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MEET THE PLATELET K. Krishnan MD Department of Internal Medicine Acknowledgements My teachers at PGI, Chandigarh, Hammersmith Hospitals, UK and U of Michigan, Ann Arbor American Society of Hematology for images LEARNING OBJECTIVES Understand platelet development and function Understand the classification of platelet disorders Understand the clinical manifestations of platelet disorders Understand the methods available to diagnose platelet disorders Understand the pharmacological agents used to treat platelet disorders PLATELET HEMATOLOGY Platelet development and kinetics Platelet tests Clinical aspects of platelet disorders Qualitative platelet disorders Platelet function disorders Congenital Acquired Quantitative platelet disorders Thrombocytopenia Thrombocytosis Platelet therapeutics PLATELET DEVELOPMENT Small anucleate fragments formed from the megakaryocyte cytoplasm Characteristic discoid shape Hematopoeitic stem cells are converted into MGKs by exposure to the specific growth factor, thrombopoietin Tpo initiates a maturation program Amplifies the megakaryocyte DNA Synthesis of platelet-specific proteins Cytosketal elements, membrane systems and receptor proteins are bulk produced Platelet production begins when microtubules aggregate in the cell cortex, elaborate pseudopodia These pseudopodia develop into proplatelets Platelets are assembled at the end of proplatelets Microtubules deliver intracellular organelles into these proplatelets Platelets are released from the ends of proplatelets PLATELET KINETICS Platelets are produced in bone marrow by megakaryocytes MGKs produce platelets by cytoplasmic shedding into bone marrow sinusoids 1000-5000 platelets per MGK 35k to 50k platelets per microl of whole blood per day Platelet life span 8-10 days Removed from circulation by monocytemacrophage system Determinants of megakaryocytopoiesis and thrombopoiesis. Battinelli E et al. PNAS 2001;98:14458-14463 ©2001 by National Academy of Sciences EARLY MEGAKARYOCYTE INTERMEDIATE STAGE MEGAKARYOCYTE MATURE MEGAKARYOCYTE PLATELET FUNCTIONS Adhere to sites of vascular injury Generate biological mediators Secrete granule contents Form multicellular aggregates Serve as a nidus for plasma coagulation reactions PLATELET FUNCTIONS For these platelet functions, Structural rearrangements Utilize multiple membrane receptors Bind small molecule mediators Bind adhesive glycoproteins and constituents of vascular endothelium Activate a network of complex signaling pathways HOW TO ASSESS PLATELETS Automatic/Manual Platelet count Peripheral smear Bone marrow examination and specialised tests Platelet function testing PFA test/screening test Specific tests using platelet aggregometry (many methods/instruments) Thrombin, Collagen, ADP, Arachidonic acid, Ristocetin Antibody assays CLINICAL FEATURES IN PLATELET DISORDERS Splenomegaly/Chronic liver disease Petechiae or dry purpura Begins in the dependent portions of the body due to venous pressure-ankles and feet in an ambulatory patient Occurs when platelet count decreases; not seen in disorders of platelet function Differentiate dry non-palpable purpura from palpable purpura seen in vasculitis eg. Henoch-Schonlein purpura Wet purpura- look in mouth, oral mucosa Sign of severe thrombocytopenia Denotes risk for significant hemorrhage Excessive bruising Seen in disorders of platelet function and number CLINICAL FEATURES OF PLATELET DISORDERS HIGH PLATELET COUNT Thrombocytosis Symptoms due to high platelet count Easy bruising Bleeding due to platelet dysfunction Thrombotic tendencies TIAs Erythromelalgia Mild splenomegaly BRUISING PURPURA PURPURA PURPURA Seen in dependent areas of the body Palpable purpura: Henoch-Schonlein Purpura SCURVY Arch Dermatol. 