肝素诱导的血小板减少症
史旭波
首都医科大学同仁医院
XIa
XIIa
IXa
VIIa - III
组织因子途径抑制物
抗凝血酶
IIa
纤维蛋白原
纤维蛋白
蛋白C，蛋白S系统
Xa
VIIIa
Va
内源性凝血系统
外源性凝血系统
凝血与抗凝系统
Epidemiology
the chance of significant exposure to heparin exceeds 50% in hospitalized patients
acute coronary syndrome (UA / MI)
pulmonary embolism
deep venous thrombosis and prophylaxis
atrial fibrillation / stroke
heparinized pulmonary wedge catheters
PCI
IABP
Semi Thromb Hemost 1999;25 Suppl 1:57-60
U.S. Estimated Causes of Accidental Deaths
〈 1000
40,000
90,000
Deaths per year
Medication Errors – Hospital Audit
%
REFERENCE
血小板减少症（HIT/HITS）
美国每年有1200万人因肢体或肺部血栓、心脏病或血管成
型术而接受肝素治疗
36万人发生HIT
12万人出现血栓并发症（静脉、动脉）
3.6万人死亡
Heparin-induced Thrombocytopenia
Heparin-induced thrombocytopenia (HIT), an antibody-mediated syndrome, is associated with significant morbidity and mortality
considered a rarity in the past
unrecognized by many clinicians
diagnoses can be difficult to confirm
until recently there was no therapeutic options other than discontinuation of heparin
Epidemiology
thrombocytopenia is one of the most common laboratory abnormalities found among hospitalized patients
serologically proven HIT occurs in 1.5% to 3% of patients with heparin exposure
N Engl J Med 1995;332:1330-5
Cascade of events leading to formation of HIT antibodies and prothrombotic components
www.thrombosite.com
Bleeding and Clotting
the most feared consequence in these patients with a low platelet count is not bleeding but clotting
present with mucocutaneous bleeding, ranging from petechiae and ecchymoses to life-threatening gastrointestinal and intracranial hemorrhage
Thrombosis
thrombosis is mostly venous not arterial
may result in
bilateral deep venous thrombosis of the legs
pulmonary embolism
venous gangrene of fingers, toes, penis, or nipples
myocardial infarction, stroke
mesenteric arterial thrombosis
limb ischemia and amputation
Circulation 1999;100:587-93 Am J Med 1996;101:502-7 Thromb Haemost 1993;70:554-61
Other Clinical Features
Skin lesions at heparin injection site
Skin necrosis
Acute platelet activation
Acute inflammatory reactions (fever, chills, etc.)
Skin Necrosis
Used with permission from Warkentin TE. Br J Haematol. 1996;92:494–497.
Venous Limb Gangrene
Used with permission from Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. Ann Intern Med. 1997;127:804–812.
Morbidity and Mortality
HIT-associated mortality is high (about 18%)
5% of affected patients require limb amputation
Overt bleeding or bruising is rare even with severe thrombocytopenia
Appropriate management can limit morbidity and mortality
HIT Syndrome
Type I
nonimmunologic mechanisms (mild direct platelet activation by heparin)
associated with an early (within 4 days) and usually mild decrease in platelet count (rarely <100 x 109/L)
typically recovers within 3 days despite continued use of heparin
not associated with any major clinical sequelae
occurs primarily with high dose iv heparin
HIT Syndrome
Type II
induced by immunologic mechanisms
substantial fall in platelet count (> 50%)
count in the 50,000 - 80,000 /mm range
typical onset of 4-14 days
occurs with any dose by any route
potential for development of life-threatening thromboembolic complications
rarely causes bleeding
Risks for HIT
Type I
intravenous high-dose heparin
Type II
varies with dose of heparin
unfractionated heparin > LMWH
bovine > porcine
surgical > medical patients
Diagnosis of HIT
absence of another clear cause for thrombocytopenia
the timing of thrombocytopenia
the degree of thrombocytopenia
adverse clinical events (most often thrombocytpenia)
positive laboratory tests for HIT antibodies
Pathogenesis of Drug-induced thrombocytopenia
Certain drugs (quinine, quinidine, sulfa antibiotics) link non-covalently to platelet membrane glycoproteins
very rarely, IgG antibodies are produced that recognize these drug-glycoprotein complexes
macrophages remove the complexes causing severe thrombocytopenia
Comparison of HIT and other Drug-Induced Thrombocytopenia
HIT Quinine/Sulfa
Frequency ~1/100 ~1/10,000
Onset 5-8 days ? 7 days
Platelet count 20-150x109/L <20x109/L
Sequelae Thrombosis Bleeding
Laboratory Immunoassay Platelet-
(heparin/PF4) associated IgG
Unusual Clinical Events Suspicious for HIT
mild to moderate thrombocytopenia, often in conjunction with thrombosis
adrenal hemorrhagic infarction (caused by adrenal vein thrombosis)
warfarin-induced venous limb gangrene
fever, chills, beginning 5 to 30 minutes after an IV heparin bolus
heparin-induced skin lesions associated with HIT antibodies, even in the absence of thrombocytopania
Other Clinical Features Suspicious for HIT
a rapid drop in platelets may also be indicative of HIT, particularly if the patients received heparin within the previous 3 months
a fall in platelet count of >50% that begins after 5 days of heparin therapy, but with the platelet count > 150 x 109/L, should also raise the suspicion of HIT
Common Laboratory Tests for HIT
Test Advantages Disadvantages
PAA Rapid and simple Low sensitivity - not suitable for
testing multiple samples
SRA Sensitivity >90% Washed platelet (technically
demanding), needs radiolabeled
material 14C
HIPA Rapid, sensitivity >90% Washed platelets
ELISA High sensitivity, High cost, lower specificity for
clinically significant HIT
Thromb Haemost 1998;79:1-7
platelet aggregation assay (PAA)
serotonin release assay (SRA)
heparin induced platelet activation (HIPA)
Functional Assay
Platelet aggregation assay (PAA)
performed by many laboratories
incubate platelet-rich plasma from normal donors with patient plasma and heparin
limited by poor sensitivity and specificity because heparin can activate platelets under these conditions, even in the absence of HIT antibodies
Antigen Assay
Antibodies against heparin/PF4 complexes (the major antigen of HIT) are measured by colorimetric absorbance
Two ELISA have been developed
Stago
GTI
limited by high cost
Management of HIT
risk for thrombosis is high in HIT, prevention of thrombosis is the goal of intervention
heparin is contraindicated in patients with HIT
discontinuation of heparin -