Pathophysiology of Heparin-Induced Thrombocytopenia.Clinical and Diagnostic Implications--A Review
Among the known side effects Side effects
Effects of a proposed project on other parts of the firm. of heparin therapy, thrombocytopenia Thrombocytopenia Definition
Thrombocytopenia is an abnormal drop in the number of blood cells involved in forming blood clots. These cells are called platelets. is without doubt the most frequent and dangerous. There are 2 types of heparin-induced thrombocytopenia heparin-induced thrombocytopenia Acquired thrombocytopenia affecting some heparin-treated Pts–HTPs, defined as a ↓ platelet count during or shortly after heparin exposure; HIT is a markedly prothrombotic disorder seen in Pts who are at a high baseline (HIT). Heparin-induced thrombocytopenia I is characterized by a transitory and asymptomatic reduction in the platelet count Platelet Count Definition
A platelet count is a diagnostic test that determines the number of platelets in the patient's blood. Platelets, which are also called thrombocytes, are small disk-shaped blood cells produced in the bone marrow and involved in , rarely below 100 x [10.sup.9]/L, that resolves spontaneously and does not require removal of the drug. The origin of HIT I is not yet completely known, but is thought to be related to a phenomenon of heparin-induced platelet clumping.[1-3] No immunologic components are involved in HIT I, and pathologic manifestations are rare.
Heparin-induced thrombocytopenia II has an immunologic origin[4,5] and is characterized by a significant reduction in platelets ([is greater than] 30%), generally after the fifth day of therapy; in the case of previous exposure to heparin, thrombocytopenia may appear earlier. The thrombocytopenia usually resolves 5 to 15 days after heparin has been removed, but in some cases it may take months.[6-8] The pathophysiologic manifestations of HIT II are complex and involve thrombosis at arterial, venous, and microvascular sites.
The true incidence of HIT II is not well defined because reported studies are mostly retrospective and differ regarding the characteristics of the patients considered, type of heparin administered, dosage, route of administration, duration of therapy, definition of thrombocytopenia, and laboratory tests employed for diagnostic confirmation (Table 1).[7,9,10] With reference to prospective studies in which the diagnosis was clinically based, there are important differences in the definition of thrombocytopenia. In some studies, the threshold value is 150 x [10.sup.9]/L,[11-17] while in others it is 100 x [10.sup.9]/L[18-30]; other investigators use the percent decrease as their reference. A relationship between the incidence of HIT II (defined only on a clinical basis), dosage, and type of unfractionated heparin used emerged from a study by Warkentin. The incidence was about 5% for therapeutic dosages of bovine heparin and 1% for porcine porcine /por·cine/ (por´sin) pertaining to swine.
pertaining to pig. See also hog (1), swine.
porcine circovirus 1
a nonpathogenic virus. heparin, while it was less than 1% with prophylactic dosages of porcine heparin. In this series, the incidence of secondary thrombotic complications was about 20%. In a later review of prospective clinical trials, the incidence of HIT II varied from 1% to 30% in patients treated with high dosages of intravenous heparin, while it was less than 2% in patients administered low dosages of subcutaneous heparin.
Table 1. Epidemiology of Heparin-Induced Thrombocytopenia (HIT) General consensus of incidence <5% due to treatment with bovine heparin 1% due to treatment with porcine heparin <1% due to prophylaxis Thrombotic complications in 20% to 30% of HIT patients Incidence numbers depend on Patient characteristics Type of heparin Dose Route of administration Duration of therapy Definition of thrombocytopenia Confirmation by laboratory test
Schmitt and Adelman reviewed 23 randomized ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. or cohort prospective studies for a total of 2160 patients in order to evaluate the impact of the various methodologic characteristics, such as HIT II definition, frequency with which platelet count was verified, and diagnostic criteria. This analysis confirmed that the incidence of HIT is overestimated in studies that do not include a "repeatedly abnormal platelet count." The cumulative incidence of HIT II in studies that employed "a reproducibly lowered platelet count" was 2.9% for bovine heparin and 1% for porcine heparin, and 1.7% for intravenous administration and 0% for subcutaneous administration. Even if this trend does not reach statistical significance, it speaks in favor of porcine heparin and subcutaneous administration of low dosages.
Our retrospective study retrospective study,
a study in which a search is made for a relationship between one phenomenon or condition and another that occurred in the past (e.g. disclosed a higher incidence. Independent of the route of administration, 6% of the patients had a clinical score suggestive of suggestive of Decision making adjective Referring to a pattern by LM or imaging, that the interpreter associates with a particular–usually malignant lesion. See Aunt Millie approach, Defensive medicine. HIT II, with a 30% incidence of thrombotic complications and a 30% mortality rate; these values are in line with other published reports.[6,8,34] However, using more selective clinical criteria, the percent incidence lowered to 3% and the diagnosis was confirmed by the presence of anti-heparin-platelet factor 4 (anti-H-PF4) antibodies in only a fraction of patients.
On the other hand, Kappers-Klunne et al reported a particularly low (0.3%) HIT incidence in 558 cardiologic and neurologic patients treated with intravenous heparin. In this study, both functional and immunologic tests were used for laboratory confirmation of the clinical diagnosis. Anecdotal reports[36,37] describe HIT II induced by low-molecular-weight heparin (LMWH LMWH Low Molecular Weight Heparin ), but one clinical study indicated that its use is associated with a lesser incidence of thrombocytopenic thrombocytopenic
of the nature of or pertaining to thrombocytopenia. and thrombotic complications than heparin.
A recent double-blind randomized study compared subcutaneous heparin with LMWH in 655 patients undergoing orthopedic surgery Orthopedic Surgery Definition
Orthopedic (sometimes spelled orthopaedic) surgery is surgery performed by a medical specialist, such as an orthopedist or orthopedic surgeon, trained to deal with problems that develop in the bones, joints, and ligaments ; the clinical diagnosis of HIT II was confirmed by means of the radioactive carbon ([sup.14]C)-serotonin-release assay (SRA SrA
senior airman ). Heparin-induced thrombocytopenia II was documented in 2.7% of the patients treated with subcutaneous heparin and in none of the patients receiving LMWH (P = .0018). Thrombotic complications were also more frequent in the former (88.9%) than in the latter (17.8%) group (P [is less than] .001). In a subgroup of patients, independent of the presence of HIT II, more heparin-treated than LMWH-treated patients had a positive functional test (7.8% vs 2.2%, P = .02); thrombotic episodes, however, were more frequent in the patients who developed HIT II than in those with only a positive functional test. Thus, the frequency of laboratory-confirmed HIT II seems to be about 2% in patients receiving heparin, while it is much lower in those who receive LMWHs.