2010;146(8):938-938. doi:10.1001/archdermatol.2010.162 Date of download: 6/10/2012 Copyright © 2012 American Medical Association. All rights reserved. PLATELET FUNCTION DISORDERS Defects of platelet-vessel wall interaction (disorders of adhesion) Defects in platelet- platelet interaction (disorders of aggregation) Defects in platelet- agonist interaction (TXA2, COX, Collagen, ADP) Defects in cytoskeletal regulation Storage pool deficiency Quebec platelet disorders Disorders of platelet secretion and signal transduction Congenital afibrinogenemia Glanzman’s thrombasthenia Disorders of platelet secretion and abnormalities of granules Von Willebrand disease Bernard Soulier syndrome Wiskott- Aldrich syndrome Disorders of platelet coagulant-protein interaction (membrane phospholipid defects) Scott syndrome INHERITED PLATELET DISORDERS Rare, heterogenous group Not often seen in clinical practice Yet fascinating abnormalities that provide insight into normal platelet biochemistry and physiology INHERITED PLATELET DISORDERS Disorders of Platelet membrane Platelet granule packaging Hereditary macrothrombocytopenias Platelet signaling disorders Platelet coagulant function disorders PLATELET MEMBRANE DISORDERS GLANZMAN’S THROMBASTHENIA “Weak platelets” Platelets carry out most of the functions Platelet count is normal Platelet morphology is normal Platelets adhere normally to vascular endothelium Platelets secrete granules and perform normal signalling functions Platelets DO NOT AGGREGATE due to loss of GpIIb/IIIa receptor Normally this complex binds fibrinogen linked into multicellular aggregates PLATELET MEMBRANE DISORDERS GLANZMAN’S THROMBASTHENIA Inherited Most are compound heterozygotes Life long mucosal bleeding Life long platelet transfusions Recombinant Factor VII Acquired Rare, autoantibodies that bind to GpIIb/IIIa epitopes Seen in ITP and in patients with normal counts Steroids may not work Immunotherapy/Rituxan may work BERNARD SOULIER SYNDROME Autosomal recessive Gp1b deficiency or defect Gp1b is the principal receptor for vWF No functioning Vwf receptor Platelets cannot adhere to vascular endothelium Giant platelets and thrombocytopenia Large size due to lack of interaction between actin binding proteins in platelet cytoskeleton and cytoplasmic domain of gp1b Lack of gp1b bound sialic acid residues causes shortening of platelet survival leading to thrombocytopenia Platelet transfusions, DDAVP and fibrinolytic inhibitors like EACA WHAT IS THIS? ACQUIRED QUALITATIVE PLATELET DISORDERS Drugs Aspirin Treat with platelet transfusions for severe bleeding NSAIDs Glycoprotein inhibitors like Abciximab ADP receptor antagonists like Clopidrogel Uremia Toxic effects of uremia plasma, impaired plateletvessel wall adhesion and increased production of NO Platelet transfusions ineffective Treat with dialysis, DDAVP, conjugated estrogens Myeloproliferative disorders Myelodysplastic disorders WHAT IS THIS? How does it happen? PSEUDO-THROMBOCYTOPENIA Pseudothrombocyt openia secondary to platelet satellitism is illustrated in this image. Platelets are shown to adhere to the cytoplasmic membrane of two of the PMNs present on this peripheral blood smear. This phenomenon is an in vitro artifact that occurs with EDTA anticoagulant. Collection of the blood specimen in either sodium citrate or heparin corrects the abnormality. CLASSIFICATION OF THROMBOCYTOPENIA Impaired or decreased production Congenital May –Hegglin anomaly Bernard- Soulier syndrome Wiskott- Aldrich syndrome TAR Congenital amegakaryocytic thrombocytopenia Neonatal Infective/viral Drug induced Acquired Increased platelet destruction Immune ITP Drug induced HIT