Page 2053 - Williams Hematology ( PDFDrive )

2028 Part XII: Hemostasis and Thrombosis Chapter 118: Heparin-induced Thrombocytopenia 2029

counterintuitive in that it may prevent HIT by partially or completely CLINICAL DIAGNOSIS
removing surface-bound PF4 (Fig. 118–3). If the level of circulat-
35
ing, free human PF4 in the mice was initially low relative to the level The clinical hallmark of HIT is development of thrombocytopenia in
of infused heparin, all surface-bound PF4 and detectable surface anti- the setting of a proximate heparin exposure. The combination of throm-
genicity would be removed and the circulating HIT antibodies would bocytopenia and heparin exposure in hospitalized patients is common
have no targets on platelets and other vascular cells (Fig. 118–3). HIT and has poor specificity for HIT. Therefore, other clinical clues must
50
therefore would not develop in spite of the presence of heparin and cir- be sought in estimating the clinical likelihood of HIT. These include
culating HIT antibody. On the other hand, if the level of circulating free timing, degree of platelet count fall, nadir platelet count, presence of
human PF4 in the mice was initially high relative to the infused heparin, thromboembolism or hemorrhage, and the likelihood of other causes
not all surface-bound PF4 would be removed. Circulating HIT antibod- of thrombocytopenia.
ies could then target and activate platelets and other vascular cells, lead-
ing to thrombocytopenia and thrombosis (Fig. 118–3). TIMING
Most patients likely begin with little PF4 bound to surface gly-
cosaminoglycans (GAGs). After therapeutic heparinization, the level of The platelet count in HIT characteristically begins to fall 5 to 10 days
23
surface PF4 goes down markedly so that the platelets cannot be tar- after initial heparin exposure. There are three exceptions to this
geted by anti-PF4–heparin HIT antibodies. However, patients with high rule: (1) in rapid-onset HIT, patients with recent heparin exposure
levels of surface PF4 and significant surface PF4 antigenic complexes (within the previous 90 days) and preformed anti-PF4–heparin IgG
remaining after heparinization may be at risk for binding of pathogenic experience a fall in platelet count immediately upon reexposure; (2)
anti-PF4–heparin HIT antibodies to platelets and other vascular cells. in delayed-onset HIT, clinical manifestations develop a median of 10
Bound pathogenic antibodies lead to thrombocytopenia by clearance to 14 days after heparin is discontinued 51,52 ; and (3) a small number
of antibody-coated platelets by the reticuloendothelial system. Bound of patients with spontaneous HIT have been reported. These patients
antibodies also lead to platelet activation through FcγRIIA and the present with a thrombotic thrombocytopenic disorder reminis-
53
formation of procoagulant platelet microparticles that contribute to cent of HIT in the absence of recognized heparin exposure. Both
thrombosis. 36 delayed-onset HIT and spontaneous HIT occur in the absence of
As part of this activation, HIT antibodies also bind to endothelial circulating heparin and may involve pathogenic HIT antibodies that
4,37
cells likely via PF4–surface GAG complexes, leading to local vascular recognize complexes of PF4 and endogenous GAGs on blood and vas-
activation and contributing to further local thrombosis. Additionally, cular cells.
40
HIT antibodies activate PF4-targeted monocytes 38,39 and neutrophils.
Monocyte activation may involve its surface Fcγ receptors with subse- DEGREE OF FALL IN PLATELET COUNT
41
quent increased tissue factor expression and other changes consistent The percentage fall in platelet count is measured from the peak platelet
with a prothrombotic and inflammatory state. Monocyte and neu- count after initiation of heparin to the nadir platelet count. Most patients
trophil GAGs are more complex than GAGs on the surface of platelets, with HIT experience a 50 percent or greater fall in platelet count; a more
which are mostly chondroitin sulfate and have relatively low affinity modest decline (30 to 50 percent) occurs in approximately 10 percent
42
for PF4. Monocytes and neutrophils bind PF4 with greater avidity of patients. 54
43
and are more resistant to removal of bound PF4 by circulating heparin
than platelets. In HIT, they may be preferentially targeted and activated
relative to the platelets, contributing to the prothrombotic state of this NADIR PLATELET COUNT
immune thrombocytopenia. 44 As opposed to most other forms of drug-induced immune thrombo-
Are there any genetic polymorphisms that are associated with an cytopenia, thrombocytopenia associated with HIT is characteristically
increased risk of developing HIT or developing thrombosis after HIT mild or moderate. The median nadir platelet count is approximately
begins? No clear linkage has been shown with known thrombophilic poly- 60 × 10 /L and rarely falls below 20 × 10 /L in the absence of concomi-
9
9
morphisms including Factor V Leiden , Prothrombin G20210A , MTHFR C677T , tant disseminated intravascular coagulation (DIC). The nadir platelet
54
α β and α β . Studies addressing a functional FcγRIIA R/H131 polymor- count in HIT need not meet the traditional definition of thrombo-
45
IIb 3
1 2
phism had varied outcome. 46,47 It is unclear whether patients with HIT cytopenia (<150 × 10 /L). For example, patients with postoperative
9
48
have a higher density of FcγRIIA on their platelets. High IgG affinity thrombocytosis may experience a subsequent greater than 50 percent
for the heparin–PF4 complex appears to affect the risk of developing decline in platelet count attributable to HIT that does not fall below this
HIT. threshold. 55
The model shown in Fig. 118–3 suggests that individuals with
high PF4 content in their platelets and/or sustained platelet activation
as might be seen in patients with significant atherosclerosis, a postsur- THROMBOSIS
gery state, or trauma would be most likely to develop HIT after hep- Thromboembolism is the presenting feature in up to 25 percent of
arinization and HIT antibody development. However, a relationship patients with HIT and complicates approximately half of all cases. 56,57
between formation of HIT antibodies and the degree of atherosclero- Lower-extremity deep vein thrombosis and pulmonary embolism are
sis in patients undergoing cardiopulmonary bypass surgery was not the most common thrombotic manifestations, outnumbering arte-
49
56
noted. If levels of PF4 on the surface of circulating cells determine risk rial events by approximately 2:1. Major venous obstruction can lead
of developing HIT, this would offer a potential method for prescreening to limb gangrene. Catheter-associated upper extremity deep venous
58
patients prior to heparinization and eliminate those at increased risk of thrombosis is common. Arterial thromboembolism most frequently
HIT or as a useful tool in heparinized patients who develop thrombocy- involves the extremities, but may also manifest as stroke or myocar-
56
topenia to see whether they potentially can develop HIT. Theoretically, dial infarction. Thrombosis of other vascular beds including cerebral
only those heparinized individuals with detectable surface PF4 would sinuses, mesenteric vessels, and adrenal veins is well-documented as
be potential candidates for developing HIT if they concurrently develop is thrombotic occlusion of vascular grafts, fistulas, and extracorporeal
pathogenic antibodies. circuitry.

Kaushansky_chapter 118_p2025-2034.indd 2028 9/18/15 5:43 PM