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Q: Why is heparin-induced thrombocytopenia (HIT) considered a "paradoxical" disorder?

A: HIT is a "paradoxical" disorder for the following reasons:

• The thrombosis is anticoagulant-induced
• HIT is a clotting disorder, not bleeding disorder
• Platelet transfusions can increase thrombosis risk
• Simply stopping heparin may not prevent thrombosis

Diagnosis of HIT requires a very high index of suspicion, and a real understanding of the pathophysiology.

• PF-4 is released from the alpha granules of platelets. It is bound to a GAG (glycosaminoglycan), although the binding site has not been found
• Heparin binds to PF-4 to form a PF-4/heparin complex
• IgG antibodies develop which recognize and bind to the PF-4/heparin complex.
• The IgG/PF-4/heparin complex binds to the Fc receptor
• Protein kinase is activated and platelet-derived microparticles are released
• It is hypothesized that these microparticles are a significant contributor to the thrombotic events

These events are depicted in the following slide diagram.
 

Q: I have a 75-year-old patient with reduced mobility. She was recently hospitalized after a fall and received LMWH as VTE prophylaxis. She has T2DM, osteoporosis, and hypertension. Her platelets have been stable in the 90K-100K range but at her exam 3 days after leaving the hospital they had dropped to 55K. She is on many medications, including warfarin (since release). Is there a platelet threshold for suspecting HIT and how should I manage her anticoagulants at this point?

A: Because of her recent heparin exposure and falling platelet count, HIT should be considered.

Interestingly, if the patient received a pentasaccharide for DVT chemoprophylaxis the question of heparin-induced thrombocytopenia would have been moot since this class of anticoagulant is not known to cause heparin-induced thrombocytopenia.

Is there a platelet threshold for suspecting heparin-induced thrombocytopenia? The threshold for suspecting heparin-induced thrombocytopenia is not related to an absolute platelet count. Heparin-induced thrombocytopenia has been identified in patients with a normal platelet count. Rather than the absolute platelet count, it is more important to observe a 30 to 50% decline from the baseline count. In the example current patient, it would appear that there was a 45% decline in the absolute platelet count, and this would qualify for suspicion of heparin-induced thrombocytopenia.

How would I manage this patient and the dilemma at hand? I would test for the presence of a heparin-dependent antibody in this patient. Because she is already on warfarin for a period of days, I would presume that she was therapeutic and would continue her anticoagulation with warfarin. She would require anticoagulation for at least 4 weeks if the HIT antibody test returned positive.

Q: We have an anesthesiologist who is requesting dextran for a HIT patient, claiming it is better/safer than hetastarch. I don't see any recent literature that supports this. What is recommended for volume expansion in a HIT patient?

A: Dextran is a complex branched glucan (polysaccharide made of many glucose molecules) composed of chains of varying lengths. It is used as an antithrombotic (anti-platelet) and as a volume expander.

Dextran binds red blood cells, platelets, and vascular endothelium. It increases their electronegativity and reduces red cell aggregation and platelet adhesiveness. Dextrans also reduce factor VIII-binding Von Willebrand factor, thereby decreasing platelet function. Clots formed after administration of dextrans are more easily lysed due to an altered thrombus structure (more evenly distributed platelets with coarser fibrin). By inhibiting α-2 antiplasmin, dextran serves as a plasminogen activator and therefore possesses thrombolytic features. An uncommon but important adverse effect of dextran is acute renal failure, the etiology of which is unknown.

Hetastarch is a heterogeneous starch molecule. It was approved by the FDA in the late 1970s and is an excellent volume expander. It inhibits Factor VIII synthesis, and is a poor choice in patients with hemophilia.

Originally, it was observed that patients resuscitated with hetastarch sustained a coagulopathy. However, subsequent prospective randomized trials conducted in the past 3 decades in neurosurgery, cardiac surgery, aortic surgery, trauma, and sepsis patient cohorts demonstrated that all of these patient populations develop coagulopathies, independent of being resuscitated with saline, 5% albumin or hetastarch. Currently, it is not thought that hetastarch promotes bleeding from coagulopathy.

