Download HIT and associated thrombosis occurs in the subset of patients with

‫• پسر ‪ 5‬ساله که در دی ‪ 95‬با 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.‬‬
‫• پس از حدود یک هفته بیمار دچار ضایعه ایکیموتیک در حد ‪ 5X5‬سانتی متری در ناحیه‬
‫خارجی مچ پای چپ و همزمان سردی و ایکیموز بند دیستال انگشت شست راست می‬
‫شود‪.‬‬
‫• در آزمایشات وی افت پالکت گزارش می شود‪.‬‬
‫• والدین با رضایت شخصی بیمار را مرخص و به مرکز ما مراجعه می کنند‪.‬‬
• CBC
Wbc:10900 N:45% Eosinophil:12% Hgb:12.6
PT:12.7 INR:1.1 PTT:39
FDP:>5(positive)
Fibrinogen:NL
D-dimer:>500(positive)
plt:63000
‫• اکوی قلب‪:‬نرمال‬
‫• سونو داپلر‪:‬‬
‫شریان اندام تحتانی ‪:‬نرمال‬
‫شواهد ترومبوز حاد وریدی در ورید پولیتئال اندام‬
• HIT test
(ELISA):POS
‫ نوبت‬2 ‫• تست در‬
‫مثبت شد‬
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
‫‪Sickle prep:NEG‬‬
‫‪PBS:NL‬‬
‫لوپوس آنتی کواگوالن‪:‬منفی‬
Vasculitis+thrombocytopenia+thrombosis
• Buerger’s disease
• Hypersensitivity (‘allergic’) vasculitis
• Microscopic polyarteritis (MPA)
• Polyarteritis nodosa (PAN)
• Moya moya
• Behc¸et’s disease
• ANA:neg
• ds DNA:neg
• ANCA:neg
• HLA B5:Neg
• HLA B51:Neg
.‫های سلایر ائوزینوفیلی مداوم داشت‬CBC ‫• در بررسی ها بیمار ما در‬
.‫بیمار نیز باالتر از حد نرمال بود‬IgE ‫و سطح‬
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).
HIT
Heparin-induced thrombocytopenia (HIT) is a prothrombotic, immunemediated complication of unfractionated and low molecular weight
heparin (LMWH) therapy.
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.
• 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.
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)
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.
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
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 bypass
• Causes:
• 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.
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%)
HIT:
a link between
immune system and
hemostasis
FcgRIIa
Heparansulfate
Heparin
PF4
B-L
PF4 tetramer
EC
Ring of positive
charge
Tissue factor
Thrombin
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
HIT Temporal Variants
Heparin (re) Exposure
Typical HIT
Mean Day 9
(4–14 days)
Rapid-onset
HIT
(hours–days)
Day 1
Day 4
Delayed-onset
HIT
(9–40 days)
Day 14
Day 30
THROMBOCYTOPENIA (± THROMBOSIS)
Courtesy of Dr Ahjad AlMahameed Cleveland Clinic, OH.
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.
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 antiPF4/heparin antibodies because they have DVT
Factors influencing frequency of HIT
Factor
Type of heparin
Patient population
Duration of heparin
Influence
Bovine UFH > porcine UFH > LMWH
Post-surgery > medical > obstetrical
5 or more days heparin use > 1-4 days
Dose of heparin
Change from low to full dose can lead
abrupt platelet  in immunized patient
Gender
Female > male
Definition of thrombocytopenia
Proportional platelet count fall (e.g. >50%)
more sensitive than absolute platelet 
“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
Positive
PF4
antigen
assay
Numbers of Patients
Adapted from Warkentin TE. Br J Haematol 2003,121:535
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.
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 citrateanticoagulated platelet-rich plasma)
• Platelet microparticles (flow cytometry)
• Antigen assays
•
•
•
•
PF4/heparin-enzyme immunoassay (ELISA)
PF4/polyvinyl sulfonate EIA
Fluid-phase EIA
Particle gel immunoassay
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.
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.
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.
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.
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.
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.
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)
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%.
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.
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.
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.
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.
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.
Rivaroxaban
Apixaban
Laboratory monitoring
no specific laboratory parameters available to monitor :
• .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 frequency
Once-twice
twice
Renal failure
•
minimize need for dose adjustment
•
Dose reduction is necessary in patients
with stable chronic 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
On going clinical trials
RECORD; EINSTEIN-EXT; EINSTEIN-
AMPLIFY-EXT;ADVANCE; ARISTOTLE
DVT;ROCKET; MEGALLEN
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.
‫• بیمار تحت درمان با‪ Rivaroxaban‬قرار گرفت‪.‬‬
‫• پس از ‪ 12‬روز از درمان با پالکت ‪ 258000‬و بهبود نسبی زخم پا و انگشت با توصیه‬
‫به پیگیری با سونو مرخص شد‪(.‬انتهای اسفند)‬
‫•‬
‫•‬
‫•‬
‫•‬
‫•‬
‫بیمار در ‪ 16‬فروردین 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.‬‬
• CBC
WBC:9200 N:72% EOS:1%
PT:14 INR:1.2 PTT:33
FDP:pos
D dimer : pos
Fibrinogene:decreased
HGB:13.3
PLT:194000
‫• فورا درمان با ‪ Alteplase‬آغاز گردید‪.‬‬
‫• درمان همزمان با ‪ Rivaroxaban‬ادامه یافت‪.‬‬
‫• پس از ‪ 96‬ساعت سونو داپلر شریانی و وریدی نرمال گردید‪.‬عالیم بالینی بهبود یافت‪.‬‬
‫• در پاسخ ازمایشات ترومبوفیلی‬
‫‪• Factor VIII:230%‬‬