CASE

PRESENTATION
DR WARKHA THAKUR
CASE SUMMARY

 2 yr male children came to us with complain of nose bleed 2 month

back On further questioning patient mother told that bleeding was
spontaneous Fresh. Without clots half cup in quantity.
 Patinet was taken to any hospital emergenvy where forcefully
bleeding was stopped.
 Then after 2 months patient has history of trauma to tongue
 Cbc was done with hb 7.3,, mcv 54,5..wbc 20,,plt……platelates
clumps observed but could nt be counted low normal on film,,,
 No h/0 fever at the time of bleeding
 No h/o any kind of joint pain or any symptom of autoimmune
disease
 No h/o any cough
 Systemic history was unremarkable
 No any family history positive…
 No any significant drug history
 No h/o weight loss
EXAMINATION

Vitaly stable…

Patinet was pallor no any bruises or ptechaie rest of the physical

examination were unremarkable…

Oral cavity was clear other than that healing scar mark

No any spleen or liver was palpabl e ascites was nt present

Muskuloskeltal examination was unremarkable.

Rest of the system was normals

INVESTIGATIONS

 Coagulation profile was normal,,,

BT was more than 7 minute
Platelate aggregations study was performed and it was conclusive of
BERNARD SOULIER SYNDROME..
Ristocetin0.5mg‘:0% (0-8)
EPINEPHRINE:51%(48-103)
ADP 56%(50-110)
COLLAGEN 68%(46-112)
RISTOCETIN 1.25mg 1%(53-110)
 Another cbc was done on 23/4/19
 Hb 7,3
 Mcv 54
 Wbc 11,26
 Plt 18

 Peripheral smear showed anisocytosis,hypochromic microcytosis

 Platelates are low on film.large and giant platelates seen.
 As BSS was diagnosed patient family was fully counselled about the
nature of disease and about the mode of inheritance.

 Thy counselled for any kind of life threating bleeding and avoid any
kind of sport contact.

 Patinet was prescribed oral tranxemic acid and iron replacement

and called for follow up.
INTRODUCTION

 BSS is autosomal recessive disorder characterized by prolong bleeding time

and presence of a macro thrombocytopenia.

 It is moderate to severe hemorrhagic disorder with mainly mucocutaneous

bleeding

 Due to mutation in GP 1b-1X-V complex specialy the 1b part that consist of

4 sub unit 1b a ,,1b B s and 9……
 In 1948 2 heamatologist Bernard and soulier discovered this disease.

 The male index case described by Bernard and soulier suffered repeated
bleeds throughout his life and died when aged 28 yrs of a brain
heamorrhage
PATHOPHYSIOLOGY

 NORMAL PLATELET FUNCTION

 Platelet adherence — Platelet-mediated hemostasis is initiated by

exposure of the vascular subendothelium following injury to the
endothelial surface.

 Circulating platelets are recruited to the site of injury and bind to

exposed components of the subendothelium, including collagen,
fibronectin, von Willebrand factor (VWF), fibrinogen, and
thrombospondin via glycoprotein (GP) receptors on the platelet
surface including GPIb/IX, GPIa/IIa, and integrin αIIbβ3
 Platelet activation — Receptor-ligand binding leads to platelet
activation, mediated through calcium-dependent cytoskeletal
changes in the platelet.

 This outside-in signaling is followed by the release of substances from

two sources.
 Platelet alpha granules (VWF, platelet factor 4, thrombospondin,
fibrinogen, beta-thromboglobulin, and platelet-derived growth
factor)
 Platelet dense granules (adenosine diphosphate (ADP) and
serotonin)
 ADP, in turn, mediates inside-out signaling leading to a
conformational change in integrin αIIbβ3 on the platelet surface.

 Platelet aggregation — The integrin αIIbβ3 conformational change

allows the third step in platelet-mediated hemostasis: platelet
aggregation.

