Thrombocytopenia
An overview PRESENTED BY: ALAA HABBAL
Outline
Platelets production review
Define thrombocytopenia
Pathophysiology
Causes
Thrombocytopenia in pregnancy.
Thrombocytopenia in neonates
When to worry about bleeding
When to worry about thrombosis
Evaluation of thrombocytopenia
Glance at platelets collection & transfusion.
Platelets
are
produced in the
bone marrow
from
megakaryocytes
(1000-5000 plts)
35,000 to 50,000
plts/ µL of blood
production can be
increased up to
eightfold
One third of
platelets are
sequestered
in spleen
Platelets life
span is 5 -9 days
Normal platelet
count:
150,000 -
450,000 \µL.
What is a low platelet count
(Thrombocytopenia)
platelet count below the lower limit of
normal <150,000/microL [150 x 109/L] for adult.
Degrees of thrombocytopenia can be further subdivided into:
o mild (platelet count 100,000 to 150,000/microL),
o moderate (50,000 to 99,000/microL), and
o severe (<50,000/microL) greater risk of bleeding but not absolute.
CONT…
variation of the platelet count in a given individual is limited.
A small proportion of the population (approximately 2.5 percent) will have a baseline platelet count lower than 150,000/microL.
50 percent reduction in platelet count, but count is still >150,000/microLmay be a clinical significant.
- decreased platelet
production in the bone marrow
- peripheral platelet
destruction by antibodies or
- consumption in thrombi
- dilution from fluid
resuscitation or - massive
transfusion
- sequestration of platelets in
the spleen
(splenomegaly)
Thrombocytopenia pathophysiology
Causes of Thrombocytopenia
Disorder of
production
Ineffective
production
Decrease in
Megakaryocytes
Congenital
Disorder
Fanconi,s
anemia
Acquired Disorders
Radiation, Alcohol
Thiazide diuretics,
Chloramphenicol,
Cancer
chemotherapy
Marrow replacement
by Malignant Cell
Metastatic carcinoma
Leukemia, lymphoma,
myeloma
Myelofibrosis
• Vitamin B12 or folate
deficiency .
• Di Guglielmo’s syndrome
(erythroleukemia)
Distribution &
Dilution
Splenomegaly or
hypersplenism
Hypothermia; transfusion
Disorder of
Destruction
Isolated
consumption
Combined
consumption
Immune
Destruction
DIC & its causes
Obstetric complication
Neoplasms (promylelocytic
leukemia)
Bacterial and viral infections
TTP-HUS
Drug induced
Quinidine,
heparinITP
Disseminated intravascular coagulation (DIC)
Pathophysiology
● Hyper-activated coagulation system.
● Hyper-activated fibrin-lytic
system, or both
simultaneously.
●Coagulation factors and
plts consumed as soon as
they are made.
● Secondary to an
underlying disease or
condition. Ex; sepsis,
placenta abruption, snake
bites, toxin, trauma, graft vs.
host disease, and burns.
Clinical Finding
● Patients are at risk of bleeding and thrombosis.
Laboratory Finding
• Thrombocytopenia
• Prolonged PT, APTT, thrombin time.
• Decreased fibrinogen.
• Elevated D-dimers.
• Schistocytes on the peripheral blood smear.
Treatment of DIC
• Treatment of the underlying disorder .
• Transfusion support of Red Blood Cells or Fresh Frozen Plasma (FFP) to replace coagulation factors.
Thrombotic
Thrombocytopenic
Purpura (TTP)-
Hemolytic Uremic
Syndrome (HUS)
TTP-HUS (small-vessel platelet-rich thrombi)
Acute syndromes with abnormalities in multiple organ systems and evidencing microangiopathic hemolytic anemia and thrombocytopenia.
uncommon.
HUS is thought by some to be the same condition as TTP because both disorders have the same underlying pathology.
HUS is more often associated with renal failure.(diarrhea/ Shiga toxin-producing Escherichia coli (E. coli O157:H7))
TTP with neurological manifestations.
precipitating factors including:
infection,
Carcinoma,
pregnancy.
