Heparin-induced thrombocytopenia (HIT) is a rare but serious antibody-mediated complication of heparin therapy. It occurs after exposure to unfractionated heparin or low-molecular-weight heparin (LMWH) but is more commonly associated with the former.¹ A few cases of acute aortic occlusion associated with HIT have been reported in the literature. We present a case of aortic occlusion from HIT after treatment of a venous thromboembolism with LMWH.

This rare complication has a poor prognosis and a high mortality rate. Immediate discontinuation of heparin therapy and therapeutic anticoagulation with a direct thrombin inhibitor are indicated.

Case report
A 68-year-old woman presented to the hospital for an elective lumbar laminectomy. She reported left lower extremity pain and swelling and was found to have acute deep venous thrombosis. The procedure was cancelled, and she was immediately started on a therapeutic dose of enoxaparin, a LMWH. She was discharged from the hospital, and the low-molecular weight was continued as outpatient therapy.

The patient’s medical history was significant for deep venous thrombosis and pulmonary embolism 4 years earlier, initially treated with unfractionated heparin and then warfarin for 1 year. Her surgical history was significant for a modified radical mastectomy with radiation on the right and lumpectomy on the left to treat bilateral breast cancer.

Two weeks after being on LMWH therapy, she returned to the hospital after sustaining a fall and reported bilateral lower extremity weakness, numbness with severe pain, and an inability to walk. On physical examination, both lower extremities were cool to the touch and there was markedly delayed capillary refill and cyanosis of her toes. No palpable pulses were noted. Neurological examination revealed flaccid paralysis and the absence of deep tendon reflexes.

Initial laboratory results demonstrated a platelet count of 27,000/mm³. This was a considerable drop from the platelet count of 252,000/mm³ at her previous admission (Figure 1). Workup for HIT revealed a positive antibody titer. The patient underwent magnetic resonance angiography (MRA), which revealed an occluded infrarenal aorta (Figure 2). Imaging of the spine showed degenerative disc disease without evidence of acute cord compression.

Enoxaparin was abruptly discontinued and the patient was started on lepirudin (r-hirudin), a direct thrombin inhibitor, to achieve therapeutic anticoagulation. She was advised to undergo surgery immediately but opted to wait until she had consulted with her family; she finally consented to surgery approximately 14 hours later. By this time, her left lower extremity ischemia had progressed to the point where there was some mottling of her toes and the dorsum of her foot. Our initial approach was to cut down on both femoral arteries and attempt transfemoral embolectomy, but this was unsuccessful. Transabdominal aortic exposure was then performed with aortotomy after infrarenal cross-clamping. A large clot was removed from the infrarenal aorta. Because the aorta was somewhat diseased and calcified, aortic reconstruction was performed, with an aorta-bifemoral graft. The operation proceeded smoothly without significant blood loss in the patient. Fasciotomy of the left leg was performed, and the muscle in all compartments appeared viable. A right transfemoral Greenfield^® filter was placed, which concluded the operation. Lepirudin was used intraoperatively and was continued through the immediate postoperative period.

The patient’s postoperative recovery was complicated by profound hypotension and shock. She experienced bleeding complications that required transfusion, and lepirudin therapy was discontinued. She developed severe acute respiratory distress syndrome and multiorgan dysfunction and subsequently died.

Discussion
Thrombocytopenia has been associated with a number of medications, including quinine, antibiotics, histamine-2 receptor blockers, sulfa, unfractionated heparin, and LMWH. There are two causes of thrombocytopenia in heparin-treated patients. Heparin-associated thrombocytopenia, previously known as type I HIT, is associated with mild thrombocytopenia (platelets, 100,000”-”120,000/mm³), and occurs within 2 to 5 days after initiation of heparin therapy. Type II HIT is a less common but more serious condition. HIT is a clinicopathologic syndrome characterized by unexplained thrombocytopenia in conjunction with the presence of antiplatelet-factor 4/heparin platelet-activating immunoglobulin G antibodies.² The formation of antibodies occurs in up to 20% of patients exposed to heparin.³ The drop in these patients’ platelet counts usually exceeds 50%, even if the platelet count nadir is above 150,000/mm³; however, the platelet count nadir typically ranges between 20,000/mm³  and 150,000/mm³.^4,5

The reported incidence of HIT varies depending on the patient population and can range from 1% to 30%.⁶ The frequency is highest in postoperative patients and is influenced by the heparin preparation; bovine unfractionated heparin is associated with the greatest risk followed by porcine unfractionated heparin and LMWH.^2,4 One prospective randomized study reported that the incidence of HIT associated with unfractionated heparin and LMWH was 2.7% and less than 1%, respectively.

HIT is assigned to one of three categories, based on the time that it takes to develop:

• Typical-onset HIT—Occurs 5 to 10 days after heparin exposure in heparinnaïve patients and is the most common presentation (70%).

