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