1t is a disease "ith hemolytic hemolytic anemia4 acut renal failure &uremia) and thrombocytopenia. 1t 1t predominantly but not e,clusively affects children. %auses# ! classical form form -( ? of cases D!HUS &post!diarrhoeal HUS) occurs after bloody diarrhoea caused caused by a strain of 9. coli that that e,presses veroto,in &Shiga!li3e to,in). To,in enters to bloodstream4 attaches to glomerular endothelium renal failure. Damage to blood vessels in all tissues microangiopathies. microangiopathies. #ctivate platelets thrombocytopenia. thrombocytopenia.
acute acute
! less common form '( ? of cases &adult HUS4 familial HUS) %o diarrhoea.
5. $ualitative platelet disorders
$ualitative (functional) platelet disorders are suggested by a prolonged bleeding time &abnormal platelet function screen) or clinical evidence of bleeding in the setting of a normal platelet count and coagulation studies. Platelet dysfunction is fre7uently associated "ith e,cessive bleeding.
Platelet morphology may be characteristic of certain types of the thrombocytopathy
%ormal platelets &peripheral blood smear)
;iant platelets size / <50 <50 ound in increased platelet turnover myeloproliferative sy. 2DS
8arge platelets size <504 but / '+ '+ <50 ound in increased plt. turnover myeloproliferative sy. 2DS 5ernard!Soulier sy. 2ay Hegglin anomaly ;ray platelet sy.
Degranulated4 gray coloured platelets ound in gray platelet sy. discharge of platelet granules ! in vivo &cardiopulmonary bypass4 hairy cell leu3emia)
! in vitro &poor venesection techni7ue) techni7ue
Small platelets ound in 6is3ott #ldrich sy.
unctional platelet disorders •
1. #c7uired common –
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'. Drug induced platelet dysfunction
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11. 1nherited rare (frequency
is probably underestimated because diagnostic difficulties) –
'. #dhesion defects •
C. Disease associated platelet dysfunction
• •
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C. #ggregation defects • •
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;lanzmann thrombasthenia #fibrinogenemia
+. Secretion disorders •
•
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5ernard FSoulier sy. Platelet type v6 0ollagen receptor deficiency
;ranule abnormalities && 4 4 ) Defects of signal transduction
=. Defects of platelet coagulant activity
1. #c7uired disorders of platelet function
1'. Drug induced platelet dysfunction #nalgesics #spirin &irreversible inhibition of cycloo,ygenase 0:J enzym)4 '*!+( min after ingestion =(!'(( mg4 persists =!* days) %onsteroidal anti!inflammatory drugs %S#1Ds &reverzible 0:J inhibition) Ticlopidin &Ticlid)4 clopidogrel &Plavi,) 5loc3 platelet! #DP #DP receptors4 C=!=L hours after ingestion4 persists '( days) ;P11b111a receptor antagonists && ac7uired ac7uired ;lanzmann) Dipyridamol ! 9levates c#2P level P;1C P;1C &prostacyclin) effect inhibits platelet aggregation !lactam antibiotics penicillin4 cephalosporin 0ardiovascular drugs 0a antagonists4 nitroglicerin4 propranolol4 isosorbid dinitrate Psychotropic drugs antidepressants4 phenothiazins :thers plasma e,panders4 antihistamins4 cytostatic agents4 heparin4 fibrinolytics •
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2echanism of antiplatelet agents
1C. Disease associated platelet function disorders •
Uremia complex hemostatic defect –
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Hematopoetic disorders –
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paraproteinemias4 myeloproliferative disorders4 myelodysplastic syndrome4 leu3emia.
0ardiopulmonary bypass operation Platelet antibodies –
•
thrombocytopenia4 platelet dysfunction &adhesion4 aggregation4 secretion defects)4 mild coagulation abnormalities.
auto!4 alloantibodies
:thers –
diabetes mellitus4 liver disease4 D10
unctional platelet disorders •
1. #c7uired common –
–
'. Drug induced platelet dysfunction
•
11. 1nherited rare (frequency
is probably underestimated because diagnostic difficulties) –
'. #dhesion defects •
C. Disease associated platelet dysfunction
• •
–
C. #ggregation defects • •
–
;lanzmann thrombasthenia #fibrinogenemia
+. Secretion disorders •
•
–
5ernard FSoulier sy. Platelet type v6 0ollagen receptor deficiency
;ranule abnormalities && 4 4 ) Defects of signal transduction
=. Defects of platelet coagulant activity
11. 1nherited platelet disorders
11'. #dhesion defects
M 5ernard F Soulier syndrome
M @Platelet typeA &pseudo) v6D M 0ollagen receptor deficiency
5ernard F Soulier syndrome Soulier syndrome irst case# '-=L '-=L &N. 5ernard4 NP Soulier) "athogenesis# absence absence or decreased e,pression of the glycoprotein comple, 2" b$3$4 on the surface of the platelets. &1b 4 1b 4 ;P1J4 ;PV)
# ;P1b is the receptor of von 6illebrand factor deficient binding of v6 to the platelet membrane at sites of vascular inOury4 resulting in defective platelet adhesion.
