Refractory Heparin-Induced Thrombocytopenia in a Patient With Subarachnoid Hemorrhage—A Clinical Conundrum

Abstract

Heparin induced thrombocytopenia (HIT) often resolves with discontinuation of heparin/ heparinoid products. Severe HIT with platelet counts <20,000/µL and disseminated intravascular coagulation is frequently associated with consumptive coagulopathy and systemic thrombosis. Management of severe HIT in patients who fail to improve on discontinuing heparinoid products and argatroban infusion is not well established. We describe a patient admitted with aneurysmal subarachnoid hemorrhage (SAH) who developed severe autoimmune HIT, failed conventional anticoagulation therapy with argatroban and progressed to develop extensive deep venous thrombosis and limb ischemia. She was successfully treated using bivalirudin, immunomodulation with 2 cycles of intravenous immunoglobulin and immunosuppression with methylprednisolone. Refractory severe HIT among SAH patients is rare and pose several therapeutic challenges. We report successful treatment using alternate anticoagulant and immune suppression and modulation.

Introduction

Heparin-induced thrombocytopenia (HIT) is a rare but potentially life-threatening complication of heparin use. Current incidence is estimated to be 1-5%.¹ Severe cases of HIT cause consumptive coagulopathy and/or systemic thrombosis.^2,3 Most cases respond to discontinuation of heparin, heparinoid products, and treatment with a non-heparinoid anticoagulant. Intravenous immunoglobulin (IVIG), as an immunomodulator, is a treatment option for HIT but is often avoided for its inherent prothrombotic properties.⁴ In this report we describe a case of severe autoimmune HIT, with platelets <20,000/µL and associated disseminated intravascular coagulation (DIC), in a patient with subarachnoid hemorrhage (SAH) who was refractory to conventional treatment.

Case Description

Institutional review board at UT Southwestern Medical Center considers case reports as non-research with minimal or no risk to an unidentified subject and exempts such study from a formal review process. However, verbal informed consent was obtained from the patient.

A 63-year-old woman presented to the emergency department with persistent headaches. Computed tomography (CT) scan of head with CT angiography showed acute SAH due to ruptured anterior communicating artery aneurysm (Figure 1). The aneurysm was secured using coil embolization. External ventricular drain (EVD) was placed for management of post-hemorrhagic hydrocephalus. Subcutaneous heparin for venous thromboembolism prophylaxis was started on hospital day (HD)-3. She underwent treatment for cerebral vasospasm (CV) on HD-8. Of note, the patient received intraprocedural heparin flushes during cerebral angiogram as per protocol. She developed thrombocytopenia with platelet count dropping from 170,000/µL to 88,000/µL on HD-9. Her admission platelet count was 278,000/µL. All heparin/ heparinoid products were discontinued and argatroban infusion was started for HIT treatment.

Figure 1.

Admission CT scan shows hyperdensity in the subarachnoid space representative of subarachnoid hemorrhage (A). Cerebral angiogram on the day of admission shows anterior communicating artery aneurysm before (B) and after (C) coil embolization (open black and white arrows respectively). On hospital day (HD) 8 patient underwent cerebral angiogram for diagnosis and treatment of cerebral vasospasm (D, E)—arrows show arterial segments in vasospasm.

HIT was confirmed using Heparin Associated Antibody test. Assay estimated optical density (OD) at 2.104 and HIT, percent inhibition at 100.4. Test repeated on HD-10 and HD-15 was 1.876 OD with percent inhibition of 96.0 and 2.664 OD with percent inhibition of 100.0 respectively. In addition, her prolonged activated partial thromboplastin time (aPTT) of 41.1 s (normal range 23-35.4), prolonged prothrombin time of 17.1 s (normal range 11.9-15), and decreased fibrinogen level of 179 µg/dL (normal range 204-488) would diagnose her as having DIC and thus severe HIT.

