Heparin Induced Thrombocytopenia

1. Heparin InducedThrombocytopenia David Miller, MD Mecklenburg Medical Group January 20, 2005

2. Objectives Define and discuss the mechanism of HIT Review associated risks Describe the clinical features of HIT Present diagnostic criteria Discuss treatment options

3. Heparin Induced Thrombocytopenia (HIT) Clinicopathologic syndrome characterized by the formation of IgG antibodies against a Heparin/PF4 complex. a sudden unexpected decline in platelet count 4 – 14 days after first exposure to Heparin and a high risk for venous and arterial thrombosis

4. Pathophysiology

5. Thrombin Generation in HIT Fc mediated platelet activation Ab/PF4/GAG complex activates endothelium cells which release Tissue Factor (TF) PF4 released from activated platelets inactivates the antithrombotic effect of Heparin

6. Risk for Developing HIT Risk increases with Dose of heparin (high > low) Type of heparin (bovine > porcine) Preparation of heparin (UFH > LMWH) Clinical situation (surgical > medical) Average risk is 1-3%

7. Clinical Features of HIT Modest drop in platelet count during heparin treatment Typical timing of the drop in platelet count after first exposure High risk for thrombosis Confirmatory laboratory testing

8. Platelet Counts in HIT

9. Temporal Aspect of Thrombocytopenia in HIT Typical (70%): Rapid Onset (30%): drop in platelet count within minutes to hours after re-exposure to heparin (within 100 days of exposure) Delayed onset (Rare): Delayed thrombocytopenia days after heparin has been discontinued

10. Temporal Aspect of Thrombocytopenia in HIT Typical Onset (70%) 5 – 10 days after starting heparin HIT-IgG usually not detectable until day 5 Risk of HIT diminishes after day 5 – 10 “window” passes (Sometimes the clock can be “reset” with an intravascular procedure or surgical procedure)

11. Temporal Aspect of Thrombocytopenia in HIT Rapid Onset HIT Unexpected fall in the platelet count that begins shortly after heparin is started Invariably have had heparin exposure in the past (last 100 days) Caused by residual circulating HIT Abs Pts with typical HIT had no difference in median day of onset even if previously exposed to heparin. Pts do not develop HIT on days 2-4 Pts reexposed to Heparin following disappearance of the HIT Abs do not necessarily develop HIT Abs againPts with typical HIT had no difference in median day of onset even if previously exposed to heparin. Pts do not develop HIT on days 2-4 Pts reexposed to Heparin following disappearance of the HIT Abs do not necessarily develop HIT Abs again

12. Temporal Aspect of Thrombocytopenia in HIT Delayed Onset HIT Previous heparin exposure was uncomplicated Patient often discharged home, off heparin Patient readmitted to hospital New thrombosis (usual) Unexpected thrombocytopenia (uncommon) Delayed-onset HIT is characterized by the following: Previous heparin exposure that was uncomplicated Patient often discharged, off heparin Patient readmitted to hospital New thrombosis (usual) Unexpected thrombocytopenia (uncommon) Delayed-onset HIT is characterized by the following: Previous heparin exposure that was uncomplicated Patient often discharged, off heparin Patient readmitted to hospital New thrombosis (usual) Unexpected thrombocytopenia (uncommon)

13. Clinical Features of HIT: Temporal Aspect of Thrombocytopenia

14. Thrombotic Complications of HIT Venous Deep vein thrombosis Upper limb Lower limb Pulmonary embolism Cerebral dural sinus thrombosis Adrenal hemorrhagic infarction Disseminated intravascular coagulation (DIC) Arterial Acute limb ischemia Acute thrombotic stroke Myocardial infarction Mesenteric, renal, spinal artery thrombosis

15. Clinical Features of HIT:Thrombosis Venous thrombosis 50% develop DVT, half of whom will have a PE Severe limb ischemia Phlegmasia cerulea dolens Venous limb gangrene Adrenal thrombosis (3 – 5%) Cerebral sinus thrombosis

16. Characteristics of Warfarin-Induced Venous Limb Gangrene Acral necrosis complicating a DVT Palpable or Doppler-identifiable pulses Thrombosis of large and small veins No large artery occlusion Supratherapeutic INR

17. Clinical Features of HIT:Warfarin-induced Skin Necrosis May involve central tissues (breast, abdomen, thigh, flank, leg) HIT? Thrombin Warfarin? Low protein C

