Spontaneous Heparin-Induced Thrombocytopenia Presenting as Acute Ischemic Stroke

PRACTICAL IMPLICATIONS

Consider spontaneous heparin-induced thrombocytopenia in the differential diagnosis of a patient presenting with acute ischemic stroke in the setting of thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a disorder caused by the production of antibodies to complexes of platelet factor 4 (PF4) and heparin, which leads to the activation of platelets, causing thrombocytopenia and thrombosis.¹ In rare cases, a similar syndrome can occur in the absence of heparin exposure. This is termed spontaneous HIT.² We report a case of spontaneous HIT presenting as an ischemic stroke.

Case

A 54-year-old man with a history of hypertension, hyperlipidemia, type-2 diabetes, and tobacco use presented with acute onset left arm weakness with a NIH Stroke Scale (NIHSS) of 1 and a platelet count of 38,000/μL. He reported fever and sore throat beginning 9 days earlier, treated with amoxicillin, which had resolved before presentation. He had no history of exposure to heparin in any form.

The next day (hospital day 1), he acutely worsened, developing a dense right middle cerebral artery (MCA) syndrome with an NIHSS of 19 and was transferred to our institution for consideration of endovascular intervention. On arrival, no vessel occlusion was visualized on CT angiography. Brain MRI revealed a large right MCA territory infarction with associated petechial and subarachnoid hemorrhage and a punctate left parietal infarct (Figure).

Figure. Brain MRI.

MRI of the brain demonstrating acute infarction involving the right middle cerebral artery territory and a punctate infarct in the left parietal subcortical white matter on the diffusion-weighted imaging sequence (A) and petechial and subarachnoid hemorrhage on the susceptibility-weighted imaging sequence (B).

His thrombocytopenia was initially attributed to immune thrombocytopenic purpura because other cell lines were unaffected, and he had an elevated immature platelet fraction (indicative of platelet destruction rather than marrow suppression), with no coagulopathy to suggest disseminated intravascular coagulation (DIC), no hemolysis to suggest thrombotic thrombocytopenic purpura, and no heparin exposure to suggest HIT. He was treated with dexamethasone and IV immunoglobulin (IVIG) 2 g/kg.

On hospital day 2, his left lower extremity became mottled. Ultrasound revealed thrombi in the left superficial femoral and right posterior tibial arteries. His platelet count dropped to 19,000/μL. At this point, he developed signs of coagulopathy concerning for DIC including reduced fibrinogen (98 mg/dL), prolonged prothrombin time (12.9 seconds), and elevated d-dimer (21.55 mg/L fibrinogen equivalent units). CT of the chest, abdomen, and pelvis revealed right renal artery occlusion with right renal infarction. He received platelet and cryoprecipitate transfusions.

On hospital day 3, his HIT antibody resulted positive at an optical density of 2.3. This antibody test was sent after he had received IVIG but was confirmed with a positive serotonin release assay showing 78% serotonin release at low-dose unfractionated heparin (0.1 U/mL) and 0% release at high-dose (100 U/mL). An argatroban drip was initiated because the primary treatment for HIT involves administering a nonheparin anticoagulant.

On hospital day 6, he developed hypoxic respiratory failure requiring intubation. He was found to have a pulmonary embolus (PE), multiple deep vein thromboses (DVTs), and bilateral adrenal hemorrhages. The ongoing thrombotic events despite treatment with a nonheparin anticoagulant raised concern for refractory HIT, and a second round of IVIG 2 g/kg was added to continued anticoagulation with argatroban.

By hospital day 10, his platelet count normalized. After tracheostomy and gastrostomy tube placement, warfarin was initiated. He was discharged to an inpatient rehabilitation facility on hospital day 37, with an NIHSS of 17.

Given the presence of bilateral infarcts and the highly suggestive clinical history, his stroke was attributed to spontaneous HIT. Twenty days of telemetry reveled no arrhythmia, and transthoracic echocardiogram revealed no intracardiac thrombus, vegetation, or patent foramen ovale.

Discussion

Spontaneous HIT is a rare entity that can initially present as an acute ischemic stroke. Cases have commonly occurred after orthopedic procedures^3–6 or infections.² This has led to speculation that nonheparin polyanionic substrates, such glycosaminoglycans in cartilage³ or lipopolysaccharides on gram-negative bacteria,⁷ can cause conformational changes in PF4 similar to those induced by heparin, triggering HIT in the absence of heparin exposure.⁶ Our patient did have fevers and pharyngitis before presentation, although no specific diagnosis was established.

Although thrombocytopenia is the most ubiquitous manifestation of HIT, thrombosis is common,¹ 5%–15% develop DIC,¹ and adrenal hemorrhage has been reported.⁴ Our case included all of these manifestations: multiple thrombi (both arterial and venous) including right MCA infarction, arterial occlusions in the bilateral lower extremities, right renal infarction, bilateral adrenal hemorrhages, multiple DVTs, a PE, and DIC.

The treatment of HIT involves eliminating all exposure to heparin products and the use of a nonheparin anticoagulant. For cases of severe or refractory HIT, IVIG has been used.⁵ IVIG was used twice in our case because of continued thrombosis refractory to therapeutic anticoagulation with argatroban, although it is difficult to know how much this contributed to his clinical improvement.

Appendix. Authors

Study Funding

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Disclosure

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