Spontaneous Heparin-Induced Thrombocytopenia Presenting as Cerebral Venous Sinus Thrombosis

PRACTICAL IMPLICATIONS

Spontaneous HIT syndrome should be considered in any patient presenting with unexplained thrombocytopenia and unprovoked arterial and/or venous thrombosis, including CVST.

Spontaneous heparin-induced thrombocytopenia (HIT) syndrome is a rare entity where platelet-activating antiplatelet factor 4 (PF4)/heparin antibodies cause thrombocytopenia and thrombosis in the absence of a preceding immunizing heparin exposure. We report a case of cerebral venous sinus thrombosis (CVST) secondary to spontaneous HIT syndrome.

Case

A 26-year-old previously healthy man presented with a 2-week history of flu-like symptoms, followed by a 1-day history of new-onset headache. His initial examination was unremarkable. Routine blood work demonstrated platelet count 38 × 10⁹/L, fibrin d-dimer >20,000 μg/L, international normalized ratio 1.3, and fibrinogen 80 mg/dL (Figure 1). There was no evidence of hemolysis. The thrombocytopenia, hypofibrinogenemia, and elevated d-dimer led to a diagnosis of disseminated intravascular coagulation (DIC) of unknown etiology.

Figure 1. Clinical, Laboratory, and Treatment Course of Patient With Spontaneous Hit Syndrome Presenting as CVST.

The upper part of the graph shows results of laboratory tests for HIT antibodies. The serotonin release assay (SRA) yielded a strong positive result (100% release at 0.1 and 0.3 U/mL unfractionated heparin [UFH]), including strong serum-induced serotonin release (98%) in the absence of heparin (a characteristic feature of spontaneous HIT syndrome); the patient's serum produced <5% serotonin release at 100 U/mL UFH and at 0.3 U/mL UFH in the presence of Fc receptor-blocking monoclonal antibody (not shown), in keeping with HIT. Two PF4-dependent enzyme immunoassays (EIAs) tested strongly positive; a commercial polyspecific EIA (LIFECODES PF4 Enhanced assay; Immucor GTI Diagnostics, Waukesha, WI) that detects anti-PF4/polyvinylsulfonate antibodies of IgG, IgA, and IgM classes (EIA-GAM); and an in-house EIA that detects anti-PF4/heparin antibodies of IgG (EIA-G) class. EIA results are expressed in units of OD. The middle panel shows the coagulation test results: INR; reference range, 0.8–1.2, fibrinogen (reference range, 160–420 mg/dL), and fibrin D-dimer (reference range, <270 μg/mL fibrinogen-equivalent units), as well as transfusion of platelets, fibrinogen concentrate, and plasma. DIC resolved when UFH was switched to fondaparinux. The bottom panel shows the platelet counts, key clinical events, and treatment administered (unfractionated heparin [UFH], fondaparinux, and corticosteroids (methylprednisolone followed by prednisone). Although HIT was first suspected on day 6, an earlier blood sample from day 2 was used to demonstrate presence of HIT antibodies. CT = computed tomography; CVST = cerebral venous sinus thrombosis; DIC = disseminated intravascular coagulation; HIT = heparin-induced thrombocytopenia; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; INR = international normalized ratio; MR venography = magnetic resonance venography; OD = optical density; PF4 = platelet factor 4.

On day 2, he developed left-sided weakness. A noncontrast CT scan demonstrated multiple bilateral frontoparietal intracerebral hemorrhages and convexity subarachnoid hemorrhages with a possible hyperdense signal in the superior sagittal sinus (SSS) (Figure 2A). The patient received blood product support with platelets, fibrinogen concentrate, and plasma transfusions (Figure 1). MRI of the brain showed fluid-attenuated inversion recovery (FLAIR) hyperintensity of the bilateral frontoparietal lobes with corresponding diffusion restriction suggestive of multiple areas of infarcts with associated hemorrhage (Figure 2B). MR venogram (MRV) confirmed extensive CVST involving the SSS and right transverse sinus (Figure 2C). The patient was started on intravenous unfractionated heparin (UFH).

Figure 2. Imaging.