TTP-HUS pathophysiology
• In normal plasma ultra-large vWF is cleaved into smaller fractions
(necessary for balanced coagulation activity) by an enzyme
processed by the gene, ADAMTS13.
• In patients with TTP, the enzyme activity is < 5% of normal.
• These ultra-large VwF molecules get into circulation, resulting in
excessive platelet aggregation and microvascular thrombus formation.
● Thrombocytopenia (<20 x 109/L)
● TTP< HUS.
•
● Schistocytes in blood film◦ Microangiopathic hemolytic anemia
● LDH
● Serum bilirubin
● Reticulocyte counts
● Normal Prothrombin time (PT).
● Normal activated partial thromboplastin time (aPTT).
TTP-HUS
LABORATORY FINDING
Treatment of TTP
• Therapeutic plasma exchange (TPE).
• Fresh frozen plasma (FFP), to compensate ADAMTS13 deficiency and
lessen down the effect of autoantibody against the enzyme.
• Exchange takes place over several days until the patient's platelet count
stabilizes above 100 x 109/L.
• TPE has decreased TTP mortality rate from 90% to 15% since the treatment
first came into use as the standard primary treatment of TTP in the 1970's.
Immune thrombocytopenia
Immune thrombocytopenia purpura
The autoantibodies are directed
against GPIIb/IIIa (fibrinogen receptor)
and the complex GPIb/IX (von
Willebrand factor receptor).
Antibody-coated platelets are
subsequently removed by the spleen.
platelet production may also be
impaired (megakaryocyte injury by the
autoantibodies).
common viral or bacterial infection OR
failure of T-regulatory cells.
ITP possible treatment
Treatment guidelines recommend that patients receive treatment if they have any of the
following:
• Significant bleeding risk.
• <20 x 109/L platelets and moderate bleeding.
• <10 x 10 9/L platelets with no bleeding symptoms.
Corticosteroids are effective treatments for 50-80% of individuals with either acute or
chronic ITP.
Intravenous immunoglobulin (IVIG) contains the pooled immunoglobulin G (IgG)
immunoglobulins from the plasma.
Splenectomy may be a last resort treatment for chronic ITP sufferers if their platelet
counts are below 30 x 109/ L or if symptoms warrant it.
ITP possible treatment/ CONT…..
Intravenous immunoglobulin (IVIG) contains the
pooled immunoglobulin G (IgG) immunoglobulins
from the plasma.
Blockade of macrophage Fc receptors is
considered the primary mechanism of action of
immune globulin in persons with ITP.
Drug Induce Thrombocytopenia
Thrombocytopenia develops within
hours of drug exposure if the patient has
been previously exposed to the drug.
Within one to two weeks of daily
exposure.
Resolves within five to seven days of
drug discontinuation.
A small percentage of patients exposed to heparin (<5 percent) may develop heparin-induced thrombocytopenia (HIT).
New onset thrombocytopenia in a patient exposed to heparin within the prior 5 to 10 days.
platelet count drop >50 percent of baseline.
necrotic skin lesions at sites of heparin injection; and acute systemic reactions after intravenous heparin administration.
Heparin-induced thrombocytopenia
PATHOPHYSIOLOGY
IgG antibodies directed against
heparin complexed with platelet
factor 4 (PF4).
Platelet Fc receptors bind the
antibody heparin-PF4 immune
complex.
Platelet activated & release
micropartical, which contribute to
thrombosis.
Macrophage removal
Platelet consumption by thrombosis
PATHOPHYSIOLOGY
PF4 binds to heparin sulfate on
vascular
Antibody binding to this complex,
injure the endothelium, promotes
thrombosis.
Treatment
Immediate discontinuation of heparin and administration of a non-heparin anticoagulant.
Thrombocytopenia
in pregnancy
Incidental thrombocytopenia during pregnancy, (Gestational thrombocytopenia)
Approximately 5 percent develop incidental thrombocytopenia.
