تشخیص ۲

تشخیص ۲

اسلاید 1: به نام خدا

اسلاید 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.

اسلاید 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.

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

اسلاید 5: اکوی قلب:نرمالسونو داپلر: شریان اندام تحتانی :نرمالشواهد ترومبوز حاد وریدی در ورید پولیتئال اندام

اسلاید 6: HIT test (ELISA):POSتست در 2 نوبت مثبت شد

اسلاید 7: 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 treatmentThrombocytopenia and Thrombosis in association with heparin treatment

اسلاید 8: Sickle prep:NEGPBS:NLلوپوس آنتی کواگولان:منفی

اسلاید 9: Vasculitis+thrombocytopenia+thrombosisBuerger’s diseaseHypersensitivity (‘allergic’) vasculitisMicroscopic polyarteritis (MPA)Polyarteritis nodosa (PAN)Moya moyaBehc¸et’s disease

اسلاید 10: ANA:neg ds DNA:negANCA:negHLA B5:NegHLA B51:Neg

اسلاید 11: در بررسی ها بیمار ما در CBCهای سریال ائوزینوفیلی مداوم داشت. و سطح IgEبیمار نیز بالاتر از حد نرمال بود.hyperimmunoglobulin E 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).

اسلاید 12:

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

اسلاید 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.

اسلاید 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.

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

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

اسلاید 18: Differential diagnosis Hemodilution post-surgerySevere pulmonary embolismSepsisDIC (multiple causes besides HIT)Cancer-associated DICAntiphospholipid syndromeThrombolytic therapyEDTA-induced pseudothrombocytopeniaGP IIb/IIIa inhibitor-induced thrombocytopeniaDrug-induced thrombocytopenia (other than heparin)Post-transfusion purpuraThrombotic thrombocytopenic purpura Non-immune heparin-associated thrombocytopenia

اسلاید 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/hr for the treatment of venous thromboembolism [VTE]; 400 U/kg during cardiopulmonary bypassCauses:Supraphysiologic levels of factor VIII and/or fibrinogen (e.g., acute phase response)Antithrombin III (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.

اسلاید 20: Clinical events associated with HITVenous 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 infarctionSkin lesions at heparin injection sites (10%) Skin necrosis Erythematous plaquesAcute reactions after i.v. heparin bolus (10%)Disseminated intravascular coagulation (DIC) (10%)

اسلاید 21: Ring of positive chargeHIT: a link between immune system and hemostasisFcgRIIa HeparansulfatePF4HeparinB-LWarkentin TE, Chong BH, Greinacher A. Heparin induced thrombocytopenia: Towards consensus. Thromb Haemost 1998,79:1-7ThrombinTissue factorECLi et al, Blood 2002; 99:1230ThrombosisPF4 tetramer

اسلاید 22: HIT Temporal VariantsDay 1Day 4Day 14Day 30 Delayed-onset HIT (9–40 days)Rapid-onset HIT (hours–days)Typical HITMean Day 9(4–14 days)Heparin (re) ExposureTHROMBOCYTOPENIA (± THROMBOSIS)Courtesy of Dr Ahjad AlMahameed Cleveland Clinic, OH.

اسلاید 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.

اسلاید 24: OVERDIAGNOSIS OF HEPARIN-INDUCED THROMBOCYTOPENIAAt 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

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اسلاید 26: Factors influencing frequency of HIT

اسلاید 27: “Iceberg model” of HITThrombocytopeniaPositivewashedplatelet activationassayPositivePF4 antigenassayThrombosisHITsyndromeNumbers of PatientsAdapted from Warkentin TE. Br J Haematol 2003,121:535HIT and associated thrombosis occurs in the subset of patients with platelet-activating anti-PF4/H antibodies

اسلاید 28: LABORATORY STUDIES Currently, the 2 classes of tests used to assist in the diagnosis ofHIT 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.

اسلاید 29: Detection of HIT antibodiesPlatelet activation assaysSerotonin 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 assaysPF4/heparin-enzyme immunoassay (ELISA)PF4/polyvinyl sulfonate EIAFluid-phase EIAParticle gel immunoassay

اسلاید 30: enzyme-linked immunosorbent assay (ELISA), have a high degree ofsensitivity (99%) and thus have high negativepredictive value, making them excellent tests to ruleout 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.

اسلاید 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.

اسلاید 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.

اسلاید 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.

اسلاید 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 serotoninfrom platelets.

اسلاید 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 heparinDisadvantages of this test are the use of radioactive substances and it is technically demanding.

اسلاید 36: Three types of assays are highly sensitive for the diagnosis of HITwashed 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)

اسلاید 37: MANAGEMENT AND TREATMENTCessation 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 as52%.

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اسلاید 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.

اسلاید 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 transfusionduring the performance of an invasive procedure with a high risk for bleeding.

اسلاید 41: ALTERNATIVE ANTICOAGULATION. Two groups of alternative nonheparin anticoagulant are currentlyavailable:a) Direct Thrombin Inhibitors which reduce thrombinactivityb) Antifactor Xa which reduce thrombin generation.

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اسلاید 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.

اسلاید 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.

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اسلاید 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.

اسلاید 48: بیمار تحت درمان با Rivaroxaban 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)

اسلاید 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 شدهاندام 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.

اسلاید 50: CBCWBC:9200 N:72% EOS:1% HGB:13.3 PLT:194000PT:14 INR:1.2 PTT:33FDP:pos D dimer : posFibrinogene:decreased

اسلاید 51: فورا درمان با Alteplase آغاز گردید.درمان همزمان با Rivaroxaban ادامه یافت.

اسلاید 52: پس از 96 ساعت سونو داپلر شریانی و وریدی نرمال گردید.علایم بالینی بهبود یافت.در پاسخ ازمایشات ترومبوفیلیFactor VIII:230%