PATHOPHYSIOLOGY pathophysiology /patho·phys·i·ol·o·gy/ (-fiz?e-ol´ah-je) the physiology of disordered function.
An immunologic basis of HIT II was first advocated by Rhodes et al, who showed that the immunoglobulin (Ig) G fraction from the serum of patients with HIT caused in vitro in vitro /in vi·tro/ (in ve´tro) [L.] within a glass; observable in a test tube; in an artificial environment.
In an artificial environment outside a living organism. platelet aggregation Platelet aggregation
The clumping together of blood cells, possibly forming a clot.
Mentioned in: Herbalism, Traditional Chinese in the presence of therapeutic concentrations of heparin. It has been reported that immunoglobulin-heparin complexes form only in the presence of platelets (Table 2). The proaggregating effect of heparin depends on the degree of sulfation and the molecular weight,[41-43] and is mediated by the release of substances from platelet [Alpha]-granules. Several platelet proteins/chemokines were proposed as the putative receptors of heparin-dependent antibodies, and PF4 was identified as the main cofactor cofactor
An atom, organic molecule, or molecular group that is necessary for the catalytic activity (see catalysis) of many enzymes. A cofactor may be tightly bound to the protein portion of an enzyme and thus be an integral part of its functional structure, or it may .[46,47] The ratio of heparin to PF4 is critical for the constitution of the multimolecular antigenic complex, with an optimal heparin-PF4 ratio ranging from 1:4 to 1:6.[6,43,48-50] The antibody is not exclusively specific for the heparin-PF4 (H-PF4) complex, but also marks complexes of PF4 and other glycosaminoglycans.[41-43,51]
Table 2. Pathophysiology of Heparin-Induced Thrombocytopenia(*)
Current knowledge Antibody to heparin-PF4 complex Antibody to other chemokines and glycosaminoglycans IgG, also IgA and IgM Antibody binds to platelet Fc receptor and/or direct binding to platelet Functional heterogeneity of antibodies Up-regulation of cell and adhesion molecules/inflammatory response Preactivation of platelets/endothelial cells/white blood cells? Predisposing factors for thrombosis
(*) Ig indicates immunoglobulin.
The Figure shows a diagrammatic representation of a modified version of the currently accepted mechanism of action and pathophysiology of HIT (Table 2). At therapeutic concentrations ranging from 0.1 to 1.0 U/mL, heparin displaces PF4 from endothelial endothelial /en·do·the·li·al/ (-the´le-al) pertaining to or made up of endothelium.
A layer of cells that lines the inside of certain body cavities, for example, blood vessels. heparan sulfate heparan sulfate /hep·a·ran sul·fate/ (hep´ah-ran) a glycosaminoglycan occurring in the cell membrane of most cells, consisting of a repeating disaccharide unit of glucosamine and uronic acid residues, which may be acetylated and or releases it directly from the platelets. Numerous PF4 molecules bind to heparin components, and the complex becomes immunogenic im·mu·no·gen·ic
Producing an immune response.
producing immunity; evoking an immune response. . As illustrated in the Figure, the immune complexes Immune complexes
Clusters or aggregates of antigen and antibody bound together.
Mentioned in: Wegener's Granulomatosis made up of anti-H-PF4 antibodies leading to the generation of 3 groups of antibodies (mainly IgG) activate the platelets and provoke an immune-mediated endothelial lesion[4,6,47,51,52] with thrombocytopenia, thrombosis, or both. The IgG anti-H-PF4 immune complex immune complex
Any of various complexes of an antigen and an antibody in the blood, to which complement may also be fixed, and which may form a precipitate. activates the platelets through the bond with the Fc[Gamma]RIIa (CD32) receptor, whose platelet surface expression ranges from 700 to 4000 binding sites and is further increased by the immune complex bond.[54,55] Platelet activation is blocked by both the monoclonal antibody monoclonal antibody, an antibody that is mass produced in the laboratory from a single clone and that recognizes only one antigen. Monoclonal antibodies are typically made by fusing a normally short-lived, antibody-producing B cell (see immunity) to a fast-growing (IV.3) specific for the Fc[Gamma]RIIa receptor[50,56] and the [F(ab').sub.2] fractions from patients with HIT II.[56,57] The Arg/His polymorphism polymorphism, of minerals, property of crystallizing in two or more distinct forms. Calcium carbonate is dimorphous (two forms), crystallizing as calcite or aragonite. Titanium dioxide is trimorphous; its three forms are brookite, anatase (or octahedrite), and rutile. at position 131 of the Fc[Gamma]RIIa receptor influences platelet reactivity to the immune complexes; in particular, the His/ His phenotype is more reactive to the Ig[G.sub.2] isotype i·so·type
An antigenic marker that occurs in all members of a subclass of an immunoglobulin class.
i . Nonetheless, while some studies have demonstrated a greater prevalence of HIT II and thrombotic complications in subjects with the His/His phenotype, others have not confirmed these findings. Other data are consistent with the hypothesis that H-PF4 complexes bind directly to platelets, and these complexes are the target for the [F(ab').sub.2] fraction of the antibody.
[Figure ILLUSTRATION OMITTED]
How the anti-H-PF4 antibodies cause thrombosis is not clear In general, Ig[G.sub.2]-isotype antiheparin antibodies are not particularly more frequent than the other subclasses in patients with HIT II, and IgM and IgA, which are not able to bind to to contract; as, to bind one's self to a wife s>.
See also: Bind Fc[Gamma]RIIa receptors, are also present in a significant percentage of these patients.[62-65] This finding suggests that the mechanism of platelet activation may occur independent of the Fc[Gamma]RIIa receptor for IgG. Moreover, the antibody isotype tends to modify in relation to the duration of the treatment.[49,61-64] The antibodies are still detectable in patient serum for about 4 to 6 weeks, and cases of antibody persistence for longer periods of time have been described.[6,33] Although the thrombotic complications in HIT syndrome are well described, only limited data have become available on the inflammatory components in this disease.