nheritance# autosomal autosomal recessive ncidence# ' ' million %linical presentation# epista,is4 epista,is4 ecchymoses4 menorrhagia4 gingival bleeding4 gastrointestinal bleeding. 'aboratory findings# ! Prolonged bleeding time ! moderate thrombocytopenia &platelet life time ) platelet aggregation by ristocetin is deficient -
&#DP4 arachidonic acid4 epinephrin4 collagen norm.) -
clot retraction norm. clot abnormally large platelets &/+4* Em ! C(!+( Em)
@Platelet typeA &pseudo) von 6illebrand disease "athogenesis# de fect of platelet 2"b increased avidity for defect increased normal v6 leading leading to the binding of the largest v6 multimers to resting platelets and to their clearance from the circulation results results thrombocytopenia and adhesion defect. nheritance# autosomal dominant 'aboratory findings# $ prolonged bleeding time ! moderate thrombocytopenia ! loss of large v6 multimers ! enhanced ristocetin!induced platelet aggregation &ifferential dg# from from Type C5 v6D &molecular characterisation of platelet ;P1b )
*reatment# platelet concentrate v6 concentrate.
0ollagen receptor deficiency
"athogenesis# abnormalities of platelet 2"4 and 2"a$a &receptors for collagen) defect of adhesion and collagen!induced platelet defect aggregation.
11C. Platelet aggregation defects
M ;lanzmanns thrombasthenia M #fibrinogenemia
;lanzmanns thrombasthenia "athogenesis# abnormalities of platelet 2"b$a &fibrinogen &fibrinogen receptor) platelets platelets less able to adhere to each other and to the underlying tissue of damaged blood vessels.
irst case# '-'L '-'L &;lanzmann) nheritance# autosomal autosomal recessive manner *ypes# Type ' absence of ;P11b!111a & *?) Type C reduced surface e,pression of ;P11b!111a &'(!C(?) 9ssentialis athrombia clot retraction is normal Type + dysfunction of ;P11b!111a
'aboratory features# !! normal platelet count and morphology ! platelet aggregation occurs in response ristocetin4 but not to other agonists &such as #DP4 thrombin4 collagen or epinephrine). ! clot clot retraction in absent
ymptoms# mucocutaneous mucocutaneous bleeding in the neonatal period4 menorrhagia4 ecchymoses4 epista,is4 gingival hemorrhage.
#fibrinogenemia nheritance# autosomal autosomal recessive4 incidence# 'C 'C million "athogenesis# f f ibrinogen ibrinogen helps platelets to glue together to form the initial QplugA in response to an inOury in afibrinogenemia combined bleeding disorder because both platelets and clotting are abnormal. 'aboratory findings# ! absence of f ibrinogen ibrinogen from the blood ! abnormal platelet aggregation4 bleeding time4 #PTT4 PT4 TT ! may be moderate thrombocytopenia %linical symptoms# bleeding umbilical cord4 bruising4 nosebleeds4 gastrointestinal bleeding4 miscarriage4 e,cessive bleeding after inOury or surgery.
11+. #bnormalities of platelet secretion M #. #bnormalities of platelet granules gray platelet sy4 V $uebec4 Nacobsen! Paris! Trousseau sy. storage storage pool deficiency4 Hermans3y!Pudla3 sy4 0hedia3!Higashi4 6is3ott!#ldrich4 T#< and combined combined deficiency
M 5. #bnormalities of the signal transduction and secretion abnormalities of the arachidonatethrombo,ane #C path"ay
Platelet ultrastructure
# #bnormalities of platelet granules 1. bnormalities o f platelet $ granules of $ granules# M ;ray platelet syndrome very rare disorder "athogenesis# mar3ed decrease or absence of platelet $ granules and of platelet$specific $ granule proteins no P=4 T;4 PD; secretion ymptoms# lifelong lifelong mild or moderate mucocutaneous bleeding tendency. "latelet morphology# large and contain fe" granules4 giving them a gray appearance in light microscopy microscopy "ith the 2ay!;rn"ald!;iesma stained blood film.
M $uebec platelet disorder &V $uebec) "athogenesis# abnormal proteolysis of $granule proteins &V4 fibrinogen4 thrombospondin4 multimerin4 v64 P! selectine)4 probably is due to u!P# activity. irst case '-= &Tracy) nheritance# autosomal autosomal dominant 'aboratory findings# moderate moderate thr. penia4 normal plazma V activity4 decreased platelet!V activity4 normal platelet V antigen. Uro3inase!plasminogen activator &u!P#) e,pression . %ormal morphology of
!granules.
ymptoms# severe post!traumatic bleeding manifestations4 unresponsive to platelet transfusion. *herapy# antifibrinolytic agent.
