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Presentation on theme: 'Hereditary Platelet Function Defects Rob McFarlane, MD January 20, 2006.'— Presentation transcript:

1 Hereditary Platelet Function Defects Rob McFarlane, MD January 20, 2006

Color Atlas of Veterinary Histology, 3e Wiley Desktop Edition Set by William J. See more like this. Color Atlas of Histology. Craigmyle Paperback. 15% off 4+ Buy It Now. Free Shipping. Color Atlas of Histology See more like this. Color Atlas of Hematology: An Illustrated Field Guide Based on Proficiency Testing - PUB210 Eric F. Glassy, MD, FCAP Since its introduction, this outstanding atlas from the CAP Hematology and Clinical Microscopy Resource Committee has proven its value to laboratories around the world.

2 Objectives Review platelet morphology and its role in primary hemostasis Review platelet morphology and its role in primary hemostasis Understand the pathophysiology of the major inherited platelet defects, including: Bernard- Soulier syndrome, Glanzmann’s thrombasthenia, and the storage pool defects Understand the pathophysiology of the major inherited platelet defects, including: Bernard- Soulier syndrome, Glanzmann’s thrombasthenia, and the storage pool defects Understand the laboratory methods used to diagnose and classify the hereditary platelet function defects Understand the laboratory methods used to diagnose and classify the hereditary platelet function defects

3 Primary Hemostasis: The Platelet Anuclear discoid cell (3-5 microns) arising from megakaryocytes in bone marrow Anuclear discoid cell (3-5 microns) arising from megakaryocytes in bone marrow 4-5 day maturation, 9-10 day life span 4-5 day maturation, 9-10 day life span Bilamellar membrane contains multiple invaginations with an open canalicular system: Bilamellar membrane contains multiple invaginations with an open canalicular system: Attached to intracellular dense tubular system, forming an interconnecting network (membrane complex) throughout the cell Attached to intracellular dense tubular system, forming an interconnecting network (membrane complex) throughout the cell Facilitates secretion of granules Facilitates secretion of granules

Cap Color Atlas Of Hematology

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5 Platelet organelles Mitochondria, golgi, ribosomes, peroxisomes, lysosomes Mitochondria, golgi, ribosomes, peroxisomes, lysosomes Two platelet-specific storage granules: Two platelet-specific storage granules: Alpha granules: Platelet Factor 4 (heparin binding chemokine), PDGF, fibrinogen, fibronectin, plasminogen activator inhibitor I (PAI I), Factors V, VIII,and vWF Alpha granules: Platelet Factor 4 (heparin binding chemokine), PDGF, fibrinogen, fibronectin, plasminogen activator inhibitor I (PAI I), Factors V, VIII,and vWF Dense bodies: histamine, epinephrine, serotonin, ADP, calcium Dense bodies: histamine, epinephrine, serotonin, ADP, calcium

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7 Platelet cytoskeleton Composed of cross-linked actin filaments coating the inner surface of the lipid bilayer Composed of cross-linked actin filaments coating the inner surface of the lipid bilayer Regulates the shape of the resting platelet Regulates the shape of the resting platelet Interacts with transmembrane receptors Interacts with transmembrane receptors Platelet activation, intracellular protein phosphorylation cascade and subsequent contraction leads to extrusion of platelet organelles Platelet activation, intracellular protein phosphorylation cascade and subsequent contraction leads to extrusion of platelet organelles

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9 Platelet morphology Numerous G-protein receptors or adhesion receptors (integrins) are present on the cell surface Numerous G-protein receptors or adhesion receptors (integrins) are present on the cell surface transmembrane heterodimers composed of alpha and beta subunits, responsible for adhesion and signal transduction transmembrane heterodimers composed of alpha and beta subunits, responsible for adhesion and signal transduction Glycoproteins are designated I (large) to IX (small); a and b were added when electrophoretic techniques allowed for resolution of single bands to separate bands Glycoproteins are designated I (large) to IX (small); a and b were added when electrophoretic techniques allowed for resolution of single bands to separate bands

