Thrombocytopenia

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Thrombocytopenia

• Rahul Gladwin, MS3
• University of Health Sciences-Antigua
• School of Medicine

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Thrombocytopenia

• Causes of Thrombocytopenia
• TTP/ITP
• Drug-induced Thrombocytopenia
• HIV-associated Thrombocytopenia
• Disseminated intravascular coagulation
• Pancytopenia
• Complications
• Management
• Case study

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Definition

• Thrombocytopenia is defined as a decrease in the
  number of platelets.
• Normal platelet counts range from
  150,000-300,000/µL.
• Anything below 100,000/µL constitutes
  thrombocytopenia.

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Why does platelet count matter?

• Platelets help form blood clots.
• Unexplained epistaxis, petechiae, gingivorrhagia,
  and vaginal bleeding imply decreased platelet
  counts.
• Platelet count below 20,000/µL causes spontaneous
  internal bleeding.
• Platelet count between 20,000-50,000/µL
  aggravates post-traumatic bleeding.

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Causes of thrombocytopenia

• Causes of thrombocytopenia can be divided into
  four main classes
• 1. Decreased production of platelets
• 2. Decreased platelet survival
• 3. Sequestration
• 4. Dilutional

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Decreased production of platelets

• Bone marrow diseases e.g., aplastic anemia,
  Fanconis anemia, leukemia, disseminated cancer.
• Medications alkylating agents, benzene,
  chloramphenicol, streptomycin, chlorpromazine,
  antimetabolites.
• Insectides DDT, parathion
• Viruses hepatitis, EBV virus, CMV.

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Decreased production of platelets

• Alcohol, thiazides, cytotoxic drugs, measles,
  HIV.
• Vitamin B12 and folic acid deficiency.
• Megaloblastic anemia, myelodysplastic syndromes.

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Decreased platelet survival

• Autoimmune idiopathic thrombocytopenic purpura,
  systemic lupus erythematosus, hemolytic-uremic
  syndrome, anti-platelet antibodies.
• Isoimmune post-transfusion and neonatal.
• Drug-associated quinidine, heparin, sulfa-drugs.
• Infections infectious mononucleosis, HIV, CMV.

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Sequestration

• The spleen sequesters 30-40 of the bodys total
  platelets.
• Splenomegaly secondary to hypersplenism.
• Treatment is splenectomy.
• Bone marrow biopsy shows increased megakaryocytes.

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Question

• What test do you order in order to differentiate
  between thrombocytopenia caused by decreased
  platelet production (ie., by cancer, drugs,
  autoimmune, chemotherapy, etc.) vs
  thrombocytopenia caused by increased
  sequestration?

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Answer

• Bone marrow biopsy shows increased megakaryocytes
  in thrombocytopenia caused by increased
  sequestration.
• Presence of megakaryocytes implies that the
  bone-marrow is working over time in order to
  compensate for increased platelet loss.

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Dilutional

• Massive transfusions can produce thrombocytopenia
  because stored blood contains very little
  platelets.
• Packed blood doesnt contain many thrombocytes.

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Immune Thrombocytopenic Purpura

• Causes autoimmune destruction of platelets
  secondary to HIV, SLE, viruses, and drugs.
• IgG antibodies target platelet glycoprotein
  complexes IIb-IIIa and Ib-IX.
• Sensitized platelets are removed by the spleen.
• Increased bleeding time normal PT PTT.

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Petechiae and Purpura due to ITP
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Acute Immune Thrombocytopenic Purpura

• Similar to ITP but occurs only in childhood.
• Abrupt thrombocytopenia due to viral cause.
• Resolves spontaneously within 6 months.

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Drug-induced thrombocytopenia

• Drugs involved are heparin, quinine, quinidine,
  sulfonamide antibiotics.
• Type I HIT less severe, occurs rapidly after
  therapy.
• Type II HIT more severe, occurs 5-16 days after
  therapy.
• HIT is caused by an immune reaction against a
  complex of heparin and platelet factor 4, which
  produces immune complexes.

