تشخیص 2

صفحه 1:
به نام خدا 

صفحه 2:
‎٠‏ يسر © ساله که در دی 0 با شکایت ضایعات پوستی به گفته همراهان چرکی در قدام ران جب به بيمارستان مراجعه و يس از درمان آنتی بیوتیک و به دلیل عدم پاسخ به درمان تحت جراحى و درناز قرار مى كيرد.(جندين 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. 

صفحه 3:
* پس از حدود یک هفته بیمار دچار ضایعه ایکیموتیک در حد 565 سانتی متری در ناحیه خارجی مج 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. 

صفحه 4:
٠١ 8 Wbc:10900 N:45% ‏1296:اأطمهماومع‎ 6 plt:63000 ۶۲:12. INR:1.1 ۳99 FDP:>5(positive) D-dimer:>500(positive) Fibrinogen:NL 

صفحه 5:
*» اکوی قلب:نرمال * سونو داپلر: شریان اندام تحتانی :نرمال شواهد ترومبوز حاد وریدی در ورید پولیتنال اندام 

صفحه 6:
۰ ۲۱۱۲ test (ELISA):POS Platelet-derived microparticles. (procoagulant) معم . 7 (neutralizes ‏تست در 6 نوبت‎ * heparin) ‏ثبت شد‎ t Thrombin generation Platelet (and ۲ ۲ ‏یه‎ endothelial 24 ates pee its 558 2 HIT-specific thrombosis (white clot”) 1. ff Venous and/or arterial thrombosis 2. t Risk for warfarin-associated microvascular thrombosis (e-g., venous limb gangrene) 

صفحه 7:
۱ Thrombocytope! Pseudo-HIT Pathogenesis of Thrombocytopenia and 3 Disorder Thrombosis a and Thrombosis in Adenocarcinoma DIC secondary to procoagulant material(s) association with 05 0 ‏مر ا‎ heparin treatment PE Platelet activation by clot-bound thrombin Diabetic ketoacidosis Hyperaggregable platelets in ketoacidosis APLS. Multiple mechanisms described, including platelet activation by APLAs Thrombolytic Platelet activation by thrombin bound to therapy FDPs Infective endocarditis Infection (sepsis}-associated thrombocytopenia (see also septicemi: associated purpura fulminans); ischemic events caused by septic embol Septicemia- Symmetrical peripheral gangrene resulting PTP: causes bleeding but not fulminans (anticoagulants (©.g., protein ©, ATI) thrombosis; however, PTP may Hepatic necrosis/ Hypotension-associated ischemic hepatitis resemble HIT in that both mi necrosis (Ushock liver") and DIC with depletion disorders usually occur about a syndrome of natural anticoagulants (e.g., PC, ATI) week after major surgery ‏فیس یت باس یط ی‎ requiring blood transfusion and 0 postoperative heparin ‏مجم‎ “Pseudospecific” alloantibady-mediated treatment jlatelet destruction (exception: ‏م‎ Modified from Warkentin TE, Cuker A. Differential diagnosis of heparin-induced thrombocytopenia and scoring systems. In Woerkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia, ed 5, Boca Raton, Fla, 2013, CRC Press, PP 77-109, with permission. 

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

صفحه 9:
Vasculitist+thrombocytopenia+thro mbosis * Buerger’s disease ٠ Hypersensitivity (‘allergic’) vasculitis * Microscopic polyarteritis (MPA) * Polyarteritis nodosa (PAN) * Moya moya + Behc, et’s disease 

صفحه 10:
«3 9 ۰ 05 9 ۰ ۸۸:9 * HLA B5:Neg ٠ HLA B51:Neg 

صفحه 11:
* در بررسی ها بیمار ما در 080 های سریال ائوزینوفیلی مداوم داشت. و سطح ] وابیمار 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). 

صفحه 12:
ung ‘Bronchial artery pseudoaneurysm (U) Pulmonary ats ‏إلا‎ قمر ‎‘Aneurysm (AR, AD, U)‏ Heart ‘Coronory aneurysm (AD,S, U) Psewdoaneurysm (U) Ban ‘Aneurysm (AR, U) ‘Occusion of vessels (AR) Vasculis (AR, S) Under pertuson of erge ateres (AR) ‘Thrombosis (AD, ‏إل‎ ‎Veseularexasia(U) ‎Vercus angioma (U) Veins ‘Veracava superior syntome () gavin ‏إلا ماه‎ ‘Congenital patent ducts venosus (AD) Skin Vasc (U) H. Yavuz and R. Chee Fig. 1. Spectrum and localization of vascular abnormalities of hyperimmunoglobulin E syndrome (HIES) patients, AR, autosomal recessive; AD, autosomal dominant; S, sporadic; U, unstated. 

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

صفحه 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. 

صفحه 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. 

صفحه 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) 

صفحه 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. 