10 Glycoprotein receptors GP Ib-V-IX; complex of four gene products, serves as a receptor for vWF; adhesion; Bernard-Soulier GP Ib-V-IX; complex of four gene products, serves as a receptor for vWF; adhesion; Bernard-Soulier GP IIb-IIIa; most abundant, recognizes four adhesive receptors: fibrinogen, fibronectin, vitronectin, and vWF; aggregation; Glanzmann’s GP IIb-IIIa; most abundant, recognizes four adhesive receptors: fibrinogen, fibronectin, vitronectin, and vWF; aggregation; Glanzmann’s Others: Others: GP Ia, IIa; GP VI: collagen receptors GP Ia, IIa; GP VI: collagen receptors

11 Primary hemostasis Extremely dynamic, complicated, and continuous interaction between vessel, platelet, and plasma components Extremely dynamic, complicated, and continuous interaction between vessel, platelet, and plasma components Adhesion, Activation (Secretion), Aggregation Adhesion, Activation (Secretion), Aggregation

12 Adhesion Vascular injury exposes the pro-coagulant components of the sub-endothelial extracellular matrix: collagen, proteoglycans, and fibronectin Vascular injury exposes the pro-coagulant components of the sub-endothelial extracellular matrix: collagen, proteoglycans, and fibronectin Platelets are exposed to these components in a rolling fashion Platelets are exposed to these components in a rolling fashion vWF acts as an adhesion bridge between the platelet GP Ib-V-IX complex and exposed collagen; platelets also adhere to fibronectin vWF acts as an adhesion bridge between the platelet GP Ib-V-IX complex and exposed collagen; platelets also adhere to fibronectin However, vWF-GPIb bridge is the only association strong enough to overcome blood flow shearing force However, vWF-GPIb bridge is the only association strong enough to overcome blood flow shearing force

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14 Secretion Shape change via cytoskeletal activation: spherical with extending pseudopods Shape change via cytoskeletal activation: spherical with extending pseudopods Platelet granules are released thru canalicular system Platelet granules are released thru canalicular system Cytoplasmic activation of eicosanoid pathway (TXA2), decreased cAMP, and mobilization of Ca++ Cytoplasmic activation of eicosanoid pathway (TXA2), decreased cAMP, and mobilization of Ca++ Phospholipids are translocated to cell surface membrane (phosphatidylserine) Phospholipids are translocated to cell surface membrane (phosphatidylserine) Binding surface for factor Va and Xa (along with Ca++) forms prothrombinase complex; secondary hemostasis Binding surface for factor Va and Xa (along with Ca++) forms prothrombinase complex; secondary hemostasis

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17 Aggregation Promoted by ADP and TXA2 release Promoted by ADP and TXA2 release ADP induces a conformational change of the IIbIIIa receptor, allowing fibrinogen binding ADP induces a conformational change of the IIbIIIa receptor, allowing fibrinogen binding Platelets aggregate via fibrinogen bound to IIbIIIa receptors Platelets aggregate via fibrinogen bound to IIbIIIa receptors Auto-catalytic reaction activating other platelets Auto-catalytic reaction activating other platelets Formation of primary hemostatic plug Formation of primary hemostatic plug

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19 Glanzmann’s Thrombasthenia Eduard Glanzmann (1887-1959), Swiss pediatrician Reported a case of a bleeding disorder starting immediately after birth W. E. Glanzmann:Hereditäre hämorrhägische Thrombasthenie. Ein Beitrag zur Pathologie der Blutplättchen. Jahrbuch für Kinderheilkunde, 1918; 88: 1- 42, 113-141.

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21 Glanzmann’s IIbIIIa most abundant platelet surface receptor (80,000 per platelet) IIbIIIa most abundant platelet surface receptor (80,000 per platelet) IIbIIIa complex is a Ca++ dependent heterodimer IIbIIIa complex is a Ca++ dependent heterodimer Genes for both subunits are found on Chromosome 17 Genes for both subunits are found on Chromosome 17 Disease is caused by mutations (substitution, insertion, deletion, splicing abnormalities) in genes encoding for IIb or IIIa resulting in qualitative or quantitative abnormalities of the proteins Disease is caused by mutations (substitution, insertion, deletion, splicing abnormalities) in genes encoding for IIb or IIIa resulting in qualitative or quantitative abnormalities of the proteins

