Diagnosis and management of thombocytopenic disorders
Diagnosis and Management ofThombocytopenic Disorders Dr Hamid Hassan Registrar Dept. of Gastroenterology CMCH
Overview• Normal Physiology• Categories of Thrombocytopenias• ITP• TTP• HIT• DIC• HUS
Early Haemostatic response & coagulation Role of platelet
Pre-injury conditions encourage flow.The vascular endothelium produces substances (including nitric oxide, prostacyclin andheparans) to prevent adhesion of platelets and white cells to the vessel wall. Platelets andcoagulation factors circulate in a non-activated state
• At the site of injury the endothelium is breached, exposing subendothelial collagen. Small amounts of tissue factor (TF) are released. Platelets bind to collagen via a specific receptor, glycoprotein Ia (GPIa), causing a change in platelet shape and its adhesion to the area of damage by the binding of other receptors (GPIb and GPIIb/IIIa) to von Willebrand factor and fibrinogen respectively. Coagulation is activated by the tissue factor (extrinsic) pathway, generating small amounts of thrombin
Normal Physiology- Production and Number• 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
Thrombocytopenia- How low is too low?• 150,000 - 50,000: no symptoms – No treatment generally required.• 50,000 - 20,000: first symptoms – Generally need to begin therapy• 20,000-10,000: life-threatening - spontaneous bleeding – Generally requires hospitalization• <10,000: risk for spontaneous intracranial hemorrhage
Evaluation of Patient with Low Platelets• History – Has the patient ever had a normal platelet count? – Carefully review medications, including OTC meds. • Antibiotics, quinine, anti-seizure medications – Ask about other conditions which may be associated with low platelets • Liver Disease/hepatitis • Thyroid Disease - both hypo- and hyper- • Infections: viral, rickettsial • Pregnancy – Ask about other conditions which may be associated with ITP • Lupus, CLL, lymphoma
Evaluation of Patient with Low Platelets• Physical – Evaluate for lymphadenopathy and splenomegaly – Look for stigmata of bleeding – Blood blisters and oral petechiae, ie “Wet Purpura” • best harbinger of intracranial hemorrhage• Laboratory Data – Other blood counts should be normal. – Check B12 and folate levels. – Look at peripheral smear to exclude pseudothrombocytopenia, also exclude TTP (especially if anemia also present.) – Send coagulation screens (PT/PTT) to exclude DIC – Send HIV, hepatitis serologies and TSH• Consider doing a bone marrow biopsy – Megakaryocytes should be present.
ITP• Definition: isolated thrombocytopenia with no clinically apparent associated conditions or other causes of thrombocytopenia.• Etiology: autoantibodies directed against glycoprotein IIb/IIIa on platelet surface. IgG- coated platelets are taken up by RE system.• Incidence: approximately 100 per million; half of these are children. In adults, two peaks: – one are young (<40) with female predominance, – one are older (>60), no gender predominance. Association ; connective tissue disease , HIV infection ,B cell malignency ,drugs
Workup• CBC – Isolated thrombocytopenia. – Truly giant platelets on peripheral smear suggest congenital thrombocytopenia. – The WBC count and hemoglobin typically are normal, unless severe hemorrhage has occurred. bone Marrow : increase megakaryocyte• Coagulation studies are normal, and a bleeding time is not useful.
Management ITP• Asymptomatic pt• Symptomatic pt - initial management -subsequent management. Relapsed ITP by steroid, splenectomy, anti D immune globulin. Refractory ITP
Management of ITP Asymptomatic Adult• If platelet count is >30 K, no therapy is required. Check platelet counts at intervals.• If platelet count is < 30 K, begin therapy with corticosteroids.• Stop all NSAIDS and ASA to improve platelet function.
Initial Management of ITP Adult with Symptomatic Purpura• If platelet count is >10, prednisone alone - use 1 mg/kg.• If platelet count <10, treat with prednisone, but also add IVIg 1g/kg/d x 2d. - may require admission• Along with prednisone, add Calcium and Vitamin D to prevent bone loss.• If patient has severe bleeding, may need platelet transfusions.
Subsequent Management of ITP Adult with Symptomatic Purpura• Follow platelet counts daily until >20, then can d/c patient with close follow-up• Once platelet count normalizes, commence a slow steroid taper over 6-8 weeks.• 1/3 of adults will have gone into remission.• 2/3 of patients will relapse during or after steroid taper.
Management of Relapsed ITP• Once the patient relapses, may need to re-introduction of steroids to increase the platelet count out of the danger range, but THIS CANNOT SUBSTITUTE FOR DEFINITIVE THERAPY.• Prednisone is now a crutch to support a dangerously low platelet count.• Options now include splenectomy (standard of care if 2 relapse) or intermittent treatment with anti-D immune globulin .
Management of Relapsed ITP by Splenectomy• effective in 2/3 of patients• Complete remission 70% ,• improvement in 20-25%• via open method or laparoscopically.• vaccinate against encapsulated bacteria (Pneumococcal ,meningococcal, H. influenzae) 2 weeks before procedure.• Pen V 500mg BD life long• May need steroids and/or IVIg before procedure to boost platelet counts preoperatively.
Management of Relapsed ITP Anti-D Immune Globulin• Can be used as a substitute for IVIg for maintenance therapy• Especially useful in patients with contraindications to splenectomy.• Coats red cells with IgG and allows red cells to serve as decoy for splenic macrophages.• Patient must be Rh positive.• Not effective after splenectomy.• Designed to cause hemolytic anemia--Hgb may drop as much as 3g/dl.• Intermittent dosing may allow patients to avoid splenectomy.