• Acute-onset HIT—Develops immediately in patients with preexisting antibodies who are exposed to heparin within 100 days of their inital treatment (25%–30%).⁷

• Delayed-onset HIT—This is rare and can occur up to 40 days after heparin therapy is discontinued.⁸

The risk of thrombosis occurring in patients with HIT is estimated to range between 20% and 40%.^2,3 HIT thrombotic syndrome is associated with both the presence of platelet factor 4 antibodies and thrombocytopenia.³ The pathogenesis of the thrombotic complications is due to several factors that contribute to a relative “hypercoagulable state,” including in vivo platelet activation,⁹ generation of procoagulant platelet-derived microparticles,¹⁰ and endothelial activation via the recognition by HIT antibodies of platelet factor 4/endothelial-heparin sulfate complexes.¹¹

Venous thrombotic complications, especially proximal deep vein thrombosis and pulmonary embolism, are the most common sequela of HIT and are reported to be four times as likely as arterial thrombosis.¹ Arterial thrombosis primarily affects the large lower limbs or cerebral vessels. Patients present with acute limb ischemia or thrombotic stroke, with diseased or injured vessels being at greatest risk¹²; however, acute aortic thrombosis is rare.

Our patient received enoxaparin, a LMWH, to treat her deep vein thrombosis. This resulted in a dramatic drop in her platelet count (Figure 1). Since this drop occurred almost 2 weeks after her initial treatment, she likely had typical-onset HIT, even though her platelet counts were not evaluated after enoxaparin therapy was initiated. Our patient’s lower extremity paralysis was due to severe ischemic neuropathy and is one of the pitfalls that can cause delays in diagnosis and management.¹³ 

Dossa and associates reviewed their experience with acute aortic occlusion over 40 years and found that moderate-to-severe motor or sensory deficits correlate with poor outcomes and a mortality rate between 33% and 47%.¹⁴ According to Babu and colleagues, acute aortic occlusion has a uniformly poor prognosis and a mortality rate of 83% when it results from a hypercoagulable state.¹⁵ Their strategy for treating acute aortic occlusion starts with bilateral femoral artery exposure followed by attempted transfemoral embolectomy; this approach was effective in patients who had no evidence of preexisting occlusive disease. They also propose aortic reconstruction in patients with good left ventricular function and extra-anatomic bypass in those with suboptimal left ventricular function.¹⁵ 

There have been some reports on using thrombolytic therapy for arterial thrombosis in HIT.^16,17 This was not attempted in our patient because of the severity and advanced nature of her ischemia and because lyses of her clot burden would have been time consuming.

According to Arthur and associates, bilateral adrenal hemorrhage is another complication of HIT.¹⁸ This may have caused our patient’s profound refractory hypotension; her randomized cortisol level and cosyntropin test were both suboptimal.

The major challenge in treating our patient was maintaining anticoagulation perioperatively. Our decision to use an alternative anticoagulation agent was based on the fact that they are safe and effective for prophylaxis and treatment and because they do not generate or cross-react with antiplatelet-factor 4 antibodies. Sobel and colleagues presented a series of cases in which a combination of dextran and warfarin was used without causing new thrombotic or bleeding complications.¹⁹ The use of warfarin in acute HIT may be deleterious because it has been linked to the development of a syndrome of venous limb gangrene in which deep venous thrombosis advances to tissue necrosis, requiring amputation.²⁰ This negative sequela is thought to be due to a disturbance in balancing procoagulation and anticoagulation during the use of warfarin to treat HIT.²¹ To avoid venous limb gangrene, the introduction of warfarin in a patient with HIT should be deferred until the platelet count has recovered.²²

Chevalier and associates used danaparoid sodium to successfully treat a patient with aortic and renal thrombosis from HIT.²³ This drug has a 5% in vivo  cross-reactivity with HIT antibodies and is not available in the United States. Hassell’s report recommends using direct thrombin inhibitors in patients with active HIT to provide adequate anticoagulation.²² Direct thrombin inhibitors, such as lepirudin, argatroban, and bivalirudin, differ from heparin in structure and do not generate or cross-react with HIT antibodies. Lepirudin and argatroban are the only two direct thrombin inhibitors approved by the Food and Drug Administration for the treatment of HIT.

Lepirudin is an rDNA derivative of natural hirudin, a direct thrombin inhibitor produced from leech salivary glands. Lepirudin irreversibly binds to thrombin and inhibits fibrin-bound thrombin, which ultimately blocks the activation of platelet factors V, VIII, and XIII. Direct thrombin inhibitors can be monitored via the activated partial thromboplastin time (aPTT).^24,25 Unfortunately, lepirudin does not have a reversing agent, such as heparin does with protamine.  

Lepirudin was administered intraoperatively and postoperatively in our patient, with a therapeutic goal of maintaining the aPTT in the 1.5 to 2.5 times the baseline range. Our patient experienced bleeding that required a transfusion when her aPTT was greater than 60 seconds. Greinacher and colleagues indicate that lepirudin has a narrow therapeutic window and a relatively high risk of causing bleeding even when administered in clinically relevant doses to patients with HIT.²⁵ Lepirudin has been shown to be effective for treating patients with HIT and ongoing thrombosis. There is also evidence that oral anticoagulation can be started safely with no risk of inducing venous limb gangrene once the platelet count has recovered.²⁵ These agents should be used cautiously in surgical patients with retroperitoneal dissection because there is no available antidote and more investigation is needed in this subgroup.

Conclusion
This case shows that HIT can occur with the use of LMWH and underscores the importance of monitoring platelet counts after therapy is initiated. When platelet counts drop more than 50% from baseline, clinicians should develop a high level of suspicion. Acute aortic thrombosis from HIT has a poor prognosis and is associated with high mortality rates; early diagnosis and surgical management may be effective in some cases.²³ Unfractionated heparin or LMWH use should be discontinued immediately, and therapeutic anticoagulation should be initiated with a direct thrombin inhibitor.

References
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