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23 Fundamental defect of thrombasthenic patients is the inability of the platelets to aggregate Fundamental defect of thrombasthenic patients is the inability of the platelets to aggregate Other problems: platelets do not spread normally on the subendothelial matrix (due to lack of IIbIIIa – vWF/fibronectin interaction) Other problems: platelets do not spread normally on the subendothelial matrix (due to lack of IIbIIIa – vWF/fibronectin interaction) Also, alpha granule fibrinogen is decreased to absent Also, alpha granule fibrinogen is decreased to absent

24 AR inheritance AR inheritance Patients present with wide spectrum of disease Patients present with wide spectrum of disease Like thrombocytopenic bleeding: skin, mucous membrane (petichiae, echymoses), recurrent epistaxis, GI hemorrhage, menorrhagia, and immediate bleeding after trauma/surgery Like thrombocytopenic bleeding: skin, mucous membrane (petichiae, echymoses), recurrent epistaxis, GI hemorrhage, menorrhagia, and immediate bleeding after trauma/surgery ICH, joint, muscle bleeding uncommon ICH, joint, muscle bleeding uncommon

25 Glanzmann’s patients are stratified into three groups based on complex expression: Glanzmann’s patients are stratified into three groups based on complex expression: Type I less than 5 percent GPIIbIIIa, absent alpha granule fibrinogen Type I less than 5 percent GPIIbIIIa, absent alpha granule fibrinogen Usually as a result of IIb gene mutation Usually as a result of IIb gene mutation Type II <20 percent, fibrinogen present Type II <20 percent, fibrinogen present Type III >50 percent; “variant” thrombasthenia; qualitative disorder Type III >50 percent; “variant” thrombasthenia; qualitative disorder

26 Diagnosis Platelet count and morphology are normal Platelet count and morphology are normal Bleeding time prolonged Bleeding time prolonged The hallmark of the disease is severely reduced or absent platelet aggregation in response to multiple agonists ie ADP, thrombin, or collagen (except Ristocetin) The hallmark of the disease is severely reduced or absent platelet aggregation in response to multiple agonists ie ADP, thrombin, or collagen (except Ristocetin) Flow cytometry: decreased mAb expression of CD41 (GPIIb) and CD61 (GPIIIa) Flow cytometry: decreased mAb expression of CD41 (GPIIb) and CD61 (GPIIIa)

27 Platelet Aggregation Studies Platelet-rich plasma (PRP) is prepared from citrated whole blood by centrifugation Platelet-rich plasma (PRP) is prepared from citrated whole blood by centrifugation Inactive platelets impart a characteristic turbidity to PRP Inactive platelets impart a characteristic turbidity to PRP When platelets aggregate after injection of an agonist, the turbidity falls, and light transmission through the sample increases proportionally When platelets aggregate after injection of an agonist, the turbidity falls, and light transmission through the sample increases proportionally The change in light transmission can be recorded on an aggregometer The change in light transmission can be recorded on an aggregometer

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29 Agonists Different concentrations of each agonist are used Different concentrations of each agonist are used ADP: biphasic pattern: ADP: biphasic pattern: First wave: low concentration, reversible First wave: low concentration, reversible Second wave: high concentration, irreversible Second wave: high concentration, irreversible

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31 Other agonists Epinephrine: triphasic (resting platelets, primary aggregation, secondary aggregation) Epinephrine: triphasic (resting platelets, primary aggregation, secondary aggregation)

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33 Other agonists Collagen, arachidonic acid, Calcium ionophore, PAF are potent agonists and induce a single wave of irreversible aggregation Collagen, arachidonic acid, Calcium ionophore, PAF are potent agonists and induce a single wave of irreversible aggregation Ristocetin (antibiotic): aggregation can be reproduced with metabolically inert, formalin-fixed platelets Ristocetin (antibiotic): aggregation can be reproduced with metabolically inert, formalin-fixed platelets Defective risto-induced aggregation is characteristic of Bernard-Soulier Defective risto-induced aggregation is characteristic of Bernard-Soulier

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35 Problems with platelet aggregation studies Numerous variables affect aggregation: Numerous variables affect aggregation: Anticoagulant (sodium citrate best) Anticoagulant (sodium citrate best) Plt count in PRP Plt count in PRP Plt size distribution Plt size distribution Time of day Time of day Temporal relation to meals and physical activity Temporal relation to meals and physical activity

