Download 5. Thrombocytopenia

Thrombocytopenia
Rahul Gladwin, MS3
University of Health Sciences-Antigua
School of Medicine
Thrombocytopenia
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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 20,00050,000/µL aggravates post-traumatic
bleeding.
Causes of thrombocytopenia
 Causes of thrombocytopenia can be
divided into four main classes:
1.
2.
3.
4.
Decreased production of platelets
Decreased platelet survival
Sequestration
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, sulfadrugs.
 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 bonemarrow 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 upregulates 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
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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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