 Fibrinogen binds to the conformationally altered integrin

αIIbβ3 receptor on two or more adjacent platelets , resulting in
platelet aggregation and accumulation at the site of the vascular
injury.
 Interaction with coagulation factors — Finally, platelets interact with
circulating coagulation factors by providing a scaffold for the
activation of phospholipid-dependent coagulation factors.

 Activation of platelets alters their phospholipid membranes,

allowing enhanced binding of coagulation factor complexes.
MOLECULAR BASIS

Underlying defect is absence or decreased expression of GP1b/1X/v

complex on the surface of platelates.

This complex is receptor for vWF so that defects result in deficient

binding of vWF resulting in defective platelate adhesion

GP1b is a major sialyted GP on the platelate surface ,,so the absence

or reduction leads to thrombocytopenia and decreased survival..
EPIDEMIOLOGY

 Rare disease affects early in male and female

 Affects 1 in million people

 Upto now only 100 cases has been reported.

Most often found in population of cousin marriage

Clinical Presentation

 Symptoms of BSS varies considerably from one individual to the next,

from very mild to potentially life-threatening bleeding.

 Bleeding is mostly mucocutaneous including:

 Easy bruising
 Nose bleeds
 Bleeding from gums
 Heavy or prolonged menstrual bleeding (menorrhagia) or bleeding
after childbirth

 Abnormal bleeding after surgery, circumcision, or dental work

 It is important to note that deep visceral hematomas, and bleeding

into joints characteristic of coagulation disorders such as
hemophilia, are not usually seen.
HISTORY AND EXAMINATION:

History taking is a key part of assessment of a possible bleeding

disorder
Patient should be assessed for any acquired pathology or vasculitis
Drug history should be taken

 Family history of a bleeding disorder may or may not exist.

 Physical examination should involve skin and oral mucosa

inspection for any bleeding manifestation. The spleen should
normally be unpalpable.
INVESTIGANTIONS:

 Complete blood cell (CBC) count

 Prothrombin time (PT)/Activated partial thromboplastin time (aPTT)
 Bleeding time
 Platelet Function Analyzer 100 (PFA-100) study
 Flow cytometry
 Monoclonal antibody assays
 Platelet aggregation studies
INVESTIGATIONS:

 CBC and peripheral smear examination:

 Platelet count is reduced and peripheral smear shows giant and
abnormal looking isolated platelets .

 BLEEDING TIME:
 The bleeding time (BT) has long been used as a screening test for
platelet function
 Platelet aggregation assays:
 Traditional platelet aggregation assays employ a panel of platelet
agonists to measure platelet activation and aggregation in vitro.

 Since many common medications can affect platelet function,

care must be taken to avoid their use in patients prior to testing.
Common agonists used in these assays include ADP, arachidonic
acid, collagen, epinephrine, thrombin, and ristocetin.
 Normal platelet aggregation in vitro in response to ADP and
epinephrine involves a biphasic respon

 The first wave of aggregation reflects activation of

integrin GPIIb/IIIa and subsequent crosslinking of platelets via
fibrinogen binding. The second wave reflects platelet degranulation
and enhanced aggregation due to the release of platelet agonists
 Curve A: A normal response to addition of
adenosine diphosphate (ADP) is shown,
with a first and second wave (phase) of
aggregation. Curve B: Only a first phase of
aggregation is seen. This pattern is seen in
platelets taken from a patient with a
storage pool defect after addition of an
intermediate dose of ADP. Curve C: No
response. This pattern is seen in platelets
from a patient with Bernard-Soulier
syndrome after addition of ristocetin or in
patients with Glanzmann thrombasthenia
after addition of all agonists except high
dose ristocetin.
 Platelet Function Analyzer (PFA-100) :
 Results of PFA-100 and standard platelet aggregometry are
comparable in terms of sensitivity and specificity.

