1. Glanzmann’s thrombasthenia and ICH
3 case reports
non-hematological journals
1 prenatal bleeding associated with transplacental antiplatelet isoantibodies
1 bleeding due to a coexisting intracerebral angioma
No data concerning treatment
accessed nov, 21, 2006

2. Bleeding pattern in Glanzmann’s Thrombastenia
382 patients, South Iran
Epistaxis %
Gingival bleed %
Ecchymosis %
Menorrhagia %
Excessive bleed. at
surgery/circumcis %
GI bleeding %
Hematoma %
Petechia/purpura %
Umbilical cord bl %
CNS bleeding %
Hemarthrosis %
64 patients, France,
+ 113 patients, literature
Menorrhagia %
Easy bruising/purpura 86%
Epistaxis %
GI bleeding %
Hematuria %
Hemarthrosis %
CNS bleeding %
Visceral hematoma %
George et al, Blood, 1990
Toogeh et al, Am J Hematol, 2004

3. Clinical data of ICH in GT
French review (George et al, Blood, 1990): 3 cases (2 children)
meningeal hemorrhage after head trauma
intracerebral bleeding after a fall
one case not described
Iranian population (Toogeh et al, Am J Hematol, 2004):
no data provided
TREATMENT ???

4. Reported rates of patients with ICH in congenital bleeding disorders
Prevalence
References
Platelet function defects
0.3-2%
George et al, 1990
Tooegeh et al, 2004
VWD type 1-2
0.5-2%
Federici et al, 2000
Hemophilia
2-7%
Lijung et al, 1994
Klinge et al, 1998
Stieltjes et al, 2005
VWD type 3 8%
Other rare factor deficiencies
4-10%
Mariani et al, 1978; Lak et al, 1998; Peyvandi et al, 1998; Perry et al, 2002;

5. THE INTERNATIONAL REGISTRY ON rFVIIa AND GT
rFVIIa for treatment of 108 bleeding episodes (76 severe, 32 moderate):
45 nose
29 oropharynx
17 gastrointestinal tract
17 miscellaneous
no data on ICH and
its treatment !?!
Poon et al, J Thromb Haemost 2004

6. ICH IN ACQUIRED GLANZMANN THROMBASTHENIA

7. ICH associated with glycoprotein IIb/IIIa inhibitors
PTCA
4 placebo controlled double-blind RT, 8555 patients (5476 abciximab, 3079 placebo)
ICH rates:
0.15 % abciximab
0.10 % placebo
Higher risk in patients receiving standard than low-dose heparin (0.27% vs. 0.04%)
n = 1369, p<0.001 <75 vs >75 yr
Iakovu et al, Am J Cardiol, 2003
Akkerhuis et al, JAMA, 2001

8. ICH associated with glycoprotein IIb/IIIa inhibitors
Neurointerventional procedures
Potential higher risk:
Patients usually experienced recent ischemic events
Reperfusion injury (increased regional cerebral blood flow + altered autoregulation + microemboli from site of angioplasty)
Elevated blood pressure
Combination of antithrombotic treatments
Piepgras et al, J Neurosurg, 1999; Meyers et al, Neurosrgery, 2000; Abiciximab Stroke Investigators, Stroke, 2000; Qureshi et al, Stroke 2002

9. Rate of CNS bleeding during antiplatelet treatment (RT)
Trial
Population, mean age
Asp
Cl/Ticl
Asp+Cl
CAPRIE
Vascular disease, 63 y
0.3%/y
0.2%/y
CURE
Acute coronary syndromes, 64 y
0.1%/y
0.15%/y
AASPS
Recent ischemic stroke, 61 y
MATCH
Recent ischemic stroke/TIA, 66 y
0.4%/y
0.7%/y
Atrial Fibr. Inv.
Atrial fibrillation, 72 y
CHAMP
Recent myocardial infarction, 64 y
WARIS II
Previous myocardial infarction, 60 y
HOT
Well-controlled hypertension, 62 y
0.04%/y
WHS
Healthy women, 60 y
0.02%/y
RT: randomized trials; Asp: aspirin; Cl: clopidogrel; Ticl: ticlopidine

