PLATELET DISORDERSPLATELET DISORDERS

Nazzal Bsoul,MDNazzal Bsoul,MD

HEMOSTASIS-1HEMOSTASIS-1 In health hemostasis ensures that the blood In health hemostasis ensures that the blood remains fluid and contained in the vasc.system.remains fluid and contained in the vasc.system.If a vessel wall is damaged,a number of If a vessel wall is damaged,a number of mechanisms are activated promptly to limit mechanisms are activated promptly to limit bleeding,involvingbleeding,involving

1-Endothelial cells.1-Endothelial cells.2-Plasma coag.factors.2-Plasma coag.factors.3-Platelets.3-Platelets.4-Fibrinolytic system.4-Fibrinolytic system.

HEMOSTASIS-2HEMOSTASIS-2These activities are finely balanced between keeping the These activities are finely balanced between keeping the blood fluid and preventing intravasc.thrombosis.blood fluid and preventing intravasc.thrombosis.

1-Primary hemostasis: vasoconstriction and platelet adhe- 1-Primary hemostasis: vasoconstriction and platelet adhe-

sion and aggregation leading to the formation of thesion and aggregation leading to the formation of the platelet plug.platelet plug.2-Secondary hemostasis: involves activation of coag.sys-2-Secondary hemostasis: involves activation of coag.sys- tem leading to the generation of fibrin strands and tem leading to the generation of fibrin strands and reinforce the platelet plug.reinforce the platelet plug.3-Fibrinolysis: activation of fibrin-bound plasminogen 3-Fibrinolysis: activation of fibrin-bound plasminogen

resulting in clot lysis.resulting in clot lysis.

ROLE OF PLATELETS IN ROLE OF PLATELETS IN HEMOSTASISHEMOSTASIS

1.1. Each megacaryocyte produces 1000-2000 Each megacaryocyte produces 1000-2000 platelets,which platelets,which

2.2. Remain in the circulation for about 10 days. Remain in the circulation for about 10 days.

3.3. Releasing of hemostatic proteins.Releasing of hemostatic proteins.4.4. Platelet adhesion.Platelet adhesion.5.5. Platelet aggregation.Platelet aggregation.

Clinical Features of Bleeding Clinical Features of Bleeding DisordersDisorders

Platelet Coagulation disorders factor disorders

Site of bleeding Skin Deep in soft tissues Mucous membranes (joints, muscles) (epistaxis, gum, vaginal, GI tract)

Petechiae Yes No

Ecchymoses (“bruises”) Small, superficial Large, deep

Hemarthrosis / muscle bleeding Extremely rare Common

Bleeding after cuts & scratches Yes No

Bleeding after surgery or trauma Immediate, Delayed (1-2 days), usually mild often severe

Classification of platelet Classification of platelet disordersdisorders

Quantitative Quantitative disordersdisorders

– Abnormal distributionAbnormal distribution– Dilution effectDilution effect– Decreased Decreased

productionproduction– Increased Increased

destructiondestruction

Qualitative disordersQualitative disorders

– Inherited disorders Inherited disorders (rare)(rare)

– Acquired disordersAcquired disordersMedicationsMedicationsChronic renal failureChronic renal failureCardiopulmonary Cardiopulmonary bypassbypass

ThrombocytopeniaThrombocytopenia

Immune-mediated:IdioapthicDrug-inducedCollagen vascular diseaseLymphoproliferative diseaseSarcoidosis

Non-immune mediated:DICMicroangiopathic hemolytic anemia

IDIOPATHIC THROMBOCYTOPENICIDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)PURPURA (ITP)

Idiopathic Thrombocytopenic Idiopathic Thrombocytopenic Purpura (ITP)Purpura (ITP)

Idiopathic thrombocytopenic purpura (ITP,Idiopathic thrombocytopenic purpura (ITP, also referred to as immune thrombo-also referred to as immune thrombo- cytopenic purpura) is an acquired cytopenic purpura) is an acquired disorder.There are 2 diagnostic criteriadisorder.There are 2 diagnostic criteria 1-Thrombocytopenia,with otherwise normal1-Thrombocytopenia,with otherwise normal blood counts,including bl.filmblood counts,including bl.film 2-No clinically apparent associated conditions2-No clinically apparent associated conditions that may cause thrombocytopenia.that may cause thrombocytopenia.

