GLANZMANN S THROMBASTHENIA. Stacey Shiovitz January 13, 2012

Transcription

1 GLANZMANN S THROMBASTHENIA Stacey Shiovitz January 13, 2012

2 HELP!! MY PATIENTHASGT DO YOU EVEN KNOW WHAT THAT IS?

3 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

4 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

5 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

6 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

7 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

8 LET S GET TOGETHER?

9 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

10 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

11 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

12 MUTATION DATABASE

13 MANIFESTATIONS Review of 177 patients with GT Mostly mucocutaneous bleeding: George et al, Blood 1990

14 WHAT TO DO, WHAT TO DO

15 TREATMENT - 1 Transfuse platelets Try and minimize blood products given y p g propensity to form isoantibodies

16 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

17 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

18 PREGNANCY High risk ikfor hemorrhageh Often require platelets pre partum and post partum for up to 1 week Prefer HLA compatible platelets

19 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

20 ONE PERSON S DISEASE CAN BE A DRUG COMPANY S TREASURE

21 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

22 BACK TO THE CASE

23 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

24 REFERENCES Arnold DM, Rao AK. ASH SAP: Disorders of platelet number and function Bellucci S, et al. Bone marrow transplantation in severe Glanzmann s thrombasthenia with antiplatelet alloimmunization Bone marrow Transplantation: (25) Connor P, et al. Stem cell transplantation for children with Glanzmann thrombasthenia Brit J Haemat: (140) Dent GA, Eby CS. ASH SAP: Laboratory hematology George JN, et al. Glanzmann s Thrombasthenia: the Spectrum of Disease Blood: (75) Gunaydin B, et al. Recombinant activated factor VII and epsilon aminocaproic acid treatment of a patient with Glanzmann s thrombasthenia for nasal polipectomy J Anesth: (21) OMIM. Glanzmann s thrombasthenia. # Accessed 1/11/12. Nurden AT. Glanzmann thrombasthenia Orph J Rare Disease: 1:10. Nurden A, Nurden P. Advances in our understanding of the molecular basis of disorders of platelet function J Thromb Haemost: (9) Seligsohn U. Glanzmann thrombasthenia: a model disease which paved the way to powerful therapeutic agents Pathophysiol Haemost Thromb: (32) Toogeh G, et al. Presentation and Pattern of Symptoms in 382 Patients with Glanzmann Thrombasthenia in Iran Amer J Hemat: (77):