DISSEMINATED INTRAVASCULAR COAGULATION

Definition Generalized activation of hemostasis secondary to a systemic disease

Systems involved: • Vascular intima

• Platelets
• WBCs
• Coagulation
• Coagulation control pathways
• Fibrinolysis

Features seen in DIC • Acute/Uncompensated

• Chronic/Compensated

Causes of DIC

Pathophysiology of DIC • Thrombin activation

• Circulating plasmin
• Loss of control
• Thrombocytopenia
• Thrombin cleaves fibrinogen, creating fibrin monomers.

• A percentage of fibrin monomers fail to polymerize and circulate in plasma as SOLUBLE FIBRIN
MONOMERS
• The monomers coat platelets and coagulation proteins, creating an ANTICOAGULANT
EFFECT.

• LEUKOCYTES – particularly MONOCYTES

- may be induced to secrete TF by the cytokines released during inflammation

• Thrombin cleaves fibrinogen, creating fibrin monomers.

• In DIC, a percentage of fibrin monomers fail to polymerize and circulate in plasma as SOLUBLE
FIBRIN MONOMERS.
- The monomers coat platelets and coagulation proteins, creating an anticoagulant
effect.

• SOLUBLE FIBRIN MONOMERS

• FIBRIN POLYMER ALL ACTIVATE PLASMINOGEN
• CROSS-LINKED FIBRIN

• Plasma circulates in the plasma and digests all forms of fibrinogen and fibrin

Consequently:
• FDPs labeled are detectable in plasma in concentrations exceeding 20,000 ng/mL.

• D-dimer arises from cross-linked fibrin polymer, whereas the other FDPs may be produced from
fibrinogen or fibrin monomers or polymers.

• Platelets become enmeshed in the fibrin polymer or are exposed to thrombin.

-both events trigger platelet activation, which further drives the coagulation system and
produces thrombocytopenia.

• At the same time, coagulation pathway control is lost as protein C, protein S, and AT are
consumed.

• The combination of thrombin activation, circulating plasmin, loss of control, and

thrombocytopenia contributes to the overall hemorrhagic outcome of DIC.

• Free plasmin digests factors V, VIII, IX and XI, as well as other plasma proteins.
• Plasmin also may trigger complement, which leads to hemolysis, and the kinin system, which
results in inflammation, hypotension, and shock.
 SYMPTOMS OF DIC

• The symptoms signaling DIC frequently are MASKED BY THE SYMPTOMS OF THE
UNDERLYING DISORDER.
• May be CHRONIC, ACUTE, or FULMINANT.

THROMBOSIS in the microvasculature of major organs may produce symptoms of organ

failure such as:
• renal function impairment
• adult respiratory distress syndrome
• and CNS manifestation

SKIN, BONE, & BONE MARROW may be seen.

Purpura fulminans is seen in:

• Meningococcemia
• Chickenpox
• Spirochete infections

LABORATORY DIAGNOSIS OF DIC

Platelet Count

Blood smear evaluation

PRIMARY PROFILE PT and APTT

D-dimer

Fibrinogen

TREATMENT OF DIC
• Treatment of the underlying disease that caused the DIC.
 LOCALIZED THROMBOSIS MONITORS
• Thrombin-Antithrombin (TAT)
• Prothrombin fragment 1 + 2 (PF 1+2)

Both immunoassays are SENSITIVE and SPECIFIC for

THROMBOSIS, which occurs in:
• DIC
• Thrombin-Antithrombin • Septicemia
(TAT) • Eclampsia
• Pancreatitis
• Prothrombin fragment 1 + • Leukemia
2 (PF 1+2) • Liver Disease
• Trauma

These assays are of particular value in clinical trials of

anticoagulants.

HEPARIN INDUCED THROMBOCYTOPENIA (HIT)

• Adverse effect of treatment with unfractionated heparin

CAUSES SIGNIFICANCE PLATELET COUNT

• Between 1% & 5% of px • Venous thrombosis • Patients receiving heparin

receiving unfractionated
heparin (UFH) for more
than 5 days develop an
IgG antibody specific for
heparin-platelet factor 4
complexes.
predominated 5:1, but must have platelet counts
arterial thrombosis accounts performed every other day.
for the most disturbing
symptoms.