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Heparin-induced thrombocytopenia
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Heparin-induced thrombocytopenia
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Heparin-induced thrombocytopenia

• HIT is not usually severe, with low counts rarely
  lt20,000/µL.
• Not associated with bleeding
• Increases the risk of thrombosis.
• Caused by low-molecular weight heparin (LMWH)
• More commonly caused by unfractionated heparin
  (UFH).
• HIT (antiheparin/PF4) antibodies can be detected
  using enzyme-linked immunoassay (ELISA) with
  PF4/polyanion complex as the antigen.
• A platelet activation assay confirmatory test can
  also be used.
• Heparin given with warfarin has decreased chance
  of causing HIT compared to giving heparin alone.

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Autoimmune thrombocytopenia vs HIT
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Question

• What test would you order in order to confirm HIT?

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Answer (two tests)

• Test for PF4 antibodies (PF4 ELISA).
• Serotonin release assay.

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Chloramphenicol-induced thrombocytopenia

• Chloramphenicol affects the bone-marrow causing
  anemia, leukopenia, thrombocytopenia.
• Chloramphenicol causes an idiosyncratic response
  manifested by aplastic anemia in patients
  receiving prolonged therapy.

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HIV-associated thrombocytopenia

• Decreased platelet production and increased
  platelet destruction. Three causes
• Existence of CD4 receptor on megakaryocytes makes
  them prone to destruction.
• HIV causes hyperplasia and dysregulation of B
  cells, producing IgG antibodies which target
  platelet glycoprotein complexes IIb-IIIa and
  Ib-IX resulting in thrombocytopenia.
• Autoantibodies may cross-react with
  HIV-associated gp120 acting as opsonins, thus
  promoting phagocytosis of platelets in the spleen.

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TTP HUS

• TTP is caused by bone marrow transplantation,
  cancer, chemotherapy and manifested as
  microangiopathic hemolytic anemia,
  thrombocytopenia, renal failure, neurologic
  findings, and fever.
• HUS caused by infection and is manifested as
  acute renal failure, microangiopathic hemolytic
  anemia, and thrombocytopenia.
• Deficiency of ADAMTS 13 produces a defective
  protease causing very high molecular weight
  multimers of vWF to accumulate in plasma
  promoting platelet microaggregate formation
  leading to thrombocytopenia.

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Thrombotic ThrombocytopenicPurpura
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Disseminated Intravascular Coagulation

• DIC is an acute, subacute, or chronic
  thrombohemorrhagic disorder occurring secondary
  to a variety of conditions.
• Begins with extrinsic (release of tissue factor)
  and intrinsic (factor XII activation) clotting
  cascade activation.
• Both pathways cause platelet consumption and
  thrombi formation leading to thrombocytopenia.

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Arterial thrombosis secondary to sepsis-induced
DIC
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Endothelial injury induced thrombocytopenia

• Endothelial injury can activate tissue factor,
  which activates TNF, which up-regulates leukocyte
  adhesion, which damages endothelial cells and
  releasing free radicals and proteases causing
  activation of both the extrinsic and intrinsic
  pathways leading to thrombocytopenia.

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Pancytopenia

• Caused by bone marrow failure, radiation,
  auto-immune diseases, drugs, infections.
• Pancytopenia is a combination of anemia,
  leukopenia, and thrombocytopenia.

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Thrombocytopenia Management

• Rule out pseudothrombocytopenia (in vitro
  artifactual IgG or IgM-induced clumping of
  platelets).
• HP (splenomegaly, liver disease).
• CBC.
• Peripheral blood smear.
• Medication list.
• Bone marrow biopsy.