10. ICH and antiplatelet agents
%/y estimated absolute rate (Hart et al, Stroke, 2005)
21-26% of patients admitted for ICH on antiplatelet treatment (Toyoda et al, Neurology, 2005; Saloheimo et al, Stroke 2006; Foerch et al, Stroke 2006)
Age, previous vascular disease (mainly stroke), hypertension, combination treatment (ASA + clopidogrel, antiplatelet + warfarin) increase the risk (Hart et al, Stroke, 2005)
Treatment as a predictor of unfavorable outcome (?) (Saloheimo et al, Stroke 2006; Foerch et al, Stroke 2006)

11. Aspirin use preceding ICH as a predictor of outcome
yes no
1691 pts, 26% on antiplatelet agents (AA), 12% on oral anticoagulants (OA)
Univariate analysis: significant predictors of in-hospital death or unfavourable functional outcome
AA: OR 1.42, p=0.008
OA: OR 1.53, p<0.001
After adjustment for age and pre-hospital mRS, only oral anticoagulants significant (OR 1.45, p<0.001)
n=138
n = 44
n = 26
Foerch et al, Stroke, 2006
Saloheimo et al, Stroke, 2006

12. ICH AND PLATELET FUNCTION ABNORMALITIES
CONGENITAL
Rare disorders
Unusual bleeding manifestation
Often in neonates and children
Concomitant pro-hemorrhagic conditions
ACQUIRED
Common conditions
Not uncommon bleeding
Elderly patients
Concurrent diseases and predisposing conditions

13. Possible concurrent pro-hemorrhagic conditions in patients with platelet disorders
Prematurity
Birth-related trauma
Trauma
Intracerebral malformations or lesions
Coexisting VWD
Concomitant diseases/drugs
Neonates
Children
Adults

14. ICH in acquired bleeding disorders
ICH and antiplatelet agents
ICH in neonatal age
ICH and liver disease
ICH and uremia

15. Bleeding in neonatal age
Impaired hemostatic system in newborn
 plasma levels of clotting factors and inhibitors
 platelet function (impaired TX receptor- mediated signal transduction and calcium mobilization; abnormal VWF multimeric pattern and platelet adhesiveness
Saxonhouse & Sola, Clin perinatol, 2004; Israels et al, Semin Thromb Hemost, 2003
Increased bleeding risk in pre-term infants (immaturity of vascular bed) due to birth-related trauma
Vacuum/forceps delivery → ICH
2-3-fold increase in risk
Townen et al, NEJM 1999; van Overmeire, Lancet, 2004

16. Platelet dysfunction in liver disease
 platelet count (spleen pooling,  thrombopoietin, antiplatelet antibodies)
Chronic platelet activation and consumption.
Proteolytic degradation of platelet GPs
Interference by FDP, endotoxins, NO, prostacyclin, alcohol, circulating antibodies.
Laffi et al, 1993; Beer et al, 1995; Escolar et al, 1999

17. ICH in liver disease Incidence ???
Anedoctal or case series reports and pathologic studies.
Role for alcohol consumption (independent predictor of enlargement)
Relationship to severity of liver disease (2AP significantly affected) .
Specific sites reported (putamen).
Fujii et al, 1993; Niizumi et al, 1998; Fujii et al, 1998

18. Bleeding tendency in uremia
Association first described in Morgagni’s “Opera Omnia” (1764)
Platelet dysfunction and impaired platelet-vessel wall interaction
? Uremic toxins, Abnormal platelet activation? Proteolytic abnormalities of platelet cytoskeleton proteins/ membrane receptors?
Remuzzi et al, Thromb Res, 1978; Di Minno et al, Am J Med, 1985; Castillo et al, Blood, 1986
platelet dysfunction and bleeding-related morbidity and mortality reduced but not corrected by Dialysis
Remuzzi et al, Nephron, 1978; Di Minno et al, Am J Med, 1985
Relationship with hematocrit
Livio et al, Lancet, 1982; Moia et al, Lancet 1987

