HIT – About the Condition
Heparin induced thrombocytopenia (HIT) is a clinicopathological syndrome that occurs when heparin-dependent IgG antibodies bind to heparin/platelet factor 4 complexes to activate platelets and produce a hypercoagulable state manifested by mild to moderate thrombocytopenia and a high risk (20%-50%) of thrombosis.
Classification of HIT according to presence or absence of clot:
- Isolated HIT – HIT without thrombosis
- HITT – HIT with thrombosis:
- Venous (most common)
- Small vessel
Classification of HIT according to timing:
- Typical-onset HIT – begins 5-14 days after initiation of heparin.
- Rapid-onset HIT:
- Abrupt fall in platelet count (within 24 hours).
- Occurs in patients who already have circulating anti-PF4/heparin antibodies because of recent heparin exposure (usually < 30 days, occasionally < 90-100 days earlier).
- Delayed-onset HIT:
- Develops or worsens after heparin has been discontinued.
- Typically presents 2 to 3 weeks after prior heparin exposure.
- Functional assays show strong serum-induced platelet activation even in the absence of heparin.
- Antibodies have gained autoreactivity, recognizing platelet factor 4 bound to endogenous glycosaminoglycans on platelets and therefore activate platelets even in the absence of heparin.
- Vaccine-induced immune thrombotic thrombocytopenia (VITT) – reported in individuals vaccinated with certain coronavirus disease 2019 (COVID-19) vaccines, especially including the ChAdOx1 CoV-19 vaccine (AstraZeneca) and the Ad26.COV2.S vaccine (Johnson & Johnson).
- Autoimmune (spontaneous) HIT:
- Occurs without any exposure to heparin.
- Platelet factor 4 (PF4):
- Binds to polyanions other than heparin, such as lipopolysaccharide on bacteria or RNA/DNA (released during major surgery).
- Undergoes the same changes in its conformation as when binding to heparin, with resulting complex serving as trigger for autoimmune HIT.
Risks for developing HIT:
- HIT can occur with any heparin dose, schedule, and administration route:
- Risk with unfractionated heparin (UFH) 5-10 higher compared to low-molecular-weight heparin (LMWH).
- HIT occurs in 0.2% to 5% of adults exposed to UFH.
- More common in females.
- 3-fold greater incidence in surgical than in medical patients.
- Highest incidence of HIT (1% to 3%) in patients with cardiac assist devices and those undergoing cardiac surgery.
Note: There is another type of heparin-induced thrombocytopenia that used to be called HIT type I that is associated with a mild, transient drop in platelet count typically occurring within the first two days of heparin exposure. The platelet count normalizes with ongoing heparin administration. The mechanism involves a direct effect of heparin on platelets, causing non-immune platelet aggregation. Platelet count rarely falls below 100 x 109/L. HIT type I does not cause thrombosis and heparin does not need to stopped.
Binding of PF4 (a small cationic chemokine stored in platelet alpha-granules and released in high quantities at sites of platelet activation) to heparin leads to exposure of neoepitopes on PF4 which are recognized by HIT antibodies (IgG, IgA, or IgM). These antibodies then bind the Fc gamma RIIA receptor on platelets, leading to platelet activation, moderate thrombocytopenia and a prothrombotic state. HIT antibodies are transient: they appear around 4 days after exposure to heparin and they disappear by 100 days after recovery from HIT. There is no immune memory for HIT so that repeat exposure to heparin does not lead to recurrent episodes of HIT. Once antibodies disappear (i.e., HIT laboratory testing becomes negative), it is safe to re-expose patients to heparin during a cardiovascular procedure or surgery.
Not all anti-PF4/heparin antibodies are pathogenic; some do not result in HIT.
Patients may present:
- With venous thrombosis:
- Deep vein thrombosis/pulmonary embolism, including venous limb gangrene
- Adrenal infarction secondary to adrenal vein thrombosis
- Central venous catheter–associated deep vein thrombosis
- With arterial thrombosis, including:
- Myocardial infarction
- Acute limb ischemia from peripheral arterial occlusion
- Organ infarction (mesentery, kidney)
- With microvascular thrombosis
- Thrombosis in unusual sites, including:
- Cerebral sinuses
- Vascular grafts
- Visceral vessels
- Skin necrosis:
- Most commonly at heparin injection sites.
- May occur in fat-rich areas such as the abdomen.
- Anaphylactoid reactions after an intravenous heparin bolus.
- Disseminated intravascular coagulation (DIC) – often present with platelet counts below 20 × 109/L.
Thrombosis occurs in up to 50 percent of individuals with HIT who are not treated with a non-heparin anticoagulant. Thrombosis is the presenting finding in up to 25 percent of patients. Bleeding is uncommon but has been reported.
Diagnosis requires appropriate clinical presentation (as assessed by clinical scoring system) and detection of platelet-activating anti-PF4/heparin antibodies.