ITP: is an ITP: is an isolatedisolated,,unexplainedunexplained thrombocyto-thrombocyto- peniapenia..

PathogenesisPathogenesis

Is related to peripheral PLT destructionIs related to peripheral PLT destruction only ?. only ?.

Is related to a combination of increasedIs related to a combination of increased PLT destruction along with inhibition PLT destruction along with inhibition of megakaryocyte PLT productionof megakaryocyte PLT production

Clinical ManifestationsClinical Manifestations

There is marked interpatient variability.There is marked interpatient variability.Bleeding: can range from severe bleeding Bleeding: can range from severe bleeding

to only petechiae and easy bruising.to only petechiae and easy bruising. Usually mucocutaneous bleeding.Usually mucocutaneous bleeding.

Comparison to vasculitic purpura: Comparison to vasculitic purpura: asymptomatic and not palpable.asymptomatic and not palpable.

Intracranial hemorrhage is uncommon. Intracranial hemorrhage is uncommon.

Incidence of adult ITP increases Incidence of adult ITP increases with agewith age

Incidence (per 105 / year)

Age (yrs) Female Male Total

15-39 2.3 1.3 3.640-59 3.2 1.1 4.360+ 4.6 4.4 9.0

Total 10,1 6,8 16,9

Frederiksen and Schmidt, Blood 1999:94;909

Initial Treatment of ITPInitial Treatment of ITPPlatelet count Symptoms Treatment (per µl)

>50,000 None None

20-50,000 Not bleeding NoneBleeding Steroids

IVIG

<20,000 Not bleeding SteroidsBleeding IVIG

Treatment of ITPTreatment of ITPSteroids:Prednisolone.Steroids:Prednisolone.

Dexamethasone.Dexamethasone. Methyleprednisolone-Pulse therapy.Methyleprednisolone-Pulse therapy.

Splenectomy.Splenectomy.Intravenous immunoglobulin (IVIG).Intravenous immunoglobulin (IVIG).Other immunosuppressive drugs: myco-Other immunosuppressive drugs: myco-

phenolate,azathioprine(imuran)phenolate,azathioprine(imuran)Rituximab (Mabthera).Rituximab (Mabthera).Thrombopoiesis-stimulating agents.Thrombopoiesis-stimulating agents.Recombinant FVIIa.(NOVOSEVEN).Recombinant FVIIa.(NOVOSEVEN).

Second-line TreatmentSecond-line Treatment

Splenectomy ?Splenectomy ?Rituximab (Mabthera) ?Rituximab (Mabthera) ?Thrombopoiesis-stimulating agents ?Thrombopoiesis-stimulating agents ?

Second-line ManagementSecond-line Management

Splenectomy: traditional second-line Splenectomy: traditional second-line treatment for many years.treatment for many years. It remains the most effective treatmentIt remains the most effective treatment with the highest rate of complete andwith the highest rate of complete and durable remissions.durable remissions.

Thrombopoiesis-stimulating agents: Thrombopoiesis-stimulating agents: support the PLT count as long as theysupport the PLT count as long as they are continued,but do not induce are continued,but do not induce remissions.Romiplostin,Eltrombopag.remissions.Romiplostin,Eltrombopag.

Rituximab (Mabthera)Rituximab (Mabthera)

May induce lower frequency of durable May induce lower frequency of durable remissions than splenectomy,but remissions than splenectomy,but avoidance of surgery may be the preferred avoidance of surgery may be the preferred choice for some patientschoice for some patients..

