Transcript PLATLET DISORDERS

PLATELET DISORDERS
Nazzal Bsoul,MD
HEMOSTASIS-1
In health hemostasis ensures that the blood
remains fluid and contained in the vasc.system.
If a vessel wall is damaged,a number of
mechanisms are activated promptly to limit
bleeding,involving
1-Endothelial cells.
2-Plasma coag.factors.
3-Platelets.
4-Fibrinolytic system.
HEMOSTASIS-2
These activities are finely balanced between keeping the
blood fluid and preventing intravasc.thrombosis.
1-Primary hemostasis: vasoconstriction and platelet adhesion and aggregation leading to the formation of the
platelet plug.
2-Secondary hemostasis: involves activation of coag.system leading to the generation of fibrin strands and
reinforce the platelet plug.
3-Fibrinolysis: activation of fibrin-bound plasminogen
resulting in clot lysis.
ROLE OF PLATELETS IN
HEMOSTASIS
1. Each megacaryocyte produces 10002.
3.
4.
5.
2000 platelets,which
Remain in the circulation for about 10
days.
Releasing of hemostatic proteins.
Platelet adhesion.
Platelet aggregation.
Clinical Features of Bleeding
Disorders
Platelet
disorders
Coagulation
factor disorders
Site of bleeding
Skin
Mucous membranes
(epistaxis, gum,
vaginal, GI tract)
Deep in soft tissues
(joints, muscles)
Petechiae
Yes
No
Ecchymoses (“bruises”)
Small, superficial
Large, deep
Hemarthrosis / muscle bleeding
Extremely rare
Common
Bleeding after cuts & scratches
Yes
No
Bleeding after surgery or trauma
Immediate,
usually mild
Delayed (1-2 days),
often severe
Classification of platelet
disorders
Quantitative
disorders
– Abnormal distribution
– Dilution effect
– Decreased
production
– Increased
destruction
Qualitative disorders
– Inherited disorders
(rare)
– Acquired disorders
Medications
Chronic renal failure
Cardiopulmonary
bypass
Thrombocytopenia
Immune-mediated:
Idioapthic
Drug-induced
Collagen vascular disease
Lymphoproliferative disease
Sarcoidosis
Non-immune mediated:
DIC
Microangiopathic hemolytic anemia
IDIOPATHIC THROMBOCYTOPENIC
PURPURA (ITP)
Idiopathic Thrombocytopenic
Purpura (ITP)
Idiopathic thrombocytopenic purpura (ITP,
also referred to as immune thrombocytopenic purpura) is an acquired
disorder.There are 2 diagnostic criteria
1-Thrombocytopenia,with otherwise normal
blood counts,including bl.film
2-No clinically apparent associated conditions
that may cause thrombocytopenia.
ITP: is an isolated,unexplained thrombocytopenia.
Pathogenesis
Is related to peripheral PLT destruction
only ?.
Is related to a combination of increased
PLT destruction along with inhibition
of megakaryocyte PLT production
Clinical Manifestations
There is marked interpatient variability.
Bleeding: can range from severe bleeding
to only petechiae and easy bruising.
Usually mucocutaneous bleeding.
Comparison to vasculitic purpura:
asymptomatic and not palpable.
Intracranial hemorrhage is uncommon.
Incidence of adult ITP increases
with age
Incidence (per 105 / year)
Age (yrs)
Female
Male
Total
15-39
40-59
60+
2.3
3.2
4.6
1.3
1.1
4.4
3.6
4.3
9.0
Total
10,1
6,8
16,9
Frederiksen and Schmidt, Blood 1999:94;909
Initial Treatment of ITP
Platelet count
(per µl)
Symptoms
Treatment
>50,000
None
None
20-50,000
Not bleeding
Bleeding
None
Steroids
IVIG
<20,000
Not bleeding
Bleeding
Steroids
IVIG
Treatment of ITP
Steroids:Prednisolone.
Dexamethasone.
Methyleprednisolone-Pulse therapy.
Splenectomy.
Intravenous immunoglobulin (IVIG).
Other immunosuppressive drugs: mycophenolate,azathioprine(imuran)
Rituximab (Mabthera).
Thrombopoiesis-stimulating agents.
Recombinant FVIIa.(NOVOSEVEN).
Second-line Treatment
Splenectomy ?
Rituximab (Mabthera) ?
Thrombopoiesis-stimulating agents ?
Second-line Management
Splenectomy: traditional second-line
treatment for many years.
