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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