19. ICH and uremia Cerebrovascular events: ~ 9% of pts
Incidence of ICH: 8.7/1000 pt/y
Concurrent predisposing conditions: vascluar disease, hypertension, age, drugs (heparin? rhEpo?), duration/ amount of hemodialysis.
Poor prognosis after ICH (60-70% death at 6 mo., poor functional outcome of survivors)
Kawamra et al, 1998; Lin et al, 1999

20. ICH in patients with platelet function disorders Treatment
Lack of guidelines: only anedoctal reports, especially in patients with congenital abnormalities
Multiple platelet abnormalities
Multifaceted pathophysiology of bleeding
Possible Approaches
Platelet Transfusions
Desmopressin (DDAVP)
rFVIIa
NO SPECIFIC DATA ON ICH TREATMENT !!!

21. Platelet function defects Desmopressin (DDAVP) I
1977 use in hemophilia A and vWD
(Mannucci et al, Lancet, 1977; 1:869)
1983 use in uremia
(Mannucci et al, N Engl J Med, 1983; 308:8)
and in liver disease
(Agnelli et al, Lancet, 1983; 1:645)
use in several inherited platelet function defects
(Kobrinsky et al, Lancet, 1984; 1:1145; Schulman et al, Thromb Res, 1987; 45, 165; Nieuwenhuis et al, Ann Int Med, 1988; 108, 65; DiMichele et al, Am J Hematol, 1990; 33, 39)

22. ICH and DDAVP: open issues
Data only in patients with VWD
Prolonged treatment?
Adverse events (thromboembolic risk? thrombocytopenia?)
“Thrombosis following desmopressin for uremic bleeding” Byrnes et al, Am J Hematol 1998
“Desmopressin induces reduction in platelet count in uremia” Rydzewski et al, TH 1986

23. Platelet function defects Desmopressin (DDAVP) II
Responsive*: 202/237 patients (85%)
64 / 77 congenital disorders (83%)
138 /160 acquired disorders (86%)
Usually respond
Storage pool diseases
Receptor or signal transduction defects
May-Hegglin anomaly
Mostly respond
Bernard-Soulier’s disease
Cyclooxigenase deficiency
Usually do not respond
Glanzmann Thrombasthenia
Defects in calcium mobilization
dose test for
each patient
(or family)
* BT normal or  20% shortening,
Schulman et al, 1991

24. DDAVP and inherited platelet function abnormalities
Disorder n
respons.
partial
resp.
no resp.
Bernard-Soulier syndrome 1
Glanzmann’s thrombasthenia 2
Pseudo von Willebrand
ADP receptor defects
Other receptor/trasd. def. 8 3
Storage pool disease 5
May Hegglin abnormality
TOTAL 21
9 (43%) 9
Patients newly diagnosed, single center observational survey,
Coppola et al, Haematologica, XIX SISET Congress, 2006

25. Inherited platelet functional disorders rFVIIa
1996: first report in a boy with Glanzmann’s thrombasthenia (GT) and severe epistaxis
Tengborn & Petruson, Thromb Haemost, 1996
1998: case reports in other inherited and acquired platelet dysfunctions
Bernard-Soulier’s syndrome Peters & Heijboer, Thromb Haemost, 1998
pseudo von Willebrand disease Fressinaud et al, Haemophilia, 1998
uremia Résvéz et al, Thromb Haemost, 1998
myelodisplasia Meijer et al, Thromb Haemost, 1998
: International Registry for rFVIIa in GT: success in 77% of bleeding episodes treated by “optimal regimen” (≥3 bolus infusions ≥85μg/Kg 2.5 hr intervals). No data concerning treatment of ICH Poon et al, J Thromb Haemost, 2004
Breve storia dell’utilizzo dal primo report nel Glanzmann, alle segnalazioni in altre piastrinopatie, la prima case-series di Poon e l’istituzione del Registro