Defined by the following five criteria:
Mild and asymptomatic thrombocytopenia. Platelet counts are typically >70,000/microL, with approximately two-thirds between 130,000 and 150,000/microL.
No past history of thrombocytopenia (except possibly during a previous pregnancy).
Occurrence during late gestation.
No association with fetal thrombocytopenia.
Spontaneous resolution after delivery.
When to concern thrombocytopenia
in pregnant woman?
•?? ITPplatelet count is less than 70,000/microL.
• renal insufficiency, hypertension, microangiopathichemolytic anemia.
• ??the hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, ??preeclampsia, or ??thrombotic thrombocytopenic purpura (TTP).
• Severe thrombocytopenia.
• Thrombocytopenia accompanied by other findings during pregnancy.
Thrombocytopenia
In Neonates
Etiology of neonatal
thrombocytopenia
Increased destruction
( Most common)
• Neonatal alloimmunethrombocytopenia.
• Autoimmune thrombocytopenia.
• Drug-related destruction.
• Sequestration and trapping – Hypersplenism
• Platelet activation and consumption – DIC
decreased production of platelets
• Preeclampsia
• Genetic disorders
• Bone marrow infiltrative diseases
Increase destruction and
decrease production/others
• bacterial, viral, or fungal infection
• Perinatal asphyxia
• Dilution
Neonatal Allo-immune Thrombocytopenia
when fetal platelets contain an antigen
inherited from the father that the mother
lacks.
The mother forms IgG (immunoglobulin G)
class antiplatelet antibodies against the
"foreign" antigen.
IgG cross the placenta and destroy fetal
platelets that express the paternal
antigen.
Incidence — 1 in 1000 to 10,000 births.
Symptoms Seen in Thrombocytopenia
If a platelet count is less than 30 x 109/L
bruisingPetechiaePurpuraEpistaxis
Bleeding into the central nervous system may occur
If a platelet count is less than 10 x 109/L
Do all thrombocytopenic patients have symptoms?
asymptomatic, isolated thrombocytopenia
?? (ITP)
Symptoms varies depend on
severity??autoimmune disorders, ??nutrient deficiencies,
thrombotic microangiopathies,
acutely ill, hospitalized
patientsplatelet consumption,
??bone marrow suppression from sepsis/infection, or DIT
When to worry about bleeding?
Patients with severe thrombocytopenia.
Prior bleeding at a similar platelet count and the presence of wet purpura (mucosal
membranes).
The following may be used as guides, but should not substitute for clinical judgment based
on individual patient and disease factors:
Surgical bleeding generally with platelet counts <50,000/microL (<100,000/microL for
some high-risk procedures such as neurosurgery or major cardiac or orthopedic
surgery).
Severe spontaneous bleeding is most likely with platelet counts <10,000/microL.
When to worry about thrombosis?
Heparin-induced thrombocytopenia
Disseminated Intravascular Coagulation
TTP-HUS
Paroxysmal nocturnal hemoglobinuria
Initial questions in thrombocytopenia
evaluation
When a patient presents with unexpected thrombocytopenia, we
want to know:
Is the thrombocytopenia real?
Is the thrombocytopenia new?
Are there other hematologic abnormalities?
PTCP
What
Dose
PTCP
Stands
for?
Pseudo-
thrombocytopenia
Pre-analytic Variable Leading to False
Thrombocytopenia (PTCP)
The platelet count is only as good as the sample collected.
for coagulation purposes should be inverted 5-10 times for proper mixing of
the anticoagulant and the blood. If the tube is not mixed, small fibrin clots
may form, causing a falsely decreased platelet count.
Analytic Variable Leading to False
Thrombocytopenia
• Cell cytoplasmic fragments
• Microcytic RBCs
Giant platelet
Platelet Clumps
spurious
increase in
the platelet
count
spurious
decrease in
the platelet
count
Platelet Clumps &
platelet satellitism
Case study 1
A 57-year-old retired farmer with no personal or family history of bleeding
was found to have thrombocytopenia on routine blood work.
