به نام خدا

1. به نام خدا

2. پسر 5 ساله که در دی 95 با شکایت ضایعات پوستی به گفته همراهان چرکی در قدام ران چپ به بیمارستان مراجعه و پس از درمان آنتی بیوتیک و به دلیل عدم پاسخ به درمان تحت جراحی و درناژ قرار می گیرد.(چندین نوبت) • در ابتدای اسفند ماه و به دنبال یکی از جراحی ها دچار تورم اندام تحتانی چپ از نیمه ران به پایین می شود که در سونو داپلر شواهد ترومبوز وریدی دیده شده و جهت وی هپارین آغاز می شود.

3. پس از حدود یک هفته بیمار دچار ضایعه ایکیموتیک در حد 5X5 سانتی متری در ناحیه خارجی مچ پای چپ و همزمان سردی و ایکیموز بند دیستال انگشت شست راست می شود. • در آزمایشات وی افت پلاکت گزارش می شود. • والدین با رضایت شخصی بیمار را مرخص و به مرکز ما مراجعه می کنند.

4. CBC Wbc:10900 N:45% Eosinophil:12% Hgb:12.6 plt:63000 PT:12.7 INR:1.1 PTT:39 FDP:>5(positive) D-dimer:>500(positive) Fibrinogen:NL

5. اکوی قلب:نرمال • سونو داپلر: شریان اندام تحتانی :نرمال شواهد ترومبوز حاد وریدی در ورید پولیتئال اندام

6. HIT test (ELISA):POS • تست در 2 نوبت مثبت شد

7. Thrombocytopenia and Thrombosis in association with heparin treatment PTP: causes bleeding but not thrombosis; however, PTP may resemble HIT in that both disorders usually occur about a week after major surgery requiring blood transfusion and postoperative heparin treatment

8. Sickle prep:NEG PBS:NL لوپوس آنتی کواگولان:منفی

9. Vasculitis+thrombocytopenia+thrombosis • Buerger’s disease • Hypersensitivity (‘allergic’) vasculitis • Microscopic polyarteritis (MPA) • Polyarteritis nodosa (PAN) • Moya moya • Behc¸et’s disease

10. ANA:neg • ds DNA:neg • ANCA:neg • HLA B5:Neg • HLA B51:Neg

11. در بررسی ها بیمار ما در CBCهای سریال ائوزینوفیلی مداوم داشت. و سطح IgEبیمار نیز بالاتر از حد نرمال بود. hyperimmunoglobulinE syndrome (HIES)=???? Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency characterized by recurrent staphylococcal infections of skin and lungs and elevated levels of immunoglobulin E (IgE).

13. HIT Heparin-induced thrombocytopenia (HIT) is a prothrombotic, immune-mediated complication of unfractionated and low molecular weight heparin (LMWH) therapy.

14. moderate thrombocytopenia 5-10 days after initial heparin exposure, detection of platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies, and an increased risk of venous and arterial thrombosis.

15. In adult patients receiving heparin,the prevalence of HIT is reported to be 0.5-5%. • published case series/reviews of HIT in children suggest that the prevalence of HIT may be lower than in adults (1.5%-3.7%) and as low as 0.33% in non-neonates receiving cardiopulmonary bypass.

16. The term HIT has been used to describe 3 groups of patients: - those for whom laboratory testing for HIT was sent because of clinicalsuspicion(“suspected HIT”) -patients with expert clinician opinion HIT and positive laboratory testing (HIT) -HIT with thrombosis (HITT)

17. Definition of HIT/HITT Thrombocytopenia (platelet count fall >50% or platelet nadir >20000 cells/mL) with Recent or concurrent heparin exposure and the absence of other causes for thrombocytopenia, were positive PF4/heparin ELISA, and met expert consensus.

