Heparin Induced Thrombocytopenia: Its Significance in Cardiac Surgical Patient

Intravenous heparin remains main stem therapy during cardiac and vascular surgical procedures. Heparin therapy is often continued after surgery as part of prophylactic treatment (deep venous thrombosis) or bridging therapy (for atrial fibrillation, prosthetic valve(s) or Dacron grafts implanted in the heart) until INR levels reach therapeutic levels with warfarin therapy. Complications resulting from the use of heparin are relatively rare. Among the most common are bleeding initiated by excessive inhibition of thrombin and other clotting factors and thrombosis caused by inadequate anticoagulation. Heparin Induced Thrombocytopenia (HIT) is a rare but potentially life-threatening complication. The literature, which is describing HIT is still somewhat confusing since it uses a variety for terms for HIT. Type I HIT, sometimes called non-immune heparin-associated thrombocytopenia, is a benign process and presents as a mild thrombocytopenia with the platelet count rarely decreasing below 100.000/ml. Type I HIT develops early after heparin exposure, typically within 2-3 days. It probably results from a direct effect of heparin on platelets and occurs in about 10%–30% of patients receiving heparin (1). In contrast, and of greater clinical concern, is type II HIT and immune mediated syndrome associated with platelet activation, increased thrombin production and thrombogenesis leading to thrombo-embolic complications. The following chapter will briefly discuss the epidemiology, pathogenesis and management options for ICU and cardiac surgical patients diagnosed with true HIT.

Intravenous heparin remains main stem therapy during cardiac and vascular surgical procedures.Heparin therapy is often continued after surgery as part of prophylactic treatment (deep venous thrombosis) or bridging therapy (for atrial fibrillation, prosthetic valve(s) or Dacron grafts implanted in the heart) until INR levels reach therapeutic levels with warfarin therapy.Complications resulting from the use of heparin are relatively rare.Among the most common are bleeding initiated by excessive inhibition of thrombin and other clotting factors and thrombosis caused by inadequate anticoagulation.Heparin Induced Thrombocytopenia (HIT) is a rare but potentially life-threatening complication.The literature, which is describing HIT is still somewhat confusing since it uses a variety for terms for HIT.Type I HIT, sometimes called non-immune heparin-associated thrombocytopenia, is a benign process and presents as a mild thrombocytopenia with the platelet count rarely decreasing below 100.000/ml.Type I HIT develops early after heparin exposure, typically within 2-3 days.It probably results from a direct effect of heparin on platelets and occurs in about 10%-30% of patients receiving heparin (1).In contrast, and of greater clinical concern, is type II HIT -and immune mediated syndrome associated with platelet activation, increased thrombin production and thrombogenesis leading to thrombo-embolic complications.The following chapter will briefly discuss the epidemiology, pathogenesis and management options for ICU and cardiac surgical patients diagnosed with true HIT.

Epidemiology and pathogenesis
HIT is a rare complication of heparin therapy primarily affecting the surgical population.It occurs in 1-2% of cardiovascular surgery patients, 3%-10% of orthopaedic surgery patients and in less than 1% of obstetrical patients.It is higher in the orthopaedic population since they usually require prolonged treatment with heparin for DVT prophylaxis following surgery.Within the cardiac surgical population, patients who require implantation of a left ventricular assist device are at very high risk of developing HIT (> 10%).The incidence of HIT in patients treated in medical wards is usually very low (< 0.25%).discharged from hospital.There are some cases of super-acute HIT, which occurs almost immediately after a second dose of heparin and presents in the form systemic syndrome with dramatic picture of disseminated intravascular coagulation (DIC).Among patients who develop thrombocytopenia caused by HIT, 30-50 % have thrombotic complications (Table 1).For many clinicians this is a paradoxical phenomenon since heparin is supposed to prevent thrombosis.Venous thrombosis commonly occurs in the lower extremities frequently leading to pulmonary embolism (PE) or venous gangrene with distal necrosis of the limb.

Vasculature Venous Arterial
Lower As mentioned before HIT can be only confirmed by a specific laboratory tests.First, a screening test is performed to detect HIT antibodies.This screening test detects all classes of immunoglobulins but as mentioned earlier, only IgG can trigger HIT.For example, in the case of cardiac surgical patients 20-40% of them develop antibodies, but only 1-2% are truly HIT-positive.On the other hand, if the screening test does not detect any immunoglobulins the presence of HIT can be ruled out.In the case of a positive HIT screen we need further confirmation to be able to show that these (detected) antibodies can trigger platelet activation.The most popular assay used is the Serotonin Release Assay (SRA), which uses plasma obtained from the patient, heparin and specially prepared, radio-labeled platelets.If the patient's plasma activates platelets (ie: causes release of serotonin) the patient can be diagnosed as having HIT (positive).Unfortunately, SRA is performed in only a few centers and thus the results of the test are usually not available for several days.An alternative to the SRA performed by some laboratories is the heparin-induced platelet aggregation assay (HIPA), which also demonstrates the presence of a clinically relevant antibody.In the meantime, the medical team needs to initiate treatment based on the clinical symptoms and probability of a positive diagnosis of HIT (>6 points in scale proposed by Warkentin).