(A) Initial axial CT demonstrating multifocal intraparenchymal hemorrhages, convexity subarachnoid hemorrhage, and hyperdense SSS (thin arrow). (B) Axial diffusion-weighted images from initial MRI demonstrate cortical and subcortical increased FLAIR signal intensity in the right greater than the left frontal lobes (thick white arrows). Also, note multiple intraparenchymal hemorrhages with associated edema (black arrowheads) (C) MRV demonstrating extensive thrombosis of the SSS (white arrowheads). (D) Axial FLAIR images from 6-week follow-up MRI show improvement in FLAIR signal intensity in bilateral frontal lobes. FLAIR = fluid attenuated inversion recovery; MRV = MR venogram; SSS = superior sagittal sinus.

The following day, he developed left eye proptosis. Repeat CT venogram confirmed new thrombosis of the left cavernous sinus and redemonstrated the previously described CVST. Given the extensive and progressive CVST, which was unresponsive to heparin, the patient underwent emergency endovascular intervention. Postintervention, angiography showed ∼50% improvement in patency of sinuses, without clinical change.

Repeat imaging the following morning demonstrated worsening CVST despite heparin therapy with rethrombosis of the SSS and right transverse sinus, as well as new thrombosis of the right occipital vein. Severe thrombocytopenia persisted, whereas all viral, bacterial, and fungal cultures returned negative. A diagnosis of spontaneous HIT syndrome was considered on day 6, with an available day 2 serum sample tested by screening anti-PF4/heparin enzyme-immunoassay (EIA), which yielded a strong positive result. UFH was switched to fondaparinux, and methylprednisolone was started. Twenty-four hours later, the patient's clinical condition improved rapidly. The diagnosis of spontaneous HIT syndrome was confirmed by strong positive serotonin release assay (SRA) (100% serotonin release at 0.1 and 0.3 U/mL UFH), including substantial (98%) serotonin release at 0 U/mL UFH (see Discussion).

The patient was discharged home on day 22 on warfarin therapy with only a right pronator drift. A follow-up MRI 6 weeks postdischarge demonstrated reversal of a majority of areas of diffusion-weighted imaging and FLAIR changes, indicating little permanent tissue damage (Figure 2D). A follow-up MRV demonstrated near-complete resolution of the CVST. Clinically, the patient's pronator drift resolved and he was able to return to work.

Discussion

HIT is a transient prothrombotic disorder that is triggered by exposure to heparin. “Spontaneous HIT syndrome” is when a clinical picture identical to HIT (thrombocytopenia, thrombosis, and detectable HIT antibodies) is triggered by naturally occurring polyanions, such as microbial surfaces and nucleic acids, rather than (polyanionic) heparin.¹ Diagnostic criteria² (all met by our patient) include thrombocytopenia (without alternate explanation), thrombosis, lack of preceding immunizing heparin exposure, strong positive PF4-dependent EIAs (≥2 different assays), and a strong positive SRA (>80% peak serotonin release at 0.1–0.3 U/mL heparin) that also features strong heparin-independent platelet activation (>50% serotonin release at 0 U/mL heparin), as well as exhibiting the other characteristic features of HIT sera (lack of serotonin release at 100 U/mL heparin and with platelet Fc receptor-blocking monoclonal antibody).² In our patient, the likely immunologic trigger was a preceding viral infection. Our patient's serum (obtained preheparin exposure) induced strong heparin-dependent and heparin-independent serotonin release. Notably, subsequent sera tested SRA-negative but EIA-positive, consistent with the known transient nature of spontaneous HIT syndrome^1–3 and the patient's platelet count recovery and resolution of DIC. A literature review⁴ revealed 9 cases of this condition, including 1 patient with fatal CVST.⁵ The role of corticosteroids in spontaneous HIT is unclear, although its use was associated with clinical and laboratory recovery in our patient.

Appendix. Authors

Study Funding

No targeted funding reported.

Disclosure

G. Moores reports no disclosures. T.E. Warkentin reports research funding from Instrumentation Laboratory and W.L. Gore and consulting fees from Bayer AG, CSL Behring, Ergomed, Octapharma, W.L. Gore, and for medical-legal testimony. M.A.M. Farooqi reports no disclosures. S.D. Jevtic reports no disclosures. M.P. Zeller reports no disclosures. K.S. Perera reports honoraria from Bayer AG, Abbott, and Servier and research grants from Bayer AG. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.