صفحه 18:
Differential diagnosis * Hemodilution post-surgery * Severe pulmonary embolism * Sepsis * DIC (multiple causes besides HIT) * Cancer-associated DIC ٠ Antiphospholipid syndrome * Thrombolytic therapy + EDTA-induced pseudothrombocytopenia * GP Ilb/Illa inhibitor-induced thrombocytopenia ٠ Drug-induced thrombocytopenia (other than heparin) * Post-transfusion purpura * Thrombotic thrombocytopenic purpura * Non-immune heparin-associated thrombocytopenia 

صفحه 19:
HEPARIN RESISTANCE * Definition: * Inadequate prolongation of the partial thromboplastin time (PTT) or activated clotting time despite administration of pcre nie dosages of unfractionated heparin (er I-40 U/hr for the ism : treatment of venous thromboembo 00 U/kg during cardiopulmonary bypass * Causes: * Supraphysiologic levels of factor VIII and/or fibrinogen (e.g., acute phase response) + Antithrombin Ill (Arty deficiency: primary OR secondary (DIC , extensive thrombosis, CABG) * increased levels of binding proteins; * Increased clearance (e.g., during pregnancy). * Management: * If ATI level is low (e.g., <70% of normal): consider administering of FFP or an ATIIl infusion to boost levels above 100%. ٠ If ATII level is normal : monitor heparin therapy with regular assay of anti-factor Xa levels. 

صفحه 20:
Clinical events associated with HIT * Venous thrombosis (30-70%) * Deep vein thrombosis (DVT) + Pulmonary embolism (PE) + Adrenal necrosis (adrenal vein thrombosis) ٠ Cerebral venous (sinus) thrombosis ٠ Venous limb gangrene (VKA associated) : Arterial thrombosis (“white clots”) (15-30%) + Limb artery thrombosis * Stroke * Myocardial infarction =| ۲ * Skin lesions at heparin injection sites (10%) * Skin necrosis + Erythematous plaques ۲ * Acute reactions after i.v. heparin bolus (10%) * Disseminated intravascular coagulation (DIC) (10%) 

صفحه 21:
HIT: a link between ‏هر‎ é ‏عا هه و‎ reper immune system 92 2 and hemostasis ae Tissue factor ل Thrombosis Warkentin TE, Chong BH, Greinacher A. Heparin induced thrombocytopenia: Towards consensus. Thromb Haemost 1998,79:1-7 Ring of positive | charge 

صفحه 22:
HIT Temporal Variants Heparin (re) Exposure 3 ' THROMBOCYTOPENIA (+ THROMBOSIS) Courtesy of Dr Ahjad AlMahameed Cleveland Clinic, 

صفحه 23:
CLINICAL SCORING SYSTEMS + HIT Expert Probability Score by Cuker et al. * a post-CPB scoring system by Lillo-Le Louét et al. * 4T’s scoring system by Warkentin et al. 

صفحه 24:
OVERDIAGNOSIS OF HEPARIN-INDUCED THROMBOCYTOPENIA + 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 

صفحه 25:
TABLE 2 The 4T°s Clinical Scoring System Category 2 Points 1 Point 0 Points Thrombocytopenia Platelet count falls >50% and platelet Platelet count falls 30%-50% and ——_—Platelet count falls <30% and platelet nadir =20 x 10°/L platelet nadir 10-19 x 10°/l nadir <10 x 10°/L Timing Clear onset between 5 and 10 days or Consistent with days 5-10 fall, but Platelet count fall <4 days without platelet fall <1 day (prior heparin not clear (e.g,, missing platelet recent heparin exposure exposure within 30 day) counts), or onset after day 10, or fall =1 day (prior heparin exposure 30-100 days ago) Thrombosis New thrombosis (confirmed), or skin Progressive or recurrent thrombosis, None necrosis at heparin injection sites, or non-necrotizing (erythematous) or acute systemic reaction after skin lesions, or suspected intravenous heparin bolus thrombosis (not proven) Other causes of Nonapparent Possible Definite thrombocytopenia Probability of HIT: high, 6 to 8 points (21.4% to 100%); intermediate, 4 or S points (7.9% to 28.6%); low, O to 3 points (0% to 1.6%). Reprinted with permission from Lo et al, (45). HIT = heparin-induced thrombocytopenia, 

صفحه 26:
Factors influencing frequency of HIT Pwr + ‏عصدصس‎ ۲ Bovine UFH > porcine UFH > Type of heparin LMWH ۲ ۲ Post-surgery > medical > Patient population obstetrical ۲ 1 5 or more days heparin use > 1-4 Duration of heparin days Change from low to full dose can Dose of heparin lead abrupt platelet | in immunized patient Gender Female > male Proportional platelet count fall ‎(e.g. >50%) more sensitive than‏ إن تروت لمت با ‎thrombocytopenia ‎ ‎ ‎ ‎ ‎ ‎ ‎ 

صفحه 27:
“Iceberg model” of HIT HIT and associated thrombosis occurs in the subset of patients with platelet-activating anti-PF4/H an hrombosis HIT ١ syndrome Thrombocytopentapocitive washed platelet | positi activatio’ yepF4 n antige assay | ‏م‎ 9 assay +——Numbers of Patients 

صفحه 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. 

صفحه 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/polyviny! sulfonate EIA + Fluid-phase EIA ۰ Particle gel immunoassay 

صفحه 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. 

صفحه 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. 

صفحه 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. 

صفحه 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. 

