117 Heparin-Induced Thrombocytopenia

Question 1

A complication of heparin therapy that leads to a fall in platelet count and a high incidence of arterial and/or venous thromboembolic complications

Answer 1

Heparin-induced thrombocytopenia (HIT)

Question 2

Types of HIT

Answer 2

HIT type I: a benign nonimmune condition associated with a mild, immediate, and transient drop in platelet count and no increased risk of thrombosis

HIT type II: the classic immune-mediated prothrombotic disease

HIT antibodies activated both platelets and endothelial cells

Question 3

Heparin is bound to this platelet-specific chemokine

Answer 3

Platelet factor 4 (PF4, CXCL4)

Question 4

The most important determinant of risk for HIT

Answer 4

Whether the patient is exposed to unfractionated heparin (UFH) or low-molecular-weight-heparin (LMWH)

Table of risk factors

Question 5

Etiology and pathogenesis of HIT

Answer 5

The primary immune response in HIT is nonclassical in that antibodies appear as IgG without IgM precedence or class switching.

The secondary immune response in HIT is also weak and antibodies typically disappear after a few months and may not reappear with heparin reexposure.

Question 6

A 7.8-kDa protein synthesized by megakaryocytes and packaged into platelet α granules as a tetrameric complex bound to the intracellular proteoglycan serglycin

Answer 6

PF4

Upon platelet activation, PF4 is released into the circulation where it rapidly binds to polyanionic GAGs found on the surface of hematopoietic and vascular cell types.

Question 7

Anticoagulant that is a synthetic heparin pentasaccharide, is shorter than LMWH and contains fewer negatively-charged side chains

Answer 7

Fondaparinux

It does not form large complexes with PF4,explaining the negligible incidence of HIT with this agent and supporting its potential utility in the prevention or treatment of HIT.

Question 8

TRUE OR FALSE

Although platelets are central to the pathophysiology of HIT, PF4 interacts with other cells to contribute to the high risk of thrombosis.

Answer 8

TRUE

Although platelets are central to the pathophysiology of HIT, PF4 interacts with other cells to contribute to the high risk of thrombosis.

ULCs form preferentially on monocytes as a result of their high expression of surface heparan sulfate that binds PF4 more avidly than the chondroitin sulfate GAG side chains that predominate on the platelet surface.

Neutrophils, which may be affected directly by HIT antibodies,PF4/heparin immune complexes, or cross-talk with activated platelets, become incorporated into thrombi where they can release NETs that contribute to thrombus growth by capturing red cells and platelets.

Question 9

The clinical hallmark of HIT

Answer 9

Development of thrombocytopenia after a proximate heparin exposure

The combination of thrombocytopenia and heparin exposure in hospitalized patients is common and has poor specificity for HIT.

Question 10

Other clinical clues must be sought to estimate the clinical likelihood of developing HIT:

Answer 10

• Timing
• Degree of platelet count fall
• Nadir platelet count
• Presence of thromboembolism or hemorrhage
• The likelihood of other causes of thrombocytopenia

Question 11

The platelet count in HIT characteristically begins to fall ______ days after initial heparin exposure

Answer 11

5–10 days

Exceptions to this rule:
* Rapid onset HIT: patients with heparin exposure in the past 90 days who have recently formed anti-PF4/heparin IgG antibodies, experience a fall in platelet count immediately upon heparin reexposure
* Delayed-onset HIT: clinical manifestations develop a median of 10–14 days after heparin is discontinued

Question 12

Both delayed-onset HIT and spontaneous HIT occur in the absence of circulating heparin and are termed

Answer 12

Autoimmune HIT

May exhibit atypical clinical features including more severe or prolonged

Question 13

How is the percentage fall in platelet count measured

Answer 13

From the peak platelet count after initiation of heparin to the nadir platelet count

Question 14

TRUE OR FALSE

The nadir platelet count is approximately 60 X 109/L and rarely falls below 20 X 109/L in the absence of concomitant DIC.