Non-immune Thrombocytopenia in pregnancy and pre-eclampsia HIV TTP DIC HUS Drugs Disorders related to distribution or dilution Splenic sequestration Kasabach-Merritt syndrome Hypothermia Loss of platelets- massive blood transfusion, extracorporeal circulation THROMBOCYTOPENIA Impaired or decreased platelet production Megakaryocyte hypoplasia Ineffective thrombopoeisis Usually congenital and include Fanconi anemia, thrombocytopenia with absent radii (TAR syndrome), Wiskott- Aldrich syndrome, BernardSoulier syndrome, May Heglin anomaly, congenital amegakaryocytic thromobocytopenia Megaloblastic anemia Miscellaneous Viral Marrow infiltration by malignancy, myelofibrosis MAY-HEGGLIN ANOMALY MAY-HEGGLIN ANOMALY A macrothrombocyte is present in this view. The PMNs have blue cytoplasmic inclusions bordering the cell surface membrane. These inclusions contain precipitated nonmuscle myosin heavy chains characteristic of this group of congenital quantitative platelet disorders. Neutrophil function in this disorder is normal. CONGENITAL AMEGAKARYOCYTIC THROMBOCYTOPENIA AR disorder causing bone marrow failure Seen in infancy Platelet count <20 Petechiae and physical anomalies Develop aplastic anemia, MDS and leukemia Stem cell transplantation is curative Mutations in the c-mpl gene leading to loss of the thrombopoietin receptor function Loss of TPO receptor function causes reduction in MGK progenitors and high TPO levels ACQUIRED HYPOPLASIA Drugs Chemotherapy drugs Zidovudine Ethanol Interferon therapy Anticonvulsants Antibacterial agents like chloramphenicol INFECTION INDUCED THROMBOCYTOPENIA Many viral and bacterial infections without DIC Infections affect platelet survival and production; immune mechanisms can also be at work (Infectious mononucleosis, early HIV) At times, bone marrow exam may be required for occult infections THROMBOCYTOPENIA INCREASED PLATELET DESTRUCTION Immune thrombocytopenic purpura Acute Disorder of children Abrupt onset Follows an infection usually nonspecific respiratory or GI virus Diagnosis is clinical Most patients recover without treatment within 3 weeks Severe cases can be treated with IVIG, platelet transfusions and splenectomy Occasionally seen in adults THROMBOCYTOPENIA INCREASED PLATELET DESTRUCTION Chronic ITP 20-50 yrs of age Females:males 2:1 Mucocutaneous bleeding, menorrhagia, recurrent epistaxis or easy bruising Immune mediated destruction of platelets Autoantibodies against platelet glycoproteins CLINICAL PICTURE OF ACUTE AND CHRONIC ITP Characteristics Acute Chronic Age at onset 2-6 yrs 20-50 yrs Sex predilection None Female over male 3:1 Prior infection Common Unusual Onset of bleeding Sudden Gradual Platelet count <20 30-80 Duration 2-6 wk Months to years Spontaneous remission 90% Uncommon Seasonal pattern High in winter/spring None Therapy 70% steroid responsive 30% steroid responsive Splenectomy rare Splenectomy <45 yr 90% response >45 yr 40% response BONE MARROW IN ITP MEGAKARYOCYTIC HYPERPLASIA PhlWHWWegmasia Cerulea Dolens Bawrham K, Shah T. N Engl J Med 2007;356:e3.WHA HEPARIN-INDUCED THROMBOCYTOPENIA (HIT) Differs from other drug induced thrombocytopenias Thrombocytopenia never severe ie <20k Not associated with bleeding but with thrombosis Antibody to a complex of platelet specific PF4 and heparin (anti-PF4/heparin) Antibody activates platelets through the FcYR II a receptor; also activates endothelial cells Many patients exposed to heparin develop this antibody though not all develop HIT and even less develop HITT HIT Both standard heparin and LMWH can cause HIT-former more common Heparin exposure 5-10 days Rarely HIT can develop several days after heparin discontinued called delayed onset HIT Diagnostic algorithm 4Ts Thrombocytopenia