184
F I G U R E 1 1 -8
Schematic representation of the molecular organization of structural
elements in cartilage matrix. Collagen fibrils provide tensile forces, and
proteoglycans, because of their large solvent domains, accommodate
reversible compressible forces. LP = link protein; HA = hyaluronate;
KS = keratan sulfate; CS = chondroitin sulfate; PC = core protein.
[Reproduced with permission from L. C. Junqueira, J. Carneiro, and
J. A. Long,
B a sic H istology,
5th ed. Appleton & Lange, Norwalk, CT,
1986. ©1986 Appleton-Century-Crofts.]
Heparin is a heterogeneous glycosaminoglycan found
in tissues that contain mast cells (e.g., lungs and perivas-
cular connective tissue). Its primary physiological func-
tion is unknown, but it is a powerful inhibitor of blood
clotting and is used therapeutically for that purpose. The
therapeutic anticoagulant action of heparin is due to its
ability to produce conformational changes in the pro-
teinase inhibitor antithrombin. Both activated factor X
(factor Xa) and thrombin are inactivated by a heparin-
antithrombin complex (Chapter 36). The antithrombin is
homologous in structure with the
a
i -antitrypsin family
of proteinase inhibitors and is a suicide substrate for fac-
tor Xa and thrombin. The proteinase binds to a specific
Arg-Ser peptide bond present at the reactive site of an-
tithrombin. This 1:1 antithrombin-thrombin is a stable
inactive complex. The function of heparin is catalytic.
After the formation of the heparin-mediated anti thrombin-
thrombin complex, heparin is released to initiate another
cycle. Factor Xa is inhibited by a specific heparin pen-
tasaccharide bound to antithrombin. However, the inhi-
bition of thrombin requires an antithrombin bound to
the heparin consisting of the specific pentasaccharide
that consists of chains of at least 18 monosaccharide
units.
Heparin therapy has a serious risk. In about 3% of pa-
tients on heparin therapy, thrombocytopenia (low platelet
levels) develops. This can be life threatening if it leads to
thromboembolic complications such as disseminated in-
travascular coagulation. Thrombocytopenia is caused by
a heparin-induced immune-mediated process. The anti-
body is directed against a cryptic epitope present on a
platelet factor (PF4) that appears only after the prot-
ein binds to heparin. The multimolecular complex consist-
ing of antibody-heparin-PF4 causes platelet activation by
binding to specific receptors (FcYRIIA) on the platelet
membrane. A genetic predisposition to this disorder is
due to a specific mutation in the FcYRIIA gene changes
arginine to histidine at position 131. This amino acid
change causes a strong affinity for the Fc region of
immunoglobulin IgGi and IgG
2
. Thus, identification of
patients with homozygosity for the Arg 131 —^ His 131
mutation in FcYRIIA and who are on heparin therapy
has important therapeutic implications. Heparin-induced
thrombocytopenia occurs less frequently with the use of
low-molecular-weight heparin (M.W. 5,000) compared to
unfractionated heparin (M.W. 3,000-30,000). The treat-
ment of life threatening complications of heparin-induced
thrombocytopenia requires cessation of heparin therapy.
Heparin’s anticoagulant action can be reversed rapidly
by intravenous administration of prolamine sulfate. Pro-
tamines are basic proteins, isolated from fish sperm and
bind tightly to heparin.
One of the laboratory tests used in the identification of
patients with heparin-induced thrombocytopenia, employs
a micro-ELISA plate coated with purified PF4-heparin
complex. Upon incubation of patient’s plasma, if antibody
is present, it binds to the PF4-heparin complex. The bound
antibody is detected with goat antihuman antibody cou-
pled to peroxidase, followed by incubation with substrates
(T-phenylenediamine/HaCE (Chapter
8
).
Tendons have a high content of collagen and sulfated
glycosaminoglycans (chondroitin and dermatan sulfates).
Tendons are fibrous cords that fuse with skeletal muscle
at each end and penetrate bones at the two sides of a joint.
Thus, tendons are aligned along their long axis, providing
flexible strength in the direction of the muscle pull.
Remarkable progress has been achieved in understand-
ing the organization of the macromolecular components
of cartilage. Cartilage is one type of dense connective
tissue; bone is the other (Chapter 37). Cartilage is less
resistant to pressure than is bone, and its weightbearing
capacity is exceeded by that of bone. It has a smooth,
resilient surface. During growth and development of an
embryo, cartilage provides the temporary framework for
the formation and development of bone. In postnatal life,
it permits the long bones of the extremities to grow until
chapter 11
Heteropolysaccharides II: Proteoglycans and Peptidoglycans
