Hit cdh

Heparin Induced Thrombocytopenia

Dr. Imad Hassan El-SadekKuwaiti Board of Anesthesia (PGY3)

March 21st, 2012

Outline

• Definition &Types• Incidence• Pathophysiology• Diagnosis• Treatment• HIT in CABG patients• Protocol

Definition

• HIT is an antibody-mediated adverse drug reaction to heparin that can lead to devastating thromboembolic complications

Types Type 1 Type 2

Nature Non immune Immune-mediated

Onset 1-4 5-10

Incidence 10-20% 0.2-5%.

Pathophysiology Heparin-induced platelet aggregation

Platelet Count nadir 100,000 30,000-60,000

Manifestation Asymptomatic Thrombosis (30-80%): venous-arterial (3– 4:1)

Management Strategy Observation; improves while on heparin

Heparin alternatives

HOW DOES HIT HAPPEN?

PathogenesisHeparin or Heparin/PF4 complex: trigger an antibody response (IgG, IgM, and IgA).

WHO WOULD GET HIT?

Risk factors for developing HITRisk Factor Risk

Prolonged Heparin use

UFH > LMWH (2.6% with UFH and 0.2% with LMWH) RR 5.3; 95% CI 2.8-9.9

Surgical > medical patients RR 3.2; 95% CI 2.0-5.4

Female > male patients RR 2.4; 95% CI 1.4-4.1

The highest risk for HIT was seen in female surgical patients receiving UFH

RR 17; 95% CI 4.2-72

Prior Exposure to Heparin (UFH or LMWH) 1.7 vs 0.3%,OR 4.9; 95% CI 1.5-16

Cardiac and Orthopedic Surgery have a higher risk of HIT (1%-5%) than medical or obstetric patients (0.1%-1%)

• Warkentin TE, Sheppard JA, Sigouin CS, et al. Gender imbalance and risk factor interactions in heparin-induced thrombocytopenia. Blood 2006; 108:2937.• Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96:1703.• Prandoni P, Siragusa S, Girolami B, et al. The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecular-weight heparin: a

prospective cohort study. Blood 2005; 106:3049.

Cardiac and Orthopedic Population

Patient population

Days of treatment

Frequency of HIT antibodies Frequency of clinical HIT

Activation assay

Antigen assay

Cardiac, UFH 5.1 ± 2.2 (SD) 20.0 % 50.0 % 1.0 %

Orthopedic, UFH

9.2 ± 2.2 9.3 % 14.1 % 4.9 %

Orthopedic, LMWH

9.5 ± 3.0 3.2 % 7.5 % 0.9 %

Warkentin TE, Sheppard JA, Horsewood P, et al. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood 2000; 96:1703.

Iceberg Model of HIT

HOW DOES HIT PRESENT

Diagnosis of HIT

HIT is a clinico-pathologic syndrome

• Onset Variations– Typical-onset HIT: 5-10 days

– Rapid-onset HIT: within 24 hrs

– Delayed-onset HIT: as long as 3 weeks after cessation of heparin

Diagnosis of HIT

Gruel Y, Pouplard C. Post-operative platelet count profile: the most reliable tool for identifying patients with true heparin-induced thrombocypenia after cardiac surgery. J Thromb Haemost 2010; 8:27.

90% to 95%<150,000 or 30-50% fall

Thrombocytopenia

• Rarely severe, platelet counts typically >20,000/µL; median platelet count nadir of about 60,000/µL

• Cardiac Surgical Patients: “a secondary fall in the platelet count ≥50 percent that begins between the 5th-10th postop day appears to be highly predictive of HIT”

30-80%Thrombosis

• venous-arterial (3-4:1)• Manifestations: DVT, PE, distal ischemic necrosis following DVT, cerebral sinus thrombosis,

adrenal hemorrhage secondary to adrenal vein thrombosis, and transient global amnesia.• Necrotic skin lesions at heparin injection sites.

Within 30min of exposureAcute Systemic

Reactions• fever/chills, tachycardia, hypertension, dyspnea, cardiopulmonary arrest occurring after IV

heparin bolus administration.

Differential Diagnosis

DIC ITP TTP-HUS

Drug-induced Thrombocytopenia SLE

4T’s for Diagnosis of HIT

6-8Very likely

4-5Possible

0-3Unlikely

Pretest Probability

Laboratory Diagnosis of HIT

ELISA

particle gel immunoassay

Antigen Assays

SRAserotonin release assay

HIPAHeparin-induced platelet activation

Functional Assays

MANAGEMENT OF HIT

BivalirudinDesirudin

Fondaparinux

argatroban

Danaparoid

Management of HITTACCP 2012 Recommendations

1. Stop Heparin2. Treatment With Nonheparin Anticoagulants

Recommendation LoE

In patients with HIT/HITT, we recommend the use of nonheparin anticoagulants, in particular lepirudin, argatroban, and danaparoid, over the further use of heparin or LMWH or initiation/continuation of VKA

1C

No prospective head-to-head trials comparing one agent with another

Characteristics of Anticoagulants Used to Treat Patients with HIT

Management of Clinically suspected HITPharmacological Treatment

• Two DTIs are available in the United States:Lepirudin Argatroban

Caution Prolonged in Renal Failure Prolonged in liver dysfunction (decrease by 75%)

