Authors: Sean Murnan, MD and Richard Slama, MD (EM Resident Physicians, NMCP Emergency Medicine Residency) // Edited by: Erica Simon, DO, MHA (@E_M_Simon), Brit Long, MD (@long_brit), & Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

A 56 year-old female with a PMHX of lung cancer presents to the ED for “abnormal labs.” Review of systems is significant for hospitalization five days prior secondary to multiple sub-segmental pulmonary emboli. The patient notes that during her hospital stay heparin therapy (unfractionated heparin (UFH)) was initiated, and that she was subsequently transitioned to lovenox (low molecular weight heparin (LMWH)). The patient states that she has been compliant with her lovenox injections, but that she was directed to the ED after her PCM follow-up due to her “abnormal blood counts.” Current labs demonstrate a platelet count of 16 x103/L. Review of the patient’s record reveals a platelet count of 140 x103/L just prior to her hospitalization.

What is the underlying cause of this patient’s thrombocytopenia? How will you manage her condition? What laboratory studies will you order? If it’s time for a HIT refresher, we have you covered:

First, let’s talk Heparin:

Heparin produces its anticoagulant effect through inhibition of thrombin and factor Xa through an antithrombin dependent binding process.1

What is HIT?

When heparin is administered exogenously, platelet factor 4 (PF4) (a neutralizing chemokine of heparin and heparin-like compounds released from alpha granules upon platelet activation), binds to heparin, forming heparin-PF4 complexes. 1,2

Formation of the heparin-PF4 complex results in an intrinsic conformational change of the PF4 protein, thereby generating a neoantigen. 3

Although the autoimmune system mounts an allogenic response to the neoantigen through the generation of IgG, IgM, and IgA antibodies; the formation of IgG antibodies (the only subclass recognized by the platelet Fc receptor) is thought to result in HIT.4,5

HIT comes in two flavors:

HIT Type I is defined as a transient decrease in platelets (nadir commonly around 100 x10 3 /L) that occurs during the first few days of heparin exposure. HIT Type 1 is not immune-mediated , and can be managed without discontinuation of heparin therapy. 6,7

is defined as a transient decrease in platelets (nadir commonly around 100 x10 /L) that occurs during the first few days of heparin exposure. HIT Type 1 , and can be managed without discontinuation of heparin therapy. HIT Type II references the aforementioned immune-mediated process by which IgG antibodies bind the heparin-PF4 complex, leading to platelet activation, and subsequent venous or arterial thrombosis.6,8 The thrombocytopenia observed in HIT Type II is a result of platelet consumption and removal by macrophages in the reticuloendothelial system.2

The Clinical Presentation of HIT: A Spectrum of Disease

Early Features

85-90% of patients present with thrombocytopenia: platelet count < 150 x10 3 /L OR a decrease in the patient’s baseline platelet count by ≥ 50%. 6,9,10 Thrombocytopenia typically occurs within 5-10 days of the initiation of UFH or LMWH therapy. 6 It is important to note that HIT may occur independent of the heparin dose, schedule, or administration route (even heparin flushes are not excluded). 8,11

platelet count < 150 x10 /L OR a decrease in the patient’s baseline platelet count by ≥ 50%.

Delayed Features: “White Clot Syndrome” 6,12

Venous Thrombosis: Lower limb DVT – present in roughly 20-50% of patients with HIT 6,13 Upper extremity DVT – associated with IV catheter use 14

Arterial Thrombosis: Occurs in 3-10% of patients with HIT 6,13 Typically involves the heart, central nervous system, and limbs. 15



Rare Presentations of HIT

Anaphylaxis: Case reports detail acute, fatal systemic anaphylactic reactions in patients experiencing HIT. 6,16



Alright, that sounds great, but why should I care about HIT in the emergency department?

The acute presentation of HIT is rare, occurring in 2.6% of patients receiving UFH and 0.2% receiving LMWH,6,17 however, as outpatient DVT/PE therapy becomes increasingly commonplace, we are likely to see an increase in the number of incident cases of HIT presenting to the ED.18

I hear that HIT is often misdiagnosed, are there any tools to help me in determining how likely it is that my patient actually has HIT?

Thrombocytopenia is a common finding in ill patients. Some studies suggest that 46% of individuals admitted to the ICU will have a platelet count <150,000.19 What is even more challenging is that only 10% of patients initially investigated for HIT, will ultimately have laboratory studies confirming the diagnosis.10

This is where the 4T Score comes in handy: allowing for the determination of a patient’s pretest probability of HIT, and thus aiding in the clinical decision to initiate HIT evaluation and treatment.