Answer 14

TRUE

The nadir platelet count is approximately 60 X 109/L and rarely falls below 20 X 109/L in the absence of concomitant DIC.

Most patients with HIT see a 50% or greater fall in platelet count; a more modest decline (30–50%) occurs in approximately 10% of patients

Thus, as opposed to other forms of drug-induced immune thrombocytopenia, the decrease in platelet count in HIT is characteristically mild or moderate.

Question 15

TRUE OR FALSE

The nadir platelet count in HIT needs to meet the traditional definition of thrombocytopenia (<150 x 109/L).

Answer 15

FALSE

The nadir platelet count in HIT does not need to meet the traditional definition of thrombocytopenia: less than 150 x 109/L

Question 16

The most common thrombotic manifestations of HIT

Answer 16

Lower-extremity deep vein thrombosis and pulmonary embolism

Outnumbering arterial events by approximately 2:1

Thromboembolism is the presenting feature in up to 25% of patients with HIT and develops in half of all cases.

Question 17

TRUE OR FALSE

Spontaneous hemorrhage is common in HIT, specially when thrombocytopenia is severe.

Answer 17

FALSE

Spontaneous hemorrhage is rare in HIT, even when thrombocytopenia is severe.

Although the risk of bleeding is lower in HIT than other immune thrombocytopenias, the prothrombotic nature of HIT is not protective against hemorrhage

Question 18

Clinical scoring system for HIT composed of:
* Thrombocytopenia
* Timing
* Thrombosis or other sequelae
* Other causes of Thrombocytopenia

Answer 18

4T score

Scores of 0–3, 4–5, and 6–8 are classified as low, intermediate, and high probability, respectively.

Question 19

Clinical scoring system which differs from the 4T system by using more incremental scoring for the degree of platelet fall and alternative causes of thrombocytopenia, adding points for the presence of skin necrosis, and subtracting points in patients with bleeding.

Answer 19

HIT Expert Probability (HEP) Score

The HEP score had better reliability and favorable operating characteristics in a retrospective study, and these results were validated in a prospective study of 310 patients at a single health institution

Question 20

Screening recommendations

Intermediate- or high-risk patients include those receiving postoperative UFH or those receiving LMWH after major surgery or trauma.

These individuals should have platelet counts drawn every ____________

Answer 20

Every 2–3 days from days 4 through 14,every 2–3 days from days 4 through 14

Surgical and trauma patients receiving postoperative UFH are classified as high-risk and should have platelet counts drawn every other day.

Low-risk patients including those receiving LMWH after minor surgery or trauma and those receiving fondaparinux do not require screening.

Confirmatory laboratory testing should be restricted to patients with an intermediate to high probability of HIT

Question 21

Detect the presence of circulating anti-PF4/heparin antibodies, irrespective of whether they are able to activate platelets and cause disease

Answer 21

Immunoassays

The prototypical immunoassay is the solid-phase ELISA, in which dilute patient serum is added to microtiter wells coated with complexes of PF4/heparin (or PF4-polyvinylsulfonate).

A key limitation of the polyspecific ELISA is its specificity.

Question 22

Principle used in functional assays

Answer 22

Plasma or serum from HIT patients are incubated with platelets from healthy donors in the presence of UFH and the resulting platelet activation is measured

Functional assays are more specific than commercial immunoassays because they detect antibodies capable of inducing platelet activation in a heparin-dependent manner.

Question 23

The prototypical functional assays are the:

Answer 23

14C-serotonin release assay (SRA) and the heparin-induced platelet-activation assay (HIPA)

All of these methods are limited by the continued need for donor-derived fresh platelets.

Question 24

Drugs that may interfere in SRA

Answer 24

• Danaparoid: impairs the formation of PF4/heparin complexes
• P2Y12 antagonist, ticagrelor: blocks platelet activation

Question 25

Phases of HIT

Those who are thought to have HIT based on clinical grounds for which confirmatory test results have not yet been obtained

Answer 25

Suspected HIT

PC: decreased
FA: ?
IA: ?