30% - 50% of these cases:
• The immune complexes that
are formed bind platelet Fc
receptors
• Leads to platelet activation,
thrombocytopenia, &
formation of microvascular
thrombi.
Patients may develop:
• Pulmonary emboli
• Limb gangrene requiring
amputation
• Stroke
• Myocardial infarction
Immediate, Benign, & Limited
Thrombocytopenia:
• HIT Type I
• This benign form of
thrombocytopenia usually
develops in 1-3 days.
 • HIT is often a MEDICAL
EMERGENCY
• Mortality Rate is 20%
LABORATORY TESTS FOR HIT
• Heparin-induced Antibody Immunoassay
• Aggregometry or Lumi-aggregometry
REFERENCE METHOD:
• Carbon 14 Serotonin washed platelet release
Assay
Thrombotic HIT
• HIT Type II
• Develops after 5 days
In HIT (HIT Type II)
• Decrease in platelet count
may exceed 40%
Benign Thrombocytopenia
• DECREASE is relatively
small
THERAPY FOR HIT
• When heparin-induced Antibodies are
detected, the administration of UFH or
LMWH is immediately discontinued.
• SYNTHETIC PENTASACCHARIDE
(FONDAPARINUX), mimics heparin’s
antithrombin-binding sequence
• RECOMBINANT BIVALIRUDIN is a direct
thrombin inhibitor modeled after leech saliva.
• ARGATROBAN is an amino acid analogue
direct thrombin inhibitor.
• Lab practitioners may monitor using the PTT.
• The Activated Clotting Time (ACT); the ecarin
clotting time, which uses a reagent derived
from Echis carinatus snake venom; or the
plasma-diluted thrombin time may also be
employed to monitor these direct thrombin
inhibitors.
 THROMBOCYTOPENIA AND THROMBOCYTOSIS

THROMBOCYTOPENIA
Definition • Platelet count: <100,000/uL
• Most common cause of clinically important bleeding

Type of bleeding • Mucocutaneous bleeding

Unusual for clinical bleeding to occur when:

• Platelet count: >50,000/uL

Risk of clinical bleeding increases progressively as the:

• Platelet count: <50,000/uL

In general:
• Px with plt counts of fewer than 10,000/uL → considered to be at HIGH RISK for a
SERIOUS HEMORRHAGIC EPISODE

IMPAIRED PLATELET PRODUCTION

• 2 CATEGORIES OF ABNORMAL PLATELET PRODUCTION:
1. Megakaryocytic hypoplasia
2. Ineffective Thrombopoiesis

MEGAKARYOCYTIC HYPOPLASIA
A. Congenital hypoplasia
B. Congenital Amegakaryocytic thrombocytopenia
C. Autosomal dominant & X-linked thrombocytopenia
D. Neonatal hypoplasia
E. Acquired hypoplasia

• Fanconi Anemia
• Thrombocytopenia w/ absent radii (TAR) syndrome
A. Congenital • Wiscott-Aldrich Syndrome
Hypoplasia • Bernard-Soulier Syndrome
• May-Hegglin Anomaly
• Sebastian Syndrome
• Fechtner Syndrome
 • An autosomal recessive disorder reflecting the bone marrow
failure
Affected infants usually have:
• platelet counts of <20,000/uL at birth
• Petechiae
• Evidence of bleeding at or shortly after birth
B. Congenital • Frequent physical anomalies
Amegakaryocytic
Thrombocytopenia • About half of the infants develop aplastic anemia in the 1st year
of life
• Reports of myelodysplasia & leukemia later in childhood.