We have proposed a functional heterogeneity of anti-H-PF4 antibodies, based on the fact that heparin is a heterogeneous mixture of sulfated mucopolysaccharides mucopolysaccharides
n. with molecular, structural, and physical heterogeneity. Thus, heparins likely form multiple complexes with PF4, and depending on the nature of this interaction, the allosteric allosteric /al·lo·ster·ic/ (al?o-ster´ik) pertaining to allostery.
pertaining to an effect on the biological function of a protein, produced by a compound not directly involved in that function (an allosteric modifications in PF4 leading to a neoantigen formation may also vary. To characterize the anti-H-PF4 antibody in terms of functional heterogeneity, we obtained IgG fractions from the serum of patients with HIT II utilizing ammonium sulfate precipitation Ammonium sulfate precipitation is a method of protein purification by altering solubility of protein. It is a specific case of a more general technique known as salting out. (ASP) and H-PF4-sepharose 4B affinity chromatography Affinity chromatography is a chromatographic method of separating biochemical mixtures, based on a highly specific biologic interaction such as that between antigen and antibody, enzyme and substrate, or receptor and ligand. methods. With affinity purification, 2 major components, peaks 1 and 2, with high anti-H-PF4 antibody titers were eluted (purity was established by sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel electrophoresis
Electrophoresis performed in a gel composed of agarose, polyacrylamide, or starch. ). While peak 1 (despite having a high anti-H-PF4 antibody titer) did not induce serotonin release from platelets in a heparin-dependent manner, peak 2 and the IgGs obtained with the ASP method exhibited a strong and concentration-dependent activation in the presence or absence of heparin (as well as LMWHs) (Table 3). These data suggest the generation of "superactive" HIT antibodies capable of activating platelets without heparin. The anti-H-PF4 antibody titers of peak 1, peak 2, and the ASP-IgG as measured by the heparin-induced platelet aggregation test-enzyme-linked immunosorbent immunosorbent /im·mu·no·sor·bent/ (-sor´bent) an insoluble support for antigen or antibody used to absorb homologous antibodies or antigens, respectively, from a mixture; the antibodies or antigens so removed may then be eluted in pure assay (ELISA ELISA (e-li´sah) Enzyme-Linked Immuno-Sorbent Assay; any enzyme immunoassay using an enzyme-labeled immunoreactant and an immunosorbent.
n. ) (Stago, Asnieres, France) were similar.
Table 3. Platelet Activation in the Presence of 0.1 U/mL Heparin and Heparin-Induced Thrombocytopenia (HIT) Immunoglobulin Preparations(*)
% Serotonin Release Sample Range Mean [+ or -] SD HIT-negative serum 0-5 3.2 [+ or -] 1.1 HIT-positive serum 60-92 76 [+ or -] 6.2 Ig peak 1([dagger]) 2-8 4.1 [+ or -] 3.2 Ig peak 2([dagger]) 70-95 79 [+ or -] 3.6 IgG-ASP([double dagger]) 35-92 63 [+ or -] 9.7
(*) Ig indicates immunoglobulin; ASP, ammonium sulphate precipitation.
([dagger]) Isolated from patients (n = 6) clinically diagnosed with HIT II; protein content adjusted to 5 [micro]g/mL.
([double dagger double dagger
A reference mark () used in printing and writing. Also called diesis.
Noun 1. ]) Isolated from plasma samples of patients (n = 6) clinically diagnosed with HIT II; protein content adjusted to 50 [micro]g/mL.
To rule out the possible presence of a heparin contamination in these IgG preparations (and thus to confirm antibody activity independent of heparin), heparinase digestion, the use of an ion-exchange resin ion-exchange resin
Any of a wide variety of synthetic polymers containing positively or negatively charged sites that can interact with or bind to an ion of opposite charge from a surrounding solution. (Heparsorb), and dialysis against 1x phosphate-buffered saline were performed on the HIT sera, peak 2, and IgG-ASP. None of these treatments resulted in a significant decrease in the activation of platelets. These observations underscore the complex pathophysiology of HIT syndrome and suggest that there may be an HIT antibody active in a non-heparin-dependent manner.
Because the pathophysiology of HIT II involves the activation of platelets, endothelial cells Endothelial cells
The cells lining the inner walls of the blood vessels.
Mentioned in: Von Willebrand Disease , and leukocytes, it is reasonable to assume that cellular activation products, such as soluble selectins, cellular adhesion Cellular adhesion
The process whereby cells interact and attach to other cells or to inanimate surfaces, mediated by interactions between the molecules on the surface of the cell. molecules, or both, would be increased in HIT. Our studies showed that selectin levels were markedly elevated in HIT II patients (Table 4). Treatment of these patients with the direct thrombin inhibitor Direct thrombin inhibitors (DTIs) are a class of medication that act as anticoagulants (delaying blood clotting) by directly inhibiting the enzyme thrombin. Some are in clinical use, while others are undergoing clinical development. argatroban (Novastan, Texas Biotechnology Corp, Houston, Tex) was associated with some decrease in the level of selectins at 24 and 72 hours posttreatment. A similar decrease of soluble P-selectin levels was also noted when HIT patients were treated with other direct thrombin thrombin: see blood clotting. agents (eg, hirudin hirudin /hi·ru·din/ (hi-rldbomacd´in) the active principle of the buccal secretion of leeches; it prevents coagulation by acting as an antithrombin.
n. and hirulog) as alternative anticoagulation therapies. Since thrombin plays an important role in the activation of platelets, resulting in microparticle formation, the selectin-level down-regulation may be related to the inhibition of thrombin generation. In addition, we have observed an increase in the intracellular adhesion molecules and the vascular cell adhesion molecules in HIT patients.
