Heparin-induced thrombocytopenia (HIT) type II is a complex clinical syndrome. It is an immune reaction to heparin in which the formation of antibodies targeted against the heparin-platelet factor 4 complex results in platelet activation. Platelet activation plays a central role in HIT; however, platelet activation does not occur as an isolated physiologic response. To elucidate further the mechanism of thrombogenesis in HIT, we undertook studies to determine the effect of heparin antibodies on endothelial cells, leukocytes, and the inflammatory state. We summarize our previous and new findings. For endothelial cells: Antiheparin antibodies bind to and directly activate microvascular endothelial cells, whereas binding to and activating macrovascular endothelial cells requires preactivation by platelets or tumor necrosis factor alpha (TNFα). Increased circulating levels of hemostatic activation factors as observed with thrombosis, particularly soluble P-selectin, plasminogen activator inhibitor type 1 (PAI-1), tissue factor, and thrombomodulin, were associated with endothelial cell activation and were also found in the blood circulation of patients with HIT. For the inflammatory state: Neutrophils and monocytes (but not lymphocytes) bind to and form complexes with platelets in the presence of HIT antibodies. Activated monocytes bind to endothelial cells and produce a procoagulant state. Patients with HIT have an increased level of cytokines in their blood circulation. For HIT antibodies: Only heparin fractions larger than 5 kd interacted with HIT antibodies, explaining why low-molecular-weight heparin (LMWH) usually does not generate antibodies. HIT antibodies are heterogeneous in structure, affinity, and specificity. These data suggest that, in addition to the platelet component, several other mechanisms are associated with the pathophysiology of HIT. These include an inflammatory state, endothelial cell remodeling, and the known procoagulant state. Differences between patients in the levels of the inflammatory markers may relate to various stages of the inflammatory/procoagulant state that exists in patients with HIT. The variations within the HIT antibodies may influence their ability to activate platelets, endothelial cells, and leukocytes, and thus contribute further to the variations in the pathogenicity of HIT.
KEYWORDS
Heparin-induced thrombocytopenia (HIT) - platelet factor 4 - endothelium - inflammation - antibodies - thrombosis
REFERENCES
-
1
Chong B H.
Heparin-induced thrombocytopenia (review).
Br J Haematol.
1995;
89
431-439
-
2
Warkentin T E, Kelton J G.
A 14-year study of heparin-induced thrombocytopenia.
Am J Med.
1996;
101
502-507
-
3
Wallis D E, Workman D L, Lewis B E, Pifarré R, Moran J F.
Failure of early heparin cessation as a treatment for heparin-induced thrombocytopenia.
Am J Med.
1999;
106
629-635
-
4
Amiral J, Bridey F, Dreyfus M et al..
Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia.
Thromb Haemost.
1992;
68
95-96
-
5
Kelton J G, Sheridan D, Santos A et al..
Heparin-induced thrombocytopenia: laboratory studies.
Blood.
1988;
72
925-930
-
6
Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C.
Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen.
Thromb Haemost.
1994;
71
247-251
-
7
Kelton J G, Smith J W, Warkentin T E, Hayward C P, Denomme G A, Horsewood P.
Immunoglobulin G from patients with heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4.
Blood.
1994;
83
3232-3239
-
8
Amiral J, Marfaing-Koka A, Ponce M, Meyer D.
The biological basis of immune heparin-induced thrombocytopenia.
Platelets.
1998;
9
77-91
-
9
Suh J S, Malik M I, Aster R H, Visentin G P.
Characterization of the humoral response in heparin-induced thrombocytopenia.
Am J Hematol.
1997;
54
196-201
-
10
Amiral J, Bridey F, Wolf M et al..
Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases.
Thromb Haemost.
1995;
73
21-28
-
11
Mikhailov D, Young J C, Linhardt R J, Mayo K H.
Heparin dodecasaccharide binding to platelet factor-4 and growth related protein-α. Induction of a partially folded state and implications for heparin-induced thrombocytopenia.
J Biol Chem.
