HEPARIN INDUCED

THROMBOCYTOPENIA

By
SESHU
 INTRODUCTION
• Heparin-induced
thrombocytopenia (HIT) without or
with thrombosis (HITT) is the
development of thrombocytopenia 
(low platelet counts) due to the
administration of the 
anticoagulant  (blood clotting
inhibitor) heparin, either in its
"unfractionated" or "low molecular
weight" form.
• It predisposes to thrombosis, the
 INTRODUCTION Contd…
• If someone receiving heparin develops
new or worsening thrombosis, or if the
platelet count falls, HIT can be confirmed
with specific blood tests.
• The treatment of HIT requires both
protection from thrombosis and choice of
an agent that will not reduce the platelet
count further.
• Several agents exist for this purpose,
mainly  lepirudin  and  argatroban.
• While heparin was discovered in the
1930s, HIT was not reported until the
1960s and 1970s.
 Thrombocytopenia and Heparin
• Heparin - • Heparin -
associated induced
Thrombocytopenia Thrombocytopenia
(HAT) (HIT)
– Non-immune – Immune-mediated
mediated – Moderate/severe
– Slight/moderate decrease in
decrease in platelet count
platelet count – Occurs 5-10 days
– Occurs 1-4 days after
after start of start of heparin
heparin
– Frequency ~ 1-3%
 CLASSIFICATION
• Types of HIT
– Isolate HIT (thrombocytopenia
only)
– HIT with thrombosis syndrome
(HITTS)
 Heparin-Induced Thrombocytopenia
(HIT): Pathophysiology
IgG antibody
PF4 Heparin
Formation of
immune complexes
(PF4-heparin-IgG)

Formation of
PF4-heparin
complexes
Microparticle
release

EC injury
Platelet PF4
release

Platelet
activation*

Heparin-like
Fc receptor molecules

Blood vessel
Pathophysiology of HIT and
Thrombosis

7
4

6
3
1 5
2

Platelets

Heparin Glycosaminoglycan molecule PF4

Pathophysiology of HIT and
Thrombosis (cont.)

7
4

6
3
1 5

Platelets

Heparin Glycosaminoglycan molecule PF4

Pathophysiology of HIT and
Thrombosis (cont.)

7
4

6
3
1 5

Platelets

Heparin Glycosaminoglycan molecule PF4

Pathophysiology of HIT and
Thrombosis (cont.)

6
3
1 5
2

Platelets

Heparin Glycosaminoglycan molecule PF4

HIT is a clinico-pathological syndrome
Clinical
– Thrombocytopenia and/or
– Thrombosis

• Pathological
– Heparin-dependent, platelet-activating
IgG antibodies
Heparin-induced thrombocytopenia (HIT)

• Less frequent clinical

manifestations
– Anaphylactoid reaction after i.v. heparin
bolus
– Skin lesions at s.c. heparin injection
sites
– Overt (decompensated) disseminated
intravascular coagulation (DIC)
Clinical events associated with HIT
• Venous thrombosis (30-70%)
– Deep vein thrombosis (DVT)
– Pulmonary embolism (PE)
– Adrenal necrosis (adrenal vein thrombosis)
– Cerebral venous (sinus) thrombosis
– Venous limb gangrene (VKA associated)
• Arterial thrombosis (“white clots”) (15-30%)
– Limb artery thrombosis
– Stroke
– Myocardial infarction
• Skin lesions at heparin injection sites (10%)
– Skin necrosis
– Erythematous plaques
• Acute reactions after i.v. heparin bolus (10%)
• Disseminated intravascular coagulation (DIC) (10%)
 Drugs associated with HIT
• Unfractionated heparin
– Prophylactic dose
– Therapeutic dose
– Flushes
– Heparin-coated devices
• Low-molecular-weight heparin
– Prophylactic dose
– Therapeutic dose
• Other highly sulfated polysaccharides
– Pentosan polysulfate
– Hypersulfated chondroitin sulfate
– PI-88 (anti-angiogenic drug)
 Risk of developing HIT
Risk Factor Risk
• Sex • Female > male
• Patient population • Orthopedic >
cardiac
• Source of heparin Surgical >
• Type of heparin medical
• • Bovine > porcine
Dose
• UFH > LMWH
• Route of
administration • High > low dose
• IV > Sub cutaneous
HIT has occurred with all types of heparin

Risk factor Highest risk Moderate

risk
Route/Dose IV use SC use
High dose Low dose
Type UFH LMWH

Source Bovine Porcine

Patient type Surgical Medical

CABG,
orthopedic
 Approach to diagnose HIT
Yes HIT

Possible
Thrombocytopenia (> 50% decrease) +

Timing 5-14 days after starting heparin +

Thrombosis +

Unusual thromboembolism;
skín lesions; anaphylaxis +

OTher cause not apparent +

Strongly Suspected

Confirmed when positive

Test for HIT antibodies positive + in context of strong
(usually strongly positive) clinical suspicion
 HIT - a vicious cycle of
platelet activation and coagulation
PF4/Heparin/HIT-IgG