Timing of platelet drop Thrombosis oTher cause of thrombocytopenia not evident CLINICAL TEACHING POINTS ABOUT HIT Early recognition; HIT remains a clinical diagnosis Thrombosis can be arterial and/or venous When HIT suspected, doppler legs Anticoagulate when HIT suspected even in the absence of thrombosis because of higher rate of thrombosis (alternate AC followed by 3-6 months of warfarin) Risk of thrombosis persists for about 1 month after diagnosis of HIT Do not introduce warfarin alone in setting of HIT or HITT as it may precipitate thrombosis especially venous gangrene. Start after several days of alternate anticoagulation ALTERNATE ANTICOAGULANTS IN HIT/HITT Direct thrombin inhibitors Argatroban Lepirudin Bivalirudin Both approved in the US Effective but not FDA approved Antithrombin-binding polysaccharide Fondaparinux Effective but not FDA approved in the US Anti-Xa Danaproid No longer available in the US PREGNANCY AND THROMBOCYTOPENIA You are asked to see a pregnant patient with thrombocytopenia. What is the differential diagnosis? Differential diagnosis of thrombocytopenia in pregnancy MAHA Thrombocyto penia Coagulopath y HTN Liver disease Renal disease CNS Time of onset ITP ------ Mild to severe ------- -------- --------- --------- --------- Anytime common in first tri Gestational -------- Mild ------- --------- --------- --------- --------- 2nd-3rd tri Preeclampsia Mild Mild to moderate Absent to mild Mod- to severe ------- Protein Seizures 3rd trim HELLP Moderate to severe Mod to severe Mild Absent to severe Mod to severe Absent to moderate Absent to moderate 3rd trim HUS Mod to severe Mod to severe Absent Absent to mild Absent Mod to severe Absent to mild Post partum TTP Mod to severe Severe Absent Absent Absent Absent to moderate Absent to severe 2nd- 3rd trim AFLP Mild Mild to mod Severe Absent to mild Severe Absent to mild Absent to mild 3rd tri NON-IMMUNE MECHANISMS OF PLATELET DESTRUCTION Thrombocytopenia in pregnancy and preeclampsia Gestational thrombocytopenia Commonest cause Usually mild Healthy with no prior history of thrombocytopenia Mechanism unknown Return to normal a few weeks after delivery NON IMMUNE CAUSES OF PLATELET DESTRUCTION Thrombocytopenia in preeclampsia and hypertensive states in pregnancy Thrombocytopenia occurs in about 15- 20% of preeclampsia Some have microangiopathic hemolysis, elevated liver enzymes, and low platelet count-HELLP syndrome Thrombocytopenia is due to platelet destruction Perhaps an underlying low grade DIC or ? Immune process Delivery is the treatment for this conditionthrombocytopenia will resolve in a few days post delivery MICROANGIOPATHIC HEMOLYTIC ANEMIA (MAHA) NON IMMUNE CAUSES OF PLATELET DESTRUCTION Thrombotic thrombocytopenic purpura Triad of microangiopathic hemolytic anemia, thrombocytopenia, neurological abnormalities Sometimes the pentad- fever + renal dysfunction Four types Single acute episode Recurrent episodes Drug induced Chronic relapsing-rare form, starts in infancy TTP Hyaline thrombi in end arterioles and capillaries Hyaline thrombi are composed of platelets and von Willebrand factor with little or no fibrin or fibrinogen Deposition of these platelet-vWf thrombi leads to thrombocytopenia Degree of thrombocytopenia is related to extent of microvascular platelet aggregation RBCs flowing under arterial pressure fragment when they have to manouever these thrombi in the microvessels TTP Thrombotic lesions give rise to other manifestations Organ ischemia Neurological Visual Abdominal-pain due to mesenteric ischemia, bleeding due to thrombocytopenia Renal Overwhelming renal damage is not usual; if so, consider HUS TTP Hemolysis can be severe Smear shows marked decrease in platelets, RBC