M Nacobsen !Paris!Trousseau syndrome "athogenesis# platelets platelets have giant $ granules4 "hich are unable to release their content upon platelet stimulation. Deletion of the distal part of chromosome ''. irst case# '-+ '-+ &Nacobsen)
# #bnormalities of platelet granules 11.
bnormalities of platelet &elta ( , dense) $ granules# M Storage pool disease isolated deficiency of $ granules in mega3aryocytes and platelets. 1nheritance autosomal recessive or dominant. 2ild to moderate bleeding tendency.
M Hermans3y!Pudla3 syndrome 1nheritance autosomal recessive 5leeding diathesis. $granules deficiency 6 others# oculocutaneous albinism &strabism4 &decreased pigmentation F s3in4 hair)4 eye problems photophobia4 nystagmus4 impaired vision)4 inflammatory bo"el disease4 progressive pulmonary fibrosis &maOor complication4 fetal).
Hermans3y Pudla3 syndrome &oculocutaneous albinism)
M 0hedia3!Higashi syndrome
&ecrease in platelet $ granules, partial oculocutaneous albinism4 dysfunctional neutrophils "ith giant lysosomal granules4 abnormal natural 3iller cell function4 impaired bacteriolysis recurrent pyogenic infections. recurrent 2ild bleeding diathesis.
M 6is3ott!#ldrich syndrome
%linical symptoms# microthrombocytopenia4 bleedings4 immunodeficiency, e,tensive ec7ema, recurrent recurrent infections &due to impaired function of lymphocytes and neutrophils)4 malignancy &lymphoma4 leu3emia). 2ilder form of the disease @J!lin3ed thr. peniaA &"ithout immunodeficiency and eczema).
6is3ott #ldrich syndrome
Small platelets in blood film.
" rognosis poor. rognosis# poor. The average individual lives about >4* years years those "ho survive into adolescence often develop cancer. Death usually occurs from severe bleeding or over"helming infection in the first fe" years of life. *reatment# $ transfusions of platelets ! antibiotics ! iv. infusions of immune globulin ! splenectomy &severe thrombocytopenia "ith bleeding) ! bone marro" transplantation "ith H8#! identical marro" ;ene therapy is promising.
M Thrombocytopenia absent radius &T#< ) syndrome syndrome "athogenesis# a congenital malformation syndrome characterised by bilateral absence of the radii and a thrombocytopenia. nheritance# autosomal autosomal recessive. ncidence# ''(((((
8ther findings# hypomega3aryocytic neonatal thrombocytopenia &due to defective4 thrombopoiesis)4 granules granules deficiency4 other abnormalities gastrointestinal4 s3eletal4 hematologic4 cardiac system.
8o"er limb involvement in t"o children "ith "ith T#< syndrome.
ymptoms# easy bruising4 hemorrhage &the maOor cause of mortality). The The incidence of hemorrhage is limited to the first '= months of life.
5 Defects of intracellular signal transduction and secretion #bnormalities of the arachinodatethrombo,ane #C path"ay path"ay platelet function defects4 mild bleeding. M 1mpaired liberation of #rachidonic acid from membrane phospholipids M 0ycloo,ygenase deficiency &@aspirin li3e diseaseA) M Thrombo,ane synthetase deficiency M Thrombo,ane #C receptor abnormalities
11=. Disorders of platelet procoagulant activity M Scott syndrome rare bleeding disorder. nheritance# autosomal autosomal recessive "athogenesis# is lin3ed to the lac9 of exposure of procoagulant phosphatidylserine (") to the external leaflet of the plasma membrane of activated platelets and other hematologic lineages impaired impaired thrombin formation. ymptoms# defective defective "ound healing4 bleeding tendency.
Treatment of 7ualitative platelet disorders 1. •
Desmopressin &DD#VP) is a vasopressin analog4 improves hemostasis "ithout the ris3s of transfusion. 1t releases V111 and large multimeres of v6 from tissue stores. –
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1neffective in patients "ith Scott syndrome and ;lanzmanns thrombasthenia. %o in Pseudo &platelet type) v6D.
Transfusion of normal platelets –
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D (4+!(4= Eg3g &in *( ml %a0l infusion4 during '*!+( min).
D '9'( 3g &pooled)4 (4* ,'( '' thr'( thr'( 3g &apheresis) 1t should be reserved for life!threatening bleeding because of the divelopment of alloantibodies. 5ecause bleeding is a lifelong problem4 H8#!matched platelets should be considered &apheresis).
rV11a in severe bleeding &D -( Eg3g)
Treatment of 7ualitative platelet disorders 11. •
#dOuvant treatment –
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8ocal hemostatic agents #ntifibrinolytic agent &trane,amic acid) &the only effective treatment of patients "ith V $uebec disorder)
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Hormonal control of menses &oral contraceptives)
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1ron supportation &if necessary)
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0orticosteroids are not beneficial.
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Some patients patients "ill re7uire stem cell transplantation.
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#void drugs "ith antiplatelet effectG