Pentastarch, a derivative of hetastarch, is used outside the USA and recently has been associated with acute renal failure, the etiology of which is unknown.

There are no data known to me that are a consequence of trying to answer the question as to the preferred choice for volume resuscitation.

Therefore, either a crystalloid, such as normal saline or lactated Ringers solution, or a colloid, such as 5% albumin or 6% hetastarch, would be a reasonable and evidence-based choice in the hypovolemic patient.

However, colloids are a more efficient choice in that less volume is required over a shorter time period to achieve the desired endpoint. Since patients with HIT should already be receiving a direct thrombin inhibitor, drugs with anticoagulant properties, such as dextran should be avoided.

Q: What is the onset of thrombocytopenia after the induction of heparin-induced thrombocytopenia in time, and how can one use the time course of onset to assist in making the diagnosis?

A: Classic HIT, first described in the 1950s by a NY surgeon as White Clot Syndrome, has an onset of between 4-14 days from the first heparin exposure. During the past decade, subtypes of this have been observed including rapid onset HIT from re-exposure, and the more insidious delayed onset HIT, which may develop weeks after heparin exposure. These time courses are shown in Figure 1.

One important distinction is the rate of change in thrombocytopenia, as seen in Figure 2. The slow drift downward in platelet count, often seen in hospitalized patients, is not typical of HIT. The immunologic process that results in HIT yields a more sudden downward slope in platelet count. This slope of change can assist in raising the probability of making an accurate diagnosis.

Q: There are currently 3 main direct thrombin inhibitors available. What are their pharmacologic properties and features distinguishing one from another? How do I choose one over another?

A: The direct thrombin inhibitors (DTIs), including lepirudin, argatroban, and bivalirudin, are administered by continuous infusion, are fairly expensive, and are highly effective anticoagulants with predictable pharmacokinetic profiles. They all have relatively short half-lives, and there are no available antidotes should a patient exhibit significant bleeding. However, the short half-life means the bleeding should be short-lived.

One important distinction is clearance. Lepirudin is cleared renally, and is a poor choice for patients in renal failure. Bivalirudin has the shortest half-life, and is cleared intravascularly and renally. Argatroban blood concentrations are not affected by renal failure because argatroban is cleared by the liver. Given the other available choices, argatroban should not be used in patients with hepatic failure.

Direct Thrombin Inhibitors

Q: I frequently see patients with HIT whose platelet counts are below 20,000/µL. I stop all forms of heparin. However, my colleagues repeatedly question giving direct thrombin inhibitors (DTIs) to a patient with a very low platelet count who has comorbid conditions. What are the guidelines for starting anticoagulation in such cases and what platelet level is safe for starting DTIs? Which comorbidities present bleeding dangers or contraindications for DTIs?

A: The median platelet count in the setting of HIT is typically about 60,000/µL, as seen in Figure 1. HIT is associated with arterial or venous thrombosis, not bleeding. It is uncommon in HIT for platelet counts to decrease to ≤ 20,000/µL, although it is possible. Extreme thrombocytopenia, as shown in Figure 2, is associated with other drugs, including antibiotics such as vancomycin and linezolid, and is more likely to result in bleeding.

Figure 2
Drug Induced Thrombocytopenia Bleeding
Warkentin TE. N Engl J Med. 2007; 356(9):891.

Bleeding is uncommon in HIT, even at low platelet counts. Figure 3 shows data from a classic study of patients with immune thrombocytopenic purpura, demonstrating that spontaneous bleeding occurs primarily when platelet counts decline below 10,000/µL.

DTIs should be started and all heparin exposure discontinued whenever HIT is strongly suspected or proven, to prevent arterial or venous thrombosis. In 4 studies, the probability of thrombosis ranged from 30-75%, even after discontinuing heparin.