Table 4. Soluble P-, E-, and L-Selectin Levels in Patients From the ARG See argument.
arg - argument 911 Clinical Trial of Heparin-Induced Thrombocytopenia(*)
Normal Marker (n = 20) sP-Selectin, ng/mL 27 [+ or -] 8 sE-Selectin, ng/mL 63 [+ or -] 12 sL-Selectin, ng/mL 1245 [+ or -] 140 Pretreatment Marker (n = 30-40) sP-Selectin, ng/mL 98 [+ or -] 10([dagger]) sE-Selectin, ng/mL 101 [+ or -] 15([double dagger]) sL-Selectin, ng/mL 1690 [+ or -] 40([double dagger]) 24 h Posttreatment Marker (n = 30-40) sP-Selectin, ng/mL 78 [+ or -] 7([dagger]) sE-Selectin, ng/mL 95 [+ or -] 14([double dagger]) sL-Selectin, ng/mL 1525 [+ or -] 165([sections]) 72 h Posttreatment Marker (n = 30-40) sP-Selectin, ng/mL 69 [+ or -] 6([dagger]) sE-Selectin, ng/mL 80 [+ or -] 11([double dagger]) sL-Selectin, ng/mL 1406 [+ or -] 149([sections])
(*) Citrated blood plasma blood plasma
The yellow or gray-yellow, protein-containing fluid portion of blood in which the blood cells and platelets are normally suspended. samples were collected at pretreatment pretreatment,
n the protocols required before beginning therapy, usually of a diagnostic nature; before treatment.
n See predetermination. and after 24 and 72 hours of argatroban anticoagulation (2-10 [micro]g/kg/min infusion adjusted to a therapeutic activated partial thromboplastin time Activated partial thromboplastin time
Partial thromboplastin time test that uses activators to shorten the clotting time, making it more useful for heparin monitoring. of 60-100 seconds). The selectins were measured using ELISA-based assays (R&D Systems). NS indicates not significant.
([dagger]) P < .01 compared to the normal control.
([double dagger]) P < .05 compared to the normal control.
([sections]) Not significant.
In an experimental mouse model, the formation of autoantibodies against the H-PF4 complex produced thrombocytopenia but not thrombosis. From a pathogenic point of view, it is likely that a state of platelet and endothelial cell preactivation and probably other unidentified factors contribute to the thrombotic phenomena.[6,52,69,70]
In HIT II, the onset of thrombocytopenia appears to be independent of the type of heparin, dosage, and route of administration. The entity of thrombocytopenia usually varies from 50 to 100 x [10.sup.9]/L, but severe cases are frequent (Table 5).[7,71] There is no gender predominance, although elderly patients undergoing postsurgical prophylaxis prophylaxis (prō'fĭlăk`sĭs), measures designed to prevent the occurrence of disease or its dissemination. Some examples of prophylaxis are immunization against serious diseases such as smallpox or diphtheria; quarantine to confine or treatment for deep vein thrombosis A blood clot (thrombos) in a vein deep within the muscle, typically in the thigh or calf. It is caused by disease or the lack of activity such as sitting for hours at a computer screen. ,[71,72] in particular orthopedic and cardiovascular surgery cardiovascular surgery Heart surgery An operation for repairing structural defects of the cardiovascular system Examples CABG, repair of congenital heart defects, varicose veins, aortic aneurysms, ventricular remodeling, transmyocardial , seem to be at higher risk. In more than 60% of the cases, other concomitant prothrombotic factors exist, such as diabetes, neoplasm neoplasm or tumor, tissue composed of cells that grow in an abnormal way. Normal tissue is growth-limited, i.e., cell reproduction is equal to cell death. , cardiac insufficiency cardiac insufficiency
See heart failure.
cardiac insufficiency Heart failure, see there , systemic lupus erythematosus Systemic Lupus Erythematosus Definition
Systemic lupus erythematosus (also called lupus or SLE) is a disease where a person's immune system attacks and injures the body's own organs and tissues. Almost every system of the body can be affected by SLE. , antiphospholipid syndrome Antiphospholipid syndrome (or antiphospholipid antibody syndrome) (APS) is a disorder of coagulation, which causes blood clots (thrombosis) in both arteries and veins, as well as pregnancy-related complications such as miscarriage, preterm delivery, or severe preeclampsia. , infection, and trauma. Besides thrombocytopenia, cutaneous cutaneous /cu·ta·ne·ous/ (ku-ta´ne-us) pertaining to the skin.
Of, relating to, or affecting the skin.
Pertaining to the skin. allergic manifestations and skin necrosis may be present.
Table 5. Clinical Presentation of Patients With Heparin-Induced Thrombocytopenia
Typically 50-100 x [10.sup.9]/L or less; no apparent thrombocytopenia observed in some patients No gender predominance Higher risk of thrombosis in elderly, following orthopedic surgery, and following cardiovascular surgery Other concomitant prothrombotic factors Skin necrosis/cutaneous allergic manifestation Arterial and venous thrombosis
Despite the thrombocytopenia, hemorrhagic Hemorrhagic
A condition resulting in massive, difficult-to-control bleeding.
Mentioned in: Hantavirus Infections
pertaining to or characterized by hemorrhage. events are not frequent, while the major clinical complication is thrombosis. Both arterial and venous thrombosis can complicate the course of HIT II. A worsening of the thrombosis or a new thromboembolic thromboembolic
pertaining to or emanating from thromboembolism.
see thromboembolic colic. complication necessitates the initial heparin treatment.[8,9,32,73] The thrombotic complications may appear even in the absence of thrombocytopenia. Arterial thrombosis was the first reported event to be associated with HIT[39,75]; nonetheless, today arterial and venous thrombotic complications are commonly found in HIT patients. Arterial thrombosis seems to be more frequent in patients with cardiovascular disease Cardiovascular disease
Disease that affects the heart and blood vessels.
Mentioned in: Lipoproteins Test
cardiovascular disease ,[34,71] and venous complications are found more often in patients undergoing postsurgical prophylaxis.[8,9,34,71] The most common arterial complications are thromboses of the large vessels with gangrene gangrene, local death of body tissue. Dry gangrene, the most common form, follows a disturbance of the blood supply to the tissues, e.g., in diabetes, arteriosclerosis, thrombosis, or destruction of tissue by injury. and limb amputation amputation (ăm'pyətā`shən), removal of all or part of a limb or other body part. Although amputation has been practiced for centuries, the development of sophisticated techniques for treatment and prevention of infection has greatly , stroke, myocardial infarction myocardial infarction: see under infarction. , and cardiac thrombosis.[4,5,32,34,71] Venous complications are deep vein thrombosis, pulmonary embolism Pulmonary Embolism Definition
Pulmonary embolism is an obstruction of a blood vessel in the lungs, usually due to a blood clot, which blocks a coronary artery. , thrombosis of the cerebral venous sinus venous sinus
A cavity at the caudal end of the embryonic cardiac tube in which veins from the intra- and extraembryonic circulatory arcs unite. In adults it develops into the sinuses of the venae cavae. , and closure of arterial-venous fistula fistula (fĭs`chlə), abnormal, usually ulcerous channellike formation between two internal organs or between an internal organ and the skin. in dialyzed di·a·lyze
tr. & intr.v. di·a·lyzed, di·a·lyz·ing, di·a·lyz·es
To subject to or undergo dialysis.
