1 Chapter 43 Thrombocytopenia and Thrombocytosis Bleeding Disorders Platelet abnormalities Skin, mucous membranes, mucocutaneous Petechiae, purpura, ecchymosies,

s, epistaxis, gingival bleeding vs. vascular disorders Clotting factor deficiencies Deep tissue bleeding hematoma, hemarthrosis Genetic defect not established yet Epstein deafness, ocular problems, glomerulonephritis Neonatal thrombocytopenia and congenital absence or extreme hypoplasia of the radial bones with absent, short or malformed ulnae Transient leukemoid reactions, cardiac lesions Fetal injury at 8 weeks of gestation Radiation sensitivity syndrome

TAR

Thrombocytopenia
(<100,000/cu.mm) Decreased / Impaired Production Megakaryocyte hypoplasia Ineffective thrombopoiesis Accelerated Destruction Abnormal Distribution/Sequestration Congenital Hypoplasia May Hegglin Bernard Soulier Fechtner Sebastian Epstein Montreal platelet Fanconi anemia Wiskott Aldrich TAR Congenital amegakrayocytic thrombocytopenia Autosomal dominant and x linked thrombocytopenia May Hegglin Mutation in MYH9 gene that encodes for nonmuscle myosin heavy chain abnormal size Asympotomatic; BT may be prolonged Disorders involving MYH9 gene Sebastian autosomal dominant; large platelets, thrombocytopenia, granulocytic inclusions Fechtner similar abnormalities with deafness, cataracts and nephritis

Fanconi anemia Bony abnormalities Visceral organ abnormalities pancytopenia Congenital Amegakaryocytic Thrombocytopenia Autosoma recessive BM failure 20,000/uL at birth Physical anomalies Petechiae and evidence of bleeding 1st year of life aplastic anemia, MDS, leukemia Mutation in c-mlp gene (thrombopoietin receptor) Autosomal Dominant and X Linked Thrombocytopenia Autosomal Dominant mild bleeding, normal platelet function and megakaryocyte number and morphology X linked mutation in WASP (Wiskott Aldrich Syndrome protein) or GATA-1 gene; mild thrombocytopenia or macrothrombocytopenia with severe bleeding Neonatal Hypoplasia CMV(most common), toxoplasmosis, rubella, HIV CMV inhibits megakaryocytes & precursors impaired platelet production Drugs in utero chlorothiazide, oral hypoglycemics, tolbutamide direct

2 cytotoxic effect on the fetal marrow megakaryocytes Acquired Hypoplasia Methotrexate, busulfan, cytosine arabinoside, cyclophosphamide, cisplatin, zidovudine Chronic ethanol ingestion Interferon therapy Estrogen or estrogenic drugs like DES Chloramphenicol Tranquilizers Anticonvulsants Anagrelide affects platelet lineage only Ineffective Thrombopoiesis Megaloblastic Anemias Large platelets decreased survival time and may have abnormal function Miscellaneous Viruses act on megakaryocytes or circulating platelets, either directly or in the form of viral Ag-Ab complexes CMV, varicella, rubella, EBV, Thai hemorrhagic fever 6 to 8 days post Live measles vaccine degenerative vacuolization of megakaryocytes Bacteria toxins, direct interaction between bacteria and platelets, extensive damage to endothelium (meningococcemia) Malignant cells infiltrating BM myeloma, lymphoma, metastatic cancer, myelofibrosis Increased Platelet Destruction Immune Acute and Chronic ITP Drug Induced: Immunologic Heparin Induced Thrombocytopenia Neonatal alloimmune (isoimmune neonatal) thrombocytopenia Neonatal autoimmune thrombocytopenia Post transfusion isoimmune thrombocytopenia Secondary autoimmune thrombocytopenia Nonimmune Thrombocytopenia in pregnancy and preeclampsia HIV HDN TTP DIC HUS Drugs : Nonimmune mechanisms of platelet destruction

Immune (Idiopathic) Thrombocytopenic Purpura Acute ITP: Extensive petechiae, hematuria, epistaxis, GI bleeding, mucous membrane bleeding, retinal hemorrhage, cranial hemorrhage Chronic ITP: offending antibodies attach to platelets; the Ab-labelled platelets are removed from circulation by RES cells, spleen; cytotoxic T cell mediated lysis of platelets have been shown in vitro using CD3/CD8; shortened lifespan of platelets Findings: Remission and exacerbation High MPV Marrow megakaryocytic hyperplasia Treatment: IVIG Prednisone Anti-D Splenectomy (if prednisone is ineffective)