The 4T Score ranges from 0-8, with 0-3 = low pre-test probability, 4-5 = intermediate pre-test probability, and 6-8 = high pre-test probability of HIT.6

Categories include: Thrombocytopenia 0 Pts = <30% platelet fall or nadir <10,000/microL 1 Pts = 30-50% platelet count fall, or >50% directly resulting from surgery, or nadir 10,000-19,000/micoL 2 Pts = > 50% platelet fall to nadir ≥ 20,000/microL Timing 0 Pts = Platelet count fall <4 days without recent exposure 1 Pts = Consistent fall 5-10 post treatment, but not entirely clear (missing platelet counts) OR ≤ 1 day or less exposure to heparin within past 31 to 100 days 2 Pts = Clear onset between 5 and 10 days or platelet count fall ≤ 1 day if prior heparin exposure within the last 30 days Thrombosis 0 Pts = None 1 Pts = Progressive or recurrent thrombosis, or erythematous skin lesions (at an injection site), or suspected thrombosis that has not been proven 2 Pts = Confirmed new thrombosis or skin necrosis (at injection site), or acute systemic reaction after IV UFH bolus Other Causes of Thrombocytopenia 0 Pts = Definite other cause is present 1 Pts = Possible other cause is evident 2 Pts = No explanation for the decrease in platelet count is evident



Key Points Regarding the 4T Score

The 4T Score is meant to capture the MAJOR clinical features of HIT (thrombocytopenia, thrombosis, etc.) and the likelihood that these findings are due to a temporal relationship with heparin administration.6 A 4T Score ≥ 4 should prompt hematology consultation for consideration of evaluation and therapy.

Treatment and Management of HIT in the Emergency Setting

Consult Hematology

Discontinue all forms of heparin (to include heparin flushes administered for IV catheters).

Initiate an alternative anticoagulant based upon discussions with a hematologist. Options include:6,20,21

Bivalirudin – direct thrombin inhibitor – 0.15mg/kg/hr IV Renal dosing for GFR <30 Dose adjustment required for impaired hepatic function Monitor activity with aPTT: Goal = 1.5-2x normal

– direct thrombin inhibitor – 0.15mg/kg/hr IV Argatroban – direct thrombin inhibitor – 2mcg/kg/min IV No dose adjustment in isolated renal impairment Dose adjustment required for impaired hepatic function Monitor activity with aPTT: Goal = 1.5-3x normal

– direct thrombin inhibitor – 2mcg/kg/min IV Fondaparinux – synthetic pentasaccharide subunit of heparin that lacks endogenous interaction with PF4 – 5-10mg/day SQ Not first line for HIT per the 2012 Chest Guidelines, 20 but may be an option in patients with hepatic dysfunction (no dosing adjustment for hepatic impairment required) Not for use in patients with renal dysfunction secondary to renal elimination No activity monitoring, non-titrateable

– synthetic pentasaccharide subunit of heparin that lacks endogenous interaction with PF4 – 5-10mg/day SQ

Laboratory Studies for The Confirmation of HIT 6,9,10,22-24

If a presumed clinical diagnosis of HIT is made based upon history, physical exam, platelet count, and the 4T score, the following laboratory studies should be ordered as their processing time often requires >48 hours:

Immunoassay (ELISA) – HIT antibody testing Sensitivity and specificity of 97.5 and 83.4% 6 If low, optical density (OD) <0.40, then the diagnosis of HIT is excluded 6 If high, OD >2.00, then diagnosis of HIT 6 If intermediate, OD 0.40-2.0, then a functional assay should be ordered by the inpatient team 6

HIT antibody testing

Functional Assays Serotonin Release Assay – Quantifies the platelet activation capacity of the patient’s serum HIT antibodies Sensitivity and Specificity of > 95% 23 Heparin Induced Platelet Aggregation (HIPA) – Quantifies platelet aggregation in the presence of heparin (when donor platelets are placed in the platelet poor serum of a patient with suspected HIT) and aggregation in the absence of heparin >90% specific, but lacks sensitivity 25



If the Shoe Doesn’t Fit

Remember, HIT evaluation in the emergency department should be based upon clinical suspicion (with the help of the 4T Score). If the patient is thrombocytopenic and bleeding or the platelet count is <10,000, this is not consistent with HIT6 => Broaden your differential diagnosis:

Differential Diagnosis6

DIC, Sepsis, Infection Both accompanied by thrombosis DIC also has bleeding AND abnormal coagulation studies – PT, aPTT, low Fibrinogen, Elevated D-Dimer Sepsis – look for marrow suppression – anemia, leukopenia, decreased bone marrow megakaryocytes

Immune Thrombocytopenia – ITP Both caused by antibodies – BUT only HIT antibodies activate platelets HIT will resolve without heparin – ITP will persist

Post Transfusion Purpura – postpartum patient previously sensitized to platelet antigens during pregnancy

– postpartum patient previously sensitized to platelet antigens during pregnancy Thrombotic Microangiopathy – includes TTP and HUS Fragmented RBC – Schistocytes à Hemolysis AND low platelets

– includes Drug Induced Thrombocytopenia – antibiotics, glycoprotein IIb/IIIa inhibitors, quinine

– antibiotics, glycoprotein IIb/IIIa inhibitors, quinine Platelet reactive antibodies

VTE unrelated to heparin D-Dimer can be a clue

Lupus and/or antiphospholipid antibody syndrome Platelet counts <50,000 are rare



Summary

HIT is relatively rare, but can occur even after receiving the smallest dose of heparin. Despite thrombocytopenia, HIT is a prothrombotic state that can cause disastrous vascular complications. In the ED, clinical history and a CBC can be suggestive of the diagnosis. Use the 4T Score and consult as appropriate. Suspect HIT? Treatment = stop heparin and discuss an alternative agent for anticoagulation with a hematologist.