One of the reasons the DTIs are relatively safe is because of their short half-lives: argatroban, 39-51 min; lepirudin, 1.3 hours; and bivalirudin, 25 min.

The only contraindication to using the DTI anticoagulants would be active bleeding.

Q: I would like to use a serotonin release assay to confirm HIT. However, I can't find a local lab that does it. Can you suggest a practical strategy that gives a confident diagnosis without the SRA?

A: HIT is a clinical diagnosis that requires confirmation in the laboratory. I would recommend using the 4T score developed by Warkentin (magnitude of Thrombocytopenia, Timing of thrombocytopenia, presence of Thrombosis, presence of an alTernate cause of thrombocytopenia) first to assess pre-test clinical likelihood of HIT. In patients with an intermediate or high pretest probability, ELISAs for the heparin-platelet factor 4 complex can help confirm the diagnosis. These assays are highly sensitive for the diagnosis (ie, a result of < 0.4 OD units with the widely used commercially available GTI assay rules out HIT), but lack specificity which is greatly affected by the clinical pretest probability of HIT. If the laboratory performing the heparin-PF4 ELISA only reports a result as positive without giving the OD, call them to obtain your patient's optical density reading. A recent study by Warkentin et al (J Thromb Haemost. 2008; 6:1304-1312) indicates that the ELISA OD value predicts a positive SRA as follows:

Q: A trauma patient was referred after emergency surgery following a traffic accident. He is receiving LMWH and his platelets are 30K. He is also receiving interferon/ribavirin for HCV infection. How do I decide which treatment is associated with the thrombocytopenia and what is the best way to proceed?

A: Heparin-induced thrombocytopenia (HIT) is a clinical diagnosis that requires confirmation in the laboratory by demonstrating the presence of antibodies against the heparin-platelet factor 4 complex (usually by ELISA). While the incidence of HIT with LMWH is lower than with unfractionated heparin, it still can occur in ~0.5% of patients receiving this medication. Clinical evaluation is greatly assisted by using the 4T score developed by Warkentin. Even if one does not use the scoring system for quantitative evaluation, (0-2 points for each of the 4 features to assess the clinical likelihood of HIT - low, intermediate, or high), it represents a very useful algorithm to decide whether HIT is likely or unlikely.

• Thrombocytopenia - magnitude of thrombocytopenia generally is 50% decrease in platelet count from baseline, median platelet count in HIT is ~60,000
• Timing - typical-onset HIT occurs from 5-14 following a new heparin or LMWH exposure provided no heparin was administered to patient in previous 100 days
• Thrombosis includes skin, deep vein, and systemic manifestations
• The diagnosis accounting for thrombocytopenia - in this case, the patient is receiving drugs (interferon/ribavirin) that could result in thrombocytopenia, has chronic liver disease that could lead to thrombocytopenia at baseline, and has recently undergone surgery

Thus, additional details regarding the patient's baseline and subsequent platelet counts as well as the timing of onset of the thrombocytopenia are required to decide whether HIT should be in the differential diagnosis for the thrombocytopenia in this patient and the appropriate management (ie, discontinuation of LMWH, sending off ELISA assay for heparin-PF4 antibodies, starting an alternative anticoagulant such as a direct thrombin inhibitor).

Q: What is the current status of fondaparinux with regard to HIT?

A: HIT is less likely to develop following therapy with fondaparinux than with heparin or LMWH. While fondaparinux-associated HIT is rare, there are several case reports suggesting that it can occur. Fondaparinux is not FDA approved for the management of HIT.

Fondaparinux induces heparin PF-4 antibodies at about the same rate as UFH or LMWH. The fondaparinux-associated antibodies tend to be non-activating and usually are negative in the serotonin release assay, but this assay is useful if HIT is suspected. Most patients with a negative heparin/PF-4 EIA result can be treated with heparin, fondaparinux, or LMWH.

