What every physician needs to know:
Heparin-induced thrombocytopenia (HIT) is arguably the most important medication reaction encountered in hospitals today, because of the frequency of real HIT, the frequency with which it comes up as a consideration, and the devastating or fatal venous or arterial thrombotic complications that can ensue. With awareness and vigilance, complications can be prevented or minimized most of the time. Heparin use is ubiquitous in hospitals, so every physician needs basic knowledge of when to suspect this disorder and how to proceed at that point. With moderate suspicion, stop all heparin, begin an alternative anticoagulant and order a confirmatory serologic test. Consider consultation from an experienced hematologist.
Are you sure your patient has heparin-induced thrombocytopenia? What should you expect to find?
Platelets fall more than 50% from baseline (or, almost always, more than 30%). This typically occurs 5 to 12 days after beginning heparin exposure. In generating a degree of suspicion, it is crucial to note whether there are other likely causes for thrombocytopenia in your patient, such as sepsis, suspicious medications other than heparin, surgery (particularly cardiac) and medical devices, e.g., intra-aortic balloon pump (IABP).
Be wary of thrombotic complications, venous or arterial; if they occur concurrent with the platelet fall, this greatly increases the likelihood of the diagnosis.
The most common thromboses are: lower extremity deep vein thrombosis (DVT), line-related DVT, pulmonary embolism, ischemic stroke, myocardial infarction, and acute thromboses of coronary bypass grafts. Relatively common are ischemic extremities due to arterial or venous thromboses. (Replacing unfractionated heparin with LMWH for prophylaxis and treatment markedly decreased HIT cases, HIT testing, and overall hospital expenditures.)Well recognized but less common are: necrotic skin lesions, bowel ischemia/necrosis, cerebral venous sinus thrombosis, and hemorrhagic adrenal infarction.
A clinical decision support called the “4Ts” incorporates whether Thrombocytopenia is typical for HIT, whether Timing is typical, whether Thromboses have accompanied the fall, and whether or not there are likely oTher causes for the thrombocytopenia (see below). A low 4T score provides strong evidence against consideration of HIT and would generally mandate that no serologic investigation be launched.
Beware of other conditions that can mimic heparin-induced thrombocytopenia:
Other common causes of iatrogenic thrombocytopenia are sepsis (with or without disseminated intravascular coagulation [DIC]) and medications, including: vancomycin, levofloxacin, linezolid, beta-lactam antibiotics, H2 blockers, anticonvulsants, etc. It should be remembered that platelets normally fall by 25-50% after a cardiopulmonary bypass with the nadir at 2-3 days, and to a lesser degree after other surgeries. Devices such as IABPs and left ventricular assist devices cause thrombocytopenia.
Thrombotic diatheses that can mimic HIT include DIC (especially Trousseau’s syndrome, the chronic DIC seen with cancer), anti-phospholipid antibody syndrome, and cholesterol emboli syndrome. Ischemic extremities can result from pressor medications, especially if there is pre-existing atherosclerotic disease or catheter-induced injury to blood vessels.
Which individuals are most at risk for developing heparin-induced thrombocytopenia?
The clinical situation greatly affects the propensity for HIT. The highest incidences are seen after heart or orthopedic surgeries. HIT is clearly more common in surgical versus medical patients and HIT is rare in obstetric patients.
The type of heparin administered (unfractionated is 10 times more likely than low molecular weight heparins (LMWH)), the dose, and the duration can all affect the risk of HIT; nevertheless, HIT can sometimes occur after miniscule exposures (such as a single catheter flush). One large hospital has reported that substituting LMWH for prophylactic and therapeutic unfractionated heparin resulted in 79% less HIT, 91% less HIT with thrombosis, and saved the hospital more than one quarter of a million dollars per year in associated expenses.
The increased HIT risk reported with female gender and platelet Fc receptor polymorphisms are not clinically relevant.
What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
HIT diagnosis must be made by clinical parameters (above) matched eventually with results of a confirmatory laboratory test. When there is reasonable suspicion for HIT, a serologic test should always be ordered. With moderate or strong suspicion, one should not wait on tests results. Tests should only be ordered with reasonable suspicion, never for “screening” or when suspicion is very low. In these circumstances, test results can mislead and result in harm.