• Caused by mutations in the MPL gene on chromosome 1

(Ip34)
-Results in complete loss of thrombopoietin receptor function

• Mutation(s) in the ANKRD26 gene on the short arm of

Chromosome 10 (10p11-12)

• Mutations in this gene appear to lead to incomplete

C. Autosomal Dominant megakaryocyte different and the resultant thrombocytopenia
Thrombocytopenia
• Platelet morphology & size are usually normal.

• Bleeding in these patients is usually absent or mild

• Platelet – usually normal

X-linked thrombocytopenia can result from:

• Mutations in the WAS (Wiskott-Aldrich Syndrome) gene on the
X chromosome (Xp11)
• Mutations in the GATA I gene
D. X-linked • Mutation on the X chromosome at XpII.
Thrombocytopenia
• X-linked thrombocytopenia range from mild thrombocytopenia &
small platelets and absent or mild bleeding to
macrothrombocytopenia with severe bleeding

Causes include infection with:

• Toxoplasma, rubella, CMV, herpes (TORCH)
• HIV
• Utero exposure to certain drugs; particularly chlorothiazide
diuretics & the oral hypoglycemic tolbutamide and other agents.
E. Neonatal Hypoplasia
• TORCH infections cause thrombocytopenia w/
characteristically small platelets.

• CMV – is the most common infectious agent causing congenital

thrombocytopenia

Chemotherapeutic agents
F. Acquired Hypoplasia Anagrelide
(Drugs) Ethanol
Interferon Therapy
Estrogen
 Antibiotics
Tranquilizers
Anticonvulsants
Viruses
G. Miscellaneous Bacteria
Malignant cells

II. INEFFECTIVE THROMBOPOIESIS

• Megaloblastic anemia
- Pernicious anemia
- Folic acid deficiency
- Vitamin B12 Deficiency

• Thrombocytopenia
- Is caused by impaired DNA synthesis
- Bone marrow may contain grossly abnormal megakaryocytes with
deformed, dumbbell-shaped nuclei, sometimes in large numbers.

Stained peripheral blood films

- reveal large platelets that may have a decreased survival time and
may have abnormal function.
Thrombocytopenia is usually mild, and there is evidence of increased platelet
destruction

INCREASED PLATELET DESTRUCTION

A. IMMUNE MECHANISMS B. NONIMMUNE MECHANISMS

• Immune thrombocytopenia purpura (ITP) • Pregnancy and eclampsia

• Immunologic drug-induced thrombocytopenia
• Neonatal alloimmune thrombocytopenia
• Neonatal autoimmune thrombocytopenia
• Post-transfusion purpura
• Secondary thrombocytopenia
• Thrombotic thrombocytopenia purpura (TTP)
• Hemolytic uremic syndrome (HUS)
• Disseminated Intravascular Coagulation
(DIC)
• Drugs

IMMUNE MECHANISMS
ACUTE ITP
• Primarily a disorder of children
• Although a similar condition is seen occasionally in adults
• The disorder is characterized by the abrupt onset of the
following in a previously healthy child:
- Abrupt onset of bruising
- Petechiae
IMMUNE - Sometimes mucosal bleeding (e.g. epistaxis)
THROMBOCYTOPENIC
PURPURA (ITP) • Primary hematologic feature is:
- THROMBOCYTOPENIA – frequently occurs 1-3
weeks after an infection.

• Infection is most often a nonspecific URT or GIT viral

infection, but acute ITP also may occur after:
- Rubeola
- Rubella
- Chickenpox
 - Or other viral illnesses and may follow live virus
vaccination.

CHRONIC ITP
• This disorder can be found in patients of any age, although
most cases occur in patients between ages 20-50 years.

• Females w/ this disorder outnumber males 2:1 to 3:1, with the

highest incidence in women between 20-40 years.

