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PLATELET 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.

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PLATELET DISORDERS

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  1. PLATELET DISORDERS Nazzal Bsoul,MD

  2. 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.

  3. 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.

  4. ROLE OF PLATELETS IN HEMOSTASIS • Each megacaryocyte produces 1000-2000 platelets,which • Remain in the circulation for about 10 days. • Releasing of hemostatic proteins. • Platelet adhesion. • Platelet aggregation.

  5. 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, Delayed (1-2 days), usually mild often severe

  6. Quantitative disorders Abnormal distribution Dilution effect Decreased production Increased destruction Qualitative disorders Inherited disorders (rare) Acquired disorders Medications Chronic renal failure Cardiopulmonary bypass Classification of platelet disorders

  7. Thrombocytopenia Immune-mediated: Idioapthic Drug-induced Collagen vascular disease Lymphoproliferative disease Sarcoidosis Non-immune mediated: DIC Microangiopathic hemolytic anemia

  8. IDIOPATHIC THROMBOCYTOPENICPURPURA (ITP)

  9. Idiopathic Thrombocytopenic Purpura (ITP) • Idiopathic thrombocytopenic purpura (ITP, also referred to as immune thrombo- cytopenicpurpura) is an acquired disorder.There are 2 diagnostic criteria 1-Thrombocytopenia,with otherwise normal blood counts,includingbl.film 2-No clinically apparent associated conditions that may cause thrombocytopenia. • ITP: is an isolated,unexplainedthrombocyto- penia.

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

  11. 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.

  12. 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 1999:94;909

  13. Initial Treatment of ITP Platelet count Symptoms Treatment (per µl) >50,000 None None 20-50,000 Not bleeding None Bleeding Steroids IVIG <20,000 Not bleeding Steroids Bleeding IVIG

  14. Treatment of ITP • Steroids:Prednisolone. Dexamethasone. Methyleprednisolone-Pulse therapy. • Splenectomy. • Intravenous immunoglobulin (IVIG). • Other immunosuppressive drugs: myco- phenolate,azathioprine(imuran) • Rituximab (Mabthera). • Thrombopoiesis-stimulating agents. • Recombinant FVIIa.(NOVOSEVEN).

  15. Second-line Treatment • Splenectomy ? • Rituximab (Mabthera) ? • Thrombopoiesis-stimulating agents ?

  16. 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.

  17. Rituximab (Mabthera) May induce lower frequency of durable remissions than splenectomy,but avoidance of surgery may be the preferred choice for some patients.

  18. 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)

  19. THROMBOCYTOSIS

  20. 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.

  21. 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.

  22. 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%

  23. GLANZMANN’S THROMBASTHENIA (GT)

  24. Background-1 • Glanzmann’s 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.

  25. 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.

  26. 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.

  27. 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 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.

  28. 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.

  29. 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.

  30. 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.

  31. THANK YOU

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