3 Refractory cases immunosuppresive / chemotherpeutic agents like azathioprine +/- steroids Thrombocytopenia in Pregnancy and Preeclampsia Incidental/Pregnancy associated/Gestational thrombocytopenia Idiopathic and recurrent in subsequent pregnancies 100,000 to 150,000/uL HELLP syndrome Microangiopathic hemolysis, elevated liver enzymes and low platelet count 4-12% of patients with preeclampsia Increased platelet destruction Elevated D-Dimer (low-grade DIC) Elevated platelet associated Ig HDN Platelets may be destroyed due to interaction with products of RBC breakdown, rather than their direct participation in an immunologic reaction TTP DIC Moschowtiz syndrome Microangiopathic hemolytic anemia, thrombocytopenia and neurologic abnormalities Fever and renal dysfunction Severe deficiency of vWF-cleaving protease (ADAMTS-13) Adult HUS renal failure is more prominent

Disorders Related to Distribution or Dilution Splenic Sequestration Kasabach Merritt syndrome Hypothermia Loss of platelets: massive blood transfusions, extracorporeal circulation

Thrombocytosis
Reactive /secondary (450,000 to 800,000/uL) Blood loss & surgery, postsplenectomy, IDA, inflammation and disease, stress, exercise, trauma Marked and persistent high platelet counts (>1,000,000/uL) Myeloproliferative disorders : PV, CML, myelofibrosis with myeloid metaplasia, thrombocythemia: essential or primary Essential (Primary) Thrombocytosis Uncontrolled proliferation of marrow megakaryocytes; persistent/marked elevation Middle / older aged; M=F Hemorrhage (GI-most common), platelet dysfunction, thrombosis (most common cause of death) leading to digital pain/gangrene or erythromyalgia arteriolar inflammation and occlusive thrombosis

Formation of microthrombi in microcirculation Trigger mechanisms: Release of tissue factor or thromboplastic substances into the circulation Widespread injury to endothelial cells HUS Described by Gasser in 1955 MAHA, thrombocytopenia and acute renal failure in young children

4 Bleeding time usually normal; adhesion may be decreased B. Acquired Disorders of Secondary Hemostasis I. Hereditary Hemorrhagic Coagulation Disorders II. Acquired Hemorrhagic Coagulation Disorders Disorders of Primary Hemostasis I. Platelet Disorders A. Qualitative Platelet Disorders 1. Disorders of Platelet Adhesion a. Bernard Soullier/Giant Plt Syndr. b. von Willebrand Disease 2. Disorders of Platelet Aggregation a. Glanzmanns thrombasthenia b. Acquired von Willebrand Disease 3. Disorders of Platelet Secretion or Release Rxs. a. Storage Pool Diseases 1. Electron dense/delta granules deficiency - Hermansky Pudlak, Wiskott Aldrich, Chediak Higashi, TAR 2. Alpha granules deficiency - Gray Platelet Syndrome, Quebec platelet disorder 3. Primary granules deficiency Hemmeler anomaly b. Thromboxane Pathway Disorders 1. Hereditary aspirin like defects 2. Acquired due to inhibitors of prostaglandin pathway (chronic aspirin intake or inhibitors of thromboxane or cyclooxygenase pathway) Quantitative Platelet Disorders 1. Thrombocytopenia 2. Thrombocytosis Platelet disorders

Thrombosis Hereditary deficiencies of natural inhibitors of coagulation deficiency of plasminogen Deficiency of Factor XII Dysfibrinogenemia Homocystinuria Deficiency in heparin co-factor II Defects in fibrinolysis Acquired Malignancy Pregnancy Nephrotic syndrome DM Polycythemia vera, sickle cell anemia Anagrelide Treatment for thrombocytosis with essential thrombocythemia and other myeloproliferative disorders MOA unknown / inhibits megakaryocyte maturation and platelet release; affects megakaryocytopoiesis without significantly affecting the other marrow elements Excessive Bleeding Increased fragility of vessels Platelet deficiency or dysfunction Derangement of coagulation Combination of these Normal Hemostatic Response Blood vessel wall Platelets Clotting cascade Disorders of Primary Hemostasis I. Platelet Disorders A. Qualitative B. Quantitative II. Vascular Disorders A. Hereditary