[Back-formation from dialysis. patients; disseminated intravascular coagulation disseminated intravascular coagulation
Abbr. DIC A hemorrhagic disorder that occurs following the uncontrolled activation of clotting factors and fibrinolytic enzymes throughout small blood vessels, resulting in tissue necrosis and and hemorrhagic adrenal adrenal /ad·re·nal/ (ah-dre´n'l)
2. adrenal gland.
3. pertaining to an adrenal gland.
1. necrosis have been documented occasionally.[4-7,32]
It is commonly believed that HIT II is underdiagnosed. During heparin therapy, platelet counts must be checked regularly, at least twice weekly, especially in patients receiving treatment for more than 4 days, in those who show resistance to heparin, or in patients who have treatment-related skin manifestations (Table 6). Once thrombocytopenia is confirmed, the diagnosis of HIT II should be formulated on the basis of clinical criteria and the in vitro demonstration of heparin-dependent antiplatelet antibodies.[5,7] Nonetheless, the diagnosis is still only clinically based (associated with negative laboratory results) in more than 20% of cases. To evaluate the clinical probability of HIT II, various scoring systems have been proposed based on the presence of thrombocytopenia, recovery following drug suspension, onset of thrombotic or cutaneous complications, and the exclusion of other causes of thrombocytopenia.[77,78] A score less than 3 is not associated with a diagnosis of HIT II. Heparin-induced thrombocytopenia II is possible with a score from 4 to 6, and a score greater than 6 is highly probable for HIT II.
Table 6. Diagnosis of Heparin-Induced Thrombocytopenia (HIT)
Platelet counts twice weekly, especially in patients with Heparin treatment > 4 d Heparin resistance Related skin manifestations Clinical score system(*) Thrombocytopenia Recovery following heparin discontinuation Thrombosis Cutaneous complications Exclusion of other causes Laboratory confirmation [sup.14]C-Serotonin release assay (platelet function test) HIT serum/heparin-induced platelet aggregation (platelet function test) Antibody titer to heparin-platelet factor 4 ELISA (immunologic test)
(*) Score <3 indicates not HIT; 4-6, possible HIT; >6, highly probable HIT.
Among the functional laboratory tests, the SRA is the reference procedure. This test is based on the capacity of heparin-dependent HIT antibodies to induce the release of [sup.14]C-serotonin from platelets. Serum from a patient suspected of having HIT II is incubated with therapeutic heparin concentrations (0.1-1.0 U/mL) and washed donor platelets labeled with [sup.14]C-serotonin. If heparin-dependent antibodies are present, platelets are activated and the labeled serotonin is released. In the presence of high heparin concentrations (10-100 U/mL) the release is inhibited. This method has several disadvantages in that it requires the use of radioactive material radioactive material Radiation A substance that contains unstable–radioactive–atoms that give off radiation as they decay. See Radioactive decay. , the result is highly dependent on the characteristics or reactivity of the donor platelets,[79,80] and it is time-consuming.
The platelet aggregation test Platelet Aggregation Test Definition
Platelets are disk-shaped blood cells that are also called thrombocytes. They play a major role in the blood-clotting process. The platelet aggregation test is a measure of platelet function. , which utilizes a principle similar to that of the SRA, is able to furnish quicker results. This test measures platelet aggregation induced by the HIT patient serum in the presence of therapeutic concentrations of heparin. While this method is widely used due to its relative simplicity, the results vary considerably more than those reported for SRA in relation to the different heparin concentrations and donor platelet variability.[5,7,32,80,81] The overall sensitivity of this test is less than that of the SRA.[80,81]
The heparin-induced platelet aggregation test on micro-ELISA plates demonstrates greater reliability and correlation with the SRA than the platelet aggregation test. This test is based on the visual evaluation of the aggregation of washed platelets from different donors in the presence of heparin utilizing a magnetically shaken microplate.
Regardless of the functional method used to detect HIT antibodies, the selection of the donor platelets is crucial.[79,80] Under the most optimal conditions, the sensitivity of the aggregation and the SRA methods can reach 88% and 94%, respectively.[4,5,7,32,83] The typical response, however, is 50% to 60% sensitivity of these assays.
Recently, other functional tests have been suggested, such as the bioluminescent bi·o·lu·mi·nes·cence
Emission of visible light by living organisms such as the firefly and various fish, fungi, and bacteria.
bi adenosine adenosine /aden·o·sine/ (ah-den´o-sen) a purine nucleoside consisting of adenine and ribose; a component of RNA. It is also a cardiac depressant and vasodilator used as an antiarrhythmic and as an adjunct in myocardial perfusion imaging nucleotide-release assay or the binding of annexin V to platelet membrane anionic an·i·on
A negatively charged ion, especially the ion that migrates to an anode in electrolysis.
[From Greek, neuter present participle of anienai, to go up : ana-, ana- phospholipids utilizing flow cytometry flow cytometry (flōˑ sī·tˑ·m . As these tests also employ donor platelets, they too would be affected by platelet variability. Other flow cytometric assays have been developed using small volumes of patient platelets or whole blood.[85,86] This approach could provide a major advantage over all other tests described if sensitivity and specificity to HIT are proven. Another recently described test employs a solid-phase adherence method to demonstrate the presence of heparin-dependent antibody.
Following the demonstration of antibodies against the H-PF4 complex in the serum of patients with HIT II, the ELISA technique for the detection of these antibodies was introduced.[46,49,50] Patient serum is incubated with the H-PF4 complex, and the presence of antibodies is detected with a secondary antibody A secondary antibody is an antibody that binds to primary antibodies or antibody fragments. They are typically labeled with probes that make them useful for detection, purification or cell sorting applications. conjugated conjugated
estrogens, conjugated Warning - Hazardous drug!