18. Heparin-induced Skin Necrosis Inflammatory, plaque-like or necrotic lesions Begin 6 or more days after starting SQ UFH or LMWH Most pts. do not have low platelets Considered a marker for HIT syndrome Thrombocytopenia and thrombosis can occur after heparin is discontinued

19. Heparin-induced Skin Necrosis Warkentin TE. Br J Haematol. 1996;92:494-497.

20. Adrenal Hemorrhagic Infarction Thrombosis of the adrenal veins leading to hemorrhagic necrosis of the glands Abdominal pain Hypotension Fever Hyponatremia Requires corticosteroid replacement

21. Neurologic Consequences of HIT Stroke due to venous or arterial thrombosis Cerebral Sinus Thrombosis Headache, decreased LOC, focal neurologic defects Lower limb paralysis due to spinal cord or lumbosacral plexus infarction

22. Cardiac Syndromes of HIT Myocardial Infarction Intra-ventricular or intra-atrial thrombus formation Cardiopulmonary arrest shortly after heparin bolus

23. Acute Systemic Reaction to IV Bolus Heparin Onset within 5-30 min. Chills, rigors, fever Tachycardia, hypertension Tachypnea, dyspnea Chest pain or tightness Diaphoresis or flushing Nausea, vomiting, diarrhea Sudden death Transient global amnesia

24. Diagnosis of HIT HIT is a clinical diagnosis Confirmed with Laboratory Testing

25. Estimating the Pre-test Probability of HIT (The 4 T’s) Thrombocytopenia Timing of Thrombocytopenia Thrombosis (or other sequelae of HIT) OTher causes for platelet fall unlikely

26. Estimating the Pre-test Probability of HIT (The 4 T’s)

27. Estimating the Pre-test Probability of HIT (The 4 T’s) High probability 6-8 points Moderate probability 4-5 points Low probability 0-3 points

28. Laboratory Tests for HIT There are two types of laboratory tests available to confirm a diagnosis of HIT: a functional assay and an antigen assay. Functional assays detect HIT-IgG on the basis of their ability to activate platelets. Activation can be measured in a number of different ways, including SRA, platelet aggregation, ATP release, and flow cytometry. A washed platelet system is recommended. Of the available assays, the serotonin release assay has the most advantages. The citrated plasma assay is widely used, specifically, the platelet aggregation. This assay measures the aggregation of normal donor platelets by patient serum or plasma in the presence of heparin. However, it is not recommended because of its low sensitivity and low specificity. Antigen assays detect the binding of antibodies to immobilized PF4-heparin complexes. The most typical of the direct antigen assay performed on serum or plasma is the heparin-PF4 ELISA.There are two types of laboratory tests available to confirm a diagnosis of HIT: a functional assay and an antigen assay. Functional assays detect HIT-IgG on the basis of their ability to activate platelets. Activation can be measured in a number of different ways, including SRA, platelet aggregation, ATP release, and flow cytometry. A washed platelet system is recommended. Of the available assays, the serotonin release assay has the most advantages. The citrated plasma assay is widely used, specifically, the platelet aggregation. This assay measures the aggregation of normal donor platelets by patient serum or plasma in the presence of heparin. However, it is not recommended because of its low sensitivity and low specificity. Antigen assays detect the binding of antibodies to immobilized PF4-heparin complexes. The most typical of the direct antigen assay performed on serum or plasma is the heparin-PF4 ELISA.