Two types of available tests are antigen-based or platelet-activating assays:
Most used are ELISA (enzyme-linked immunosorbent assay) tests for heparin-PF4 (platelet factor 4) antibodies, either poly-class or IgG (immunoglobulin G) specific
– These are widely and inexpensively available, rapid, and reproducible; they can be exceedingly helpful if the clinician knows how to interpret them. They are 99% sensitive, so “negative” results almost always exclude HIT. Traditionally, optical density (OD) values above 0.4 are reported “positive,” but extremely high rates of “false positive” occur by this criterion. Patients with optical density (OD) values 0.4-1.0 rarely have HIT (0-2% have platelet-activating antibodies). When OD is 1.4-2.0, HIT is 40% likely; when it is >2.0, 90% likely. Experts have called for no “positive” or “negative” interpretations to be appended to ELISA results, but rather clinicians must interpret the numerical results in the context of the patient at hand (and his/her symptoms, i.e., the “pretest probability”).
Many recommend confirmation of positive ELISA results with a platelet-activating assay
– Most widely used are serotonin release assays (SRA); also used is heparin-induced platelet aggregation. More specific and regarded by some as “gold standards,” the truth is that there are still significant false positives and negatives, and these assays are labor-intensive, rarely available in real time, and may be poorly reproducible from lab to lab.
Platelet-activating assays may therefore be of little help in clinical decision making and are more useful as a research tool. Clinical decisions depend on the clinical context and eventual proper interpretation of an ELISA including the OD. Newer assays that may improve on sensitivity, specificity, and rapid availability have been reported and are being validated.
What imaging studies (if any) will be helpful in making or excluding the diagnosis of heparin-induced thrombocytopenia?
When there are symptoms or signs of venous or arterial thromboses, appropriate imaging is warranted to document this. Some published guidelines advocate routine venous Doppler imaging with HIT diagnosis in the absence of a new clot (isolated HIT).
If you decide the patient has heparin-induced thrombocytopenia, what therapies should you initiate immediately?
Because of the very high thrombotic risk, highest in the first few days after the diagnosis is made, an alternative anticoagulant should be administered immediately if there is moderate or strong suspicion for HIT.
The only available medications that are approved by the US Food and Drug Administration for the treatment of HIT are the direct thrombin inhibitors argatroban and bivalirudin (which is approved for percutaneous coronary intervention in patients with or at risk of HIT).
The direct thrombin inhibitor argatroban is given by continuous intravenous (IV) infusion, usually beginning 1ug/kg/min, monitored and adjusted by aPTT (activated partial thromboplastin time). It is hepatically cleared, so should be avoided with liver disease. Substantial effects on prothrombin time can challenge the inexperienced, especially during warfarin transition. Bivalirudin is also given by continuous IV infusion, usually beginning at 0.1 mg/kg/hr, with aPTT monitoring. It has favorable pharmacologic properties (20% renal clearance, 80% plasma proteases; half-life 25 minutes). Lepirudin is no longer marketed.
Published experience supports the “off-label” efficacy of fondaparinux, which has appeal in “less sick” HIT patients (no or uncomplicated venous thrombosis) where its subcutaneous administration, long half-life, and renal clearance may not be detrimental. Danaparoid has similar pharmacokinetics but is hampered by some cross-reactivity with heparin-PF4 antibodies and is no longer available in the U.S. Desirudin has been successfully used in a pilot trial. New oral anticoagulants are beginning to enjoy use for HIT with initially favorable experience, as initial therapy for “less sick” patients or after stabilization with a parenteral alternative agent and platelet recovery.
More definitive therapies?
The therapy of HIT is the initiation of an alternative anticoagulant and elimination of all heparin exposures. Experimentally, minimally anticoagulant forms of heparin and PF4 antagonists are being studied to disrupt pathogenic heparin-PF4 complexes. HIT antibodies are transient and are gone usually within 3 months, so other treatments are generally not required.
There are increasing reports of successful use of intravenous immunoglobulin or plasmapheresis in unusually severe or prolonged cases.