C.E.S. with peroxidase peroxidase /per·ox·i·dase/ (per-ok´si-das) any of a group of iron-porphyrin enzymes that catalyze the oxidation of some organic substrates in the presence of hydrogen peroxide.
n. or alkaline phosphatase alkaline phosphatase /al·ka·line phos·pha·tase/ (ALP) (fos´fah-tas) an enzyme that catalyzes the cleavage of orthophosphate from orthophosphoric monoesters under alkaline conditions. . The ELISA showed a good correlation with the SRA procedure,[78,81,88] but comparison with the aggregation method was less reliable.[78,81,89] The ELISA method is characterized by greater sensitivity and reproducibility than the functional tests, and this procedure is technically easier to perform. However, the ELISA has demonstrated questionable specificity, in that anti-H-PF4 antibodies are detected in heparin-treated patients who did not present thrombocytopenia and in most patients undergoing heart surgery.[31,35,51,62,64,90-92] More importantly, this test was negative in some patients with HIT confirmed clinically or by positive functional tests.[78,81,88] It has been suggested that HIT II only occurs with high antibody titers and after persistent exposure to heparin,[64,90,93] and also that antigens different from the H-PF4 complex can be involved in the pathogenesis. In addition, assays from different manufacturers have different sensitivities and specificities.
In general, however, aside from the varying sensitivity levels of the methods and the lack of standardization, ELISA tests have proven to be predictive of the diagnosis of HIT II.[64,90] Therefore, especially in the absence of a highly suggestive clinical picture, it appears appropriate to support the clinical diagnosis with a functional test, as well as with measurement of the anti-H-PF4 antibody titer by ELISA.[48,79,82,87-89,96]
The best therapeutic strategy for patients with HIT II is not established, but reasonable guidelines have a wide consensus (Table 7). If HIT II is clinically probable, heparin therapy must be discontinued immediately, even in the absence of a confirmatory laboratory test. Platelet transfusion platelet transfusion The administration of platelets to ↑ platelet concentration in the circulation. See Platelet antigens.
Platelet transfusion guidelines
Platelet count–PC < 20 x 109/L–US: < 20 000/mm is contraindicated because it may worsen the thrombotic picture. Anticoagulant therapy anticoagulant therapy Hematology The use of anticoagulants to prevent intravascular clot formation, or dissolve clots that have already formed Indications DVT/thrombophlebitis, CAD, TIA/stroke, dysrhythmia, prosthetic heart valve, cancer Monitoring Serial with vitamin K vitamin K
Any of several fat-soluble compounds essential for the clotting of blood. A deficiency of vitamin K in the body leads to an increase in clotting time. In 1929 a previously unrecognized fat-soluble substance present in green leafy vegetables was found to be required antagonists should be initiated 3 or 5 days after heparin suspension, when platelet counts are increasing, but preferably before resolution of the thrombocytopenia to avoid potential worsening of the thrombotic picture.[6,97] However, heparin discontinuation dis·con·tin·u·a·tion
A cessation; a discontinuance.
Noun 1. discontinuation - the act of discontinuing or breaking off; an interruption (temporary or permanent)
discontinuance alone and substitution with dicumaroids do not prevent the onset of severe thrombotic complications in nearly 50% of affected patients.[8,34,97] On the basis of these disappointing results, new approaches have been proposed that have included the use of LMWH, heparinoids, anticoagulating agents such as ancrod, prostaglandin prostaglandin (prŏs'təglăn`dən), any of a group of about a dozen compounds synthesized from fatty acids in mammals as well as in lower animals. (Iloprost), antiplatelet drugs, and thrombin inhibitors (argatroban and hirudin).
Table 7. Therapeutic Treatments for Patients With Heparin-Induced Thrombocytopenia (HIT)
Therapy contraindicated for patients with HIT Platelet transfusion Low-molecular-weight heparin Primary Discontinue heparin Substitute anticoagulant therapy Antithrombin drugs (argatroban, hirudin) Heparinoid (if negative laboratory test) Immunoglobulin Plasmapheresis Vitamin K antagonist (3-5 days after heparin cessation with increasing platelets) New approaches (preliminary) Antiplatelet drugs (GPIIb/IIIa inhibitors) Antithrombin agents (argatroban, hirudin) Pentasaccharide Secondary Ancrod Thrombolytics Vena cava filter Prostaglandin Thrombectomy Immune suppression
Low-molecular-weight heparins, heparinoids, ancrod, argatroban, and hirudin have been used in a significant number of patients.[4-6,9,75,98-100] A small clinical trial was conducted with ancrod, a viper-derived venom with anticoagulant anticoagulant (ăn'tēkōăg`yələnt), any of several substances that inhibit blood clot formation (see blood clotting). action that showed efficacy. Other reports describe the use of plasmapheresis plasmapheresis, see apheresis. to remove immune complexes, or high doses of immunoglobulin alone or associated with LMWH and a heparinoid. Also indicated for use in patients with HIT II are thrombolytic agents; the insertion of filters in the inferior vein cava; and, in the case of arterial thrombosis, with limb ischemia, embolectomy embolectomy /em·bo·lec·to·my/ (em?bo-lek´tah-me) surgical removal of an embolus.
Surgical removal of an embolus.
surgical removal of an embolus. , or thrombectomy thrombectomy /throm·bec·to·my/ (throm-bek´tah-me) surgical removal of a clot from a blood vessel.