36 Bernard-Soulier Syndrome First described in 1948 by Jean Bernard and Jean-Pierre Soulier; French hematologists First described in 1948 by Jean Bernard and Jean-Pierre Soulier; French hematologists Bernard J, Soulier JP: Sur une nouvelle variete de dystrophie thrombocytaire hemarroagipare congenitale. Sem Hop Paris 24:3217, 1948 Bernard J, Soulier JP: Sur une nouvelle variete de dystrophie thrombocytaire hemarroagipare congenitale. Sem Hop Paris 24:3217, 1948 AR; characterized by moderate to severe thrombocytopenia, giant platelets, and perfuse/spontaneous bleeding AR; characterized by moderate to severe thrombocytopenia, giant platelets, and perfuse/spontaneous bleeding Basis for the disease is deficiency or dysfunction of the GP Ib-V-IX complex Basis for the disease is deficiency or dysfunction of the GP Ib-V-IX complex

37 Bernard-Soulier Syndrome Decreased GP Ib-V-IX leads to decreased platelet adhesion to the subendothelium via decreased binding of vWF Decreased GP Ib-V-IX leads to decreased platelet adhesion to the subendothelium via decreased binding of vWF Approximately 20,000 copies of GP Ib-V-IX per platelet Approximately 20,000 copies of GP Ib-V-IX per platelet GP 1b: heterodimer with an alpha and beta subunit GP 1b: heterodimer with an alpha and beta subunit The gene for GP Ib alpha is located on chromosome 17; GP Ib beta: chromosome 22; GPIX and V: chromosome 3 The gene for GP Ib alpha is located on chromosome 17; GP Ib beta: chromosome 22; GPIX and V: chromosome 3 Most mutations are missense or frameshifts resulting in premature stop codons Most mutations are missense or frameshifts resulting in premature stop codons Most mutations involve GP Ib expression (rare GP IX mutations have been described; no mutations in GP V) Most mutations involve GP Ib expression (rare GP IX mutations have been described; no mutations in GP V)

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39 Diagnosis Prolonged bleeding time, thrombocytopenia (plt 3.5 microns) Prolonged bleeding time, thrombocytopenia (plt 3.5 microns)

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42 Diagnosis Platelet aggregation studies show normal aggregation in response to all agonists except Ristocetin (opposite pattern than thrombasthenia) Platelet aggregation studies show normal aggregation in response to all agonists except Ristocetin (opposite pattern than thrombasthenia) Flow cytometry: decreased expression of mAbs to CD 42b (GPIb), CD42a(GPIX), CD42d(GPV) Flow cytometry: decreased expression of mAbs to CD 42b (GPIb), CD42a(GPIX), CD42d(GPV)

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44 May-Hegglin anomaly: AD; giant platelets, thrombocytopenia, Dohle-like inclusions (larger, more angular) May-Hegglin anomaly: AD; giant platelets, thrombocytopenia, Dohle-like inclusions (larger, more angular) Neutrophils are functional; only 40% of patients may have bleeding diathesis Neutrophils are functional; only 40% of patients may have bleeding diathesis

45 Storage Pool Defects Classified by type of granular deficiency or secretion defect (ASA) Classified by type of granular deficiency or secretion defect (ASA) Dense body deficiency, alpha granule deficiency (gray platelet syndrome), mixed deficiency, Factor V Quebec Dense body deficiency, alpha granule deficiency (gray platelet syndrome), mixed deficiency, Factor V Quebec

46 Dense body deficiency decreased dense bodies (ADP, ATP, calcium, pyrophosphate, 5HT) decreased dense bodies (ADP, ATP, calcium, pyrophosphate, 5HT) Normal platelet contains 3-6, 300 micron dense bodies Normal platelet contains 3-6, 300 micron dense bodies

47 Described in inherited disorders ie Hermansky-Pudlak syndrome, Wiskott- Aldrich syndrome, Chediak-Higashi syndrome, and Thrombocytopenia with absent radius (TAR) syndrome Described in inherited disorders ie Hermansky-Pudlak syndrome, Wiskott- Aldrich syndrome, Chediak-Higashi syndrome, and Thrombocytopenia with absent radius (TAR) syndrome

