HT12 - Alterações das Plaquetas Flashcards
Platelet Structure?
► Na observação do ESP, as plaquetas evidenciam-se como pequenos grânulos arroxeados, têm uma forma discóide, anuclear e pequenas.
Peripheral zone
► No glicocálice, como recetor da glicoproteína 1B que se liga ao fator de von willebrand necessário para a adesão ao colagénio; GpIIbIIIA que se liga ao fibrinogénio, necessário à agregação; ligação ao ADP e trombina promovendo a agregação.
► Fatores I, V, VIII na superfície envolvidos na hemostase secundária.
► Camada chamada PF3 (fator plaquetário 3) na superfície, que permite a interação com fatores da coagulação.
► Onde se inicia a formação de tromboxano A2, fundamental apara a estimulação da agregação e vasoconstrição.
Platelet Functions?
► BLOOD CLOTTING
– platelets are responsible for the formation of intrinsic prothrombin activator
► CLOT RETRACTION
– in the blood clot the cells including platelets are entrapped between the fibrin threads; the cytoplasm of platelets contains the contractile proteins actin-myosin and thrombasthenia
► REPAIR OF RUPTURED BLOOD VESSEL
– the PDGF formed in the cytoplasm of platelets is useful for the repair of endothelium and other structures of the ruptured blood vessels
► DEFENSE MECHANISM
– by the property of agglutination, platelets encircle the foreign bodies and kill them by the process of phagocytosis
Megakaryopoiesis?
► Sofre influência de vários fatores de crescimento e hormonas como a Trombopoietina.
► Consiste em duas fases: Diferenciação e Maturação.
► O megacarioblasto - forma imatura dos megacariócitos - replica o seu DNA sem divisão celular, formando células gigantes chamadas de Megacariócitos, caraterizadas pela presença de núcleos multilobados.
► Os megacariócitos localizam-se junto aos sinusóides.
► Estas células possuem prolongamentos citoplasmáticos abundantes denominados Proplaquetas que protudem nos sinusóides sanguíneos para a circulação periférica, libertando pequenos fragmentos.
► São estes fragmentos de megacariócitos libertados na circulação periférica que dão origem às plaquetas.
► A taxa diária de produção de plaquetas é de 35 a 50 mil por microlitro de sangue.
60% das plaquetas estão em circulação periférica e 40% estão sequestradas a nível esplénico.
Regulation of Platelet Number?
► O número de plaquetas circulantes é altamente regulado por uma hormona - a Trombopoietina.
► Esta liga-se aos megacariócitos e cels hematopoiéticas através do recetor da TPO chamado c-mpl, levando ao aumento da produção de plaquetas e de progenitores de megacariócitos.
► Quando o número de plaquetas é normal, leva a um estímulo inibitório, com diminuição da TPO e uma diminuição da produção de plaquetas pelos megacariócitos.
► A TPO é um elemento chave na formação e ativação de plaquetas.
► É produzido constitutivamente no fígado e em menor escala no rim.
► Os níveis circulantes são determinantes para a biomassa de megacariócitos e de plaquetas.
► Quando temos poucas plaquetas em circulação periférica, há um estímulo para a TPO circulante que leva a um aumento da produção de plaquetas pelos megacariócitos.
Main Platelets Disorders?
2 grandes grupos de doenças das plaquetas:
► Caraterizado por alterações a nível da função plaquetária
► Alterações na contagem plaquetária que pode estar diminuída ou aumentada.
Trombocitose?
► Thrombocytosis is defined as a platelet count exceeding the upper limit of the reference range.
► A value of >400K can be used as a guideline;
► Thrombocytosis is usually secondary to some other condition (reactive thrombocytosis) and is not associated with an increased risk of thrombosis or other complications.
► Primary thrombocythemia, on the other hand, may be associated with thrombosis or bleeding.
► Reactive thrombocytosis is far more common than primary thrombocythemia.
► Symptoms: vasomotor (headache, visual symptoms, lightheadedness, atypical chest pain, acral dysesthesia, erythromelalgia), thrombotic, or bleeding complications
Pseudo Trombocitose?
