Platelet Biology and its Disorders SUPPLEMENTARY Slc35a1 ...
Platelet Disorders - Home Page | Department of … Conference1... · Platelet Disorders Kanwar...
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Platelet Disorders Kanwar Kahlon M.D.
Division of Hematology & Oncology
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PLT ANATOMY / FUNCTION
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PLT Anatomy
Alpha granules
Dense granules PLTs = a fundamental unit of
hemostasis
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External PLT Anatomy
PLT
GPIb-V-IX receptor (ristocetin-vWD interaction)
P2Y12 receptor (ADP receptor)
GPIIb-IIIa receptor (fibrinogen bridging)
PAR-1 receptor (thrombin)
GPVI (collagen receptor)
P2Y1 receptor (ADP receptor)
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Internal PLT Anatomy
Mito-chondria
Microtubules
Glycocalyx
TXA2
DENSE GRANULES (ADP, ATP, serotonin, Ca2+)
ALPHA GRANULES (PF4, fI, fV, fVIII/vWF, Ig, RANTES, BTG)
Surface connecting system
fXIII COX
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PLT Activation • PLTs become activated by two primary mechanisms:
• Shear-induced activation • Bypass of exposed endothelium induces shape changes and
activation • Chemical activation
• Typically arises from local environment and other activated PLTs
• Both of the pathways are at work in the bleeding individual
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PLT Shear & Chemical Release
Shear induces PLT shape change, adhesion to endothelium, and activation This enhances granule secretion, PLT recruitment, and clot propagation
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PLT shear induces adhesion (via vWF and GPIb-V-IX) and
activation (shape change & granule release)
Aggregation occurs via fibrinogen-GPIIb-IIIa interaction;
clot propagation by additional PLT activation
PLT plug formation: putting it together
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PTT, or APTT, starts here, to make fibrin:
PT goes from here to fibrin:
(also activates other factors)
(also activates IX)
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Stages of Hemostasis
• Primary Hemostasis • von Willebrand’s factor and platelets
• Secondary Hemostasis • Coagulation cascade
• Tertiary Hemostasis • Cross-linking of fibrin strands • Clot maturation and wound healing
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Thrombocytopenia
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Platelet dysfunction may show up as petechiae, but something this prominent is usually thrombocytopenic (unless its vasculitic)
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PLT related bleeding
Epistaxis Petechial rash
Cerebral hemorrhage
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Anatomic distribution of bleeding diathesis Plt dysfunction or
vWD Coagulation
factor deficiency
Petechiae Body cavity bleeding
Anatomic sites Skin
Mucosal surfaces (oral, nasal, GI, GU)
Deep tissues Muscles Joints
Petechiae Common Uncommon
Ecchymoses Superficial, small Deep, extensive (hematomas)
Bleeding after minor cuts Yes No
Bleeding after surgery Immediate Delayed
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Common thrombocytopenias
• Splenomegaly/hypersplenism • Chronic Hepatitis C • Cirrhosis • Sepsis • DIC • Drug induced • Immune thrombocytopenia (ITP, HIV) • Pseudothrombocytopenia
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Pseudothrombocytopenia
• Platelet clumping in EDTA (lavender top tubes), with decreased automated Plt quantitation
• Redraw CBC in tubes with citrate or heparin anticoagulant
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Case 1
• 66 yo man presents with petechiae of the extremities, and ecchymoses, within several weeks of an URI. Plts are 3,000. He is given IVIg (1 gm/kg), and Dexamethasone 40 mg daily for 4 days is started. His Plts increase quickly, and he is discharged the following day. CBC within 1 wk reveals a complete response. Plts remain normal several months later.
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Case 2
• 54 yo woman with “cutaneous lupus”, taking hydroxychloroquine, presents with petechiae of the extremities, oral purpura, and diffuse ecchymoses. Plts are 5,000. Steroids are started, and IVIg 2 gm/kg is given over 2 days, without a response. Despite treatment for ~10 days in the hospital, Plts remain <10,000. Weekly Romiplostim is initiated, as is a 4 wk course of Rituxan. Plts are >100,000 2 wks later. Steroids are tapered slowly over several months. However, 2 wks after steroids are stopped, she presents again with ecchymoses, purpura, and petechiae, and Plts are <1,000.