Question 26

Phases of HIT

Immediately after laboratory testing has confirmed the diagnosis

Highly prothrombotic phase that lasts until platelet count recovery

Answer 26

Acute HIT

PC: decreased
FA: +
IA: +

Question 27

Phases of HIT

The interval after platelet recovery during which the functional assay and the immunoassay remain positive

Answer 27

Subacute HIT A

PC: normal
FA: +
IA: +

Question 28

Phases of HIT

The phase that occurs after the functional assay becomes negative but the immunoassay remains positive.

Answer 28

Subacute HIT B

PC: normal
FA: -
IA: +

Question 29

Phases of HIT

When PF4/heparin antibodies are no longer detectable by immunoassay

Answer 29

Remote HIT

PC: normal
FA: -
IA: -

Question 30

Management of acute HIT

Answer 30

Immediate withdrawal of heparin
Initiation of a rapid-acting, nonheparin anticoagulant

Question 31

Parenteral direct thrombin inhibitors

Answer 31

Argatroban and Bivalirudin

Question 32

Parenteral indirect factor Xa inhibitors

Answer 32

Danaparoid and Fondaparinux

Question 33

Not approved for treatment of HIT

More convenient to use than other agents given the ease of once-daily subcutaneous administration and a lack of need for laboratory monitoring

It does not alter the INR

Answer 33

Fondaparinux

Cleared by the kidneys and should be used with caution in individuals with renal insufficiency

Long half-life of 17–21 hours

Question 34

TRUE OR FALSE

Warfarin and other vitamin K antagonists should not be prescribed as the initial anticoagulant in patients with acute HIT

Answer 34

TRUE

Warfarin and other vitamin K antagonists should not be prescribed as the initial anticoagulant in patients with acute HIT

Their use increases the risk of venous limb gangrene as a result of rapidly lowering of protein C and protein S activity

Question 35

Many practitioners DOAC of choice in the treatment of HIT because it is the agent on which most published clinical data are available.

Answer 35

Rivaroxaban

Question 36

In large-scale anticoagulation trials, ________ is the DOAC associated the lowest risk of major bleeding and is commonly chosen in patients with HIT deemed to be at a higher risk of bleeding, including those with recent surgery or with creatinine clearance below 30 mL/min.

Answer 36

Apixaban

Question 37

Who to treat

Answer 37

Patients with an intermediate- or high-probability 4T score until the results of HIT laboratory testing become available

Question 38

Patients with HIT-associated thromboembolism are typically treated with therapeutic anticoagulation for

Answer 38

3–6 months

It is therefore generally accepted that anticoagulation be continued in patients with HIT until platelet count recovery.

Question 39

In general, heparin reexposure should be avoided in patients with a history of HIT because of the risk of reoccurrence

An exception to this rule is:

Answer 39

Use of intraoperative heparin in patients with a history of HIT who are undergoing cardiovascular surgery

Patients with a negative immunologic and functional assay may safely receive UFH during surgery.

Heparin should be avoided in patients with a positive functional assay.

When heparin is administered to patients with a history of HIT, it should be limited to the intraoperative setting

Question 40

Recommended over heparin in patients with a history of HIT who require percutaneous vascular procedures, irrespective of the results of HIT laboratory testing

Answer 40

Bivalirudin

Question 41

Incidence of HIT in patients on chronic hemodialysis

Answer 41

Less than 1%

Ongoing heparin exposure during dialysis in patients with a history of HIT is contraindicated.

Alternative strategies including regional citrate, saline flushing, danaparoid, argatroban, and vitamin K antagonist use have been used.

Question 42

Anticoagulant with the largest published experience among pregnant women

Answer 42

Danaparoid

Danaparoid does not cross the placenta and there was no measurable anti-Xa activity in the cord blood of six neonates who were tested after delivery.

If danaparoid is unavailable, fondaparinux may be considered,