Q: I recently cared for a 66-year-old male patient who underwent coronary artery bypass graft (CABG) surgery. Postoperatively, he did not develop thrombocytopenia and he was discharged on postop day 4. He was readmitted 9 days later with a chief complaint of dyspnea. His CT-pulmonary angiogram was positive for bilateral pulmonary emboli. His platelet count on admission was 377,000 and he was treated with unfractionated heparin, after which his platelet count dropped to 188,000 within 36 hours. Heparin-induced thrombocytopenia (HIT) was suspected, heparin was discontinued, and the patient was placed on argatroban. Heparin-platelet factor 4 antibody test was sent and returned strongly positive (OD > 3). Would this case be considered delayed-onset HIT?

A: HIT is a clinical-pathological syndrome characterized by thrombocytopenia starting 5-14 days after the initiation of heparin; this has been termed "typical-onset" HIT. Laboratory testing must demonstrate the presence of heparin-dependent antibodies. Delayed or late-onset HIT occurs within 30 days of heparin exposure in the absence of recent heparin. As the patient was not thrombocytopenic when he developed pulmonary emboli, this patient would not qualify as having delayed-onset HIT. He had what is termed "rapid-onset" HIT, which results from the presence of pre-existent antibody that formed following heparin exposure within the previous 100 days. CABG surgery is associated with up to a 50% rate of seropositivity as determined by heparin-platelet factor 4 EIA, though the frequency of developing HIT is only about 1%.

Q: Our hospital lab doesn't have a serotonin release assay, and I've always been uncomfortable treating for HIT without this confirmation. Can our EIA test be interpreted quantitatively, and what is the correlation of the EIA test with clinical HIT?

A: There is good reason to be uncomfortable in diagnosing or treating HIT based on the basis of a positive heparin/PF4 EIA (enzyme immunoassay) result alone! HIT or HITT is a clinical diagnosis requiring laboratory confirmation. Establishing a certain diagnosis of HIT or HITT, however, can be difficult in ill thrombocytopenic patients with other potential causes of thrombocytopenia and other risk factors for thrombosis. EIAs for detecting heparin/PF4 antibodies are now widely used to establish a diagnosis of HIT or HITT; they are very sensitive, but have poor specificity. Platelet activation assays, such as the serotonin release assay (SRA), are more specific for the diagnosis, but require considerable technical expertise and are performed by few laboratories. The test can be requested from specialized reference laboratories, but results are generally not available soon enough for clinical decision-making. Warkentin et al recently reported that the probability of a positive SRA result is correlated with the magnitude of the heparin/PF4 antibody EIA result.¹This large study used one of the widely used commercial EIAs. This quantitative information can be useful to clinicians faced with establishing and treating patients with suspected HIT. Laboratories performing heparin/PF4 EIAs should be encouraged to report positive results along with the respective optical density measurement.

1. Warkentin TE, Sheppard JI, Moore SC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6:1304-1312.

Q: What is the reason for delaying the initiation of warfarin in patients with heparin-induced thrombocytopenia?

A: The initiation of the anticoagulant warfarin can result in a short period of transient hypercoagulability. This is attributable to a rapid decline in the level of protein C, a vitamin K-dependent anticoagulant protein, which has a half-life similar to factor VII (approximately 6 hours). While the levels of factor VII and protein C decline in parallel after warfarin is initiated, the levels of vitamin K-dependent coagulation factors such as factors IX, X, and prothrombin will decline more slowly as these proteins have a significantly longer half-life in vivo. This sets the stage for a paradoxical increase in thrombin generation during the initiation of oral anticoagulation, which cannot be abrogated completely by the use of parenteral direct thrombin inhibitors such as argatroban or lepirudin. The consequences of initiating warfarin before the platelet count has risen substantially from its baseline nadir include venous limb gangrene and warfarin-induced skin necrosis.

Q: Can fondaparinux be used empirically in suspected HIT patients?