Management
Principles of treatment for patient diagnosed with HIT can be outlined in the following points.
1. Discontinue all forms of heparin including line flushes, LMWH or lines coated with heparin (i.e.heparin-bound Swan-Ganz catheter).Even tiny amounts of heparin can precipitate HIT. 2. Do not transfuse platelets to treat thrombocytopenia.Transfusion may precipitate further thrombotic events because HIT antibodies will activate transfused platelets.3. Initiate treatment with heparin alternatives, the most commonly used drugs belong to 2 classes of anticoagulants: long acting, antithrombin III (ATIII) dependent factor Xa inhibiting oligosaccahrides or direct thrombin inhibitors (DTI).4. If patient is already receiving warfarin it should be reversed with vitamin K.During the early stages of warfarin therapy, levels of protein C (a natural anticoagulant) will drop before the rest of the coagulation factors are inhibited and this can make the patient even more pro-thrombotic at the initial stages of warfarin therapy. 5. Warfarin therapy may be re-instituted when the platelets recover back to the baseline level.Warfarin derivatives must overlap for 4-5 days with anti Xa inhibitors or DTI therapy.It should be stressed that stopping heparin without initiating anti-Xa inhibitors or DTI therapy is not sufficient for prevention of thrombotic complications.
The fundamental difference between heparin and Xa inhibitors or DTIs lies in the mechanism of their action.Heparin requires a cofactor, which is called antithrombin-III (ATIII), additionally it can not bind to thrombin, which is already attached to a fibrin network.A long half-life and a stable level of anticoagulation characterize indirect factor Xa inhibitors, similar to heparin since they also require ATIII.The pharmacokinetic profile of anti-Xa inhibitors makes them favorable to use in the ICU setting (one dose a day).On the other hand, the fact that they do not have antidote may complicate clinical management in case patient requires surgical intervention.Specific assays are available to measure drug levels.The second group of medications DTIs bind and inhibit thrombin directly by connecting to 2 active exosites.They have a short half-life and may interfere with the thrombin-induced protein C pathway.Similar to indirect Xa inhibitors, DTIs do not have an antidote, therefore their action cannot be reversed.All these agent s c a n b e s a f e l y u s e d i n p a t i e n t s w i t h thrombocytopenia.Currently there are five main drugs used for HIT therapy: danaparoid, fondaparinux, bivalirudin, argatroban and hirudins.Danaparoid and fondaparinux belong to ATIIIdependent anti-Xa inhibitors, lepirudin, bavalirudin and argatroban belong to group of DTI.Danaparoid, lepirudin and argatroban are approved for treatment of HIT, bivalirudin and fondaparinux are not but have high rationale to be used for HIT therapy.Those five agents will be discussed below; additionally their brief characteristics are presented in Table 3. Bivalirudin.Bivalirudin belongs to reversible DTI and among all agents used for HIT therapy presents most favorable pharmacokinetic profile.It has short half-life (25 min) and is primarily metabolized by plasma enzymatic degradation.It makes it drug of choice in patients with kidney and/or liver dysfunction (i.e.ICU patients).On the other hand due to plasma enzymatic degradation of bivalirudin any blood anticoagulated with this agent, which in stagnation will eventually clot.This property requires alternative approaches during CPB: the pump suckers must be replaced with cell saver and cardioplegia pump must be continuously flushed.Additionally, presence of clots in pericardium (stagnated blood) does not indicate that patient is not adequately anticoagulated.Therapy with Bivalirudin should be monitored with Ecarin Clotting Time (ECT), which is not available in many institutions.As an alternative one can use direct DTI assay or aPTT or plasma modified ACT if Bivalirudin is to be used for CPB purposes.Properties of Bivalirudin make it agent of choice for cardiac surgical procedures in HIT-positive patients who cannot be rescheduled beyond time when HIT antibodies disappear.