On HD-10, swelling of her right upper extremity, investigated using ultrasound, showed extensive deep vein thrombosis (DVT) involving the subclavian, axillary, and brachial veins with superficial thrombus in the right cephalic and basilic veins (Figure 2). Subsequently, she had extensive DVTs in both bilateral upper and lower extremities. On HD-12, her thrombocytopenia worsened to 8,000/µL and a 4-day course of intravenous immunoglobulin (IVIG) at a dose of 0.4g/kg/day was started. On the same day, her clinical exam deteriorated due to CV and she needed rescue therapy with intra-arterial vasodilator infusion. Due to her severe thrombocytopenia, she was transfused platelets to minimize peri-procedural bleeding risk. Additional platelet transfusion was needed on HD-15, for a platelet count of 19,000/µL, to remove EVD and for gastrostomy tube placement. Throughout her argatroban treatment, she did meet the goal aPTT targets (i.e. 1.5 to 2-times the upper limit of aPTT range), varying between 40-87 seconds. The variation in aPTT goals was multifactorial dependent on her degree of thrombocytopenia and to scheduled and emergent procedures. On HD-18, the patient developed worsening of her left upper extremity edema along with a painful, cold hand. She was transitioned to bivalirudin due to progression of thrombosis despite treatment with argatroban. On HD-20, thrombocytopenia was at its nadir of 4,000/µL with patient having multiple areas of ecchymosis. Patient’s inability to recover platelet count necessitated repeat cycle of IVIG treatment at 0.4g/kg/day for 5 days and a 3-day course of parenteral methylprednisolone 1,000 mg daily. Her thrombocytopenia resolved and along with improvement in her bilateral hand perfusion. She was subsequently transitioned to oral anticoagulation, apixaban, prior to discharge. Her relevant laboratory trends and treatment course during hospitalization is illustrated in Figure 3.

Figure 2.

Ultrasound of right upper extremity shows compressible internal jugular vein (open arrow) indicative of patency in comparison to subclavian vein which is non-compressible (open arrow shows area of the vein that can be compressed) indicative of acute thrombus (hypodense).

Figure 3.

Graphical representation of disease course and relevant clinical interventions.

Discussion

Heparin binds to platelet factor-4 (PF-4) for its normal anticoagulant effect without formation of antibodies. In HIT, abnormal IgG antibodies against PF-4 react to form a heparin-PF4-IgG complex. Platelets produce a receptor known as the Immunoglobulin G Fc gamma receptor II a (FcγRIIa) and it reacts with the crystallizable fragment (Fc) region on the IgG complex leading to platelet activation and clotting cascade mediated thrombus formation. Our case highlights several unique challenges while treating HIT, especially in the setting of SAH. First, SAH is a prothrombotic state especially during the early brain injury period with rise in activated platelets and persistence of prothrombotic factors during the CV/ delayed cerebral ischemia period.^5,6 Second, her symptomatic CV required rescue therapy using cerebral angiogram and necessitated platelet transfusion to safely perform the invasive procedure in the setting of severe thrombocytopenia. Third, despite using standard of care anticoagulant for HIT treatment, argatroban, as administered, was ineffective in preventing further thrombotic events. Last, the initial dose of immunomodulation with IVIG did not improve thrombocytopenia.

Autoimmune Heparin Induced Thrombocytopenia

Older nomenclature classified HIT into 2 types. HIT type I that usually presents within the first few days of heparin exposure is associated with mild thrombocytopenia and often resolves despite continuation of heparin products. It is generally non-thrombotic. In contrast, HIT type II, now simply referred to as HIT, is due to development of antibodies against PF-4, results in thrombocytopenia, and is associated with thrombotic events and associated with increased mortality.² Autoimmune HIT (aHIT) is characterized by the persistent activation of platelets, even in the absence of heparin which can last for several weeks.³ Principles of HIT therapy is based on prevention of thrombosis through anticoagulation (most commonly using a direct thrombin inhibitor) and prevention of platelet activation that may require use of IVIG.⁷