A: Fondaparinux (Arixtra^®) is a pentasaccharide with pure anti-Factor Xa activity, approved in the United States for surgical antithrombotic prophylaxis and treatment of deep vein thrombosis and pulmonary embolism. No case of documented HIT was observed among the several thousand patients treated in clinical trials. Despite evidence that its use in orthopedic patients can be associated with the development of HIT antibodies, fondaparinux has not been shown to induce platelet activation with HIT serum in H/PF4 functional assays.^1,2 Based on these findings, fondaparinux has been used, off label, in the management of patients with HIT.³ However, a recent report documented a case of HIT associated with fondaparinux use for patients with suspected HIT who have no evident thrombosis.⁴ Accumulating evidence suggests that fondaparinux can be used with apparent safety and efficacy. In patients with active thrombosis, I would strongly recommend using a direct thrombin inhibitor, such as argatroban or lepirudin. Patients can later be switched to fondaparinux after the platelet count has recovered. The use of fondaparinux allows for an easier transition to warfarin.

1. Warkentin TE, Cook RJ, Marder VJ et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic prophylaxis with fondaparinux or enoxaparin. Blood. 2005;106:3791-3796.

2. Savi P, Chong BH, Greinacher A, et al. Effect of fondaparinux on platelet activation in the presence of heparin-dependent antibodies: a blinded comparative multicenter study with unfractionated heparin. Blood. 2005;105:139-144.

3. Kovacs MJ. Successful treatment of heparin-induced thrombocytopenia (HIT) with fondaparinux. Thromb Haemost. 2005;93:999-1000.

4. Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med. 2007;356:2653-2654.

Q: I have a patient suffering DIC and necrotic bowel after CABG surgery. Acute renal failure was addressed with hemofiltration, but severe thrombocytopenia (platelets = 23 x 10⁹/L) raised the suspicion of HIT. Serum was submitted for a PF-4/heparin antibody test but results have not yet been received. The nephrologist placed a Quinton catheter without heparin, but will still not use acid citrate dextrose A/CaCl₂. The catheter has clotted several times but the nephrologist vetoed use of an alternative anticoagulant such as lepirudin. What are your suggestions on treating this patient?

A: While I cannot explain why your nephrologist is against using ACD for hemofiltration, except possibly for the electrolyte balance issues that may arise with long-term continuous ACD anticoagulation, I can appreciate the hesitancy in regards to using lepirudin. Lepirudin is cleared by the kidneys and clearance with extra-corporal hemofiltration may be variable. Also, since lepirudin is a protein, long-term use can result in antibody formation. The resulting antibodies do not inhibit its function, but can result in prolongation of the drug's half-life, increasing the risk of over anticoagulation and bleeding. If the patient has normal hepatic function, I would recommend the use of argatroban. Argatroban is cleared by the liver with only minimal renal clearance. Due to its short half-life (50 minutes) it can be readily adjusted to a safe therapeutic range with a target aPTT ratio of 1.5 to 3.0. Targeting the aPTT ratio at 2.0 should prevent further catheter thrombosis. We have prior experience using argatroban in patients on intermittent dialysis and have observed no significant problems.

Q: A patient had HIT several years ago. This patient is readmitted to the medical service and fondaparinux prophylaxis is ordered because of the previous diagnosis of HIT. The pharmacist calls and asks is this really necessary and switches the patient to enoxaparin prophylaxis. Is this OK?

A: This is a classic heparin risk/benefit situation. There is probably a greater than 90% chance that the patient will experience no ill effects from heparin re-exposure. The risk is the potential for devastating outcomes if heparin triggers another HIT episode. The benefit of using enoxaparin rather than fondaparinux may be cost at some institutions. Fondaparinux is the better medical choice in this case.