polychromasia and RBC fragmentation (microspherocytes, shistocytes) called MICROANGIOPATHIC HEMOLYTIC ANEMIA Coagulation tests remain normal TTP Accumulation of unusually large von Willebrand factor (ULVWF) In the plasma, ULVWF is rapidly cleaved by a VWF cleaving metalloprotease also called “ a disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs” (ADAMTS 13) SO WHAT HAPPENS IN TTP? Familial chronic relapsing TTP Sporadic Deficiency or absence of the Vwf cleaving protease Autoantibody against the protease causing deficiency or loss of function Measurement of the vWF protease enzyme (not rapid enough for clinical use) THROMBOCYTOPENIA IN THE ICU Sepsis is commonest Often multifactorial, exact cause may be difficult to pinpoint Infection, sepsis, shock Heparin Other drugs DIC Massive blood transfusion Post transfusion purpura CPR Cardiopulmonary bypass ARDS Pulmonary emboli Intravascular catheters DRUG INDUCED THROMBOCYTOPENIA Drug dependent antibodies specific for the drug structure and bind tightly to the platelets by the Fab region in the presence of the drug Platelets seem to be the favorite target of these drug dependent antibodies When should DIT be suspected? Unexpected occurrence of thrombocytopenia Recurrent episodes of thrombocytopenia with quick recovery Misdiagnosis of ITP Beware of quinine containing agents like tonic water, bittter lemon; foods such as tahini containing sesame seeds, herbal remedies like Jui herbal tea List of drugs from www.ouhsc.edu/platelets ANTITHROMBOTIC AGENTS AND THROMBOCYTOPENIA Presents as acute ITP 0.1% - 2% of patients have severe thrombocytopenia within several hours of exposure to Abiciximab, Tirobifan or Eptifibatide About 12% can become acutely thrombocytopenic after second exposure to Abiciximab Immediate reactions are due to presence of naturally occurring antibodies against structural elements of abiciximab or due to structural changes to GpIIb/IIIa induced by binding of Tirobifan and Eptifitabide. Immune-Mediated Thrombocytopenia. Warkentin TE. N Engl J Med 2007;356:891-893. THROMBOCYTOPENIA Dysplastic megakaryocytes Myelodysplastic syndromes Chemotherapy effects Failure of function of megakaryocytes due to defects in DNA synthesis B12 deficiency Folate deficiency DYSPLASTIC MEGAKARYOCYTE DYSPLASTIC MEGAKARYOCYTE APPROACH TO THROMBOCYTOPENIA Plt <150 Hb and WBC count Normal Abnormal Smear Bone marrow exam Fragmente d red cells Normal RBC, platelets normal DIC/TTP Consider Drugs, Infection, ITP, Congenital THROMBOCYTOSIS Reactive thrombocytosis Associated with blood loss and surgery Post splenectomy Iron deficiency anemia Inflammation and disease Stress or exercise Clonal thrombocytosis Polycythemia vera CML Myelofibrosis Primary or Essential thrombocythemia MDS associated THROMBOCYTOSIS IN CML MICROMEGAKARYOCYTES IN PERIPHERAL BLOOD PLATELET THERAPEUTICS Platelet transfusions Platelet pheresis Manipulation of the immune system Prevention of complications Reduction of platelet number Hydrea Suppression of megakaryocyte platelet production IVIG, Steroids, Rituxan, Splenectomy, immunosuppressives Anagrelide Stimulation of megakaryocyte production Thrombopoeitin mimetics or TPO mimetics Romiplostim Eltromobag Inhibitors of platelet aggregation Aspirin, Clopidrogel, NSAIDs Gp IIb/IIIa inhibitors Dipyridamole THROMBOPOEITIN MIMETICS Romiplostim Trade name is Nplate TPO receptor agonist Route: subcutaneous Mechanism: Like endogenous TPOincreases platelet production by binding and activating TPO receptor Indications: Chronic ITP Dose titration based on platelet count Eltromobag Trade name is Promacta TPO receptor agonist Route: oral Mechanism: similar to Nplate Indications: Chronic ITP Dose titration based on platelet count