Using Anticoagulation for HIT Treatment

Argatroban, a direct thrombin inhibitor and FDA approved for HIT management, was used to treat our patient initially. However, despite a week-long treatment, thrombotic events progressed and hence she was switched to bivalirudin. Short half-lives of these medications make them favorable in management of HIT as they can be stopped if hemorrhagic complications develop. However, both these medicines can provide varying aPTT values depending on laboratory reagent used and of note, ecarin clotting time monitoring is more specific.⁸ In addition, DIC, associated with severe HIT, also prolongs aPTT, thus leading to underdosing.³ There is limited data for bivalirudin in comparison to argatroban with no prospective studies. A retrospective study noted bivalirudin to have more thrombotic events after initiation. The retrospective design, and only 40% ELISA confirmed heparin-PF4 antibody test, makes it difficult to make any generalizations.⁹ However, some recent studies indicate that bivalirudin may reach therapeutic aPTT levels earlier.² Direct oral anticoagulants are also being investigated for their possible role in HIT. The major limitations of oral formulations are longer half-lives and lack of cost-effective reversal (in event of bleeding). Thus, these medicines are less attractive as initial anticoagulants, especially in critically ill and surgical patients.

IVIG in Treatment of HIT

Use of IVIG was originally identified as a possible treatment for aHIT over 25 years ago, however, current evidence is limited largely to case reports that results in uncertainty regarding ideal dosing. Literature reviews by Tvito et al and Al-Sadawi et al described fast and favorable platelet response to IVIG in cases of severe aHIT with no adverse effects and only one recurrence after IVIG administration.^10,11

Thrombocytopenia in our patient did not improve after the first cycle of IVIG. However, she underwent platelet transfusions twice for procedures. After both transfusions her thrombocytopenia recurred that maybe postulated to be secondary to transfused platelet related antigen (PF-4 in transfused platelets) persistence. Persistent thrombocytopenia with DVT progression, limb ischemia, and absence of any other therapeutic option led us to administer second cycle of IVIG and concurrent parenteral steroids. This approach was based on a study that described IVIG pharmacokinetics in Guillain-Barre syndrome necessitating additional dosing¹² and a case study reporting steroid effectiveness in HIT.¹³

HIT After SAH

Incidence of aHIT is reported to be 5-15% among retrospective SAH cohorts.^14,15 Although the study reporting an incidence of 15% classified HIT as per clinical definition and percentage of patients with laboratory confirmed HIT was not reported.¹⁴ Hence, actual incidence of aHIT in SAH population is unknown. Limited studies of HIT in the SAH population that are available reports higher morbidity and mortality and higher rates of symptomatic vasospasm.¹⁴ Use of enoxaparin for DVT prophylaxis is no better than unfractionated heparin in incidence of HIT.¹⁵ Endovascular treatment of aneurysm or CV exposes patients to intra-arterial heparin. Intraprocedural thrombotic complications are reported, including stent thrombosis, intra-catheter thrombosis and more endovascular treatments being associated with higher incidence of HIT.^14,15 Hence, there appears to be a need to investigate SAH patients developing thrombocytopenia and thrombotic events systematically and prospectively as these can be subtle manifestations aHIT.

Conclusion

Patients with SAH developing HIT have unique challenges in management of both thrombosis and thrombocytopenia associated complications. It may be necessary to use alternate anticoagulants and additional immunomodulation and immunosuppressive strategies to mitigate these complications as highlighted in our case. A prospective cohort investigating HIT is needed to determine actual prevalence of in SAH population.

Abbreviations Used

aHIT

autoimmune heparin induced thrombocytopenia

aPTT

activated partial thromboplastin time

CT

computed tomography

CV

cerebral vasospasm

DIC

disseminated intravascular coagulation

DVT

deep venous thrombosis

EVD

external ventricular drain

Fc

fragment crystallization region

FDA

Food and Drug Administration

HD

hospital day

HIT

heparin induced thrombocytopenia

IVIG

intravenous immunoglobulin

OD

optical density

PF-4

platelet factor 4

PT

prothrombin time

SAH

subarachnoid hemorrhage