It is very interesting that most patients who have had HIT in the distant past and are re-exposed to heparin (often by mistake) do not develop the problem again.¹ This has clear implications for pathogenesis and risk factors for HIT, indicating the greater importance of a patient's clinical situation and the lesser importance of any genetic risk factors.² Nevertheless, there is no large body of evidence on the safety of heparins in those with prior HIT. The expert consensus is to avoid unnecessary re-exposures; after all, there are highly effective and safe alternative anticoagulants available for almost any situation in which anticoagulant prophylaxis or treatment is required. The exception is in patients undergoing cardiopulmonary bypass surgery, where unfractionated heparin has unique safety advantages. Re-exposure to heparin in this case is generally allowed but limited to the procedure itself. ³ Speaking from personal experience, I have seen at least two patients with a past history of HIT who experienced recurrence and devastating complications on re-exposure, and one of them died.⁴ Why take a chance when effective non-heparin anticoagulants are available?

References:

1. Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med. 2001;344:1286-1292.
2. Warkentin TE, Sheppard JI, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood. 2000;96:1703-1708.
3. Warkentin TE, Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention. Chest. 2008;133:340S-380S.
4. Kodityal S, Manhas AH, Udden M, Rice L. Danaparoid for heparin-induced thrombocytopenia: an analysis of treatment failures. Eur J Haematol. 2003;71:109-13.

Q: We currently have a postpartum mom with liver and kidney failure who has HIT and DIC after C-section. We are not able to administer DTI per hematology recommendations. What are the best practices for treating this patient?

A: Multiorgan failure patients are often extremely challenging in terms of sorting out and managing all underlying problems. They may have multiple reasons for thrombocytopenia, such as sepsis with or without DIC, and exposures to potentially toxic medications. An increased risk of HIT has been observed in this patient group, and it is often difficult to be certain whether HIT is a contributing problem. Other causes of thromboses or limb ischemia include shock, pressors, inflammation, and atheroemboli. HIT can cause a DIC syndrome. So, it is of utmost importance to reconstruct the timing of heparin exposures with relation to changes in platelet counts and thrombotic complications to gauge the likelihood of HIT. If there is moderate or high clinical suspicion, all heparin exposure should be avoided and alternative anticoagulation should be strongly considered while the results of serology are awaited. The titer (optical density) of a positive heparin-PF4 ELISA needs to be weighed in the clinical context.¹

Because of the extreme risk of thromboses, we would begin an alternative anticoagulant in any patient believed to have HIT unless bleeding problems are substantial. We avoid lepirudin with renal impairment, and hepatic impairment presents challenges to safe and effective use of argatroban.² In the situation of both significant renal and hepatic impairment, the direct thrombin inhibitor, bivalirudin, has been used off-label.^3,4 Bivalirudin has favorable pharmacologic properties for this patient group: only 20% renal clearance, no hepatic metabolism, metabolized mainly by plasma proteases, and the shortest half-life of any DTI (less than 30 minutes).⁵ One monitors aPTT to the desired range (about twice normal), and the usual starting therapeutic dose is about 0.1 mg/kg/hr. There are a number of published studies^3,4 and this drug is commonly used for HIT even though it is FDA-approved for HIT only in the setting of PCI.

References:

1. Warkentin TE, Sheppard JI, Moore JC, Sigouin CS, Kelton JG. Quantitative interpretation of optical density measurements using PF4-dependent enzyme-immunoassays. J Thromb Haemost. 2008;6(8):1304-1312.
2. Rice L, Hursting MJ. Argatroban therapy for heparin-induced thrombocytopenia. Expert Rev Clin Pharmacol. 2008;1:357-367.
3. Berilgen JE, Nguyen PH, Baker KR, Rice L. Bivalirudin treatment of heparin-induced thrombocytopenia. Blood. 2003;102:537a.
4. Kiser TH, Burch JC, Klem PM, Hassell KL. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy. 2008;28:1115-1124.
5. Bartholomew JR. Bivalirudin in the treatment of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia. 4th ed. New York, NY: Informa Healthcare; 2007:409-439.

Q: How do you treat HIT in a pregnant woman now that danaparoid is no longer available?