For most indications for anticoagulation, there are available highly suitable alternative anticoagulants for patients with past HIT (e.g., bivalirudin for PCI, fondaparinux for orthopedic surgery). For cardiac surgery, experts and guidelines do permit re-exposure to unfractionated heparin in patients with a history of HIT in whom antibodies are no longer detectable due to unique advantages in established monitoring protocols and reversibility with protamine. (With acute or subacute HIT, there are data on the safety and efficacy of bivalirudin use on pump.)
What other therapies are helpful for reducing complications?
A key is to assure that all heparin exposure has been eliminated, including catheter flushes and the use of heparin-coated catheters.
Another key is NOT to begin warfarin early. Because warfarin impacts levels of the short-lived natural anticoagulant protein C before it impacts important procoagulants (factors II and X), it initially worsens a thrombotic diathesis. Nowhere is this more evident than in the extreme hypercoagulable milieu of HIT where early warfarin use has been associated with venous limb gangrene or central skin necrosis. Warfarin should not be initiated early, unopposed, or in excessive dose. If warfarin has been initiated within a few days of HIT diagnosis, guidelines advocate reversing it with vitamin K.
Most authorities agree that inferior vena cava (IVC) filters should be avoided in the setting of HIT. Foreign bodies increase the risk of thrombosis and alternative anticoagulation is strongly mandated (not contraindicated) with HIT.
What should you tell the patient and the family about prognosis?
Life-threatening problems are common with HIT, but mortality is most often related to the underlying disorder rather than HIT itself. Ischemia of extremities may or may not be reversible, but new thromboses can usually be prevented by therapy. If short-term complications can be overcome and the underlying disorder is amenable to therapy, the long term outlook is favorable.
What if scenarios.
Alternative temporal scenarios are not rare and require alertness. Delayed onset HIT affects patients with heparin exposure who have been off the drug for 3 or more days. Theost often, these patients return within 1-2 weeks of hospital discharge, with new thrombotic complications and usually mildly low platelets. When checked, they invariably have very high titer heparin-PF4 antibodies. If heparin is administered for their new clot, platelets fall further and clinical deterioration is common.
Rapid onset HIT occurs when a patient has been exposed to heparin, generally in the last 1-2 months, and has preformed antibodies. Heparin administration can precipitate the HIT syndrome almost immediately, and acute cardiorespiratory collapse can be one manifestation.
Patients exposed to heparin may develop antibodies against heparin-modified platelet factor 4 (PF4) that complex and coat platelet surfaces. There is intense platelet activation through their Fc receptors. The resultant extreme thrombotic diathesis is also related to platelet microparticle release, which causes thrombin generation.
Contributing factors are monocyte tissue factor expression and endothelial activation, due to the cross-reactivity of antibodies with glycosaminoglycans on endothelial surfaces. This is an atypical and incompletely understood immune reaction; anamnestic responses are not seen, and it should be borne in mind that the target antigens, heparin and PF4, are normal body constituents.
What other clinical manifestations may help me to diagnose heparin-induced thrombocytopenia?
What other additional laboratory studies may be ordered?
A DIC panel (prothrombin time [PT], partial thromboplastin time [PTT], fibrinogen, fibrin split products [FSPs] and/or d-dimer) is warranted in patients suspected of HIT, but realize that HIT can cause a DIC-like picture. In other words, if DIC parameters are positive, this does not necessarily provide an alternative explanation for thrombocytopenia, but may be consistent with HIT.
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- What every physician needs to know:
- Are you sure your patient has heparin-induced thrombocytopenia? What should you expect to find?
- Beware of other conditions that can mimic heparin-induced thrombocytopenia:
- Which individuals are most at risk for developing heparin-induced thrombocytopenia?
- What laboratory studies should you order to help make the diagnosis and how should you interpret the results?
- What imaging studies (if any) will be helpful in making or excluding the diagnosis of heparin-induced thrombocytopenia?
- If you decide the patient has heparin-induced thrombocytopenia, what therapies should you initiate immediately?
- More definitive therapies?
- What other therapies are helpful for reducing complications?
- What should you tell the patient and the family about prognosis?
- What if scenarios.
- What other clinical manifestations may help me to diagnose heparin-induced thrombocytopenia?
- What other additional laboratory studies may be ordered?