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