1. 1. An Approach to a Patient with Thrombocytopenia Dr. Amina Nur Nova Resident Internal Medicine BSMMU
2. 2. Process of Hemostasis Vascular injury Serotonin and thromboxane A2 (TxA2) for vasoconstriction Exposure of basement membrane and collagen (negatively charged surface) Platelet adhesion and activation Platelet aggregation (1o homeostatic plug) Fibrin formation via coagulation cascade (2o homeostasis) Clot retraction Fibrinolysis and healing
3. 3. Normal Physiology of Platelets Platelets are normally made in the bone marrow from progenitor cells known as megakaryocytes. Normal platelet lifespan is 10d. Every day, 1/10 of platelet pool is replenished. Normal platelet count is between 150,000 and 450,000/mm3 Contain intracellular granules ( and ) that contain coagulation factors and ADP Production stimulated by thrombopoietin from liver/kidney
4. 4. Young versus old platelets The youngest platelets in the circulation are larger and appear to be more hemostatically active. Thrombocytopenic patients with immune thrombocytopenia (ITP) do not usually have serious bleeding. The small numbers of young platelets in these patients are more hemostatically active than mixed age platelets in normal subjects. Patients with ITP also appear to have less bleeding than patients with similar severities of thrombocytopenia caused by marrow failure, such as subjects following chemotherapy, who also have a population of platelets of mixed age.
5. 5. Reticulated platelets The youngest platelets in the circulation contain RNA and have been called reticulated platelets or the immature platelet fraction (IPF). Normal subjects 1.3 percent Thrombocytopenia with "normal or decreased thrombopoietic activity" 7.5 percent Thrombocytopenia with "increased platelet turnover" 30 percent
6. 6. Thrombocytopenia Thrombocytopenia is defined as a platelet count less than 150,000/microL (150 x 10 9 /L). 2.5 percent of the normal population will have a platelet count lower than this. A recent fall in the platelet count by one-half, while still in the normal range, may herald severe clinical problems and requires active follow-up.
7. 7. How low is too low? 150,000 - 50,000: no symptoms 50,000 - 20,000: first symptoms 20,000-10,000: potentially life-threatening 50% decrease in platelet count or total platelet< 1,00,000/cumm, while the patient is on heparin. Rare(1-3 %) Median Platelet count 50,000-80000. Rarely below 20000/cumm. Clinical manifestations may include venous or arterial thrombosis, necrotic skin lesions at heparin injection sites, or acute systemic reactions subsequent to IV heparin bolus administration.
8. 25. Two types of HIT have been described. Type 1 HIT is a modest transient decrease in platelet counts. occurs within the first 2 to 3 days after heparin initiation. returns to normal spontaneously, even with continuation of heparin. It is generally of no clinical significance.
9. 26. Type 2 HIT less common, seen in about 0.3 to 5% of patients treated with unfractionated heparin. caused by antibodies against platelet factor 4-heparin complex. usually occurs 4 to 14 days after heparin initiation, but may occur earlier in patients with prior exposure to heparin.
10. 27. Mechanism of HIT
11. 28. Mechanism of HIT The antibodies bind to the PF4- heparin complexes on the platelet surface induce platelet activation by cross- linking FcIIA receptors. The activated platelets increase the release and surface expression of PF4, creating a positive feedback loop in which further release of PF4 promotes further platelet activation.
12. 29. Platelet activation results in the release of procoagulant platelet microparticles, platelet consumption, and thrombocytopenia. Marked generation of thrombin, activation of monocytes and other inflammatory cells, and endothelial injury and activation follow, producing the characteristic venous and arterial thromboses of HIT.
13. 30. Treatment Treatment consists of stopping heparin and using alternate anticoagulants like argatroban, lepirudin, bivalirudin. Fondaparinux is a heparin pentasaccharide analogue that does not bind to platelet-factor 4 and thus should not cause HIT. Low molecular weight heparin is not an appropriate anticoagulant in the setting of HIT because of cross reactivity of the antibody. Platelet transfusions are relatively contraindicated in the absence of severe thrombocytopenia with life-threatening hemorrhage
14. 31. Thrombocytopenia in the cardiac patient Several mechanisms in patients undergoing open heart surgery: Cardiopulmonary bypass may result in mechanical destruction of platelets, hemodilution in the bypass circuit, drug-induced platelet destruction. Sepsis, Post-transfusion purpura. The nadir platelet count is typically seen on the second or third day after surgery, with a rapid recovery thereafter. Severe thrombocytopenia is observed in 0.1%-2% of patients after exposure to GPIIb/IIIa inhibitors (eg, abciximab, tirofiban, eptifibatide) during percutaneous coronary intervention.
15. 32. Disseminated Intravascular Coagulation (DIC) DIC is a consumptive coagulopathy complicating several diseases. It is characterized by activation of intravascular coagulation with microvascular thrombi formation, thrombocytopenia, depletion of clotting factors, variable bleeding complications, and end-organ damage.