Platelet transfusionsPlatelet transfusions

SourceSource– Platelet concentrate (Random donor)Platelet concentrate (Random donor)– Pheresis platelets (Single donor)Pheresis platelets (Single donor)

Target levelTarget level– Bone marrow suppressed patient (>10-20,000/Bone marrow suppressed patient (>10-20,000/µµl)l)– Bleeding/surgical patient (>50,000/Bleeding/surgical patient (>50,000/µµl)l)

THROMBOCYTOSISTHROMBOCYTOSIS

THROMBOCYTOSISTHROMBOCYTOSIS

PLT Count :150,000-450,000/microLPLT Count :150,000-450,000/microL.. ThrombocytosisThrombocytosis::

11--Reactive (secondary): Reactive (secondary): due to other due to other conditions conditions..

22--Primary:Primary: due to a clonal (neoplastic due to a clonal (neoplastic,, autonomous)hematologic autonomous)hematologic

disorder disorder..

DEFINITIONSDEFINITIONS

Reactive thrombocytosis(RT)Reactive thrombocytosis(RT): thrombo: thrombo-- cytosis in the absence of a MPD/MDScytosis in the absence of a MPD/MDS..

) ) recent surgery,bact.inf.,traumarecent surgery,bact.inf.,trauma.(.(Autonomous thrombocytosis (AT)Autonomous thrombocytosis (AT): thrombo: thrombo--

cytosis in the presence of a chr.MPD orcytosis in the presence of a chr.MPD or MDS.(E.T.,CML,PMF,PV)MDS.(E.T.,CML,PMF,PV)..

Essential thrombocythemia(E.T.)Essential thrombocythemia(E.T.)::Extreme thrombocytosisExtreme thrombocytosis: PLT count more: PLT count more

than 1,000,000 /microLthan 1,000,000 /microL . .

Causes of RTCauses of RTRTRT is a much more frequent cause of thrombo is a much more frequent cause of thrombo - -

cytosis than AT even when cases of extremecytosis than AT even when cases of extreme thrombocytosis are consideredthrombocytosis are considered..

Causes of RTCauses of RT:: Infection- 31%Infection- 31%

Infection plus postsurgical status - 27%Infection plus postsurgical status - 27% Postsurgical status - 16%Postsurgical status - 16%

Malignancy - 9%Malignancy - 9% Postsplenectomy state - 9%Postsplenectomy state - 9%

Acute blood loss or iron deficiency - 8%Acute blood loss or iron deficiency - 8%

GLANZMANN’S GLANZMANN’S THROMBASTHENIA THROMBASTHENIA

(GT)(GT)

Background-1Background-1Glanzmann’s Thrombasthenia (GT): is Glanzmann’s Thrombasthenia (GT): is

the third most common inherited the third most common inherited bleeding disorder in Jordanbleeding disorder in Jordan11 . .

Was first described by Dr.Eduard Glanz-Was first described by Dr.Eduard Glanz- mann in 1918mann in 191822. .

1-Awidi AS.Thromb Haemost. 1984 Jul 29; 51 (3): 331-3.1-Awidi AS.Thromb Haemost. 1984 Jul 29; 51 (3): 331-3. 2-Nurden AT. Thromb Haemost 1999: 82: 468-80.2-Nurden AT. Thromb Haemost 1999: 82: 468-80.

Background-2Background-2Is inherited in an autosomal recessive manner.Is inherited in an autosomal recessive manner.The genes of both of these proteins are on The genes of both of these proteins are on chromosome 17.chromosome 17.Different genetic mutations of either GP IIb or Different genetic mutations of either GP IIb or IIIa genes result in a heterogeneity of IIIa genes result in a heterogeneity of thrombasthenia phenotype.thrombasthenia phenotype.Carrier detection in GT is important to control the Carrier detection in GT is important to control the disease in family members. disease in family members.Can be acquired as an autoimmune disorder.Can be acquired as an autoimmune disorder.