• It usually begins INSIDIOUSLY, with platelet counts that are

VARIABLY DECREASED & sometimes normal for periods of
time.
• Presenting symptoms are those of the ff:
- mucocutaneous bleeding w/ menorrhagia
- recurrent epistaxis
- easy bruising (ecchymoses) – most common

• Platelet destruction in chronic ITP:

- Result of an immunologic process

• The OFFENDING Abs attach to platelets, and as a result, the

antibody-labeled platelets are removed from the circulation by
REC, primarily in the spleen
• Autoantibodies that recognize platelet surface glycoproteins
such as GP IIb, GP IIIa (aIIb/b3). GP Ia/IIa and others.
• In most cases, platelets number between 30,000/uL and
80,000/uL
• MORPHOLOGICALLY:
- Platelets appear NORMAL, although larger in
diameter than usual.
• IVG – remains the treatment of choice.
 • Categories of Drugs
• Quinidine
• Hapten-dependent Abs
• Drug-induced autoantibodies
• Heparin-induced thrombocytopenia

DRUG-DEPENDENT ANTIBODIES
• One mechanism of drug-dependent antibodies:
- Typified by quinidine- and quinidine induced
thrombocytopenia and has been recognized for more
than 100 years.
• The Ab induced by drugs of this type interacts with platelets
only in the presence of the drug.
• Drug-dependent Abs typically occur after 1-2 weeks of
exposure to a new drug
• Quinine, quinidine, and sulfonamide derivatives
• When Ab production has begun, the platelet count falls
IMMUNOLOGIC DRUG- rapidly and often may be fewer than 10,000/uL
INDUCED • If this develops in pregnant women
THROMBOCYTOPENIA - Both she and her fetus may be affected

• The Abs responsible for drug-induced thrombocytopenia

bind to the platelets by their Fab regions, rather than by
attaching nonspecifically as immune complexes.
• The Fab portion of the Ab binds to a platelet membrane
constituent, usually the GP IIb/IX/V complex or the GP IIb/IIIa
complex, only in the presence of drug.
• Fc portion of the immunoglobulin is not involved in binding to
platelets, it is still available to the Fc receptors on phagocytic
cells. This situation may contribute to the rapid onset and
relatively severe nature of thrombocytopenia.

HAPTEN-INDUCED ANTIBODIES
• A 2nd mechanism of drug-induced thrombocytopenia is
induction of hapten-dependent Abs.
• Some drug molecules are too small by themselves to trigger
an immune response, but they may act as a hapten and
combine w/ a larger carrier molecule (usually a plasma protein
or protein constituent of the platelet membrane) to form a
complex that can act as a complete Ag.
• Penicillin and penicillin derivatives.
• Thrombocytopenia of this type is OFTEN SEVERE.
• Bleeding is often severe and rapid in onset.
• Hemorrhagic bullae in the mouth may be prominent.

DRUG-INDUCED ANTIBODIES
• 3rd mechanism of drug-induced thrombocytopenia.
• In this case, drugs stimulate the formation of an autoAb that
binds to a specific platelet membrane glycoprotein w/ no
requirement for the presence of free drug.
• Gold salts and procainamide are 2 examples of such drugs.
- Levodopa may also cause thrombocytopenia in the
same way
• The precise mechanism by which these drugs induce AutoAbs
against platelets is not known with certainty.

TREATMENT
Treatment for any drug-induced thrombocytopenia is:
• 1st to identify the offending drug.
• immediately discontinue its use
 • Substitute another suitable therapeutic agent.

IMMUNE COMPLEX-INDUCED THROMBOCYTOPENIA

• HIT
• Heparin binds to platelet factor 4, a heparin-neutralizing
protein made & released by platelets. Binding of heparin by
plasma PF4 or platelet-membrane-expressed PF4 causes a
conformational change in PF4, resulting in the exposure of
neoepitopes.
• Exposure of these neoepitopes (new antigens) stimulates the
immune system of some individuals, which leads to the
production of an Ab to one of the neoepitopes. In HIT, heparin
and PF4 form a complex on the platelet surface or circulating
free complexes to which the antibody binds.
• The Fab portion of the immunoglobulin molecule binds to an
exposed neoepitope in the PF4 molecule; this leaves the Fc
portion of the IgG free to bind to platelet FcgIIa receptor, which
causes platelet activation.
• Because the Fc portions of the IgG molecules bind to platelet
FcgIIa receptor, they are not available to the Fc receptors of
the cells of the REC system. This may explain the less severe
decline in platelet count in this thrombocytopenia.

