G LANZMANN ’ S T HROMBASTHENIA Stacey Shiovitz January 13, 2012
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GLANZMANN’S THROMBASTHENIA
Stacey ShiovitzJanuary 13, 2012
“H ! M GT “HELP! MY PATIENT HAS GT – DOYOU EVEN KNOW WHAT THAT IS?”
CASECASE
27 t d t l li i 27yo woman presented to gynecology clinic for menorrhagia x 10 days
Bleeding started after missed 1 OCP pill
Changing thick pad q2 hours; some clotsg g p q ;
Tried taking 7 then 2 OCP pills at once, but persistedpersisted
Labs: WBC 7.9, Hgb 11.4, Hct 35, Plt 211, normal PT/INR and PTTnormal PT/INR and PTT
PAST HISTORYPAST HISTORY
Glanzmann’s thrombasthenia (GT) Glanzmann s thrombasthenia (GT)
Hypothyroidism
Depression
Allergy‐induced asthma Allergy induced asthma
Medications: continuous Low‐Ogestrel, iron, levothyroxine, bupropion, albuterollevothyroxine, bupropion, albuterol
Works as a nurse, rare alcohol, no tobacco or illicit drugsillicit drugs
BLEEDING HISTORY - 1BLEEDING HISTORY 1
Diffuse bruising petechiae at birth Diffuse bruising, petechiae at birth
Diagnosed with GT at age 2 months
Platelet count 178, PT 9.5, PTT 37.9
Bleeding time 15 min
Factor VIII 140%, IX 65%, XI 70%, XII 40%; vWF 89%
Aggregation defect with collagen, ADP, arachidonicacid, epinephrine, thrombin. Normal aggregation with ristocetin
Absence of clot retraction at 24hrs Absence of clot retraction at 24hrs
BLEEDING HISTORY - 2BLEEDING HISTORY 2
Childhood: >5 episodes of epistaxis requiring Childhood: >5 episodes of epistaxis requiring platelet transfusions
11yo: esophageal laceration requiring multiple 11yo: esophageal laceration, requiring multiple units of platelets/PRBC
13yo: Menarche 13yo: Menarche
Required platelets with first period
Since has been on oral contraceptive pills (OCP) Since has been on oral contraceptive pills (OCP), currently on Low‐Ogestrel
Bleeding episode if misses pills, but typically g p p , yp yresponds to double dose
FAMILY HISTORYFAMILY HISTORY
N k bl di l tti di d No known bleeding or clotting disorders
Mother: normal bleeding time, pltaggregation
Father: bleeding time 2.5 min, plt did not g , paggregate with collagen or arachidonic acid
Abnormalities thought to be related to recent Abnormalities thought to be related to recent indomethacin use
LET’S GET TOGETHER?
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
Discovered in Switzerland in 1918 by pediatrician Eduard Discovered in Switzerland in 1918 by pediatrician Eduard Glanzmann
Hemorrhage
Prolonged bleeding time
Isolated (rather than clumped) platelets on smear
Qualitative or quantitative defect in GP IIb/IIIa complex (aka αIIbβ3 integrin) on platelets, which binds fibrinogen
Avg. 50,000‐80,000 complexes per resting platelet
Conformational change when platelet is activation
Di d f i ( i i ) d l i Disorder of aggregation (except to ristocetin) and clot retraction
CLASSIFICATIONCLASSIFICATION
Type Clot retraction
Fibrinogen content
GP IIb/IIIa levels
1 Absent Absent <5% normal
2 Delayed Decreased 10‐20% normal
3* variant
Variable VariableNormal levels (60‐100%), but functionally inactivey
*newer revision to original 1972 classification by Caen, et al
PATHOPHYSIOLOGYPATHOPHYSIOLOGY
A t l i Autosomal recessive
Genetic defect on chromosome 17
Characterized 1960s ‐ 1970s
Cloned and sequenced in 1980s
Incidence: 1/1,000,000
Clusters with consanguinity (as high as g y g1/200,000 in Iran)
Genetic defect does not predict bleeding severity
MUTATION DATABASEMUTATION DATABASE
http://sinaicentral.mssm.edu/intranet/research/glanzmannhttp://sinaicentral.mssm.edu/intranet/research/glanzmann
MANIFESTATIONS
M tl t bl di
MANIFESTATIONS
Mostly mucocutaneous bleeding:Review of 177 patientspatients with GT
George et al,Blood 1990
WHAT TO DO, WHAT TO DO
TREATMENT - 1TREATMENT 1
Transfuse platelets