Pathophysiol. Haemost. Thromb. 32 (5-6): 216-7.Pathophysiol. Haemost. Thromb. 32 (5-6): 216-7.Br. J. Haematol. 127 (2): 209-13.Br. J. Haematol. 127 (2): 209-13.

PathogenesisPathogenesisPlatelet glycoprotein IIb/IIIa (GP IIb/IIIa)Platelet glycoprotein IIb/IIIa (GP IIb/IIIa)

complex is deficient or present butcomplex is deficient or present but dysfunctional.dysfunctional.

Defect in the GP IIb/IIIa complex leads toDefect in the GP IIb/IIIa complex leads to defective platelet aggregation anddefective platelet aggregation and subsequent bleeding.subsequent bleeding.

Aggregation of PLTs occurs in response toAggregation of PLTs occurs in response to ristocetin, but not to other agonists ristocetin, but not to other agonists such as ADP, thrombin, collagen orsuch as ADP, thrombin, collagen or epinephrine.epinephrine.

George JN, Caen JP, Nurden AT.Blood 1990: 75: 1383-95.George JN, Caen JP, Nurden AT.Blood 1990: 75: 1383-95.Nurden AT. Thromb Haemost 1999: 82: 468-80.Nurden AT. Thromb Haemost 1999: 82: 468-80.

FrequencyFrequencyIs quite rare globally, but quite commonIs quite rare globally, but quite common

in Jordan.in Jordan.More common in populations where con-More common in populations where con-

sanguineous marriages are commonsanguineous marriages are common ( Iran,Israel,French Gypsies ).( Iran,Israel,French Gypsies ).

Slightly higher female preponderance.Slightly higher female preponderance.F/M ratio is 2:1 in Jordanians.F/M ratio is 2:1 in Jordanians.

Nurden AT. Orphanet J Rare Dise. Apr 6 2006;1:10.Nurden AT. Orphanet J Rare Dise. Apr 6 2006;1:10. Awidi AS.Awidi AS.Am J HematolAm J Hematol. 1992 May ;40 (1) :1-4.. 1992 May ;40 (1) :1-4.

Clinical ManifestationsClinical ManifestationsCommon: mucocutaneous bleeding at Common: mucocutaneous bleeding at

birth or early infancy(gum bleeding,birth or early infancy(gum bleeding, epistaxis)epistaxis)

Rare: muscle hematoma and hemarthrosisRare: muscle hematoma and hemarthrosisCannot be distinguished from other cong.Cannot be distinguished from other cong.

platelet function defects.platelet function defects.

Diagnostic FeaturesDiagnostic FeaturesNormal PLT count and morphology.Normal PLT count and morphology.Greatly prolonged bleeding time.Greatly prolonged bleeding time.Absence of PLT aggregation in response Absence of PLT aggregation in response

to ADP,collagen,epinephrine or thrombinto ADP,collagen,epinephrine or thrombin (Platelet aggregation test) (Platelet aggregation test)

Flow cytometry (CD 41,CD 61).Flow cytometry (CD 41,CD 61).Studies of GP IIb/IIIa receptors on the PLTStudies of GP IIb/IIIa receptors on the PLT

membrane.membrane.

TreatmentTreatmentNo effective treatment for G.T other than platelet No effective treatment for G.T other than platelet

transfusion was available till 1996.transfusion was available till 1996.With time most patients become refractory to platelets. With time most patients become refractory to platelets. Successful treatment for G.T with rFVIIa in 1996.Successful treatment for G.T with rFVIIa in 1996.Canadian pilot study and additional case studies.Canadian pilot study and additional case studies.Recently EMEA has approved recombinantRecently EMEA has approved recombinant

Factor VIIa (NovoSeven) for treatment of GTFactor VIIa (NovoSeven) for treatment of GT

Levy-Toledano S et al. Blood 1978; 51: 1065-71.Levy-Toledano S et al. Blood 1978; 51: 1065-71.Poon M-C et al. Blood 1999; 94: 3951–3.Poon M-C et al. Blood 1999; 94: 3951–3.

THANK YOUTHANK YOU