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• Secondary ITP 20% of total ITP cases
Misc systemic infection 2%
SLE 5%
APS 2%
CVID 1%
CLL 2% Evan’s 2% ALPS, post-tx 1% HIV 1% HCV 2%
H pylori 1% Postvaccine 1%
Primary 80%
Cines, Blood, 2009
Immune thrombocytopenia
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ASH-SAP, 5th ed.
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Harrington’s Classic Experiment
Harrington, J Lab Clin Med, 1951
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Epitope Spreading Leads to Diversity of Platelet Targets
Cines, N Eng J Med, 2002
Glycoprotein IIb/IIIa
autoantibody
Glycoprotein Ib/IX
Anti- glycoprotein
Ib/IX
Anti glycoprotein
IIb/IIIa
Glycoprotein Ib/IX B-cell clone 1 T-cell clone 1 Glycoprotein
IIb/IIIa
Glycoprotein Ib/IX
Activated macrophage
Glycoprotein IIb/IIIa
Antibody-coated platelet
Fcγ
CD40 CD154
CD40
TCR TCR
B-cell clone 2 T-cell clone 2
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Molecular Mimicry in ITP
Aster, Blood, 2009
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Clearance of Antibody-Coated Platelets by Phagocyte Fcγ Receptors
1. Karpatkin, Lancet, 1997 2. Psaila, J Clin Invest, 2008
Antibody-Coated Platelet[1] Fcγ Family of Receptors[2]
Low to medium
Low to medium
Low to medium
Low to medium
Low to medium
High Affinity for Fc Fragment
Cell membrane
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Production and Survival of Platelets in ITP
1. Harker, Br J Haematol, 1970 2. Branehög, Br J Haematol, 1974 3. Stoll, Blood, 1985 4. Ballem, J Clin Invest, 1987
Platelet Survival, Days
Study Platelets Normal Subjects ITP Pts Turnover
(x Normal) Harker 1970[1] Allogeneic* 9.9 0.34 4.9 Branehög 1974[2] Allogeneic† 6.9 0.67 2.3 Stoll 1985[3] Autologous 8.0 2.9 0.9 Ballem 1987[4] Autologous 9.6 2.8 0.6
*Subjects with platelet counts > 25 x 109/L received autologous platelets. †Subjects with platelet counts > 20 x 109/L received autologous platelets.
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Smears
ASH Image Bank
Blood
Marrow aspirate
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Bleeding Manifestations in ITP
Purpura
Ecchymoses, petechiae
CNS hemorrhage (rare)
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Goals of ITP Therapy in Adults • Maintain a safe platelet count with minimal toxicity • May need to individualize treatment strategy based on
Plt count (<30,000), assessment of bleeding risk, and patient preference
Neunert, Blood, 2011
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Recommended ‘Safe’ Platelet Ranges
Br J Haematol, 2003
Clinical Situation Platelets
General dentistry Extractions Regional dental block
≥ 10 x 109/L ≥ 30 x 109/L ≥ 30 x 109/L
Surgery Minor Major
≥ 50 x 109/L ≥ 80 x 109/L
Pregnancy Vaginal delivery Caesarean section Spinal/epidural anesthesia
> 50 x 109/L > 80 x 109/L > 80 x 109/L
*British Committee for Standards in Hematology General Hematology task force
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Therapy Options
Provan, Blood, 2010
Clinical Situation Therapy Options
First line (initial treatment)
Corticosteroids: prednisone, dexamethasone, methylprednisolone
IVIg Anti-D
Second line
Azathioprine Cyclosporine A
Cyclophosphamide Danazol Dapsone
Mycophenolate mofetil Rituximab
Splenectomy TPO receptor agonists (romiplostim and eltrombopag)
Vinca alkaloids Treatment for patients failing first- and second-line therapies
Category A*: TPO receptor agonists Category B†: campath-1 H, combination of first- and second-
line therapies, combination chemotherapy, HSCT *Sufficient data to support recommendation. †Minimal data to support recommendation; potential for considerable toxicity.
