Heparin-Induced Thrombocytopenia (HIT) Ashraf Warsi (R4) hematology

Heparin & HIT history 1916 heparin discovered by Mclean and Howell 1950s established as a therapy for venous and arterial thrombosis 1957 Weismann and tobin describe 10 patients who developed unexpected arterial thrombosis after starting heparin 1966-1972 Roberts and Colleagues described similar findings, speculating that the etiology could represent an antigen-antibody mechanism 1979 Towne describes the white clot syndrome 1989 Chong and Berndt, HIT type 1 & type 2

HIT HIT, HIT type II, Immune HIT: is an immune mediated transient disorder which is an adverse event of using heparin during which there is an increase in risk of thrombosis. It may also occur with the usage of highly sulfated polysaccharides like hypersulfated chondroitin sulfate Incidence:

Arepally GM, Ortel TL. Clinical practice Arepally GM, Ortel TL. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 2006;355:809-17

Clinical events in HIT Venous thrombosis (30-70%): DVT/PE, cerebral sinus thrombosis, adrenal necrosis, venous limb gangrene Arterial thrombosis (15-30%): stroke, M.I., arterial ischemia Skin lesions at heparin injection sites (10%): Skin necrosis, erythematous plaques acute reaction (anaphylactoid) after heparin bolus (10%) Disseminated intravascular coagulation (10%)

Necrotic lesions in HIT patient receiving LMWH injections

L arm

Risk of thrombosis in HIT Warkentin and Kelton. Am J Med. 1996;101:502-507

Pathophysiology In a proposed explanation for heparin-induced thrombocytopenia, IgG antibodies recognize platelet factor 4 (PF4)-heparin complexes. The resulting PF4-heparin-IgG immune complexes bind to Fc receptors on circulating platelets. Fc-mediated platelet activation releases PF4 from a-granules in platelets, establishing a cycle of platelet activation and formation of prothrombotic platelet microparticles. Removal of immune complex-coated platelets by the reticuloendothelial system results in thrombocytopenia. PF4 also binds to heparan sulfate on the surface of endothelial cells, leading to immune-mediated injury, thrombosis, and disseminated intravascular coagulation.

HIT = Thrombin Generation The Actions of Thrombin Releases from endothelium: NO PGI2 t-PA von Willebrand ADP Factor V Va Factor VIII VIIIa Prothrombin thrombin Thrombin Factor XIII XIIIa cross-linked fibrin Activation of platelets Fibrinogen fibrin

Diagnosis HIT is a clinico-pathological diagnosis Clinical: thrombosis/ ischemia Pathological: thrombocytopenia and a positive serological assay for IgG antibodies

Thrombocytopenia… <150,000 &/or a proportional (relative) platelet count fall of 50% or more from the postoperative peak. Probability of HIT ???

4 Ts Thrombocytopenia Timing of onset of platelet fall Thrombosis or other sequelae oTher causes of platelet fall

4 Ts Lo GK, et al. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4: 759–65

Warkentin, T. E. Hematology 2006;2006:408-414 Figure 1. Platelet count nadirs in heparin-induced thrombocytopenia (HIT), quinine-induced immune thrombocytopenic purpura (Q-ITP), and thrombotic thrombocytopenic purpura (TTP) with absent ADAMTS-13 activity Warkentin, T. E. Hematology 2006;2006:408-414

Delayed-onset HIT and/or Delayed Platelet Count Recovery from HIT Delayed onset of HIT ( thrombocytopenia &/or thrombosis after stopping heparin ) Delayed recovery (median time to platelet count recovery is 4 days, and 90% of patients recover to a platelet count of > 150,000 within 1 week) Spontaneous HIT: rarely, an illness that resembles HIT without preceeding exposure to heparin

Thrombosis without Thrombocytopenia but Timing Consistent with HIT Relation of onset of platelet count decrease and onset of HIT-associated thrombosis. The data summarize 209 patients with HITassociated thrombosis. About one quarter (26.3%) of patients develop thrombosis on the same day that the thrombocytopenia occurs (defined arbitrarily as the day the platelet count has fallen by more than 50%), and in 33.5% the platelet count reached thrombocytopenia levels only after the occurrence of thrombosis.