18. Differential diagnosis • Hemodilution post-surgery • Severe pulmonary embolism • Sepsis • DIC (multiple causes besides HIT) • Cancer-associated DIC • Antiphospholipid syndrome • Thrombolytic therapy • EDTA-induced pseudothrombocytopenia • GP IIb/IIIa inhibitor-induced thrombocytopenia • Drug-induced thrombocytopenia (other than heparin) • Post-transfusion purpura • Thrombotic thrombocytopenic purpura • Non-immune heparin-associated thrombocytopenia

19. HEPARIN RESISTANCE • Definition: • Inadequate prolongation of the partial thromboplastin time (PTT) or activated clotting time despite administration of therapeutic dosages of unfractionated heparin (UFH; e.g., >1500 U/hrfor the treatment of venous thromboembolism [VTE]; 400 U/kg during cardiopulmonary bypass • Causes: • Supraphysiologiclevels of factor VIII and/or fibrinogen (e.g., acute phase response) • AntithrombinIII (ATIII) deficiency: primary OR secondary (DIC , extensive thrombosis, CABG) • increased levels of binding proteins; • Increased clearance (e.g., during pregnancy). • Management: • If ATIII level is low (e.g., <70% of normal): consider administering of FFP or an ATIII infusion to boost levels above 100%. • If ATIII level is normal : monitor heparin therapy with regular assay of anti–factor Xa levels.

20. Clinical events associated with HIT • Venous thrombosis (30-70%) • Deep vein thrombosis (DVT) • Pulmonary embolism (PE) • Adrenal necrosis (adrenal vein thrombosis) • Cerebral venous (sinus) thrombosis • Venous limb gangrene (VKA associated) • Arterial thrombosis (“white clots”) (15-30%) • Limb artery thrombosis • Stroke • Myocardial infarction • Skin lesions at heparin injection sites (10%) • Skin necrosis • Erythematous plaques • Acute reactions after i.v. heparin bolus (10%) • Disseminated intravascular coagulation (DIC) (10%)

21. FcgRIIa Heparansulfate Heparin PF4 B-L EC Tissue factor Thrombin Ring of positive charge HIT: a link between immune system and hemostasis PF4 tetramer Li et al, Blood 2002; 99:1230 Thrombosis Warkentin TE, Chong BH, Greinacher A. Heparin induced thrombocytopenia: Towards consensus. Thromb Haemost 1998,79:1-7

22. Heparin (re) Exposure Typical HIT Mean Day 9 (4–14 days) Rapid-onset HIT (hours–days) Delayed-onset HIT (9–40 days) Day 1 Day 4 Day 14 Day 30 THROMBOCYTOPENIA (± THROMBOSIS) HIT Temporal Variants Courtesy of Dr Ahjad AlMahameed Cleveland Clinic, OH.

23. CLINICAL SCORING SYSTEMS • HIT Expert Probability Score by Cuker et al. • a post-CPB scoring system by Lillo-Le Louët et al. • 4 T’s scoring system by Warkentin et al.

24. OVERDIAGNOSIS OF HEPARIN-INDUCEDTHROMBOCYTOPENIA • At most, only 50% of patients with positive immunoassay results truly have HIT . • Even lower in patients in the ICU and patients who are tested for anti-PF4/heparin antibodies because they have DVT

26. Factors influencing frequency of HIT

27. “Iceberg model” of HIT HIT and associated thrombosis occurs in the subset of patients with platelet-activating anti-PF4/H antibodies Thrombosis HIT syndrome Thrombocytopenia Positive washed platelet activation assay PositivePF4 antigen assay Numbers of Patients Adapted from Warkentin TE. Br J Haematol 2003,121:535

28. LABORATORY STUDIES • Currently, the 2 classes of tests used to assist in the diagnosis of HIT are: immunologic (antigenic) and Functional (platelet activation) assays. the antigen assay detects the initial immune response, whereas the functional assay detects the activation of platelets, leading to thrombosis.

29. Detection of HIT antibodies • Platelet activation assays • Serotonin release assay (SRA; uses “washed” platelets) • Heparin-induced platelet activation (HIPA) assay (uses “washed” platelets) • Platelet aggregation test (PAT; uses citrate-anticoagulated platelet-rich plasma) • Platelet microparticles (flow cytometry) • Antigen assays • PF4/heparin-enzyme immunoassay (ELISA) • PF4/polyvinyl sulfonate EIA • Fluid-phase EIA • Particle gel immunoassay

30. enzyme-linked immunosorbent assay (ELISA), have a high degree of sensitivity (99%) and thus have high negative predictive value, making them excellent tests to rule out a diagnosis of HIT. repeating the ELISA using 2-point increases the specificity of HIT testing but can decrease the negative predictive value and sensitivity.

31. functional (platelet activation) assay These tests measure platelet activation from the heparin-PF4-antibody complex by mixing donor platelet-rich plasma with patient plasma and heparin. The 2 most common functional assays are : the heparin-induced platelet activation assay and the serotonin release assay.