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Differential Diagnosis
• Disseminated intravascular coagulation (Consumptive coagulopathy) • Thrombotic thrombocytopenic purpura/ Hemolytic uremic syndrome
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DIC (Consumptive Coagulopathy)
• Uncontrolled activation of the coagulation cascade: unregulated thrombin generation mediated by activation and injury of the endothelium or by mechanical injury to tissues leading to excessive exposure of tissue factor and/or lipid surfaces
• Infection • Malignancy • Obstetric complications • Tissue Injury
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The Coagulation Cascade
Fibrinogen
VIIIa VIIa
Phospho- lipid
Phospho- lipid
Phospho- lipid
Xa
Va
IXa TF
II IIa
Fibrin
XIa
IX
X
V
VIII
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Clinical Manifestations of DIC
• Asymptomatic • Bleeding
• The primary association with DIC when symptomatic
• Thrombosis • Rare (seems to be associated with infectious causes of DIC)
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Laboratory Diagnosis
• Microangiopathic hemolysis • Thrombocytopenia • Prolonged PT and/or PTT • Elevated thrombin time (TT) • Decreased fibrinogen • Increased D-dimer
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Caveats to Laboratory Diagnosis
• Though numerous coagulation parameters may be abnormal in DIC (elevated PT/PTT/D-dimer, decreased platelets and fibrinogen) not every one needs to be present to make the diagnosis
• Relative change may be important (dropping fibrinogen or platelets)
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Management of DIC • Treat the underlying cause • Early and aggressive blood product support in
symptomatic cases • Platelets • Plasma • Cryoprecipitate • Red cells
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Case 3
A 41 year-old woman with no significant past medical history presents to her primary care provider with shortness of breath and bruising. She is taking no medications. There is no family history of any bleeding disorder. She denies fever, chills, nausea, vomiting, diarrhea. Physical examination reveals scattered petechiae and ecchymoses, a I/VI systolic ejection murmur, and a normal mental status.
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Laboratory Data
WBC 9,600 Hct 18% Platelets 16,000 PT 12.1 s PTT 24.6 s Creatinine 0.9 LDH 775
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Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome
• Congenital • Idiopathic • Drug-related • Toxin-related
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Diagnosing thrombotic microangiopathy (TMA)
• Hemolytic Anemia • Mechanical – schistocytes • Response – reticulocytosis • Increased LDH • Hyperbilirubinemia • Suppressed haptoglobin (undetectable)
• Thrombocytopenia • Often in the range of 20-60,000/mcL
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Basic pathophysiology
• Endothelial attack upon circulating red cells and platelets; RBCs fragmented ↑LDH
• Platelets: microthrombi (& decreased Plts) organ dysfunction ↑LDH
• ADAMTS-13 testing is informative for TTP • Conditions of Intense Endothelial Activation
• Hypertensive emergency • Scleroderma Renal Crisis • Disseminated Cancer/Chemotherapy
• Hemolytic Uremic Syndrome (HUS) • Atypical HUS – complement mediated TMA
Moake JL, 2002. New England Journal of Medicine, 2002;347(8):589-600
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Clinical Pearl
• Think twice about making the diagnosis of TTP when the PT and/or PTT is abnormal - DIC is much more common
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Drugs Associated with TTP
• Clopidogrel (Plavix) • Ticlopidine (Ticlid) • Cyclosporin • Mitomycin C • Gemcitabine
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Infections Associated with TTP or HUS
• E. coli 0157:H7 • Shigella (verotoxin producing) • HIV
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Etiology of TTP
• Deficiency of von Willebrand cleaving protease • Congenital ADAMTS13 deficiency • Acquired through development of an inhibitor (antibody)
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ADAMTS 13 and TTP
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Management of TTP
• Daily plasmapheresis with plasma exchange until platelet count >150,000, then taper slowly
• Monitor CBC, retics, LDH, creatinine
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Course of TTP
• About 90% of cases of TTP improve with plasmapheresis • About 30% of these patients relapse, yet a fair number of these
respond to another course of plasmapheresis • About 10% of patients have refractory disease after a prolonged
course of pheresis
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Second Line Therapy for TTP
• Immunosuppresants • Steroids • Cyclophosphamide • Rituximab
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Keir LS. Hemolytic Uremic Syndrome. Hematol Oncol Clin N Am. 2015;29:525-539.