 A platelet function analyzer (PFA) assay simulates a damaged

vessel wall using collagen ADP- and collagen epinephrine–
embedded cartridges

 Citrated whole blood passes through these cartridges at high shear

stress and platelets bind to the membrane of the cartridge,
blocking the system, and generating the “closure time.”
 PFA is very sensitive in detecting Bernard-Soulier syndrome (BSS),
platelet-type von Willebrand disease (VWD), and Glanzmann
thrombasthenia (GT), but may be normal in patients with storage
pool deficiencies and platelet membrane phospholipid disease

 .PFA closure times are markedly increased even more than 300 sec
in both ADP and EPINEPHRINE cartridges and bleeding time is
significantly prolonged.
but it can be affected by diet ,asprin,hematocrit and low platelet
count.
 Flowcytometry:

 Flow cytometric analysis measures specific receptor densities of

platelets and is very informative for BSS and GT, which are
associated with glycoprotein (GP) deficiencies rather than
dysfunction.

 In flow cytometric analysis, absence or greatly decreased levels of

CD42a and CD42b are consistent with a diagnosis of BSS
MANAGEMENT:

 The majority of patients do not need a therapy on a regular basis,

but require treatment after injury, during surgical procedures, and
during bleeding episodes.

 Education of patients about maintaining dental hygiene, avoiding

contact sports and activities carrying bleeding risk, and avoiding
the use of antiplatelet drugs are very important.

 Bleeding from minor cuts, nose, and gingiva can be stopped by

applying pressure.
 In all patients family screening should be initiated and ciuselling for
mode of inheritance is essential

 Supportive care should include iron replacment

 SPECIFIC MEASURE

 ANTIFIBROLYTIC THERAPY tranxemic acid is widely used (15to 25

mg /kg )PO 10mg/kg if IV ….other measure sach as nasal packing
,,compression sponges or hormonal treatment are safe and
effective.

 DESMOPRESSIN. Although there is little role but may be used in mild

bleeding where antifibrinolytics are not responsive. release the VWF
and causes the platelets adhesion
 Routes IV (0-3microgram/kg )over 30 mint
 Subcutaneous and intra nasal spray..
 PLATELATES TRANSFUSION’are appropriate for life threatning
bleeding and prophylaxis in patients undergoing surgery…

 HLA compatible platelates are recommended to avoid

alloimmunization leukocyte depleted if HLA compatible are not
available.

 Recombinant FVIIa can be used in patients with life threating

bleeding or patient undergoing any invasive procedure where
platelates are not effective due to allo immunization….usual doses
are 90microgram/kg followed by 2 further doses at 2 hr interval.
STEM CELL TRANSPLANTATION;from a family matched donor may be
considered in patienets with recurrent life threating bleeding and
platelates antibody development..
DENTAL EXTRACTION;effective local heamostatic measure includimg
suturing and topical agents are essential..
Oral tranxemic acid started before a day before procedure and
continue for 5-7 days.
FVIIa may be used to cover the dental extraction .there is only case
reported of BSS treated with FVIIa during dental extraction with 4 doses
of 90microgram/kg given 90 mints apart..one dose prior to procedure
and then after with 2 hrly interval.
If bleeding does nt get controlled then HLA matched platelates..
MINOR SURGERY

International registary has successfully reported the use of FVIIa in minor

surgers with the same doses as mentioned.
If patient Does not respond to FVIIa or rebleed with furthers doses of
FVIIa then HLA matched platelates should be used and repeated as
necessary acc to situation.
Oral tranxemic acid should also be prescribed during post operative
period.
MAJOR SURGERY

International registery has successfully repoted the use of recombinant

FVIIa bt due to uncertainity concering the efficacy .

For electives procedures HLA matched platelates are

recommened.adult dose of platelates should be given prior to
procedure and then further doses given acc to clinical condition and
need of the patient.
For emergency procedures random donor platelates has to b given
rather to be delayed while HLA selected platelates are located.
Oral tranxemic acid are also b prescribed during post operative
period.
Thankyou.