32. Heparin-induced Platelet Aggregation Assay (HIPAA) The heparin-induced platelet activation assay will exhibit platelet aggregation and an increase in turbidity at therapeutic concentrations of heparin, but not at supratherapeutic concentrations.

33. The Heparin-induced Platelet Aggregation Assay (HIPAA) The HIPAA, like the SRA, employs washed platelets from normal donors platelet aggregation in the presence of heparin rather than serotonin release is used as an indicator of the presence of HIT antibodies. The assay is rapid, does not use a radioactive isotope and is less technically demanding than SRA.

34. 14C-serotonin-release assay (SRA) The serotonin release assay, generally considered the gold standard because of its high sensitivity (>95%)and specificity (>95%) , measures the sample’s radioactivity and the percentage release of serotonin from platelets.

35. 14C-serotonin-release assay (SRA) The basis of the SRA is that antibodies from patients with HIT will cause platelet activation and release of 14C-serotonin from platelet-dense granules when HIT serum is incubated with normal donor platelets at therapeutic concentrations of heparin Disadvantages of this test are the use of radioactive substances and it is technically demanding.

36. Three types of assays are highly sensitive for the diagnosis of HIT • washed platelet activation assays (serotonin release assay [SRA], • heparin-induced platelet activation test [HIPA]), • Immunoglobulin G (IgG)–specific PF4-dependent enzyme immunoassays (EIA-IgG), and polyspecific EIAs that detects anti-PF4/heparin antibodies of the three major immunoglobulin classes (EIA-IgG/A/M)

37. MANAGEMENT AND TREATMENT Cessation alone is not enough to prevent thrombotic events. The 30-day risk for subsequent thrombosis following the cessation of heparin therapy is estimated to be at least 19% and possibly as high as 52%.

39. If warfarin therapy has been started when HIT is diagnosed, reversal with vitamin K should occur because of its depletion of proteins C and S and the increased risk for venous limb gangrene.

40. PLATELET TRANSFUSION====? the 2012 American College of Chest Physicians (ACCP) guidelines do not recommend routine platelet transfusion in patients with HIT. However, they do support transfusions to severely thrombocytopenic patients with HIT who are bleeding or necessitate transfusion during the performance of an invasive procedure with a high risk for bleeding.

41. ALTERNATIVE ANTICOAGULATION. Two groups of alternative nonheparin anticoagulant are currently available: a) Direct Thrombin Inhibitors which reduce thrombin activity b) Antifactor Xa which reduce thrombin generation.

44. Several novel oral anticoagulants exist (eg, rivaroxaban,dabigatran,apixaban), and preliminary evidence suggests that they may be beneficial for HIT, particularly in cases refractory to standard therapies.

45. Rivaroxaban, sold under the brand name Xarelto  It is the first available active direct factor Xa inhibitor which is taken by mouth. The maximum inhibition of factor Xa occurs four hours after a dose. The effects last approximately 8–12 hours, but factor Xa activity does not return to normal within 24 hours, so once-daily dosing is possible. Rivaroxaban inhibits both free Factor Xa and Factor Xa bound in the prothrombinase complex.

47. PLASMAPHERESIS in a randomized controlled study performed in 1999, Robinson et al. showed decreased mortality in HIT patients when treated within 4 days of the onset of thrombocytopenia.

48. بیمار تحت درمان باRivaroxaban قرار گرفت. • پس از 12 روز از درمان با پلاکت 258000 و بهبود نسبی زخم پا و انگشت با توصیه به پیگیری با سونو مرخص شد.(انتهای اسفند)

49. بیمار در 16 فروردین با شکایت سردی اندام فوقانی راست از مچ به پایین به اورژانس مراجعه نمود!!!!!! • اندام از مچ سرد.بازگشت وریدی مختل! • فورا سونو انجام گردید: • اندام تحتانی =شریان نرمال/ورید =شواهد ترومبوز باز شده • اندام فوقانی راست=ورید نرمال/شریان=تا شریان رادیال و اولنار باز ولی نمای نرمال تری فازیک به نمای بای فازیک که نشان از انسداد دیستال بود تبدیل گردیده بود.

50. CBC WBC:9200 N:72% EOS:1% HGB:13.3 PLT:194000 PT:14 INR:1.2 PTT:33 FDP:pos D dimer : pos Fibrinogene:decreased