Excision of a thrombus. .[4-6,92]
The rationale for the use of LMWHs in HIT II resided in the diminished interaction with PF4 of these heparins with decreased molecular weight and degree of sulfation.[51,98,105] However, the cross-reactivity with heparin-induced antibodies in vitro was shown to range from 60% to 100%.[4,51,81,97,106,107] Low-molecular-weight heparins should not be administered to patients with heparin antibody unless the absence of cross-reactivity has been demonstrated by an in vitro test. Nonetheless, some reports describe cases in which the use of LMWH was efficacious in controlling HIT even though cross-reactivity with heparin had been evidenced.[104,108]
In a study from our group, 2 synthetic pentasaccharides (SR90107A/Org31540 and SanOrg34006), which are in clinical development for the prophylaxis of postsurgical deep vein thrombosis, were tested in comparison to heparin and an LMWH (enoxaparin) for their relative platelet activation potential in HIT assays. Sera from patients with HIT II (n = 25), validated for heparin-dependent aggregation responses, and antibodies purified by H-PF4-sepharose column separation were used to study the effects of the 4 drugs using platelet aggregation. At comparable concentrations, heparin and enoxaparin consistently produced platelet activation (Table 8), whereas both pentasaccharides failed to produce a response at concentrations up to 100 U/mL (~50 [micro]mol/L). Similarly, in the SRA and flow cytometric assays, both heparin and enoxaparin produced positive responses, whereas the 2 pentasaccharides consistently failed to produce any effect.
Table 8. Heparin-Induced Thrombocytopenia (HIT) Sera-Mediated Platelet Activation Determined by Functional Assays of HIT(*)
% Platelet % Serotonin Agents Aggregation Release Heparin, U/mL Saline 12 [+ or -] 3 68 [+ or -] 8 0.1 54 [+ or -] 10 76 [+ or -] 6.2 100 15 [+ or -] 4 5 [+ or -] 3 Enoxaparin, U/mL 0.1 45 [+ or -] 6 80 [+ or -] 9 100 11 [+ or -] 3.9 49 [+ or -] 7 Pentasaccharide, U/mL([dagger]) 1.0 16 [+ or -] 3 7 [+ or -] 2 10 18 [+ or -] 2 8 [+ or -] 4 100 19 [+ or -] 4 7 [+ or -] 3 % P-Selectin % Microparticle Agents Expression Formation Heparin, U/mL Saline 5 [+ or -] 2 4.1 [+ or -] 3 0.1 50 [+ or -] 7 24 [+ or -] 17 100 10 [+ or -] 2.5 8 [+ or -] 3.5 Enoxaparin, U/mL 0.1 45 [+ or -] 8 30 [+ or -] 9 100 12 [+ or -] 4 9 [+ or -] 3 Pentasaccharide, U/mL([dagger]) 1.0 6 [+ or -] 2 4 [+ or -] 1 10 5 [+ or -] 2 10 [+ or -] 3 100 7 [+ or -] 3 5 [+ or -] 2
(*) Data represent mean percent [+ or -] SEM responses of 25 HIT patient sera. Similar results were observed with 2 different pentasaccharides (see reference 109).
We have further shown that in patients from a clinical trial substudy in which pentasaccharide was administered for the prophylaxis of deep vein thrombosis after hip surgery, no anti-H-PF4 antibody was detected during the treatment period (n = 10). However, in a comparable study with enoxaparin, 6 of 20 patients without clinical thrombocytopenia showed a positive anti-H-PF4 antibody titer. The observations from these studies suggest that the pentasaccharides with highly selective anti-Xa activity are devoid of generating anti-H-PF4 antibody, do not produce HIT responses in the presence of antibody, and may inhibit active HIT antibody platelet activation.
The major reported experiences of HIT treatment concern danaparoid sodium (Org10172, danaparoid, Lomoparan; Organon or·ga·non or or·ga·num
n. pl. or·ga·nons or or·ga·nums or or·ga·na
1. An organ.
2. A set of principles for use in scientific investigation.
pl. organa [Gr.] organ. , Oss, The Netherlands), a mixture containing heparan sulfate (85%), dermatan sulfate der·ma·tan sulfate
A mucopolysaccharide that is a structural component of certain body tissues, especially the skin.
a component of the acellular ground substance of skin. (10%), and chondroitin sulfate chondroitin sulfate /chon·dro·i·tin sul·fate/ (kon-dro´i-tin)
1. a glycosaminoglycan that predominates in connective tissue, particularly cartilage, bone, and blood vessels, and in the cornea.
2. (5%), whose cross-reactivity with heparin in vitro is less than 10%.[9,33,48] More than 600 patients with HIT II have been treated successfully with this drug, with a remarkable reduction in mortality due to thrombotic complications and in overall mortality in patients treated early.[9,75,104,110,111] However, cases of failure of treatment[106,112] or of danaparoid-induced fatal thrombotic thrombocytopenia have also been reported. In particular, treatment with danaparoid resolved thrombocytopenia in 91% of cases and significantly reduced mortality due to thrombotic complications of HIT from 28% to 5%, but did not reduce total mortality, which was 20%.[9,76] Danaparoid has been approved for the treatment of HIT II in New Zealand New Zealand (zē`lənd), island country (2005 est. pop. 4,035,000), 104,454 sq mi (270,534 sq km), in the S Pacific Ocean, over 1,000 mi (1,600 km) SE of Australia. The capital is Wellington; the largest city and leading port is Auckland. , Denmark, Luxembourg, Belgium, and Portugal.
Direct thrombin inhibitors are indicated for the treatment of HIT II. The first large-scale clinical trial of HIT patients treated with a thrombin inhibitor used argatroban, a thrombin inhibitor based on the structure of L-arginine. A number of patients with HIT II-associated thrombosis requiring angioplasty were also successfully treated with argatroban.[100,115] Hirudin, another thrombin inhibitor, was evaluated for use in the treatment of HIT II (mostly in Germany), and it was found to be efficacious.[116,117]
A further theoretical possibility, especially for patients with severe thrombotic complications refractory to thrombin inhibitor treatment alone, is the use of antiplatelet agents.[4-6] It has recently been demonstrated by several in vitro studies that antagonists of GPIIb/IIIa (Abciximab, Tirofiban, and Eptifibatide) are able to inhibit platelet aggregation induced by the serum of patients with HIT II.[86,118-121] The in vitro inhibition by GPIIb/IIIa inhibitors was more effective than inhibition of platelet activation by aspirin, as shown by SRA, platelet aggregation, and flow cytometry assays. The clinical usefulness of this treatment, combined with low-dose antithrombin agents, has shown preliminary beneficial results.[118,119]
Recently, we proposed that the prevalence of HIT antibodies in patients treated with immunosuppressive agents Immunosuppressive agents are a class of drugs which act to suppress the normal activity of the immune system. They are frequently used to prevent rejection of organs after organ transplant and also in the treatment of autoimmune disorders. (such as cyclosporine cyclosporine /cy·clo·spor·ine/ (-spor´en) a cyclic peptide from an extract of soil fungi that selectively inhibits T cell function; used as an immunosuppressant to prevent rejection in organ transplant recipients and to treat severe ) would be lower than in nontreated patients. Cyclosporine is used to suppress the immune systems of transplant recipients to prevent the production of antibodies against the foreign major histocompatibility histocompatibility: see transplantation, medical.