Try and minimize blood products given y p gpropensity to form isoantibodies
TREATMENT - 2TREATMENT 2
P ti Prevention
Regular dental care to prevent severe episodes
Hormonal contraception, prior to or at onset of menarche
Local control
Nasal packing for epistaxis Nasal packing for epistaxis
Gel foam soaked in thrombin for dental bleeding
TREATMENT - 3TREATMENT 3
DDAVP DDAVP
Typically ineffective; likely works best in Type 2 (higher levels of normal GP IIb/IIIa)( g / )
Anti‐fibrinolytics
Aminocaproic acid (Amicar) Aminocaproic acid (Amicar)
Tranexamic acid (Lysteda)
Recombinant Factor VII (NovoSeven)
Approved in Europe for GT if platelet refractory
Consider for peri‐operative prevention of bleeding
PREGNANCYPREGNANCY
Hi h i k f h h High risk for hemorrhage
Often require platelets pre‐partum and post‐t f t 1 kpartum for up to 1 week
Prefer HLA‐compatible platelets
BONE MARROWTTRANSPLANTATION
Only case reports to date Only case reports to date
Consider for GT with severe clinical phenotype or anti‐platelet antibodiesor anti‐platelet antibodies
Full‐intensity and reduced‐intensity regimens have been usedhave been used
Full: busulfan, cyclophosphamide
Reduced fludarabine alemtuzumab melphalan Reduced: fludarabine, alemtuzumab, melphalan
Series of 5 children: post‐transplant resolution of bleeding symptomsof bleeding symptoms
ONE PERSON’S DISEASE CAN BE ADRUG COMPANY’S TREASURE
CLINICAL APPLICATIONSCLINICAL APPLICATIONS
Hypothesis that GT patients are protected against Hypothesis that GT patients are protected against cardiovascular disease
Decreased thrombotic occlusion of coronaries (rather than decreased arteriosclerosis as in hemophilia)decreased arteriosclerosis, as in hemophilia)
Medications blocking GP IIb/IIIa:
b i i b (R ) tifib tid (I t ili )abciximab (Reopro), eptifibatide (Integrilin), tirofiban (Aggrastat)
Create a transient “thrombasthenia‐like” state
Abciximab = humanized murine monoclonal Ab to GP IIb/IIIa complex
N d fi li f STEMI Now used as first‐line agents for STEMI
BACK TO THE CASE
PATIENT FOLLOW-UPPATIENT FOLLOW UP
Amicar Heart palpitations headache Amicar Heart palpitations, headache, general discomfort
Higher dose OCP Higher dose OCP
Platelet transfusions
Transexanic acid offered, not yet tried
Tested anti‐IIb/IIIa – markedly elevated
Consider rFVIIa in the future
REFERENCESREFERENCES
Arnold DM, Rao AK. ASH‐SAP: Disorders of platelet number and function. 2010., p
Bellucci S, et al. Bone marrow transplantation in severe Glanzmann’s thrombasthenia with antiplatelet alloimmunization. 2000. Bone marrow Transplantation: (25) 327‐330.
Connor P, et al. Stem cell transplantation for children with Glanzmannthrombasthenia. 2008. Brit J Haemat: (140) 568‐571.
Dent GA, Eby CS. ASH‐SAP: Laboratory hematology. 2010.
George JN, et al. Glanzmann’s Thrombasthenia: the Spectrum of Disease. 2010. Blood: (75) 1383‐1395.
Gunaydin B, et al. Recombinant activated factor VII and epsilon aminocaproic acid y , p ptreatment of a patient with Glanzmann’s thrombasthenia for nasal polipectomy. 2007. J Anesth: (21) 106‐107.
OMIM. Glanzmann’s thrombasthenia. #273800. Accessed 1/11/12.
Nurden AT. Glanzmann thrombasthenia. 2006. Orph J Rare Disease: 1:10.
Nurden A, Nurden P. Advances in our understanding of the molecular basis of disorders of platelet function. 2011. J Thromb Haemost: (9) 76‐91.
Seligsohn U. Glanzmann thrombasthenia: a model disease which paved the way to powerful therapeutic agents. 2002. Pathophysiol Haemost Thromb: (32) 216‐217.
Toogeh G, et al. Presentation and Pattern of Symptoms in 382 Patients with Glanzmann Thrombasthenia in Iran. 2004. Amer J Hemat: (77): 198‐199.
http://sinaicentral.mssm.edu/intranet/research/glanzmann
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