He had a history of type 2 diabetes, hypertension, hyperlipidemia, and
osteoarthritis. Medications included perindopril, insulin glargine, aspirin,
metformin, ibuprofen, and oregano oil. Physical examination was normal.
His complete blood count (CBC):
WBC: 9.4 × 109/L,
Hemoglobin: 16.0 g/dL,
Platelets: 10 × 109/L by automated counter.
CONT…
A peripheral blood film showed clumping of platelets (blood smear).
A bone marrow aspirate and biopsy, initially performed to rule out
myelodysplasia, was normal with normal-appearing megakaryocytes in
adequate numbers.
Diagnosis
The patient was diagnosed with pseudo-
thrombocytopenia.
No further treatment or blood work was
required.
Case Conclusion
Unrecognized pseudo-thrombocytopenia may result in
unnecessary diagnostic testing and clinical concern.
A microscopic examination can identify platelet clumping and
repeat CBC tests using a different anticoagulant can affirm the
diagnosis.
EDTA-dependent agglutinin/ plts Clumps
Approximately 0.1 percent of individuals
have EDTA-dependent agglutinins.
platelet membrane (GP) IIb/IIIa becomes
exposed by EDTA-induced dissociation
of GPIIb/IIIa.
"naturally occurring" platelet autoantibody
directed against a concealed epitope on
platelet membrane glycoprotein
(GP) IIb/IIIa
EDTA-dependent agglutinin/ plts satellitism
platelets may rosette around
WBCs.
presence of an EDTA-
dependent antibody with
dual reactivity against
GP IIb/IIIa and the neutrophil
Fc gamma receptor III.
What to do?
If platelet clumping is observed, the platelet count is repeated using heparin or sodium citrate as an anticoagulant in the collection tube.
If citrate is used, the platelet count should be corrected for dilution caused by the amount of citrate solution.
multiplying the platelet count that is obtained from the automated analyzer by 1.1.
no such correction is needed for heparin.
Platelets Collection &
Transfusion
Platelets Collection
Isolation from donated blood
One unit of platelets contain 7 x
1010 platelets.
Apheresis from a donor
equivalent of six or more units of
platelets from whole blood
Indication of Platelets Transfusion
Actively bleeding patient.
Preparation for an invasive procedure.
Prevention of spontaneous bleeding.
Platelets Count Increment
Following a platelet transfusion, the platelet count should rise, with
a peak at 10 minutes to one hour and a gradual decline over 72
hours.
Six units of pooled platelets or one apheresis unit should increase
the platelet count by approximately 30,000/microL in an adult of
average size.
Platelets express ABO antigens on their surface, as well as HLA class
I antigens. They do not express Rh or HLA class II antigens.
ABO and HLA compatible platelets appear to cause a greater
platelet count increment in the recipient.
Take Home Points
Thrombocytopenia is the drop in platelet count below the lower limit of normal <150,000/microL.
Thrombocytopenia can be mild, moderate or severe depend on the platelet count.
Thrombocytopenia results from decrease of platelets production, increase platelets destruction, sequestration of platelets in the spleen or Dilution.
Identification of thrombocytopenia cause is highly important to avoid the undesirable consequences ( bleeding or thrombosis).
Pseudo-thrombocytopenia result from either Incompletely mixed, inadequately anti-coagulated samples or from EDTA- dependent agglutinin.
Pseudo-thrombocytopenia should be recognized to avoid unnecessary diagnostic testing and clinical concern.
Platelet transfusion used as prophylactic or therapeutic purposes.
Transfusion of single adult dose of platelets ( six units/ one apheresis unit) should increase platelet by 30,000/µl.
References
http://www.uptodate.com/contents/approach-to-the-adult-with-
unexplained-thrombocytopenia.
http://www.uptodate.com/contents/drug-induced-thrombocytopenia.
http://www.uptodate.com/contents/causes-of-neonatal-
thrombocytopenia.
http://www.uptodate.com/contents/thrombocytopenia-in-pregnancy.
http://www.uptodate.com/contents/clinical-and-laboratory-aspects-of-
platelet-transfusion-therapy.
www.medialab.com
DIC Pathophysiology