Initial Dose: IVI: 0.10 mg/kg/h Recommended: 2mcg/kg/minACCP: 0.5-1.2 mcg/kg/min

Dose adjustment aPTT: 1.5-2.0 x baseline aPTT: 1.5-3 x baseline

Effect on INR Minimal Substantial

Adverse Effects Anaphylaxis (1st: 0.015%; re-exposure:0.16%)

According to systematic review (2004): • Lepirudin results in RRR of clinical outcome (death, amputation, etc.) to be 0.52 and 0.42

when compared to patient controls. • Argatroban showed a RRR of the above clinical outcomes to be 0.20 and 0.18.[8]

Dosing of Heparin Alternatives

Management of HITTACCP 2012 Recommendations

• Treatment With Nonheparin AnticoagulantsRecommendation LoE

In patients with HIT/ HITT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants

2C

In patients with HIT/HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants

2C

LoE

In patients with HIT and severe thrombocytopenia, we suggest giving platelet transfusions only if bleeding or during the performance of an invasive procedure with a high risk of bleeding.

2C

2. Platelet Transfusions

Management of Clinically suspected HITPharmacological Treatment

For how long?• HIT– Therapeutic anticoagulation: Until platelet count

recovers to stable plateau.– Prophylactic anticoagulation: for up to 4 weeks

• Risk of thrombosis for 2-4 weeks after initiation of Rx.

• HITT– Transition to warfarin after platelet count > 150– Overlap warfarin with DTI for >= 5 days, with >= 48 hrs

INR >2

SUSPECTED HIT MANAGEMENT PROTOCOL

Confirm HIT

• 4T’s: - Low: May continue Heparin, consider alternative diagnosis• - Intermediate: immunoassay, if positive Send functional assay• - High: Stop Heparin and initiate alternative

Stop

Heparin

• Stop all heparin or LMWH, including flushes or locks• Label all IV sites or catheters as “NO HEPARIN”

Rule-out Thrombu

s

• Order bilateral lower extremity ultrasound for DVT

Heparin alternative

• HIT/HITT: lepirudin, argatroban, and danaparoid• Renal impairment: Argatroban; RRT: argatroban or danaparoid• Pregnant: danaparoid. lepirudin or fondaparinux only if danaparoid is not available

Overlap warfarin

• Initiate late (Plt >150,000) and low( Max 5mg/d)• Overlap with nonheparin anticoagulant for >=5days and Target INR reached• If already on warfarin when HIT Reverse with Vitamin K

Avoid

Platelet

s

• Usually no bleeding• Can result in acute thrombosis

MANAGEMENT OF HIT IN PATIENTS UNDERGOING CARDIAC SURGERY

Factors Influencing HIT Management Options in Cardiac Surgery Patients

Disease Activity• Acute, Subacute, history of HIT

Patient’s Co-morbidities• Renal Impairment, liver impairment

Drug Availability• UFH, Heparin Alternatives, Plasmapheresis

Surgical Urgency• Postponement vs. Proceeding

Drug Monitoring• ACT, aPTT, ECT

Management of HITin Patients Undergoing Cardiac Surgery

Cardiac Surgery

Acute or Subacute HIT

Urgent

Bivalirudinover other nonheparin

anticoagulants and over heparin plus antiplatelet agents

Non-Urgent

Delaying the surgery until HIT has resolved and HIT antibodies are negative

History of HIT

Ab Negative

Short-term Heparin

Ab Positive

Non Heparin anticoagulant

Management of HITin Patients Undergoing Cardiac Surgery

Recommendation LoE

Acute

HIT

In patients with acute HIT (thrombocytopenic, HIT antibody positive) or subacute HIT (platelets recovered, but still HIT antibody positive) who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants and over heparin plus antiplatelet agents

2C

In patients with acute HIT who require nonurgent cardiac surgery, we recommend delaying the surgery (if possible) until HIT has resolved and HIT antibodies are negative

2C

History of HIT

In patients with a history of HIT in whom heparin antibodies have been shown to be absent who require cardiac surgery, we suggest the use of heparin (short-term use only) over nonheparin anticoagulants

2C

In patients with a history of HIT in whom heparin antibodies are still present who require cardiac surgery, we suggest the use of nonheparin anticoagulants over heparin or LMWH

2C

Possible Treatment Options for HIT patients Undergoing CBP

Heparin Based• Non-urgent: Postpone• Semi-Urgent: Brief intra-op UFH• Urgent: UFH with intra-op Plasmapheresis

Heparin with Antiplatelets• Heparin + Iloprost

• Drawback: severe hypotension• Hepain + Tirofebam (Glycoprotein IIb-IIIa antagonist)

• In renal imapirment patients (2001)

Hepain Alternatives• DTI: Lepirudin, Argatroban• Danaparoid• Defibrinogenating Agent (ancorod)

Heparin Based Treatment1. Non-Urgent CPB: Postponement

• Rationale:– A secondary immune response after reexposure to

heparin should not occur until at least three days after exposure.

– Thus, a brief exposure to heparin during CPB should not immediately elicit HIT antibodies.

– Furthermore, since the heparin would be rapidly cleared after the procedure, even if antibodies appeared, they would not be thrombogenic in the absence of heparin.

Thank You