16. 33. Acute DIC Acute DIC is commonly seen in severe sepsis and septic shock, after trauma (especially neurotrauma), after surgery, as an obstetric complication (eg, abruptio placentae, amniotic fluid embolism, and preeclampsia), after ABO- incompatible blood transfusion, and as a complication of acute promyelocytic leukemia. Consumptive coagulopathy in these cases is severe and leads to bleeding manifestations (eg, mucocutaneous bleeding and blood oozing from wound sites) and frequent organ damage (eg, renal and hepatic damage).
17. 34. Chronic DIC Chronic DIC is more frequently observed in solid tumors and in large aortic aneurysms, usually with few obvious clinical or laboratory indications of the presence of DIC. In chronic compensated DIC, such as a patient with metastatic prostate or GI malignancy in whom a slower rate of consumption of coagulation factors may be balanced by enhanced synthesis. Thus, patients may have only a modest thrombocytopenia and normal PT and aPTT. The diagnosis is based on the presence of microangiopathy on peripheral blood smear and elevated fibrin degradation products (FDP) and D-dimer levels.
18. 35. Investigations PT - increased APTT - increased Fibrinogen - decreased FDP increased BT- Increased. CT- Increased
19. 36. Treatment Focus on addressing underlying disorder Administration of Blood Components and Coagulation Factors platelet , FFP, cryopricipitate Anticoagulation heparin, protein C. Patients with DIC should not in general be treated with antifibrinolytic therapy, e.g. tranexamic acid.
20. 37. Thrombotic Thrombocytopenic Purpura TTP - Diagnostic Features Microangiopathic Hemolytic Anemia (MAHA) Elevated LDH, elevated bilirubin Schistocytes on the peripheral smear MUST BE PRESENT Low platelets - MUST BE PRESENT Fever Neurologic Manifestations - headache, sleepiness, confusion, stupor, stroke, coma, seizures Renal Manifestations - hematuria, proteinuria, elevated creatinine, BUN
21. 38. TTP - etiology An inherited or acquired deficiency (due to autoantibodies) of von Willebrand factor-cleaving protease known as ADAMTS13. leads to accumulation of large multimers of VWF which cause spontaneous platelet aggregation and thrombi. Can be induced by drugs, including ticlopidine, quinine, cyclosporine, tacrolimus, mitomycin C. Increased incidence with pregnancy or HIV
22. 39. TTP -lab CBC normal or slightly elevated WBC. Hb is moderately depressed at 8-9 g/dL. Platelet count ranges from 20,000-50,000 per microliter. PBF : Red blood cells are fragmented and appear as schistocytes. Certain schistocytes have the appearance of helmet cells (H). Spheroidal cells often are present (S). Occasional nucleated erythroid precursors may be present.
23. 40. TTP - Course and Prognosis Treatment relies on Plasma Exchange. Plasma exchange is superior to plasma infusion, but if PLEX is delayed, give FFP. Remove all inciting agents. Platelet transfusions contra-indicated. Multiple case reports of stroke and/or death during or immediately after platelet transfusion. Can consider giving if life-threatening hemorrhage is present, but avoid routine platelet transfusions. Secondary measures if no response to plasma exchange include splenectomy, vincristine
24. 41. HUS - Hemolytic Uremic Syndrome Usually classified along with TTP as TTP/HUS Has fewer neurologic sequelae, more renal manifestations. Usually precipitated by diarrheal illness, especially E. coli O157:H7 or Shigella Seen more in pediatric patients, usually has better prognosis. May respond less well to plasma
25. 42. Thrombocytopenia in pregnancy Platelet counts < 150 X 109/L have been reported in 6%-15% of women at the end of pregnancy, but counts 100 X 109/L are observed in only 1% of women. The most common causes of thrombocytopenia are gestational thrombocytopenia (GT; 70%), preeclampsia (21%), and ITP (3%).
26. 43. Mechanism of GT Accelerated platelet activation in placental circulation. Accelerated consumption of platelet due to reduced consumption during pregnancy.
27. 44. Diagnosis no past history of thrombocytopenia (except during a previous pregnancy) Usually develops in 3rd trimester Mild thrombocytopenia (>70,000/cumm) Asymptomatic resolve spontaneously within 1-2 months after delivery. No foetal complication
28. 45. Treatment no treatment needed, only monitoring. Mode of delivery considered by physician.
29. 46. Pregnancy induced ITP IgG antibody against membrane glycoprotein. Ab can cross placenta and cause foetal thrombocytopenia.
30. 47. Diagnosis Thrombocytopenia in 1st and 2nd trimester. Persistant thrombocytopenia. Increased number of megakaryocytes in bone marrow. Disease of exclusion
31. 48. Table. Suggestions for platelet transfusions Platelet counts below which transfusion should be considered: 10,000/L - prophylactic transfusion 20,000/L - in the presence of bleeding, fever, infection, platelet function defect, or coagulopathy 50,000/L - prior to minor procedures, in actively anticoagulated patients or in the presence of active bleeding 75,000/L - prior to general surgery 100,000/L - prior to neurologic or ophthalmologic surgery
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