- In a patient receiving heparin with any one of the following:
- New onset of thrombocytopenia.
- Reduction in platelet count > 50%.
- Thrombosis – venous or arterial.
- Necrotic skin lesions at heparin injection sites.
- Acute systemic reaction after IV heparin administration.
- Based on clinical presentation (4T score), which in turn depends on:
- Degree of thrombocytopenia.
- Timing of thrombocytopenia.
- Thrombosis or other sequelae.
- Other causes for thrombocytopenia.
- Predictive value of 4T score
- 0 to 3 points – Low probability (risk of HIT <1 percent).
- 4 to 5 points – Intermediate probability (risk of HIT approximately 10 percent).
- 6 to 8 points – High probability (risk of HIT approximately 50 percent).
- Further supported or ruled out by immunoassay, for example one of:
- EIA (ELISA):
- High ELISA reactivity correlates closely with the presence of platelet-activating HIT IgG.
- Positive platelet activation studies are uncommon in patients with weakly positive ELISA optical density values (0.4 to 0.9).
- Latex immunoturbidimetric assay:
- Highly standardized.
- Allow a rapid turnaround time.
- May produce false negative results in about 2% to 3% of patients.
- EIA (ELISA):
Confirm diagnosis using a functional assay, typically a serotonin release assay. Functional assays have improved specificity compared with immunoassays. While immunoassays detect pathogenic + nonpathogenic, non-platelet-activating antibodies, functional assays detect only clinically relevant pathogenic platelet-activating antibodies. Performance of functional assays is limited primarily to specialized reference laboratories.
Though the serotonin release assay is considered the gold standard for diagnosing HIT, there is increasing evidence for the rare existence of EIA-positive, serotonin release assay-negative HIT.
Management of acute HIT should begin as soon as disease is suspected (intermediate or high probability 4T score), and should include:
- Discontinuation of all heparin productions.
- Initiation of alternative anticoagulant:
- Options include:
- Drug of choice in patients with renal insufficiency.
- Cleared by liver, needs dose reduction in liver disease.
- Bivalirudin, especially in patients who require urgent cardiac surgery or percutaneous coronary intervention
- DOAC (most experience is with rivaroxaban.)
- In patients with critical illness, increased bleeding risk, or increased potential need for urgent procedures, argatroban or bivalirudin may be preferred agents because of shorter duration of effect.
- In patients with HIT complicated by life- or limb-threatening thromboembolism (eg, massive pulmonary embolism or venous limb gangrene), a parenteral non-heparin anticoagulant may be preferred over DOAC because few such patients have been treated with a DOAC
- Options include:
- Discontinuation and reversal of coumadin with administration of vitamin K.
- Avoidance of platelet transfusions unless severe bleeding or high risk of severe bleeding.
- Avoidance of inferior vena cava (IVC) filter if possible.
- Median time for resolution of thrombocytopenia after stopping heparin is 4 days.
- Platelet count normalizes within 1 week of heparin discontinuation in about 65% of patients.
Once platelets have recovered (>150 x 109/L), patients may be transitioned to one of:
- Vitamin K antagonist:
- Continue non-heparin anticoagulant with VKA therapy for ≥ 5 days until INR is in target range.
- In patients overlapping with argatroban and warfarin, INR ≥ 4 should be observed for 2 consecutive days before argatroban is stopped.
- DOAC – 2018 ASH guideline: “In patients with subacute HIT A, the ASH guideline panel suggests treatment with a DOAC rather than a VKA (conditional recommendation, moderate certainty in the evidence about effects [HIT A refers to the window of time in which platelets have recovered but the functional assay is still positive]”.
Duration of anticoagulation:
- HIT without thrombosis:
- Anticoagulation of up to 4-6 weeks.
- 2018 ASH guideline: “In patients with acute isolated HIT and no asymptomatic DVT identified by screening compression ultrasonography, the ASH guideline panel suggests that anticoagulation be continued, at a minimum, until platelet count recovery (usually a platelet count of ≥150 × 109/L). The ASH guideline panel suggests against continuing treatment of ≥3 months unless the patient has persisting HIT without platelet count recovery… there may be an additional benefit of prolonged treatment beyond platelet count recovery, but this is uncertain… Although some clinicians provide treatment of 4 to 6 weeks, the panel could not agree on a specific duration of therapy on the basis of current evidence and therefore provided a minimum (until platelet count recovery) and maximum (<3 months) duration of treatment”.
- HIT with thrombosis – anticoagulation for 3 to 6 months.
Thrombosis develops in 40% to 50% of patients with HIT.
Untreated HIT has a mortality rate as high as 20%.
Even with platelet count recovery, patients remain at risk for thrombosis for 4 to 6 weeks after diagnosis because of circulating anti-PF4/heparin antibodies.