HIT patient for CPB
One of the most challenging situations facing cardiac anaesthesiologists is intra-operative management of the patient who requires a cardiac surgical procedure who is HIT positive.Whenever possible it is recommended to delay surgery until the HIT antibodies have cleared (on average 100 days).Unfortunately, in some clinical situations it is not possible; for example: left main stenoses with symptoms of unstable angina, rapidly progressing endocarditis or heart transplantation are among the most common clinical scenarios.Among all of the presented agents (see Table 3), none of them is approved for anticoagulation during cardiopulmonary bypass (CPB).Therefore therapy with DTIs or indirect anti Xa inhibitors during cardiac surgery with use of CPB should be considered as an "off-label" application for these drugs.All of them have been used in different doses with varying protocols and outcomes were not always favorable.Their recommended doses and protocols for clinical use are presented in Table 4.When comparing all of these agents, Bivalirudin appears to offer that most favorable outcome with respect to control of anticoagulation during extracorporeal circulation.The features of Bivalirudin, which makes it a favorable agent for use with CPB are: a short half-life and metabolism that is independent from kidney and liver function.A protocol based on data from the literature and our own experience is presented in the Appendix 1.

Danaparoid
Bolus 125 units kg -1 iv, post thoracotomy CPB prime 3 units ml -1 Infusion 7 units kg It should be mentioned that there are some reports in the literature recommending the use of strategies other than using a DTI or indirect Xa inhibitor for anticoagulation during CPB.The most encouraging of those are: use of plasmapheresis prior to CPB to clear all HIT antibodies followed by use of regular doses of heparin or to use a prostacyclin infusion combined with antiplatelet therapy with GPIIb/GPIIIa inhibitors.
based on high clinical suspicion.The most important principles of therapy include: discontinuation of any form of heparin therapy, treatment with indirect inhibitors of factor Xa or direct thrombin inhibitors and reversal of vitamin K antagonists if they were used previously.Additionally, transfusion of platelets should be avoided since it will only precipitate their activation and aggravate the clinical symptoms.

Key points
 Heparin -induced thrombocytopenia (HIT) is a rare highly under-diagnosed but life threatening complication of heparin therapy. HIT is a clinico-pathological syndrome requiring multiple laboratory tests to make the final diagnosis.Most often treatment must be initiated before final diagnosis is established  The most important principles of therapy include: discontinuation of any form of heparin, avoidance of platelet transfusion, treatment with indirect inhibitors of factor Xa or direct thrombin inhibitors and reversal of vitamin K antagonists if they were used previously.


Management of a HIT-positive patient undergoing cardiac surgery with the use of CPB presents a challenge for the anesthesiologist.

Table 1 .
Thrombosis occurring in HIT.One of the most popular schemes of assessment and clinical diagnosis of HIT was developed by Warkentin and called 'four T' (Table2).T stands for thrombocytopenia, timing, thrombosis and other causes.For each category the patient receives 0, 1 or 2 points.For a score of 0-3 points, the diagnosis of HIT is unlikely, 4-5 points requires laboratory testing to confirm the diagnosis but in most cases does not require treatment, however, if patients receive a score of ≥ 6 points treatment should be initiated immediately.
antiphospholipid syndrome, disseminated intravascular coagulation caused by other precipitating factor, thrombotic thrombocytopenic purpura and post-transfusion purpura.

Table 2 .
Table describes scoring system used for clinical diagnosis of HIT.

Table 3 .
Short description of pharmacokinetic properties of alternative anticoagulants used in treatment of HIT Fondaparinux also belongs to group of indirect anti-Xa inhibitors but when compared to Danaparoid it does not have anti-thrombin properties.Half-life of Fondaparinux is 17 h.Paradoxically, Fondaparinux can trigger formation of HIT antibodies but its use is still considered to be very effective treatment of HIT.R-Hirudins.Currently, there are two formulations of r-Hirudins available on the market: lepirudin and desirudin.Hirudins belong to DTI and have very high affinity to thrombin including molecules bonded to fibrin.This high affinity makes binding practically irreversible.Half-life of R-Hirudins is 80 min., they are eliminated almost exclusively by kidneys.In patients with kidney dysfunction half-life of r-Hirudins is totally unpredictable.R-hirudins are highly efficacious but treatment is complicated by high incidence of hemorrhagic complications (15%).Literature reports on several cases of lethal anaphylactic reactions complicating re-exposure to Hirudins.Argatroban.When compared to Hirudins, Argatroban bindings to thrombin are reversible.Drug is primarily metabolized and excreted by liver therefore is recommended for use in patients with kidney dysfunction or failure.Frequency of major bleeding complicating argatroban therapy is 8%, more over patients treated with Argatroban have high incidence of limb amputation.Most likely it is related to difficulties in achieving therapeutic level and fact that Argatroban artificially elevates values of INR.It may compromise safe overlap and transition from Argatroban therapy to Coumadin.Experience with Argatroban used for cardiac surgical procedures is highly unfavorable.

Table 4 .
Dosages of alternative anticoagulants used for patients who are HIT positive and require cardiac surgery with the use of cardiopulmonary bypass