26. ICH & PLATELET DYSFUNCTION A RATIONALE FOR USING FVIIa
Possible ativation of alternative mechanisms of platelet activaton (by-pass of platelet function) (Monroe et al 2000; Kjalke et al, 2001)
Successful use in severe, often refractory bleeding episodes in pts with thrombocytopenia and/or platelet dysfunction (Poon 2000, 2004)
Promising results in patients with spontaneous ICH (Mayer et al NEJM 2005 )

27. rFVIIa for prevention of ICH in pre-term infants: a pilot study
10 pre-term infants, wks of gestation
rFVIIa bolus 100 g/Kg within 2 hrs of life and every 4 hrs for 72 hrs thereafter
2 IVH (1 fatal)
2 thrombus at umbilical artery catheter tip, no venous thrombosis or embolic complications
Veldman et al, Pediatr Crit Care Med, 2006

28. ICH and platelet function defects a case report
F, 13 yr: acute renal failure. Kidney biopsy: severe glomerulonephritis  hemodialysis and treatament with streroids.
8 mo. later: sudden onset of left hemiparesis  CT: large right intraparenchimal cerebral hemorrhage
Neurosurgery: persistent severe bleeding, uncontrolled by surgical hemostasis and fresh frozen plasma.
Urgent new hematoma evacuation needed: hemostatic coverage?

29. Laboratory and clinical evaluation
Hb: 8.9 g/dl, Platelets: 72,000/mmc
PT, aPTT, clotting factors: within normal range
Bleeding time (Ivy): > 15’ (v.n.< 7’)
Apparently spontaneous cerebral hemorrhage, in a young patient with chronic renal failure, moderate thrombocytopenia and prolonged bleeding time
Acquired platelet number/function abnormality (uremic? immunologic?)
Surgical Prophylaxis : rFVIIa
85 g/Kg, bolus infusions starting immediately before surgery and every four hours thereafter.

30. Clinical course
Absence of bleeding during surgery and over the post-operative days (Hb unchanged).
day 3:  Hb saturation; D-dimer  4-5 x
CHEST RX : negative
PULMONARY ISOTOPE SCANNING : multiple perfusion abnormalities in right lung and in lower lobe of left lung  pulmonary embolism
LOWER LIMB VEIN US : negative
Stop rFVIIa; 12 hrs i.v. unfractionated heparin, then s.c. enoxaparin (no bleeding complications)
Exitus on day 14 because of neurological complications.
Coexisting thromboembolic predisposing factors: prolonged imobilization, multiple CVC ?

31. Treatment of ICH in patients with platelet function disorders PERSPECTIVES
Need for adequate clinical trials to assess efficacy/safety of hemostatic treatments.
Careful evaluation of risk/benefit ratio of hemostatically active agents

33. ICH IN PATIENTS WITH CONGENITAL / ACQUIRED PLATELET FUNCTION DISORDERS
Antonio Coppola
Giovanni Di Minno
Centro di Coordinamento Regionale
per le Emocoagulopatie
Policlinico “Federico II”
Napoli

34. CONGENITAL DISORDERS OF PLATELET FUNCTION
Adhesion defects: Bernard-Soulier Syndrome
Collagen-receptor deficiencies
Pseudo-von Willebrand disease
Aggregation defects: Glanzmann Thrombasthenia
Secretion defects: Storage-pool diseases
Activation defects: Release-reaction disorders
Signal-transduction defects

35. ACQUIRED DISORDERS ASSOCIATED WITH PLATELET FUNCTION DEFECTS
Myeloproliferative disorders
Acute leukemia and myelodysplasia
Uremia
Liver disease
Dysproteinemia
Cardiopulmonary bypass
Acquired vWD
Acquired storage-pool disease
Antiplatelet antibodies
Drugs