PLATELET DISORDERS

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PLATELET DISORDERS

• Nazzal Bsoul,MD

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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.

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HEMOSTASIS-2

• These activities are finely balanced between
  keeping the blood fluid and preventing
  intravasc.thrombosis.
• 1-Primary hemostasis vasoconstriction and
  platelet adhe-
• sion and aggregation leading to the
  formation of the
• platelet plug.
• 2-Secondary hemostasis involves activation of
  coag.sys-
• tem leading to the generation of fibrin
  strands and
• reinforce the platelet plug.
• 3-Fibrinolysis activation of fibrin-bound
  plasminogen resulting in clot lysis.

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ROLE OF PLATELETS IN HEMOSTASIS

1. Each megacaryocyte produces 1000-2000
   platelets,which
2. Remain in the circulation for about 10 days.
   
   
   
   
3. Releasing of hemostatic proteins.
4. Platelet adhesion.
5. Platelet aggregation.

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Platelet interaction
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Clinical Features of Bleeding Disorders

• Platelet Coagulation disorders factor
  disorders
• Site of bleeding Skin Deep in soft tissues
• Mucous membranes (joints, muscles)
• (epistaxis, gum,
• vaginal, GI tract)
• 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, Delaye
  d (1-2 days),
• usually mild often severe

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Classification of platelet disorders

• Qualitative disorders
• Inherited disorders (rare)
• Acquired disorders
• Medications
• Chronic renal failure
• Cardiopulmonary bypass

• Quantitative disorders
• Abnormal distribution
• Dilution effect
• Decreased production
• Increased destruction

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Thrombocytopenia
Immune-mediated Idioapthic Drug-induced Collag
en vascular disease Lymphoproliferative
disease Sarcoidosis Non-immune
mediated DIC Microangiopathic hemolytic anemia
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• IDIOPATHIC THROMBOCYTOPENIC PURPURA (ITP)

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Idiopathic Thrombocytopenic Purpura (ITP)

• Idiopathic thrombocytopenic purpura (ITP,
• also referred to as immune thrombo-
• cytopenic 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 thrombocyto-
• penia.

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Pathogenesis

• Is related to peripheral PLT destruction
• only ?.
• Is related to a combination of increased
• PLT destruction along with inhibition
• of megakaryocyte PLT production

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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.

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Incidence of adult ITP increases with age
Incidence (per 105 / year) Age
(yrs) Female Male Total 15-39 2.3
1.3 3.6 40-59 3.2 1.1 4.3 60
4.6 4.4 9.0 Total 10,1 6,8 16,9
Frederiksen and Schmidt, Blood 199994909
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Initial Treatment of ITP
Platelet count Symptoms Treatment (per
µl) gt50,000 None
None 20-50,000 Not bleeding None Bleeding
Steroids IVIG lt20,000 Not
bleeding Steroids Bleeding
IVIG
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Treatment of ITP

• SteroidsPrednisolone.
• Dexamethasone.
• Methyleprednisolone-Pulse
  therapy.
• Splenectomy.
• Intravenous immunoglobulin (IVIG).
• Other immunosuppressive drugs myco-
• phenolate,azathioprine(imuran)
• Rituximab (Mabthera).
• Thrombopoiesis-stimulating agents.
• Recombinant FVIIa.(NOVOSEVEN).

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Second-line Treatment

• Splenectomy ?
• Rituximab (Mabthera) ?
• Thrombopoiesis-stimulating agents ?

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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.

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Rituximab (Mabthera)

• May induce lower frequency of durable
  remissions than splenectomy,but avoidance of
  surgery may be the preferred choice for some
  patients.

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Platelet transfusions

• Source
• Platelet concentrate (Random donor)
• Pheresis platelets (Single donor)
• Target level
• Bone marrow suppressed patient (gt10-20,000/µl)
• Bleeding/surgical patient (gt50,000/µl)

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Platelet transfusions - complications

• Transfusion reactions
• Higher incidence than in RBC transfusions
• Related to length of storage/leukocytes/RBC
  mismatch
• Bacterial contamination
• Platelet transfusion refractoriness
• Alloimmune destruction of platelets (HLA
  antigens)
• Non-immune refractoriness
• Microangiopathic hemolytic anemia
• Coagulopathy
• Splenic sequestration
• Fever and infection
• Medications (Amphotericin, vancomycin, ATG,
  Interferons)

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• THROMBOCYTOSIS

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THROMBOCYTOSIS

• PLT Count 150,000-450,000/microL.
• Thrombocytosis
• 1-Reactive (secondary) due to other
  conditions.
• 2-Primary due to a clonal (neoplastic,
• autonomous)hematologi
  c disorder.

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DEFINITIONS

• Reactive thrombocytosis(RT) thrombo-
• cytosis in the absence of a MPD/MDS.
• (recent surgery,bact.inf.,trauma).
• Autonomous thrombocytosis (AT) thrombo-
• cytosis 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.

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Causes of RT

• RT is a much more frequent cause of thrombo-
• cytosis 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

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• GLANZMANNS THROMBASTHENIA (GT)

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Background-1

• Glanzmanns Thrombasthenia (GT) is
• the third most common inherited
• bleeding disorder in Jordan1 .
  
• Was first described by Dr.Eduard Glanz-
• mann in 19182.
  
  
  
• 1-Awidi AS.Thromb Haemost. 1984 Jul 29 51 (3)
  331-3.
• 2-Nurden AT. Thromb Haemost 1999 82 468-80.

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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.

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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.

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Frequency

• Is quite rare globally, but quite common
• in Jordan.
• More common in populations where con-
• sanguineous marriages are common
• ( Iran,Israel,French Gypsies ).
• Slightly higher female preponderance.
• F/M ratio is 21 in Jordanians.
• 
  
• Nurden AT. Orphanet J Rare Dise. Apr 6
  2006110.
• Awidi AS.Am J Hematol. 1992 May 40 (1) 1-4.

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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.

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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.

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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 39513.

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• THANK YOU