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Chapter 43 – Thrombocytopenia and Thrombocytosis
Bleeding Disorders• Platelet abnormalities
– Skin, mucous membranes, mucocutaneous
– Petechiae, purpura, ecchymosies, epistaxis, gingival bleeding
– vs. vascular disorders • Clotting factor deficiencies
– Deep tissue bleeding – hematoma, hemarthrosis
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 à 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
• Genetic defect not established yet – Epstein – deafness, ocular problems, glomerulonephritis
TAR• 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
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 à impaired platelet production
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• Drugs in utero – chlorothiazide, oral hypoglycemics, tolbutamide – direct 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 pre-eclampsia– 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
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Treatment:• IVIG• Prednisone• Anti-D• Splenectomy (if prednisone is
ineffective)• 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• Moschowtiz syndrome• Microangiopathic hemolytic anemia,
thrombocytopenia and neurologic abnormalities
• Fever and renal dysfunction• Severe deficiency of vWF-cleaving
protease (ADAMTS-13)
DIC• 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
• 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
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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
• Bleeding time usually normal; adhesion may be decreased
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 HemostasisI. Platelet Disorders
A. Qualitative B. Quantitative
II. Vascular Disorders A. Hereditary B. Acquired
Disorders of Secondary HemostasisI. Hereditary Hemorrhagic Coagulation
DisordersII. Acquired Hemorrhagic Coagulation
Disorders
Disorders of Primary HemostasisI. 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. Glanzmann’s 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)
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Quantitative Platelet Disorders 1. Thrombocytopenia 2. Thrombocytosis Platelet disorders
• Vascular Disorders– Hereditary
• Hereditary Hemorrhagic Telangiectasia/Rendu-Weber-Osler, Hemangioma-Thrombocytopenia/ 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 Hemostasis1. Bleeding Time
2. Capillary Resistance / Fragility/ Tourniquet /Rumpel Leedes or Hess Test
3. Clot Retraction Time4. Platelet Adhesiveness Test5. Platelet Aggregation Test6. Platelet Count7. 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• Ducker’s or Clot solubility Test• Tests to evaluate circulating inhibitors of
coagualtion
Laboratory Tests for Secondary Hemostasis1. Clotting Time – slide, Dale-Laidlaw, Lee-
White, Howell2. Plasma Recalcification Time3. Activated Clotting Time4. PTT / APTT / DAPTT5. PT6. Stypven Time7. Thrombin Time / Thrombin Clotting
Time
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8. Reptilase Time9. Substitution Test (Mixing Studies)10. Prothrombin Consumption/Serum
Prothrombin Test11. Thromboplastin Generation Test12. Specific Factor Assay13. Assay of vWR:Ag and vWR:Reo –
Rockett/Laurel14. Duckert’s or Clot Solubility Test15. 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 Products2. Lysis Time3. 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 à abnormal vWF
formed• Prolonged bleeding time; normal
platelet count; reduced ristocetin cofactor activity; PTT prolonged in types 1 and 3
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