DEFINITION
• NAIT develops when the mother lacks a platelet-specific Ag
(usually human platelet antigen Ia, or HPA-Ia that the fetus has
inherited from the father
• HPA-Ia is the most often involved (80% of cases)
• HPA-5b accounts for another 10%-15% of cases.
MECHANISM
• Fetal Antigens may pass from the fetal to the maternal
circulation as early as the fourteenth week of gestation. If the
mother is exposed to a fetal Antigen she lacks, she may make
Abs to the fetal antigens. These antibodies cross the placenta,
attach to the antigen-bearing fetal platelets, and results in
thrombocytopenia in the fetus.

ANTIGENS INVOLVED
• Most frequent cause of nait in whites is HPA-Ia Antigen
expressed on GP IIIa of the surface membrane GP IIb/IIIa
complex, followed by HPA-5b (Bra ).
• The Ag HPA-3a (Baka) is present on GP IIb and is an
important cause of neonatal thrombocytopenia in Asian.
Platelet antigen HPA-4 (Penn and Yuk) accounts for the disorder
in a few affected neonates.
CLINICAL FEATURES
• Affected infants may appear NORMAL at birth but soon
NEONATAL ALLOIMMUNE
manifest scattered petechiae and purpuric hemorrhages.
THROMBOCYTOPENIA
• SYMPTOMATIC CASES:
- Platelet levels are usually below 30,000/Ul and may
diminish even further in the 1st few hours after birth
• Presence of thrombocytopenia in a neonate w/ a HPA-Ia
negative mother or a history of the disorder in a sibling is
strong presumptive evidence in a favor of the diagnosis.
• Confirmation should include platelet typing of both parents and
testing for evidence of a maternal antibody directed at paternal
platelets.
 DIAGNOSIS
• Diagnosis of ITP or SLE in the mother is a prerequisite for the
diagnosis of neonatal autoimmune thrombocytopenia.
• Neonatal autoimmune thrombocytopenia is due to passive
transplacental transfer of Abs from a mother w/ ITP or,
occasionally, SLE.
• Affected newborns may have normal to decreased platelet
numbers at birth, and have progressive decrease in the
platelet count for about 1 week before the platelet count
begins to increase.
• It has been speculated that the failing platelet count is
associated with maturation of the infant’s REC system and
accelerated removal of antibody-labeled platelets by cells of
the REC system.

TREATMENT
• CORTICOSTEROIDS are the primary treatment for pregnant
women.
• It is no longer recommended that high risk infants be delivered
cesarean section to avoid the trauma of vaginal delivery and
accompanying hemorrhage in the infant.

DEFINITION:
• Relatively rare disorder that typically develops about 1 week
after transfusion of platelet-containing blood products,
including fresh or frozen plasma, whole blood, and packed or
washed RBCs.

MANIFESTATIONS:
• Manifested by the rapid onset of severe thrombocytopenia
• Moderate to severe hemorrhage that may be life-threatening.

MECHANISMS:
• The recipient’s plasma is found to contain alloantibodies to
antigens on the platelets or platelet membranes of the
transfused blood product, directed against an antigen the
POST-TRANSFUSION recipient does not have.
PURPURA
• HPA-Ia Antigen
• PIA2 or other epitopes on GP IIb/IIIa
• Other alloantigens has been reported such as:
- HPA-3a (Bak)
- HPA-4 (Penn)
- HPA-5b (Br)

• The mechanism by which the recipient’s own platelets are

destroyed is unknown
• Most patients w/ this type of thrombocytopenia are
MULTIPAROUS MIDDLE-AGED WOMEN.
• Almost all other patients have a history of blood transfusion.

INDUCING CONDITIONS:
SECONDARY • Biologic response modifiers (Interferons, CSFs, IL-2)
THROMBOCYTOPENIA • Chronic lymhocytic leukemia
• SLE
• Malaria