صفحه 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. 

صفحه 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. 

صفحه 36:
اير ‎HIT] SRA EIA. | EIA-‏ ‎HIPA| IgG |IgG/A/M‏ Higher ODs in he EIAs increase the probability OfSRAt (oF HIPAS) status EIAJgG/A/M result (OD urits):<0.4 94 1.015 1620 22.0 Probability of SRA+ status: ~0% ~25% ~50% ~90% 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) 

صفحه 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%. 

صفحه 38:
Occurrence of symptomatic thrombosis after stopping heparin in patients confirmed to have isolated HIT 14-year retrospective study Cumulative thrombotic event-rate (%) 0 3 ‏ا سس 3 3 3 و و‎ 0 A 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 Days after isolated HIT recognized DN Tele ero go eV oo] (Ok ‏رت‎ 

صفحه 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. 

صفحه 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. 

صفحه 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. 

صفحه 42:
Side Effects * Bleeding 17.6% * Antibodies to Lepirudin 30% “No HIT antibody Bleeding 7% No HIT antibody Bleeding 2.4% No HIT antibody Monitoring aPTT 2hrs after initial dose and then daily, Optimum aPTT < 65 sec aPTT < 100sec or 1.5-3.0 times control كعم Dose ۱۷ Bolus 0.4mg/kg (max 44mg) followed by lVinfusion 0.15mg/kg/r (max 16.5mg/hr) 2ug/kg/min (max 10ug/kg/m) WV bolus 0.75mg/kg followed by infusion 1.75mg/kg/br till completion of PCI Clearance Renal half life = 1.7hrs Hepatic Enzymatic 80% (A) Direct thrombin inhibitors (DT!) Drug Approval Lepirudin FDA/US for HIT Argatroban FDA/US for HIT Bivalirudin FDA/US for PClonly Renal 20% Half life - 25min 

صفحه 43:
Side Effects Bleeding 8.1% Cross reacts with reacts with HIT antibodies in 3.2% cases Not reported Monitoring Antifactor Xa activity; Target 0.5- 0.8 U/ml Dose IV bolus 2250 U (1500- 3750U) followed by IV infusion 400U/Hr for 4 hours, 300U/hr for 4 hours and 150-200 U/hr thereafter Not established 2.5mg subcutaneously up to 14 days Clearance Rena half life = 25 hours Renal half life = 17- 20 hours Approval * Not approved by FDA/US and UK * Approved in Canada, Europe, Australia and New Zealand Not yet recommended for HIT; Approved for DVT prophylaxis in orthopedic surgery (8) Anti Factor Xa Drug Danaparoid Fondaparinux 

صفحه 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. 

صفحه 45:
Rivaroxaban, sold under the brand name ۵ 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. 

صفحه 46:
Laboratory no specific laboratory parameters available to monitor : monitoring +.A transient dose-dependent prolongation of aPTT and PT may be seen 1-4 hours after administration not applicable at therapeutic levels -Antifactor Xa levels were originally designed and calibrated for LMWH and must be specifically calibrated for Factor Xa inhibitors Reversal + no specific reversal agent exists + In patients with normal renal function, treatment of minor events may be handled simply by cessation of rivaroxaban + Four-factor PCC may be the best option currently available for major events/prompt blood stop need (Thrombosis and Hemostasis Society of North America ; German Society of Neurology ) Daily dosage Once-twice twice frequency Renal failure + Dose reduction is necessary in minimize need for dose patients with stable chronic adjustment kidney disease, + Contraindicated in patients with severe renal (CrCl < 30 mL/min) or hepatic insufficiency Hepatic failure Dose reduction and clinical F/U Dose reduction and clinical F/U 

صفحه 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. 

صفحه 48:
* بیمار تحت درمان با ۷۵۲۵۵0۵۳ قرار گرفت. * پس از 46 روز از درمان با پلاکت 06060000 و بهبود نسبی زخم پا و انگشت با توصیه به پیگیری با سونو مرخص شد.(انتهای اسفند) 

صفحه 49:
* بیمار در 8 فروردین با شکایت سردی اندام فوقانی راست از مچ به پایین به اورژانس » اندام از مچ سرد.بازگشت وریدی مختل! * فورا سونو انجام گردید: * اندام تحتانی شریان نرمال/ورید شواهد ترومبوز باز شده * اندام فوقانی راست‌حورید نرمال/شریانعتا شریان رادیال و اولنار باز ولی نمای نرمال تری فازیک به نمای بای فازیک که نشان از انسداد دیستال بود تبدیل گردیده بود. 

صفحه 50:
٠١ 8 WBC:9200 N:72% EOS:1% 3 PLT:194000 (۲ =INR:1.2 3 FDP:pos D dimer : pos Fibrinogene:decreased 

صفحه 51:
» فورا درمان با ۸۱۲60۱256 آغاز گردید. * درمان همزمان با ۳۷6۲020 ادامه یافت. 

صفحه 52:
ن 3 باليذ د یافت. ‎٠‏ يس از 060 ساعت سونو داپلر شریانی و وریدی نرمال گردید. علایم بالینی بهبود 2 ¢ Factor VIII:230% ian