29. Heparin-induced Thrombocytopenia (HIT): Consequences Heparin-Induced Thrombocytopenia (HIT): Consequences Pyramid Key Point: Although only a subset of HIT antibody-positive patients will develop thrombosis, it is not possible to predict which ones will develop thrombosis. This model reflects that only a portion (up to 10%) of all patients exposed to heparin develop antibodies, although antibodies may occur in approximately 50% of cardiopulmonary bypass surgery patients.1 A number of factors contribute to this, including the type of heparin used, the mode of administration and the dose, and patient-specific factors such as the clinical setting.1 As illustrated, only a portion of the patients who develop HIT antibodies will develop thrombocytopenia. Only a subset of those patients who develop thrombocytopenia will progress to thrombosis.1 Thrombotic events are more likely to develop in patients with thrombocytopenia who develop HIT antibodies as opposed to patients without thrombocytopenia.1 HIT can occur in the absence of thrombocytopenia. 1. Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis, frequency, avoidance and management. Drug Saf. 1997;17(5):325-341. 2. Francis JL, Drexler A, Moroose R, et al. Comparative effects of bovine and porcine heparin on heparin antibody formation following cardiovascular surgery [abstract]. Blood. 2001;98(11): 60b. Abstract 3854.Heparin-Induced Thrombocytopenia (HIT): Consequences Pyramid Key Point: Although only a subset of HIT antibody-positive patients will develop thrombosis, it is not possible to predict which ones will develop thrombosis. This model reflects that only a portion (up to 10%) of all patients exposed to heparin develop antibodies, although antibodies may occur in approximately 50% of cardiopulmonary bypass surgery patients.1 A number of factors contribute to this, including the type of heparin used, the mode of administration and the dose, and patient-specific factors such as the clinical setting.1 As illustrated, only a portion of the patients who develop HIT antibodies will develop thrombocytopenia. Only a subset of those patients who develop thrombocytopenia will progress to thrombosis.1 Thrombotic events are more likely to develop in patients with thrombocytopenia who develop HIT antibodies as opposed to patients without thrombocytopenia.1 HIT can occur in the absence of thrombocytopenia. 1. Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis, frequency, avoidance and management. Drug Saf. 1997;17(5):325-341. 2. Francis JL, Drexler A, Moroose R, et al. Comparative effects of bovine and porcine heparin on heparin antibody formation following cardiovascular surgery [abstract]. Blood. 2001;98(11): 60b. Abstract 3854.

31. Laboratory Tests for HIT

32. Laboratory Testing for HIT at CMC Antigen assay Labcorp performs the ELISA test daily Monday-Friday Esoterix performs it daily but must go through Labcorp per the hospital’s contract Functional Assay Serotonin Release assay is performed at Esoterix Tuesdays and Fridays

33. Differential Diagnosis: Pseudo-HIT Adenocarcinoma with DIC or Venous Limb Gangrene Pulmonary Embolism Diabetic Ketoacidosis Antiphospholipid Syndrome Thrombolytic Therapy Septicemia-Associated Purpura Fulminans Infective Endocarditis Paroxysmal Nocturnal Hemoglobinuria Posttransfusion Purpura

34. Differential Diagnosis: Other Causes of Thrombocytopenia Hemodilution after cardiac surgery Pseudothrombocytopenia Autoimmune Thrombocytopenia (ITP) Drug Induced Immune Thrombocytopenia DIC (due to sepsis or malignancy) TTP/HUS

35. Treatment of HIT FIRST - Remove all heparin, every little bit! Swan Arterial lines Indwelling catheters And keep it away! Cath lab Operating room Dialysis

36. Cumulative Frequency of Thrombosis After Heparin Discontinuation

37. Treatment of HIT Begin therapy with an alternative antithrombotic agent immediately. Never start warfarin therapy without another form of anticoagulation. Start warfarin therapy after platelet count has returned to normal.

38. Why Treat HIT with Thrombin Inhibitors? Thrombosis begets thrombosis! HIT is a thrombotic storm!

39. Direct Thrombin Inhibitors Advantages Lack of interaction with HIT antibodies Predictable dose-response curve Relatively short half-life Rapid therapeutic effect Easily monitored (?) Inhibits clot-bound thrombin

40. Direct Thrombin Inhibitors Problems No reversal agent Does not affect thrombin generation Possible hypercoagulable state after discontinuation Use during cardiopulmonary bypass not well established

41. Direct Thrombin Inhibitors in HIT

42. Conversion of Direct Thrombin Inhibitors to Warfarin

43. Routine Order Set for HIT

44. Guidelines for Oral Anticoagulants in HIT Do not use oral anticoagulants alone Wait for the platelet count to increase to near normal while HIT is “cooled” (100-150/µL) Initiate modest doses, avoid overshooting the INR Overlap minimum of 4-5 days Be sure INR is >2.0 for 2 consecutive days Ensure adequate levels of alternative anticoagulant during transition

45. Final Pearl The HIT Antibody is transient. Heparin Abs fall to undetectable levels a median of 50 to 85 days after cessation of heparin depending on the assay performed. Heparin-dependent Abs do not invariably appear with subsequent heparin use.

46. Heparin-dependent Antibodies over Time

47. Summary HIT is a clinical diagnosis. A positive antibody test is not diagnostic. Thrombotic complications of HIT can be devastating and have unusual presentations. Therapy involves stopping all heparin exposure and starting a direct thrombin inhibitor. Do not use Warfarin alone in a patient with HIT. Conversion from a Thrombin Inhibitor to Warfarin can be tricky. The HIT Ab is transient.