Detection of HIT antibodies Platelet activation assays: sertonin release assay (SRA) heparin induced platelet aggregation assay (HIPAA) platelet-rich plasma (PRP) aggregation platelet microparticles Antigen assays: PF4/heparin EIA pf4/polyvinyl sulfonate EIA fluid phase EIA particle gel immunoassay

HIT assays

Laboratory Testing for HIT Test Advantages Disadvantages SRA Sensitivity: high Technically demanding Specificity: high (radioisotopes) (false positives rare) Not readily available Platelet (HIPA) Specificity: high Sensitivity: low aggregation Technique-dependent Immunoassay Sensitivity: high Specificity: low (false (ELISA) Technically easy positives common for Rapid turnaround time some populations) Laboratory confirmation of the presence of HIT/IgG provides clinical support that a patient may have HIT. There are several commonly used tests. Two assays include the platelet-function test; and the immunoassay. The 14C serotonin-release assay (SRA) is considered the reference procedure for identifying HIT antibodies. Heparin-dependent HIT antibodies can induce the release of 14C serotonin from platelets; the test measures this release using washed donor platelets labeled with radioactive 14C serotonin. Although very accurate, this test has the disadvantages of being time consuming, highly complex, and requiring the use of radioactive materials. It is also highly dependent on the reactivity of the donor platelets. The platelet aggregation test takes less time to perform. It measures the degree of platelet aggregation that patient HIT serum can induce in the presence of therapeutic levels of heparin. Results of this test vary widely, depending on the heparin concentration used and the variability of donor platelets. An enzyme-linked immunosorbent assay (ELISA) for heparin/PF4 has been developed to measure the binding of IgG to heparin/PF4 complexes. This test has become the most common laboratory test to exclude the diagnosis of HIT. Although this test is easily performed, and its results are generally in agreement with SRA results; it can have a high false-positive rate. False-negatives have also occurred in some patients with SRA-confirmed HIT. Fabris F, Ahmad S, Cella G, Jeske WP, Walenga JM, Fareed J. Pathophysiology of heparin-induced thrombocytopenia: clinical and diagnostic implications—a review. Arch Pathol Lab Med. 2000;124:1657-1666. Kelton JG. The clinical management of heparin-induced thrombocytopenia. Semin Hematol. 1999;36 (suppl 1):17-21.

Platelet activation + enzyme assay HIT assays Diagnostic assay Sensitivity (%) Specificity (%) SRA 90-98 >95 HIPAA PRP 35-85 90 PF4/heparin EIA >90 85 Platelet activation + enzyme assay 100

Differential diagnosis Sepsis DIC APS EDTA- induced thrombocytopenia GP IIb/IIIa inhibitor induced thrombocytopenia TTP Other drug induced thrombocytopenia HIT type I Post transfusion purpura hemodilution

Treatment of Suspected HIT Discontinue ALL heparin immediately Initiate alternative anticoagulation Monitor carefully for thrombosis Avoid prophylactic platelet transfusions Document HIT in medical records Laboratory evaluation Monitor platelet counts recovery

treatment Once the platelet count is above 150,000 warfarin should be started Duration of anticoagulation ???? 6-8 weeks

Heparin Alternatives

Take home message HIT is a potentially fatal side effect of heparin that is more common with UFH than LMWH HIT is a clinico-pathological diagnosis HIT has a high risk of arterial thrombosis High risk patients on heparin require monitoring of their platelets Plan of management is :

Take home message 2 Do’s: stop heparin 2 Don’ts: start alternative anticoagulant in therapeutic doses 2 Don’ts: avoid platelet transfusion avoid warfarin and if started reverse with vitamin K 2 Tests: test for HIT antibodies lower limb duplex ultrasonography

Heparin-Induced Thrombocytopenia (HIT)