117 Heparin-Induced Thrombocytopenia Flashcards
A complication of heparin therapy that leads to a fall in platelet count and a high incidence of arterial and/or venous thromboembolic complications
Heparin-induced thrombocytopenia (HIT)
Types of HIT
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
Heparin is bound to this platelet-specific chemokine
Platelet factor 4 (PF4, CXCL4)
The most important determinant of risk for HIT
Whether the patient is exposed to unfractionated heparin (UFH) or low-molecular-weight-heparin (LMWH)
Table of risk factors
Heparin-Induced Thrombocytopenia Risk Factors
Patient-Specific Factors
* Age (older individuals > pediatrics > neonates)
* Patient population (surgical > medical > obstetric)
* Intervention (cardiopulmonary bypass surgery, hemodialysis, trauma, hip and knee arthroscopy)
* Major trauma > minor trauma
* Sex (female > male)
* Bacterial infection ( urinary tract infection, pneumonia, periodontal/ gingival disease)
Heparin-Specific Factors
* Type of heparin (unfractionated heparin > lowmolecular-weight heparin)
* Duration of heparin (~5 days > shorter courses)
The presence of periodontal/gingival disease, which has been shown to increase the risk of developing naturally occurring anti-PF4/heparin antibodies, has also been linked to an increased risk of developing HIT, with an incidence in affected patients nearly twice as high as the overall rate in hospitalized patients.
Etiology and pathogenesis of HIT
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.
A 7.8-kDa protein synthesized by megakaryocytes and packaged into platelet α granules as a tetrameric complex bound to the intracellular proteoglycan serglycin
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.
Anticoagulant that is a synthetic heparin pentasaccharide, is shorter than LMWH and contains fewer negatively-charged side chains
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.
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.
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.
The clinical hallmark of HIT
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.
Other clinical clues must be sought to estimate the clinical likelihood of developing HIT:
- Timing
- Degree of platelet count fall
- Nadir platelet count
- Presence of thromboembolism or hemorrhage
- The likelihood of other causes of thrombocytopenia
The platelet count in HIT characteristically begins to fall ______ days after initial heparin exposure
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
Both delayed-onset HIT and spontaneous HIT occur in the absence of circulating heparin and are termed
Autoimmune HIT
May exhibit atypical clinical features including more severe or prolonged
How is the percentage fall in platelet count measured
From the peak platelet count after initiation of heparin to the nadir platelet count
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.
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.
TRUE OR FALSE
The nadir platelet count in HIT needs to meet the traditional definition of thrombocytopenia (<150 x 109/L).
FALSE
The nadir platelet count in HIT does not need to meet the traditional definition of thrombocytopenia: less than 150 x 109/L
The most common thrombotic manifestations of HIT
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.
TRUE OR FALSE
Spontaneous hemorrhage is common in HIT, specially when thrombocytopenia is severe.
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
Clinical scoring system for HIT composed of:
* Thrombocytopenia
* Timing
* Thrombosis or other sequelae
* Other causes of Thrombocytopenia
4T score
Scores of 0–3, 4–5, and 6–8 are classified as low, intermediate, and high probability, respectively.
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.
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
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 ____________
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
Detect the presence of circulating anti-PF4/heparin antibodies, irrespective of whether they are able to activate platelets and cause disease
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.
Principle used in functional assays
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.
The prototypical functional assays are the:
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.
Drugs that may interfere in SRA
- Danaparoid: impairs the formation of PF4/heparin complexes
- P2Y12 antagonist, ticagrelor: blocks platelet activation
Phases of HIT
Those who are thought to have HIT based on clinical grounds for which confirmatory test results have not yet been obtained
Suspected HIT
PC: decreased
FA: ?
IA: ?
Phases of HIT
Immediately after laboratory testing has confirmed the diagnosis
Highly prothrombotic phase that lasts until platelet count recovery
Acute HIT
PC: decreased
FA: +
IA: +
Phases of HIT
The interval after platelet recovery during which the functional assay and the immunoassay remain positive
Subacute HIT A
PC: normal
FA: +
IA: +
Phases of HIT
The phase that occurs after the functional assay becomes negative but the immunoassay remains positive.
Subacute HIT B
PC: normal
FA: -
IA: +
Phases of HIT
When PF4/heparin antibodies are no longer detectable by immunoassay
Remote HIT
PC: normal
FA: -
IA: -
Management of acute HIT
Immediate withdrawal of heparin
Initiation of a rapid-acting, nonheparin anticoagulant
Parenteral direct thrombin inhibitors
Argatroban and Bivalirudin
Parenteral indirect factor Xa inhibitors
Danaparoid and Fondaparinux
Direct Oral Anticoagulants (DOACs)
- Rivaroxaban- direct factor Xa inhibitor
- Apixaban- direct factor Xa inhibitor
- Dabigatran- direct thrombin inhibitor
Clearance is solely hepatobilliary
Argatroban
Clearance is enzymatic and renal
Bivalirudin
Monitoring is based on aPTT of 1.5–3.0 × patient baseline
Argatroban and Bivalirudin
Monitoring is based on anti–factor
Xa
Danaparoid
Rivaroxaban
No monitoring
- Fondaparinux
- Apixaban
- Dabigatran
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
Fondaparinux
Cleared by the kidneys and should be used with caution in individuals with renal insufficiency
Long half-life of 17–21 hours
TRUE OR FALSE
Warfarin and other vitamin K antagonists should not be prescribed as the initial anticoagulant in patients with acute HIT
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
Many practitioners DOAC of choice in the treatment of HIT because it is the agent on which most published clinical data are available.
Rivaroxaban
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.
Apixaban
Who to treat
Patients with an intermediate- or high-probability 4T score until the results of HIT laboratory testing become available
Patients with HIT-associated thromboembolism are typically treated with therapeutic anticoagulation for
3–6 months
It is therefore generally accepted that anticoagulation be continued in patients with HIT until platelet count recovery.
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:
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
Recommended over heparin in patients with a history of HIT who require percutaneous vascular procedures, irrespective of the results of HIT laboratory testing
Bivalirudin
Incidence of HIT in patients on chronic hemodialysis
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.
Anticoagulant with the largest published experience among pregnant women
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