It remains the most effective treatment
with the highest rate of complete and
durable remissions.
Thrombopoiesis-stimulating agents:
support the PLT count as long as they
are continued,but do not induce
remissions.Romiplostin,Eltrombopag.
Rituximab (Mabthera)
May induce lower frequency of durable
remissions than splenectomy,but
avoidance of surgery may be the preferred
choice for some patients.
Platelet transfusions
Source
– Platelet concentrate (Random donor)
– Pheresis platelets (Single donor)
Target level
– Bone marrow suppressed patient (>10-20,000/µl)
– Bleeding/surgical patient (>50,000/µl)
THROMBOCYTOSIS
THROMBOCYTOSIS
PLT Count :150,000-450,000/microL.
Thrombocytosis:
1-Reactive (secondary): due to other
conditions.
2-Primary: due to a clonal (neoplastic,
autonomous)hematologic
disorder.
DEFINITIONS
Reactive thrombocytosis(RT): thrombocytosis in the absence of a MPD/MDS.
(recent surgery,bact.inf.,trauma).
Autonomous thrombocytosis (AT): thrombocytosis in the presence of a chr.MPD or
MDS.(E.T.,CML,PMF,PV).
Essential thrombocythemia(E.T.):
Extreme thrombocytosis: PLT count more
than 1,000,000 /microL.
Causes of RT
RT is a much more frequent cause of thrombocytosis than AT even when cases of extreme
thrombocytosis are considered.
Causes of RT:
Infection- 31%
Infection plus postsurgical status - 27%
Postsurgical status - 16%
Malignancy - 9%
Postsplenectomy state - 9%
Acute blood loss or iron deficiency - 8%
GLANZMANN’S
THROMBASTHENIA
(GT)
Background-1
Glanzmann’s Thrombasthenia (GT): is
the third most common inherited
bleeding disorder in Jordan1 .
Was first described by Dr.Eduard Glanzmann in 19182.
1-Awidi AS.Thromb Haemost. 1984 Jul 29; 51 (3): 331-3.
2-Nurden AT. Thromb Haemost 1999: 82: 468-80.
Background-2
Is inherited in an autosomal recessive manner.
The genes of both of these proteins are on
chromosome 17.
Different genetic mutations of either GP IIb or
IIIa genes result in a heterogeneity of
thrombasthenia phenotype.
Carrier detection in GT is important to control the
disease in family members.
Can be acquired as an autoimmune disorder.
Pathophysiol. Haemost. Thromb. 32 (5-6): 216-7.
Br. J. Haematol. 127 (2): 209-13.
Pathogenesis
Platelet glycoprotein IIb/IIIa (GP IIb/IIIa)
complex is deficient or present but
dysfunctional.
Defect in the GP IIb/IIIa complex leads to
defective platelet aggregation and
subsequent bleeding.
Aggregation of PLTs occurs in response to
ristocetin, but not to other agonists
such as ADP, thrombin, collagen or
epinephrine.
George JN, Caen JP, Nurden AT.Blood 1990: 75: 1383-95.
Nurden AT. Thromb Haemost 1999: 82: 468-80.
Frequency
Is quite rare globally, but quite common
in Jordan.
More common in populations where consanguineous marriages are common
( Iran,Israel,French Gypsies ).
Slightly higher female preponderance.
F/M ratio is 2:1 in Jordanians.
Nurden AT. Orphanet J Rare Dise. Apr 6 2006;1:10.
Awidi AS.Am J Hematol. 1992 May ;40 (1) :1-4.
Clinical Manifestations
Common: mucocutaneous bleeding at
birth or early infancy(gum bleeding,
epistaxis)
Rare: muscle hematoma and hemarthrosis
Cannot be distinguished from other cong.
platelet function defects.
Diagnostic Features
Normal PLT count and morphology.
Greatly prolonged bleeding time.
Absence of PLT aggregation in response
to ADP,collagen,epinephrine or thrombin
(Platelet aggregation test)
Flow cytometry (CD 41,CD 61).
Studies of GP IIb/IIIa receptors on the PLT
membrane.
Treatment
No effective treatment for G.T other than platelet
transfusion was available till 1996.
With time most patients become refractory to platelets.
Successful treatment for G.T with rFVIIa in 1996.
Canadian pilot study and additional case studies.
Recently EMEA has approved recombinant
Factor VIIa (NovoSeven) for treatment of GT
Levy-Toledano S et al. Blood 1978; 51: 1065-71.
Poon M-C et al. Blood 1999; 94: 3951–3.
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