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					Thrombocytopenia


  Rahul Gladwin, MS3
  University of Health Sciences-Antigua
  School of Medicine
Thrombocytopenia
   Causes of Thrombocytopenia
   TTP/ITP
   Drug-induced Thrombocytopenia
   HIV-associated Thrombocytopenia
   Disseminated intravascular coagulation
   Pancytopenia
   Complications
   Management
   Case study
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.
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.
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
Decreased production of platelets
 Bone marrow diseases e.g., aplastic
  anemia, Fanconi’s anemia, leukemia,
  disseminated cancer.
 Medications: alkylating agents,
  benzene, chloramphenicol,
  streptomycin, chlorpromazine,
  antimetabolites.
 Insectides: DDT, parathion
 Viruses: hepatitis, EBV virus, CMV.
Decreased production of platelets
 Alcohol, thiazides, cytotoxic drugs,
  measles, HIV.
 Vitamin B12 and folic acid deficiency.
 Megaloblastic anemia,
  myelodysplastic syndromes.
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.
Sequestration
 The spleen sequesters 30-40% of the
  body’s total platelets.
 Splenomegaly secondary to
  hypersplenism.
 Treatment is splenectomy.
 Bone marrow biopsy shows increased
  megakaryocytes.
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?
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.
Dilutional
 Massive transfusions can produce
  thrombocytopenia because stored
  blood contains very little platelets.
 Packed blood doesn’t contain many
  thrombocytes.
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.
Petechiae and Purpura due to ITP
Acute Immune Thrombocytopenic
Purpura
 Similar to ITP but occurs only in
  childhood.
 Abrupt thrombocytopenia due to viral
  cause.
 Resolves spontaneously within 6
  months.
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.
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia
Heparin-induced thrombocytopenia
 HIT is not usually severe, with low counts rarely
  <20,000/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.
Autoimmune thrombocytopenia vs
HIT
Question:
 What test would you order in order to
  confirm HIT?
Answer (two tests):
 Test for PF4 antibodies (PF4 ELISA).
 Serotonin release assay.
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.
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.
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.
Thrombotic Thrombocytopenic
Purpura
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.
Arterial thrombosis secondary to
sepsis-induced DIC
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.
Pancytopenia
 Caused by bone marrow failure,
  radiation, auto-immune diseases,
  drugs, infections.
 Pancytopenia is a combination of
  anemia, leukopenia, and
  thrombocytopenia.
Thrombocytopenia Management
 Rule out pseudothrombocytopenia (in
  vitro artifactual IgG or IgM-induced
  clumping of platelets).
 H&P (splenomegaly, liver disease).
 CBC.
 Peripheral blood smear.
 Medication list.
 Bone marrow biopsy.
Drug-induced thrombocytopenia
Normal Peripheral Blood
Pseudothrombocytopenia
Macrothrombocytopenia:
Large platelets
Schistocytes in microangiopathic
hemolytic anemia (HUS/TTP).
Complications of thrombocytopenia
   Intracranial hemorrhage.
   GI bleeding.
   Epistaxis.
   Menorrhagia.
   Gingivorrhagia.
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.
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.
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.
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.
Related medications - Bivalirudin
 Used for treatment of HIT in patients
  who have undergone percutaneous
  coronary intervention (PCI).
 Inhibits thrombin
 Very short half-life.
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.
Related medications - Eltrombopag
 Used to treat ITP.
 MOA is unknown.
 Oral thrombopoeitin (TPO) receptor
  agonist.
 May reduce antibodies to platelets.
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.
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.
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 syndrome
 B) Bernard-Soulier syndrome
 C) Felty's syndrome
 D) Thrombotic thrombocytopenic purpura
 E) Evans' syndrome
 F) Idiopathic thrombocytopenic purpura (ITP)
Answer
 Answer: E
 Evans' syndrome is the association of
  autoimmune destruction of RBC,
  WBCs, and platelets.
 TX: steroids and/or splenectomy.
References
 Robbins Pathology
 Harrison’s IM
 First Aid for USMLE
 The Pharmacological Basis of
  Therapeutics
 Dorland's Medical Dictionary
 www.usmleforum.com

				
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