5 5. Platelet Aggregation Test 6. Platelet Count 7. Platelet Morphology and MPV Disorders of Secondary Hemostasis Hereditary individual coagulation factor deficiencies Acquired DIC Liver disease Vitamin K deficiency Acquired pathologic inhibitors or the circulating anticoagulants Secondary Hemostasis Tests Clotting Time Plasma Recalcification Time Activated clotting time PTT/APTT PT Stypven time Thrombin Time / Thrombin Clotting Time Reptilase Time Substitutiion Test / Mixing Studiest Prothrombin Consumption / Serum PT Thromboplastin Generation Test Specific Factor Assay Assay of vWR:Ag, vWR:Reo Duckers or Clot solubility Test Tests to evaluate circulating inhibitors of coagualtion Laboratory Tests for Secondary Hemostasis 1. Clotting Time slide, Dale-Laidlaw, LeeWhite, Howell 2. Plasma Recalcification Time 3. Activated Clotting Time 4. PTT / APTT / DAPTT 5. PT 6. Stypven Time 7. Thrombin Time / Thrombin Clotting Time 8. Reptilase Time 9. Substitution Test (Mixing Studies) 10. Prothrombin Consumption/Serum Prothrombin Test 11. Thromboplastin Generation Test 12. Specific Factor Assay

Vascular Disorders Hereditary Hereditary Hemorrhagic Telangiectasia/RenduWeber-Osler, HemangiomaThrombocytopenia/ Kasabach Merit, Ehler Danlos, Marfan, Osteogenesis Imperfecta, Pseudoxanthoma elasticum Acquired Allergic/anaphylactoid purpura, Henoch Schonlein, Senile purpura, scurvy, purpura simplex, infectious purpura, drug induced, purpuras associated with paraproteinemias, amyloidosis, idiopathic purpuras Laboratory Tests for Primary Hemostasis 1. Bleeding Time 2. Capillary Resistance / Fragility/ Tourniquet /Rumpel Leedes or Hess Test 3. Clot Retraction Time 4. Platelet Adhesiveness Test

6 13. Assay of vWR:Ag and vWR:Reo Rockett/Laurel 14. Duckerts or Clot Solubility Test 15. Tests for Circulating Inhibitors of Coagulation Disorders of the Fibrinolytic System Hemorrhagic Disorder Thrombotic Disorder Hereditary Deficiency in plasminogen and in the activators of plasminogen or plasmin Acquired Primary fibrinolysis Secondary fibrinolysis Anticoagulant therapy Prevention of initiation or extension of venous thrombosis Heparin, oral anticoagulant, coumarin or warfarin Antiplatelet drugs arterial thromboembolic disease Aspirin, phenothiazine, antihistamine Thrombolytic agents Streptokinase, urokinase Laboratory Tests for Fibrinolysis Determination of: 1. Fibrinolytic Products 2. Lysis Time 3. Proteins involved in Fibrinolysis Hemophilia A Most common hereditary disease associated with serious bleeding Low Factor VIII amount or activity X-linked recessive males, homozygous females Excessive bleeding in heterozygous females due to lyonization Unusual inversion of X chromosome; point mutations in Factor VIII Normal bleeding time, platelet count, PT Prolonged PTT Fibrin deposition is inadequate to achieve reliable hemostasis Hemophilia B Mutations involving Factor IX gene In 14% of patients Factor IX is present but non functional Factor level assay Treatment: Recombinant Factor IX Type 1 and 3 Reduced quantity of circulating vWF Type 1 autosomal dominant; 70% of cases, mild Type 3 autosomal recessive severe; with deletions and frameshift mutations Type 2 25 % of all cases; mild to moderate bleeding Qualitative defects in vWF 2A most common; autosomal dominant Missense mutatisons abnormal vWF formed Prolonged bleeding time; normal platelet count; reduced ristocetin cofactor activity; PTT prolonged in types 1 and 3