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Drug-induced thrombocytopenia
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Normal Peripheral Blood
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Pseudothrombocytopenia
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MacrothrombocytopeniaLarge platelets
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Schistocytes in microangiopathic hemolytic anemia
(HUS/TTP).
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Complications of thrombocytopenia

• Intracranial hemorrhage.
• GI bleeding.
• Epistaxis.
• Menorrhagia.
• Gingivorrhagia.

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When do you treat?

• You treat thrombocytopenia when the platelet
  count is less than 50,000/µL.
• You do not treat when the platelet count is over
  50,000/µL.
• You do a bone-marrow biopsy in patients
  presenting with isolated thrombocytopenia who are
  older than 60 years in order to rule out
  myelodysplasia.

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Related medications - Prednisone

• Methylprednisolone sodium succinate (SOLU-MEDROL)
• Used to decrease bleeding tendency.
• Patients with refractory ITP may respond.
• Dosed as 1-1.5kg/mg.

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Related medications - Argatroban

• Anticoagulant or platelet aggregation inhibitor.
• Prevents the activation of coagulation factors V,
  VIII, and XIII protein C.
• Used to replace heparin in patients with
  heparin-induced thrombocytopenia.

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Related medications - Lepirudin

• The same as hirudin except that it contains
  leucine instead of isoleucine at the N-terminal
  end of the molecule and an absent sulfate group
  on the tyrosine at position 63.
• It binds thrombin and prevents thrombus or clot
  formation.
• Alternative to heparin in HIT.
• Can also cause thrombocytopenia.

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Related medications - Bivalirudin

• Used for treatment of HIT in patients who have
  undergone percutaneous coronary intervention
  (PCI).
• Inhibits thrombin
• Very short half-life.

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Related medications - Oprelvekin

• Recombinant IL-11
• Produced by E. coli.
• Increases platelet levels which were reduced due
  to chemotherapy.
• IL-11 is a growth factor that stimulates
  proliferation of hematopoietic stem cells and
  megakaryocyte progenitor cells resulting in
  increased platelet production.

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Related medications - Eltrombopag

• Used to treat ITP.
• MOA is unknown.
• Oral thrombopoeitin (TPO) receptor agonist.
• May reduce antibodies to platelets.

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Related medications - IgG

• Used to treat ITP.
• Removes offending immune complexes composed of
  viral particles.
• Low-dose anti-D antibodies (Rhogam) can also be
  used to treat ITP.

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Other thrombocytopenia treatments

• Splenectomy in severe cases and if there is
  recurrent bleeding after steroids.
• Plasmapheresis (TTP).
• Dialysis (RF).
• Platelet transfusion (active bleeding or severe
  cases).
• Lithium carbonate or folate.

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Thrombocytopenia case study

• A 21-year-old man with no significant PMH
  presents with complaints of hematuria and mucosal
  bleeding while brushing his teeth. The patient
  complains of intermittent "ringing in the ears."
  He denies any drug or alcohol use. He has no
  family history of bleeding disorders. Petechiae
  are noted in the oral cavity, as is dried blood
  in the nostrils.
• Hematocrit 32 WBC 8,000/mm3 with 60
  neutrophils.
• Platelet count 13,000 PT 13 seconds PTT 28
  seconds LDH 1,200 U/L.
• Elevated indirect bilirubin.
• Coombs' test is positive abdominal examination
  is normal.
• Peripheral smear shows spherocytes.
• A) Alport's syndromeB) Bernard-Soulier
  syndromeC) Felty's syndromeD) Thrombotic
  thrombocytopenic purpuraE) Evans' syndromeF)
  Idiopathic thrombocytopenic purpura (ITP)

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Answer

• Answer E
• Evans' syndrome is the association of autoimmune
  destruction of RBC, WBCs, and platelets.
• TX steroids and/or splenectomy.

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References

• Robbins Pathology
• Harrisons IM
• First Aid for USMLE
• The Pharmacological Basis of Therapeutics
• Dorland's Medical Dictionary
• www.usmleforum.com