► mixed cryoglobulinemia
► circulating cytoplasmic fragments in patients with leukemia or lymphoma
► circulating cytoplasmic fragments severe hemolysis or burns
Trombocitose Reativa?
► Chronic infection (31%)
► Inflammation (9%)
► Malignancy (non-hematologic malignancies) (14%)
► Post-splenectomy (thrombocytosis is common during the first weeks or months following splenectomy) (19%)
► Iron deficiency (8%)
► Acute hemorrhage or trauma (6%)
Trombocitose Primária?
► in the presence of an established diagnosis of a chronic myeloproliferative or myelodysplastic disorder
► chronic myeloproliferative neoplasms associated with thrombocytosis:
– thrombocythemia (ET)
– polycythemia vera (PV)
– primary myelofibrosis (PMF)
– chronic myeloid leukemia (CML)
► myelodysplastic disorders associated with thrombocytosis:
– 5q- syndrome
– RARS with thrombocytosis (anemia refratária com sideroblastos em anel)
Trombocitose Reativa vs Essencial?
► Essential absent known causes
► Contagem mais baixa na reativa do que na essencial
► Na reativa não existem habitualmente hemorragias graves e o risco trombótico é baixo ou inexistente
► Essencial apresenta esplenomegalia, fibrose da MO, Clusters de megacariócitos na MO
Trombocitopenia?
► Thrombocytopenia is defined as a platelet count below the reference range for a particular laboratory
► <150K can be used as a guide
► Most common cause of clinically important bleeding
► The relationships between platelet count and risk of hemorrhage may not be valid if the patient has a primary platelet disorder, is on medication that interferes with platelet function, or has other risk factors for bleeding
Alterações Qualitativas?
► Prolonged bleeding time (abnormal platelet function screen)
► Clinical evidence of bleeding in the setting of a normal platelet count and normal coagulation
► Platelet dysfunction is frequently associated with excessive bleeding
► Inherited / Acquired
► Platelet morphology may be characteristic of certain types of the thrombocytopathy
Assessment of Platelet Function?
Estudo da função plaquetária:
► Peripheral smear examination
► Platelet aggregation assays
► Platelet Function Analyzer (PFA-100)
► Thromboelastography (TEG)
Morfologia?
► A morfologia pode ser caraterística em algumas doenças plaquetárias funcionais.
► GIANT PLATELETS - size > RBC - Found in:
– increased platelet turnover
– MNP/MDS
► LARGE PLATELETS - size < RBC, but > 1/3 RBC - Found In:
– increased plt. turnover
– myeloproliferative sy.
– MDS
– Bernard-Soulier sy.
– May Hegglin anomaly
– Gray platelet sy.
Morfologia? (2)
► DEGRANULATED, GRAY-COLORED PLATELETS - Found in:
– gray platelet syndrome
– discharge of platelet granules
– in vivo (cardiopulmonary bypass, hairy cell leukemia)
– in vitro (poor venesection technique)
► SMALL PLATELETS - Found In:
– Wiskott Aldrich syndrome
– X-linked thrombocytopenia
Agregação Plaquetária?
► Os testes de ativação/agregação plaquetária expõem a amostra de sangue a agonistas plaquetários como ADP, colagénio e Ristocetina.
► Os vários padrões de resposta permitem inferir à cerca da doença plaquetária em causa.
PFA 100?
► Teste de agregação que procura simular o máximo possível a hemostase primária e secundária, in vitro.
► É útil para avaliar a influência da Aspirina na agregação plaquetária e estudar a doença de von Willebrand.
► Para que o teste seja válido, Ht<30% e plaq >100mil
Thromboelastography (TEG)?
► Testa a agregação e a fibrinólise
► É um teste de difícil interpretação.
► Os padrões de resposta poderão ajudar no diagnóstico diferencial de alterações de plaquetas, da coagulação e da fibrinólise.
Alterações Qualitativas - Acquired and Inherited?