A: The frequency of HIT varies considerably based on the clinical situation; so while cardiovascular surgery and orthopedic patients are at highest risk, obstetric patients may have the lowest risk. Not surprisingly, experience with alternative anticoagulants in pregnant patients is limited and none has received formal approval for such use. The greatest amount of experience had been with danaparoid, but the off-label use of fondaparinux has been increasing.

Fondaparinux shares many pharmacologic properties, both favorable and unfavorable, with danaparoid. Both drugs are indirect inhibitors of factor Xa (though fondaparinux has higher selectivity). Their 24 hour half-life in vivo permits once daily subcutaneous dosing and predictable pharmacokinetics allows dosing without monitoring. Requirements for drug-specific anti-Xa assays when monitoring is desirable. However, both drugs are renally cleared which necessitates dose reduction in patients with impaired kidney function. Unlike danaparoid, fondaparinux rarely, if ever, cross-reacts in vitro with pathogenic heparin-PF4 antibodies.¹ There is a small but growing use of fondaparinux to treat HIT² but this is mainly in "milder" cases, and the optimal dose for HIT is not well established. Only a small amount of fondaparinux crosses the placenta, and close to three dozen published reports document safe use in pregnancy. One source suggests this should be the drug of choice for HIT in early pregnancy because of possible roles of thrombin in embryogenesis.³

On the other hand, the choice of therapy in a pregnant patient with HIT may depend on the severity of the situation and complicating thrombotic diathesis. Based on available data, I would be loath to rely on fondaparinux in a very ill patient with active thrombotic problems - rather, I would use a direct thrombin inhibitor. DTIs have an established track record in severely ill HIT patients, and they can be monitored, adjusted or stopped in a timely manner when necessary. A few case reports describe successful use of argatroban, lepirudin or bivalirudin in pregnancy. The first two of these are not teratogenic in animal studies, but high doses of bivalirudin did cause embryopathy in rabbits. Lepirudin is known to cross the placenta. All are considered pregnancy category B and should be used only when clinical circumstances dictate, which would be the case with "acute hot HIT."

References:

1. Warkentin TE, Cook RJ, Marder VJ, et al. Anti-platelet factor 4/heparin antibodies in orthopedic surgery patients receiving antithrombotic therapy with fondaparinux or enoxaparin. Blood. 2005;106:3791-3796.
2. Bradner JE, Eikelboom JW. Emerging anticoagulants and heparin-induced thrombocytopenia: Indirect and direct factor Xa inhibitors and direct thrombin inhibitors. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia. 4th ed. New York, NY: Marcel Dekker; 2007:441-462.
3. Greinacher A, Warkentin TE. Treatment of heparin-induced thrombocytopenia: An overview. In: Warkentin TE, Greinacher A, eds. Heparin-induced thrombocytopenia. 4th ed. New York, NY: Marcel Dekker; 2007:283-318.

Q: A patient is treated with heparin for DVT and the platelet count drops about 30% in the first 3 days. It is suspected that this might be due to heparin exposure. Should heparin be continued until the HIT assays come back from the lab, which is typically a 48-hour turnaround?

A: No. As soon as HIT is suspected, all forms of heparin should be stopped and the patient should be converted to a DTI immediately while assays are pending.

Q: Can HIT occur within 24 hours of admission?

A: Yes, it can. Among patients with prior heparin exposure, rapid-onset HIT can occur shortly after re-exposure to heparin or LMWH. This is more common among cardiac patients, such as those who have had procedures like percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). Monitoring platelet count during any heparin exposure is mandatory.

Q: When is it safe to start warfarin in a patient with DVT who has HIT?

A: It is typically safe to start warfarin using a bridge with a direct thrombin inhibitor (DTI) after the platelet count has returned to normal (> 150k). One should monitor the anticoagulation level carefully using INR and use 5 days of overlap. The warfarin dose should be started at 5 mg or lower.

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