GLANZMANN S THROMBASTHENIA Stacey Shiovitz January 13, 2012
HELP!! MY PATIENTHASGT DO YOU EVEN KNOW WHAT THAT IS?
CASE 27yo woman presented tdto gynecology clinic i for menorrhagia x 10 days Bleeding started after missed 1 OCP pill Changing gthick pad q2 hours; some clots Tried taking 7 then 2 OCP pills at once, but persisted Labs: WBC 7.9, Hgb 11.4, Hct 35, Plt 211, normalpt/inr and PTT
PAST HISTORY Glanzmann s thrombasthenia (GT) Hypothyroidism Depression Allergy induced asthma Medications: continuous Low Ogestrel, iron, levothyroxine, bupropion, albuterol Works as a nurse, rare alcohol, no tobacco or illicit drugs
BLEEDING HISTORY - 1 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, arachidonic acid, epinephrine, thrombin. Normal aggregation with ristocetin Absence of clot retraction at 24hrs
BLEEDING HISTORY - 2 Childhood: >5 episodes of epistaxis requiring platelet transfusions 11yo: esophageal laceration, requiring multiple units of platelets/prbc 13yo: Menarche Required platelets with first period Since has been on oral contraceptive pills (OCP), currently on Low Ogestrel Bleeding episode if misses pills, but typically g p p, yp y responds to double dose
FAMILY HISTORY No known bleeding or clotting disorders d Mother: normal bleeding time, plt aggregation Father: bleeding time 2.5 min, plt did not aggregate with collagen or arachidonic acid Abnormalities thought to be related to recent indomethacin use
LET S GET TOGETHER?
PATHOPHYSIOLOGY 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 Disorder of aggregation (except to ristocetin) i and clot retraction
CLASSIFICATION Type Clot retraction Fibrinogen content GP IIb/IIIa levels 1 Absent Absent <5% normal 2 Delayed Decreased 10 20% normal 3* variant Variable Variable Normal levels (60 100%), but functionally inactive *newer revision to original 1972 classification by Caen, et al
PATHOPHYSIOLOGY 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 1/200,000 in Iran) Genetic defect does not predict bleeding severity
MUTATION DATABASE http://sinaicentral.mssm.edu/intranet/research/glanzmann
MANIFESTATIONS Review of 177 patients with GT Mostly mucocutaneous bleeding: George et al, Blood 1990
WHAT TO DO, WHAT TO DO
TREATMENT - 1 Transfuse platelets Try and minimize blood products given y p g propensity to form isoantibodies
TREATMENT - 2 Prevention Regular dental care to prevent severe episodes Hormonal contraception, prior to or at onset of menarche Local control Nasal packing for epistaxis Gel foam soaked in thrombin for dental bleeding
TREATMENT - 3 DDAVP Typically ineffective; likely works best in Type 2 (higher levels of normal GP IIb/IIIa) Anti fibrinolytics 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
PREGNANCY High risk ikfor hemorrhageh Often require platelets pre partum and post partum for up to 1 week Prefer HLA compatible platelets
BONE MARROW TRANSPLANTATION Only case reports to date Consider for GT with severe clinical phenotype or anti platelet antibodies Full intensity and reduced intensity regimens havebeen used Full: busulfan, cyclophosphamide Reduced: fludarabine, alemtuzumab, melphalan Series of 5 children: post transplant resolution of bleeding symptoms
ONE PERSON S DISEASE CAN BE A DRUG COMPANY S TREASURE
CLINICAL APPLICATIONS Hypothesis that GT patients are protected against cardiovascular disease Decreased thrombotic occlusion of coronaries (rather than decreased arteriosclerosis, as in hemophilia) Medications blocking GP IIb/IIIa: abciximab bii b(r (Reopro), eptifibatide tid (Integrilin), tirofiban (Aggrastat) Create a transient thrombasthenia like state Abciximab = humanized murine monoclonal Ab to GP IIb/IIIa complex Now used as first line agents for STEMI
BACK TO THE CASE
PATIENT FOLLOW-UP Amicar Heart palpitations, headache, general discomfort Higher dose OCP Platelet transfusions Transexanic acid offered, not yet tried Tested anti IIb/IIIa markedly elevated Consider rfviia in the future
REFERENCES Arnold DM, Rao AK. ASH SAP: Disorders of platelet number and function. 2010. 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 Glanzmann thrombasthenia. 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 treatment 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