Acquired
► Drug-induced platelet dysfunction
► Disease-induced platelet dysfunction
Inherited
► Adhesion defects
► Aggregation defects
► Secretion disorders/ Storage
► Defects of platelet coagulant activity
Drug Induced?
► Os fármacos mais comuns e mais profundos no grau de disfunção:
► ASPIRIN
- irreversible inhibition of cycloxygenase (COX1 enzyme), 15-30 min after ingestion 40-100 mg, persists 4-5 days
► TICLOPIDIN, CLOPIDOGREL
- Block platelet- ADP receptors, 24-48 hours after ingestion, persists 10 days
► GPIIB/IIIA RECEPTOR ANTAGONISTS (→acquired Glanzmann)
► DIPYRIDAMOLE
- Elevates cAMP level → PGI2 (prostacyclin) effect↑: inhibits platelet aggregation
Disease Induced?
► UREMIA
– presence of toxin or waste products affects action of platelets
► LIVER DISEASE/ALCOHOL
– reduction in clotting proteins, platelets
► DIABETES MELLITUS
– increased platelet reactivity, with intensified adhesion, activation, and aggregation
► CARDIOPULMONARY BYPASS OPERATION
► HEMATOPOETIC DISORDERS
Bernard-Soulier Syndrome?
► Absence or decreased expression of the glycoprotein complex GP Ib-IX-V on the surface of the platelets
► A GPIbα is the receptor of von Willebrand factor ⇒ deficient binding of vWF to the platelet membrane at sites of vascular injury, resulting in defective platelet adhesion.
► Rare autosomal recessive
► Involved genes GP1BA; GP1BB; GP9
► Incidence: <1: 1 million
► Clinical presentation:
– epistaxis, ecchymoses, menorrhagia, gingival bleeding, gastrointestinal bleeding.
Bernard-Soulier Syndrome - Laboratory Results and Diagnosis?
► Bleeding time is markedly prolonged
► Platelet counts are moderately decreased
► Peripheral smear - the platelets are markedly increased in size
► Aggregation in platelet-rich plasma in response to ristocetin is decreased or absent
► Diagnosis:
– demonstrating decreased platelet surface GPIb using flow cytometry
Glanzmann’s Thrombasthenia?
► Abnormalities of integrin alphaIIb-beta3 (GPIIb-IIIa or fibrinogen receptor) platelets less able to adhere to each other and to the underlying tissue of damaged blood vessels.
► Type 1:
– absence of GPIIb-IIIa (< 5%)
► Type 2:
– reduced surface expression of GPIIb-IIIa (10-20%)
► Type 3:
– dysfunction of GPIIb-IIIa
Glanzmann’s Thrombasthenia - Clínica?
► Rare autosomal recessive
► Involved genes ITGA2B; ITGB3
► Incidence: <1: 1 million
► Clinical presentation:
– mucocutaneous bleeding in the neonatal period, menorrhagia, ecchymoses, epistaxis, and gingival hemorrhage.
– may occur in combination with defects in leukocyte function - disorder leukocyte adhesion deficiency III, leukocytosis, delayed separation of the umbilical cord, severe bacterial infections
► Laboratory results:
– normal platelet count and morphology
– platelet aggregation occurs in response to ristocetin, but not to other agonists (such as ADP, thrombin, collagen, or epinephrine).
– clot retraction in absent
► Diagnosis:
– decreased platelet expression of the GPIIb- GPIIIa complex using flow cytometry
Treatment?
► DESMOPRESSIN
– Is a vasopressin analog, improves hemostasis
– It releases FVIII and large multimers of vWF from tissue stores
– Ineffective in patients with Scott syndrome and Glanzmann’s
► TRANSFUSSION
– reserved for life-threatening bleeding because of the development of alloantibodies
– HLA-matched platelets should be considered (apheresis)
► rFVIIa
– in severe bleeding
► ADJUVANT TREATMENT:
– Local hemostatic agents
– Antifibrinolytic agent (tranexamic acid)
– Hormonal control of menses (oral contraceptives)
– Corticosteroids are not beneficial.
► ► Avoid drugs with antiplatelet effect!