Platelet Activation

Thrombosis Embolism Release PF4

Coagulation

Endothelial Cell Injury

Morbidity
& Platelet Activation

Death
PF4 /HIT-IgG Release PF4 /HIT-IgG

Platelet Activation Monocyte Activation

Coagulation
 “Iceberg model” of HIT
HIT and associated thrombosis occurs in the
subset of patients with platelet-activating
anti-PF4/H antibodies
Thrombosis
HIT
Thrombocytopenia
syndrome Positive
washed
platelet Positive
activation PF4
assay antigen
assay

Numbers of Patients
 Differential diagnosis
• Hemodilution post-surgery
• Severe pulmonary embolism
• Sepsis
• DIC (multiple causes besides HIT)
• Cancer-associated DIC
• Antiphospholipid syndrome
• Thrombolytic therapy
• EDTA-induced pseudothrombocytopenia
• GP IIb/IIIa inhibitor-induced
thrombocytopenia
• Drug-induced thrombocytopenia (other
than heparin)
• Post-transfusion purpura
• Thrombotic thrombocytopenic purpura
• Non-immune heparin-associated
 Diagnosis - pretest probability : the 4 T’s
Points: Score 0, 1 or 2 for each of 4 2 1 0
categories:

A > 50% platelet 30-50% platelet <30% platelet

Thrombocytope count fall to count fall to count fall to
nia nadir ≥ 20 nadir 10-19 nadir ≤ 10

B Onset d 5-10 or > d 10, or Platelet count

Timing of fall in < 1 d (if timing unclear, fall < d 4
platelet count or heparin or < d 1 with (without recent
other sequelae exposure within recent heparin heparin
30 d) 31-100 d exposure)
New Progressive or
C thrombosis; recurrent
skin necrosis; thrombosis;
Thrombosis or post-heparin erythematous None
other sequelae bolus acute skin lesions;
systemic suspected
reaction thrombosis –
not confirmed
D
OTher cause for No other cause Possible other Definite other
thrombocytopen for platelet cause is cause is
ia count fall is evident present
 Diagnosis - pretest probability
Interpretation of 4 T’s score
• Score 0-3:
very unlikely to be HIT (<5%)

• Score 4 - 5:
a minority have HIT (10-30%)

• Score 6 – 8:
20 to >80% have HIT, depending on the
clinical setting and scorer´s experience :
these patients usually require an alternative,
non-heparin anticoagulant in therapeutic doses
 Management of HIT – treatment
When HIT is strongly-suspected:
• Stop heparin (UFH/LMWH), even in
patients without thrombosis
• Initiate alternative non-heparin
anticoagulant because of high risk
of symptomatic thrombosis
• Test for HIT antibodies
• Duplex ultrasonography for lower-
limb DVT
 Alternative Anticoagulants
Drug Indications
Argatroban FDA-approved for HIT
[also for Percutaneous
Coronary Intervention
Lepirudin (PCI)]
FDA-approved for HIT
(FDA-Food and drug
Bivalirudin administration)
PCI (including HIT patients)

Fondaparinux Prophylaxis and Rx of

(pentasac.) VTE (Venous
ThromboEmbolism)
Danaparoid Approved for HIT in
Canada, Europe, Aust.
 Management of HIT – treatment
When HIT is strongly-suspected:
• Do not start a vitamin K antagonist (VKA) -
if started prior to diagnosis it should be
reversed by vitamin K *
• Do not use low-molecular-weight heparin
(LMWH)
• Do not give platelet transfusions unless
needed to manage serious hemorrhage
* Recommendation to give vitamin K applies particularly to
direct thrombin inhibitors (DTIs), because prolongation of
the aPTT by warfarin can lead to underdosing of DTI therapy
(in contrast, danaparoid is not monitored by aPTT)
 Management of HIT – treatment
When the diagnosis of HIT is confirmed:

• Postpone starting overlapping

coumarin until the platelet count
has recovered to at least 100
(and preferably) 150 x 109/L
• Therapeutic doses of alternative,
non-heparin anticoagulants are
usually required
• If a sensitive test for HIT is
negative, heparin therapy may be
re-started with regular platelet
count monitoring
Management of HIT – treatment
When HIT is clinically possible but platelet
count decrease is more likely caused by
other reasons:
• If the patient requires therapeutic dose
anticoagulation for non-HIT reasons,
use alternative anticoagulant in
therapeutic dose.
• If patient does not require therapeutic
dose anticoagulation for non-HIT
reasons, consider prophylactic-dose
alternative anticoagulation, e.g.
danaparoid 750 U b.i.d. or t.i.d. until
HIT antibody test results are available.
 Management of HIT – treatment
• According to systematic review,
patients treated with lepirudin for
heparin-induced thrombocytopenia
showed a relative risk reduction of
clinical outcome (death, amputation,
etc.) to be 0.52 and 0.42 when
compared to patient controls.
• In addition, patients treated
with argatroban for HIT showed
a relative risk reduction of the above
clinical outcomes to be 0.20 and
LOVE = HEMOSTASIS
Everybody
talks about it,
nobody
understands