A term used to describe the genes that influence acceptance or rejection of grafts. factor of the donor organ, thus reducing the incidence of rejection. In testing the anti-H-PF4 antibody levels in cardiac surgery Cardiac surgery is surgery on the heart and/or great vessels performed by a cardiac surgeon. Frequently, it is done to treat complications of ischemic heart disease (for example, coronary artery bypass grafting), correct congenital heart disease, or treat valvular heart disease patients (n = 48) and cardiac transplant patients (n = 30), 23% of the cardiac surgery patients had positive antibody titers in contrast to 10% of transplant patients (Table 9). Of the positive cases, 6.3% of the cardiac surgery patients were positive by SRA, but none of the transplant patients were positive by SRA. Patients with rheumatoid arthritis rheumatoid arthritis
Chronic, progressive autoimmune disease causing connective-tissue inflammation, mostly in synovial joints. It can occur at any age, is more common in women, and has an unpredictable course. (n = 9) and antiphospholipid syndrome (n = 21), which was treated with heparin and immunosuppressive therapy Immunosuppressive therapy
Medical treatment in which the immune system is purposefully thwarted. Such treatment is necessary, for example, to prevent organ rejection in transplant cases. , did not exhibit a positive anti-H-PF4 antibody titer. These observations suggest that patients at high risk may be prophylactically treated with mild immunosuppression immunosuppression
Suppression of immunity with drugs, usually to prevent rejection of an organ transplant. Its aim is to allow the recipient to accept the organ permanently with no unpleasant side effects. prior to heparinization to minimize the risk of HIT II. Clinical investigations are needed to validate this hypothesis.
Table 9. Heparin-Induced Thrombocytopenia Assay Results in Cardiac Surgery and Cardiac Transplant Patients Receiving Cyclosporine
Positive Antibody No. of Titer(*) Group Patients (% Prevalence) Cardiac surgery 48 11 (22.9) Cardiac transplant 30 3 (10.0) SRA([dagger])-Positive Group (% Prevalence) Cardiac surgery 3 (6.3) Cardiac transplant 0 (0)
(*) Diagnostica Stago HPIA-ELISA; P < .01 cardiac surgery vs cardiac transplant (ELISA data).
([dagger]) SRA indicates [sup.14]C-serotonin release assay.
The pathophysiology of HIT is now known to be mediated by antibodies to the anti-H-PF4 complex. These antibodies represent a heterogeneous group of IgG, IgA, and IgM antibodies that are generated in response to the neoepitope formed by the complex formation of heparin and PF4. Their functional form is capable of interacting with Fc receptors to activate platelets and endothelial cells. Cytokines Cytokines
Chemicals made by the cells that act on other cells to stimulate or inhibit their function. Cytokines that stimulate growth are called "growth factors. are generated during this process as well. Activated platelets are consumed to form localized thrombi thrombi /throm·bi/ (throm´bi) plural of thrombus. , resulting in the white clot syndrome. Inflammation plays an important role in the overall pathophysiology of HIT, and the elevated circulating levels of inflammatory markers have been found in patients with HIT.
The clinical diagnosis of this complex syndrome is based on platelet counts and, in extreme cases, the identification of characteristic purplish lesions on the skin. The laboratory diagnosis of HIT can be accomplished by using immunologic, platelet aggregation, and serotonin-release assays; however, the diagnostic efficacy of these tests is variable.
Patients with HIT can receive alternative anticoagulation therapy with several different drugs; however, only antithrombin drugs, such as argatroban and hirudin, are approved for this indication. Ancrod, a snake venom; danaparoid, a depolymerized mixture of glycosaminoglycans; and nonheparin glycosaminoglycans (dermatans) have also been used with success for alternative anticoagulation therapy. Plasmapheresis has been used for the management of HIT as well. Currently, synthetic pentasaccharides are being developed clinically, and the initial data are strongly suggestive of antithrombotic efficacy without any heparin antibody-related complications. Low-molecular-weight heparins are not indicated for the management of these patients. It has been shown that the activation of platelets during the acute HIT syndrome is not fully controllable by anticoagulant medications. Antiplatelet drugs, especially GPIIb/IIIa receptor antagonists, have been found to produce therapeutic effects and control the platelet-mediated pathophysiologic mechanisms more effectively than thrombin inhibitors.
Although we have made progress in better understanding the pathophysiology of HIT and have found better therapeutic options, there remain unsettled diagnostic and treatment issues that need to be addressed.
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CMH Commission on Macroeconomics and Health
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[35.] Kappers-Klunne MC, Boon DMS (1) (Document Management System) See document management.
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1. Of or characterized by low blood pressure.
2. and diuretics Diuretics Definition
Diuretics are medicines that help reduce the amount of water in the body.
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Accepted for publication July 13, 2000.
From the Department of Medical and Surgical Sciences, University of Padua History
The university was founded in 1222 when a large group of students and professors left the University of Bologna in search of more academic freedom. The first subjects to be taught were jurisprudence and theology. , Medical School, Padua, Italy (Drs Fabris and Cella), and the Department of Pathology and Cardiovascular Institute, Loyola University Chicago Beginnings and expansions
Founded in 1870 as the St Ignatius College on Chicago's West Side. In 1908 the School of Law was established as the first of the professional programs. , Stritch School of Medicine This article or section has multiple issues:
* It does not cite any references or sources. Please help improve this article by citing reliable sources.
* Its notability is in question. If notability cannot be established, this article may be listed for deletion. , Maywood, Ill (Drs Ahmad, Jeske, Walenga, and Fareed).
Reprints: Jawed jawed
Having a jaw or jaws, especially of a specified kind. Often used in combination: slack-jawed; the jawed fishes.
Adj. 1. Fareed, PhD, Loyola University Chicago, Stritch School of Medicine, 2160 S First Ave, 102/2652, Maywood, IL 60153.