Case 1• A 19 y.o. female college student presents with a rash over her lower extremities. She had a viral illness 2 weeks ago. She has no other medical problems, and she takes no medications.• Physical examination reveals petechiae over the shins.• Platelet count is 20K.
Case 1…• The patient is begun on prednisone at 1 mg/kg.• Seven days later, the patient returns, complaining of acne, insomnia, severe indigestion, and visual hallucinations. The platelet count is 250K. Prednisone dose is tapered over 8 weeks, and the patient remains asymptomatic with normal platelet counts.
Case 3• A 46 y.o. woman is found to have a platelet count of 20 on routine laboratory testing. She has some easy bruising and gum bleeding, but admits to not flossing.• She has no PMHx, and is on no medications. She works as a school principal.• She is started on 1 mg/kg of prednisone.
Case 3..• After 1 week, the platelet count is 180, and the prednisone dose is tapered by 10 mg per week. When she reaches a dose of 10 mg qd, the patient develops severe menstrual bleeding and is noted to have a platelet count of 8k.• She is admitted to the hospital, and is begun on IVIg at 1g/kg IV qd x 2d. The prednisone dose is increased to 60 mg daily. By the third day, the platelet count is 60K.
Case 3..• The patient is vaccinated against pneumococcus, meningococccus, and Hemophilus influenzae.• She undergoes laparascopic splenectomy, which is uneventful. The platelet count rises to 600K. She is successfully weaned off steroids.
Management of Refractory ITP• One third of patients will have an inadequate response to splenectomy.• Management of these patients involves accepting that they have a chronic, incurable condition.• Target platelet counts should be lower--aim for about 30K or absence of bleeding.
Treatment of Refractory ITP• Immunosuppressive agents – Rituximab (anti-CD20) • 40% effective • May be used before splenectomy – Mycophenolate mofetil – Cyclophosphamide• Adjunct agents – Thrombopoietin Receptor Agonists • Romiplostim • Eltrombopag
Drugs Commonly Implicated in Thrombocytopenia• Beta-lactam antibiotics.• Trimethoprim-sulfamethoxazole and other sulfa drugs.• Vancomycin.• Quinine/quinidine.• Heparin.• Abciximab .• H2 blockers• If a patient’s platelets fall, ALL unnecessary drugs need to be stopped.• give platelet transfusions , IVIg is particularly helpful in quinine-induced ITP. ,
Case 4• A 55 y.o. woman presented with bleeding from her nose and mouth and gums.• PMHx - HTN, DM, DJD• Medications - glucotrol, glucophage, HCTZ, quinine for leg cramps• PEx - petechiae over limbs and torso, blood blisters in mouth, epistaxis.• Platelet count 2K
Case 4• Pt admitted to hospital, quinine stopped, patient treated with platelet transfusions and IVIg.• Platelet count rose to normal over the next 5-6 days.• Eight months later, thrombocytopenia recurred, and patient admitted to taking quinine again for recurrent leg cramps.
Heparin-Induced Thrombocytopenia • Seen in 1-3% of patients treated with heparin • Usually, 7-10 d after heparin started, platelets fall by at least 1/3 to 1/2. – Patients do not have to be thrombocytopenic. – Can occur earlier in patients who have been previously exposed to heparin, even as SQ injections. • Caused by antibodies against the complex of heparin and PF4. These antibodies activate platelets. • Can lead, paradoxically, to THROMBOSIS, in up to half of patients. • More common in patients with vascular disease
HIT/T treatment1. IF PLATELETS FALL ON HEPARIN, STOP HEPARIN IMMEDIATELY.2. Stop heparin3. Stop heparin4. Use a different anticoagulant 1. Lepirudin 2. Argatroban
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 BUN/Creatinine• Abdominal Pain - can see elevated lipase/amylase
TTP - etiology • May be associated with an antibody against or a deficiency of the protease which cleaves the ultra-high molecular weight multimers of von Willebrand’s factor. These very high molecular weight vWF multimers cause abnormal platelet activation. • Can be induced by drugs, including ticlopidine, quinine, cyclosporine, tacrolimus, mitomycin C. • Increased incidence with pregnancy or HIV
TTP -labCBC normal or slightly elevated WBC.• Hemoglobin is moderately depressed at 8-9 g/dL.• Platelet count ranges from 20,000-50,000 per microliter.• Peripheral smear : 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.
TTP - Course and Prognosis• 95% fatal prior to therapy, now 5% fatal.• 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
DIC• Pathophysiology 4 simultaneously occurring mechanisms:• TF-mediated thrombin generation• Dysfunctional physiologic anticoagulant mechanisms (eg, depression of antithrombin and protein C system),• Impaired fibrin removal due to depression of the fibrinolytic system – caused by high circulating levels of plasminogen activator inhibitor type 1 (PAI-1);
Underlying conditions• Infection/sepsis• Trauma• Obstetric, e.g. amniotic fluid embolism, placental abruption, pre-eclampsia• Severe liver failure• Malignancy, e.g. solid tumours and leukaemias• Tissue destruction, e.g. pancreatitis, burns• Vascular abnormalities, e.g. vascular aneurysms, liver haemangiomas• Toxic/immunological, e.g. ABO incompatibility, snake bites, recreational drugs
RX --DIC• focus on addressing underlying disorder• Administration of Blood Components and Coagulation Factors – platelet , FFP, cryopricipitate• Anticoagulation – heparin,proteinC• Patients with DIC should not in general be treated with antifibrinolytic therapy, e.g. tranexamic acid.
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 exchange.