1999;
274
25317-25329
-
12
Anderson C L, Chako G W, Osborne J M, Brandt J T.
The Fc receptor for immunoglobulin G (FcγIIA) on human platelets.
Semin Thromb Hemost.
1995;
21
1-9
-
13
Chong B H, Ismail F, Chesterman C N, Berndt M D.
Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets.
Br J Haematol.
1989;
73
235-240
-
14
Newman P M, Chong B.
Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation.
Blood.
2000;
96
182-187
-
15
Jeske W P, Walenga J M, Szatkowski E et al..
Effect of glycoprotein IIb/IIIa antagonists on the HIT serum induced activation of platelets.
Thromb Res.
1997;
88
271-281
-
16
Greinacher A, Michels I, Mueller-Eckhardt C.
Heparin-associated thrombocytopenia: the antibody is not heparin specific.
Thromb Haemost.
1992;
67
545-549
-
17
Walenga J M, Koza M J, Lewis B E, Pifarré R.
Relative heparin induced thrombocytopenic potential of low molecular weight heparins and new antithrombotic agents.
Clin Appl Thromb Hemost.
1996;
2
521-527
-
18
Cines D B, Tomaski A, Tannenbaum S.
Immune endothelial-cell injury in heparin-associated thrombocytopenia.
N Engl J Med.
1987;
316
581-589
-
19
Visentin G P, Ford S E, Scott J P, Aster R H.
Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells.
J Clin Invest.
1994;
93
81-88
-
20
Alberto M F, Bermejo E I, Lazzari M A.
Fcγ receptors on human umbilical vein endothelial cells. Evaluation by flow cytometry.
Thromb Haemost.
1997;
(suppl 1)
142
, (abst)
-
21
Herbert J M, Savi P, Jeske W P, Walenga J M.
Effect of SR121566A, a potent GPIIb/IIIa antagonist, on the HIT serum/heparin-induced platelet mediated activation of human endothelial cells.
Thromb Haemost.
1998;
80
326-331
-
22
Blank M, Shoenfeld Y, Tavor S et al..
Anti-PF4/heparin antibodies from patients with heparin-induced thrombocytopenia provoke direct activation of microvascular endothelial cells.
Intern Immunol.
2002;
14
121-129
-
23
Walenga J M, Michal K, Hoppensteadt D, Wood J J, Bick R L, Robinson J A.
Vascular damage correlates between heparin-induced thrombocytopenia and the antiphospholipid syndrome.
Clin Appl Thromb Hemost.
1999;
5:(suppl 1)
S76-S84
-
24
Fareed J, Walenga J M, Hoppensteadt D A et al..
Selectins in the HIT syndrome: pathophysiologic role and therapeutic modulation.
Semin Thromb Hemost.
1999;
25(suppl 1)
37-42
-
25
Jeske W P, Schlenker R, Bakhos M, Walenga J M.
Are leukocytes important for platelet activation in heparin-induced thrombocytopenia?.
Ann Hematol.
2000;
79(suppl I)
A46
, (abst)
-
26
Pouplard C, Lochmann S, Renard B et al..
Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia.
Blood.
2001;
97
3300-3302
-
27
Arepally G M, Mayer I M.
Antibodies from patients with heparin-induced thrombocytopenia stimulate monocytic cells to express tissue factor and secrete interleukin-8.
Blood.
2001;
98
1252-1254
-
28
Baugh M J, Prechel M, Hoppensteadt D, Wallis E R, Bick R L, Walenga J M.
The role of CD40-ligand and anti-annexin V antibodies in the pathophysiology of the APS and HIT.
Blood.
2000;
96
272
, (abst)
-
29
Ahmad S, Walenga J M, Jeske W P, Hoppensteadt D A, Bakhos M.
Molecular weight and charge dependence of heparin on the pathogenic responses of anti-heparin platelet factor 4 antibodies.
Thromb Haemost.
2001;
(suppl)
P2729
, (abst)
-
30
Warkentin T E, Levine M N, Hirsh J et al..
Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.
N Engl J Med.