48 Wiskott-Aldrich X-linked, genetic defect in WASp (protein responsible for actin cytoskeleton formation in hematopoetic cells) X-linked, genetic defect in WASp (protein responsible for actin cytoskeleton formation in hematopoetic cells) characterized by thrombocytopenia (with platelet storage pool defect), eczema,and recurrent infections characterized by thrombocytopenia (with platelet storage pool defect), eczema,and recurrent infections

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50 Hermansky-Pudlak Described in 1959 by Hermansky and Pudlak Described in 1959 by Hermansky and Pudlak AR, tyrosinase-positive oculocutaneous albinism, ceroid-like deposition in lysosomes of the RES and marrow AR, tyrosinase-positive oculocutaneous albinism, ceroid-like deposition in lysosomes of the RES and marrow Highest prevalence in Puerto Rico Highest prevalence in Puerto Rico May be associated with pulmonary fibrosis, IBD, and recurrent infections May be associated with pulmonary fibrosis, IBD, and recurrent infections quantitative deficiency of dense granules leading to mild-moderate bleeding diathesis quantitative deficiency of dense granules leading to mild-moderate bleeding diathesis

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53 Chediak-Higashi described by Beguez Cesar in 1943, Steinbrinck in 1948, Chédiak in 1952, and Higashi in 1954 described by Beguez Cesar in 1943, Steinbrinck in 1948, Chédiak in 1952, and Higashi in 1954 AR; abnormal microtubule formation and giant lysozomal granules are present in phagocytes and melanocytes AR; abnormal microtubule formation and giant lysozomal granules are present in phagocytes and melanocytes No degranulation/chemotaxis = recurrent bacterial infections No degranulation/chemotaxis = recurrent bacterial infections Partial oculocutaneous albinism Partial oculocutaneous albinism Dense-body granules decreased/absent Dense-body granules decreased/absent

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56 Thrombocytopenia with absent radius (TAR) First described in 1951 First described in 1951 AR, characterized by absent radii, thrombocytopenia (with storage pool defect), and other abnormalities of the skeletal, GI, cardiovascular system AR, characterized by absent radii, thrombocytopenia (with storage pool defect), and other abnormalities of the skeletal, GI, cardiovascular system Etiology unclear Etiology unclear Hemorrhage is the major cause of mortality Hemorrhage is the major cause of mortality PX is good if survive the two years PX is good if survive the two years

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58 Diagnosis Platelet aggregation studies may show diminished response to low concentration collagen Platelet aggregation studies may show diminished response to low concentration collagen ADP and epinephrine show diminished second wave response ADP and epinephrine show diminished second wave response Ristocetin shows normal aggregation Ristocetin shows normal aggregation EM: lack of dense bodies EM: lack of dense bodies Increased ATP:ADP ratio within platelets Increased ATP:ADP ratio within platelets

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60 Alpha granule deficiency Alpha storage pool deficiency, Gray Platelet Syndrome Alpha storage pool deficiency, Gray Platelet Syndrome First described by Raccuglia in 1971 First described by Raccuglia in 1971 Normal platelets contain approximately 50 granules (PF4, beta-thromboglobulin, PDGF, fibrinogen, vWF, Factor V, fibronectin) Normal platelets contain approximately 50 granules (PF4, beta-thromboglobulin, PDGF, fibrinogen, vWF, Factor V, fibronectin) Patients lack granules, present with lifelong, mild to moderate mucocutaneous bleeding Patients lack granules, present with lifelong, mild to moderate mucocutaneous bleeding

61 Diagnosis Prolonged bleeding time, mild thrombocytopenia Prolonged bleeding time, mild thrombocytopenia Agranular, large “gray” platelets on peripheral smear Agranular, large “gray” platelets on peripheral smear Aggregation studies: decreased to absent response to collagen Aggregation studies: decreased to absent response to collagen