References / Further Reading

Hirsh J, Anand S, Halperin L, Fuster V. Mechanism of action and pharmacology of unfractionated heparin. Arterioscler Thromb Vasc Biol. 2001; 21:1094–1096. Janz T, Hamilton G. Disorders of Hemostasis. 2013. Rosen’s Emergency Medicine (8th ed., 1606–1616). Saunders. Newman P, Chong B. Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation. Blood. 2000; 96(1);182. Napolitano L, Warkentin T, Almahameed A, Nasraway A. Heparin induced thrombocytopeniain the critical care setting: diagnosis and management. Critical Care Medicine. 2014; 34(12):2898–911. Seybert A, Coons J, Zerumsky K. Treatment of heparin-induced thrombocytopenia: is there a role for bivalirudin? Pharmacotherapy. 2014; 26(2): 229-41. Coutre S. Clinical presentation and diagnosis of heparin-induced thrombocytopenia. Up to Date. 2016. Available from: https://www.uptodate.com/contents/clinical-presentation-anddiagnosis-of-heparin-inducedthrombocytopenia?source=search_result&search=heparin+induced+thrombocytopenia&selectedTitle=1%7E150#H369779234 Thong C, Kam P. Heparin-induced thrombocytopenia. Current Anaesthesia & Critical Care.2005; 16(3):143–150. Brieger D, Mak K, Kottke-Marchant K, Topol E. Heparin-induced thrombocytopenia. Journal of the American College of Cardiology. 1998;31(7):1449–59. Warkenten T. Heparin-induced thrombocytopenia: a clinicopathologic syndrome. Thromb Haemost. 1999; 82(2):439. Warkentin T. How I diagnose and manage HIT. American Society of Hematology Education Book. 2011; 2011(1): 143-149. Levine R, Hursting M, Drexler A, Lewis B, & Francis L. Heparin-induced thrombocytopenia in the emergency department. Annals of Emergency Medicine. 2014; 44(5):511–515. Stanton P, Evans J, Lefemine A, et al. White clot syndrome. South Med J 1988; 81:616. Linkins L, Dans A, Moores L, Bona R, Davidson B, Schulman S, Crowther M. Treatment and prevention of heparin-induced thrombocytopenia: antithrombotic therapy and prevention of thrombosis; 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012; 141(2Suppl):e495S. Hong A, Cook D, Sigouin C, Warkentin T. Central venous catheters and upper-extremity deep-vein thrombosis complicating immune heparin-induced thrombocytopenia. Blood. 2003; 101(8):3049ad LaMonte M, Brown P, Hursting M. Sroke in patients with heparin-induced thrombocytopenia and the effect of argatroban therapy. Crit Care Med. 2004; 32(4):976. Singla A, Amini M, Alpert M, Gornik H. Fatal anaphylactoid reaction associated with heparin-induced thrombocytopenia. Vasc Med. 2013; 18(3):136-138. Martel N, Lee J, Wells P. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005; 106(8):2710. Foreman J, Daniels M, Stettner, E. Heparin-induced anaphylactoid reaction associated with heparin-induced thrombocytopenia in the ED. American Journal of Emergency Medicine. 2014; 32(12):1559.e5–1559.e6. Crowther M, Cook D, Guyatt G, Zytaruk N, McDonald E, Williamson D, et al. Heparin-induced thrombocytopenia in the critically ill: interpreting the 4Ts test in a randomized trial. Journal of Critical Care. 2014; 29(3): 470.e7–470.e15. Linkins L, Dans A, Moore L, Bona R, Davidson B, Schulman S, et al. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl): e495S–530S. Seybert A, Coons J, Zerumsky K. Treatment of heparin-induced thrombocytopenia: is there a role for bivalirudin? Pharmacotherapy. 2006: 26(2):229-241. Levine R, Hursting M, Drexler A, Lewis B, Francis J. Heparin-induced thrombocytopenia in the emergency department. Annals of Emergency Medicine. 2004; 44(5):511–515. Napolitano L, Warkentin T, Almahameed A, Nasraway S. Heparin induced thrombocytopenia in the critical care setting: diagnosis and management. Crit Care Med. 2006;34(12):2898–2911. Warkentin T, Sheppard J, Moore J, Sigouin C, Kelton G. Quantitative interpretation of optical density measurements using PF4-dependent enzyme immunoassays. J Thromb Haem. 2004:6(8);1304-1312. Thong C, Kam P. Heparin-induced thrombocytopenia. Current Anaesthesia & Critical Care. 2005;16(3):143–150.