1995;
332
1330-1335
-
31
Ahmad S, Haas S, Hoppensteadt D A et al..
Differential effects of clivarin and heparin in patients undergoing hip and knee surgery for the generation of anti-heparin-platelet factor 4 antibodies.
Thromb Res.
2003;
108
49-55
-
32
Ahmad S, Walenga J M, Jeske W P et al..
Lack of thrombocytopenic responses after low molecular weight heparin usage is due to the generation of non-functional anti-heparin-PF4 antibodies.
Blood.
1999;
94
624
, (abst)
-
33
Walenga J M, Ahmad S, Hoppensteadt D A et al..
Persistent use of a low molecular weight heparin, certoparin, at therapeutic dosage does not result in thrombocytopenia despite the generation of anti-heparin-PF4 antibodies.
Blood.
1999;
94
30
, (abst)
-
34
Ahmad S, Demir M, Walenga J M et al..
Prolonged subcutaneous administration of an ultra-low molecular weight heparin, OP2000, does not result in thrombocytopenia despite high prevalence of anti-heparin-PF4 antibodies.
Thromb Haemost.
2001;
(suppl)
P2727
, (abst)
-
35
Mattioli A V, Bonetti L, Sternieri S, Mattioli G.
Heparin-induced thrombocytopenia in patients treated with unfractionated heparin: prevalence of thrombosis in a 1 year follow-up.
Ital Heart J.
2000;
1
39-42
-
36
Williams R T, Damaraju L V, Mascelli M A et al..
Anti-platelet factor 4/heparin antibodies. An independent predictor of 30-day myocardial infarction after acute coronary ischemic syndromes.
Circulation.
2003;
107
2307-2312
-
37
Ahmad S, Walenga J M, Jeske W P, Cella G, Fareed J.
Functional heterogeneity of anti-heparin-platelet factor 4 antibodies: implications in the pathogenesis of the HIT syndrome.
Clin Appl Thromb Hemost.
1999;
5(suppl 1)
S32-S37
-
38
Prechel M M, Woznica D V, McDonald M K, Walenga J M.
Activation of platelets by HIT antibodies in vitro is not dependent on the presence of heparin.
J Thromb Haemost.
2003;
1(suppl 1)
1787
, (abst)
-
39
Amiral J, Pouplard C, Vissac A M, Walenga J M, Jeske W, Gruel Y.
Affinity purification of heparin-dependent antibodies to platelet factor 4 developed in heparin-induced thrombocytopenia: biological characteristics and effects on platelet activation.
Br J Haematol.
2000;
109
336-341
-
40
Walenga J M, Koza M J, Lewis B E, Pifarré R.
Relative heparin-induced thrombocytopenic potential of low molecular weight heparins and new antithrombotic agents.
Clin Appl Thromb Hemost.
1999;
2(suppl 1)
S21-S27
-
41
Haas S, Walenga J M, Jeske W P, Fareed J.
Heparin-induced thrombocytopenia: clinical considerations of alternative anticoagulation with various glycosaminoglycans and thrombin inhibitors.
Clin Appl Thromb Hemost.
1999;
5
52-59
-
42
Lewis B E, Wallis D E, Berkowitz S D et al..
for the ARG-911 Study Investigators .
Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia.
Circulation.
2001;
103
1838-1843
-
43
Greinacher A, Volpel H, Janssens U, Pötzsch B. for the HIT Investigators Group .
Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia. A prospective study.
Circulation.
1999;
99
73-80
-
44
Walenga J M, Lewis B E, Jeske W P et al..
Combined thrombin and platelet inhibition treatment for HIT patients.
Hämostaseologie.
1999;
19
128-133
-
45
Haas S, Walenga J M, Jeske W P, Fareed J.
Heparin-induced thrombocytopenia: the role of platelet activation and therapeutic implications.
Semin Thromb Hemost.
1999;
25(suppl 1)
67-76
Dr.
J.M. Walenga
Cardiovascular Institute, Loyola University Medical Center
Maywood, IL 60153
eMail: jwaleng@lumc.edu