Shiga Toxin (STx) producing E. Coli (STEC)
STx binds to Gb3 on colonic epithelium, endothelial
cells, renal mesangial cells,
Cell death with organ specific dysfunction
HUS
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vWF and thrombosis in HUS
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Etiology of atypical HUS • Appears to result from abnormalities in complement
regulatory proteins (factor H, factor I, others), complement activation, and the development of endothelial injury
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Nester CM, Barbour T, Rodriguez de Cordoba S, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship THJ, et al. Atypical HUS: State of the Art. Molecular Immunology, 2015;67:31-42) George JN, Nester CM. Syndromes of Thrombotic Microangiopathy. New England Journal of Medicine, 2014;371:654-666.
79% of episodes occur postpartum
“Thickened arteriolar and capillary walls, prominent endothelial swelling and detachment, subendothelial swelling and detachment, subendothelial accumulation of cell debris, and fibrin and platelet-rich thrombi obstructing vessel lumina is characteristic of all TMAs.” – Nester, et al.
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C3 C3b C3a
C3bBbC3b
Factor H Factor I
MCP (CD46)
Factor H
C5
C5b MAC
Eculizumab
C5a
Factor B
Fact
or D
C3b(H2O)Bb Fluid Phase C3 Convertase
C3bBb AP C3 Convertase
• Altered binding sites reduce cell surface binding/protection • Deletions predispose to FH autoantibodies • FHR dimers may competitively antagonize Factor H
Factor B
Fact
or D
• Implicated mutations in MCP – a surface bound cofactor for Factor I – primarily reduce copy number
• Other mutations in Factor I reduce C3b inactivation capacity
• Decreased binding to MCP • Increased affinity for Factor B • Decreased susceptibility of C3
convertase to normal decay
Nester CM, Barbour T, Rodriguez de Cordoba S, Dragon-Durey MA, Fremeaux-Bacchi V, Goodship THJ, et al. Atypical aHUS: State of the Art. Molecular Immunology, 2015 (67:31-42.
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Heparin-mediated destruction • Heparin-mediated destruction is a common form of drug-induced
thrombocytopenia • Also called heparin-induced thrombocytopenia (HIT)
• In this case, heparin + PLT factor 4 (PF4) form a neoantigen on the PLT surface
• This neoantigen induces an antibody response resulting in PLT clearance
• Testing revolves around detecting the heparin-dependent antibody • Stopping heparin should cause PLT count to normalize within a few
days
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HIT
• HIT is particularly dangerous because it decreases PLT counts, but may also induce a hypercoagulable state in some patients
• When the antibodies interact with the PLTs, they can cause their activation
• This can induce clotting despite the decreased counts
• Patients with HIT and Thrombosis (called HITT) require anticoagulation
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Heparin induced thrombocytopenia (HIT)
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4T score for HIT
• ≤ 3: low prob (1.6%) • 4-5: int prob (28.6%) • 6-8: high prob (100%)
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Diagnosis of HIT
• Screen for Ab to Heparin/PF4 (ELISA)
• Serotonin release assay • confirmatory test
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Management of suspected HIT
• STOP Heparin • Use non-heparin agent: direct thrombin inhibitor (eg, argatroban), or
fondaparinux • Await confirmatory testing
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Questions?