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Hematology Atlas

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65 Summary Morphology and role of the platelet in primary hemostasis Morphology and role of the platelet in primary hemostasis Adhesion: GP1b-V-IX; Bernard-Soulier; aggregates with everything but Ristocetin Adhesion: GP1b-V-IX; Bernard-Soulier; aggregates with everything but Ristocetin Activation (Secretion): dense body deficiency (associated syndromes), alpha granule deficiency Activation (Secretion): dense body deficiency (associated syndromes), alpha granule deficiency Aggregation: GPIIb-IIIa; Glanzmann’s; no aggregation except for Ristocetin Aggregation: GPIIb-IIIa; Glanzmann’s; no aggregation except for Ristocetin

66 Sources Glassy, Eric ed. Color Atlas of Hematology: An Illustrated Field Guide Based on Proficiency Testing. (Northfield, Illinois: College of American Pathologists, 1998) Glassy, Eric ed. Color Atlas of Hematology: An Illustrated Field Guide Based on Proficiency Testing. (Northfield, Illinois: College of American Pathologists, 1998) Ramasamy I. Inherited bleeding disorders: disorders of platelet adhesion and aggregation. Crit Rev Oncol Hematol. 2004 Jan;49(1):1-35. Review. Ramasamy I. Inherited bleeding disorders: disorders of platelet adhesion and aggregation. Crit Rev Oncol Hematol. 2004 Jan;49(1):1-35. Review. Janeway CM, Rivard GE, Tracy PB, Mann KG. Factor V Quebec revisited. Janeway CM, Rivard GE, Tracy PB, Mann KG. Factor V Quebec revisited. Blood. 1996 May 1;87(9):3571-8. Robbins. Pathologic Basis of Disease. 7 th ed (2004) Robbins. Pathologic Basis of Disease. 7 th ed (2004) Hoffman, et al. Hematology: Basic Principles and Practice, 3r ed (2000) Hoffman, et al. Hematology: Basic Principles and Practice, 3r ed (2000)

67 http://hematologica.pl/Stary/numerki/57n.jpg http://hematologica.pl/Stary/numerki/57n.jpg http://hematologica.pl/Stary/numerki/57n.jpg www.vh.org/.../CLIA/Hematology/Images/07.jpg www.vh.org/.../CLIA/Hematology/Images/07.jpg http://hsc.unm.edu/pathology/medlab/pappenb.jpg http://hsc.unm.edu/pathology/medlab/pappenb.jpg http://www.vet.uga.edu/vpp/CLERK/Boutureira/Fig1a.jpg http://www.vet.uga.edu/vpp/CLERK/Boutureira/Fig1a.jpg http://www.med.uth.tmc.edu/edprog/pbl/exhibits1/images/Mason_fig _1b.jpg http://www.med.uth.tmc.edu/edprog/pbl/exhibits1/images/Mason_fig _1b.jpg www.vet.uga.edu/vpp/clerk/Gunter/Fig1pb www.vet.uga.edu/vpp/clerk/Gunter/Fig1pb www.vet.uga.edu/vpp/clerk/Gunter/Fig1pb www.labmed.hallym.ac.kr/ hematol/Disease-findings.htm www.labmed.hallym.ac.kr/ hematol/Disease-findings.htm

68 http://precisionhaemostatics.com/images/mph_15.jpg http://www.whonamedit.com/synd.cfm/2075.html http://www.whonamedit.com/doctor.cfm/1860.html http://www.whonamedit.com/doctor.cfm/1861.html http://www.whonamedit.com/synd.cfm/1289.html www.bloodmed.com/home/hann2pdf/bjh_3812.pdf

Pdf

69 personal.nbnet.nb.ca/ seepat/pict9920.htm www.strokecenter.org/ education/ais_pathogenes... http://pharmacology.tmu.edu.tw/platelet.jpg www.biophysik.uni-bremen.de/.../ research.html www.cap.org/.../platelet_ disorders_feature. faculty.washington.edu/ kepeter/118/photos/blo... http://web.mit.edu/cherish/www/new%20images/platelet.jpg http://lena.jax.org/~slc/Platelets.GIF http://web2.airmail.net/uthman/blood_cell_pix/platelet.jpg www.macmed.ttuhsc.edu/.../ pages/newpage20.htm www.macmed.ttuhsc.edu/.../ pages/newpage20.htm www.macmed.ttuhsc.edu/.../ pages/newpage20.htm www.macmed.ttuhsc.edu/.../ pages/newpage20.htm

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