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FB 930.1309
HEMOSTASIS
Abbreviations used:
Hemostasis is the physiologic response that minimizes blood loss while maintaining blood flow after an
injury to a vessel. Endothelial injury triggers immediate
vasoconstriction and exposes tissue factor (TF) and
collagen in the subendothelial matrix, providing a
surface for platelet adherence and plug formation.
Traditionally, coagulation has been described as a
cascade of enzyme reactions, consisting of the extrinsic and intrinsic pathways converging on the common
pathway to produce an insoluble fibrin clot.1-3
Although the extrinsic and intrinsic pathways correlate
with the laboratory values of prothrombin time and
partial thromboplastin time, respectively, this model
has shortcomings and fails to describe the importance
of cells during the coagulation process.3 Thus, a cellbased model of coagulation has been proposed,
which consists of 3 phases: initiation, amplification,
and propagation (Fig 1), and results in platelet activation and fibrin clot production.3 TF, a cell membrane
glycoprotein, is responsible for the initiation of coagulation, which occurs on the surface of a TF-bearing
cell and results in the production of small amounts of
thrombin (activated [a] factor [F] II).3 During amplification, thrombin generated in the initiation phase
activates factors V, VIII, and XI on the negatively
charged phospholipid surface of a platelet leading to
platelet activation.3 Finally, in the propagation phase,
450
APC:
APLA:
APLS:
CVU:
DIC:
DVT:
HIT:
HS:
LMWH:
LR:
LV:
PE:
PF:
SVT:
TF:
TTP:
VTE:
activated protein C
antiphospholipid antibody
antiphospholipid antibody syndrome
chronic venous ulceration
disseminated intravascular coagulation
deep venous thrombosis
heparin-induced thrombocytopenia
hypercoagulable states
low-molecular-weight heparin
livedo reticularis
livedo vasculopathy
pulmonary embolism
purpura fulminans
superficial venous thrombosis
tissue factor
thrombotic thrombocytopenic purpura
venous thromboembolism
HYPERCOAGULABLE STATES
J AM ACAD DERMATOL
disseminated intravascular coagulation [DIC]), decreased production (hepatic failure), or excess loss
(nephrotic syndrome).
Protein C or protein S deficiency. Heterozygous
protein C deficiency is an autosomal dominant condition present in 0.2% of the population and heterozygous protein S deficiency is an autosomal dominant
condition present in less than 0.1% of the population.11
Homozygous protein C or protein S deficiency often
results in neonatal purpura fulminans (PF) and is
usually fatal.16 There have been numerous mutations
of the protein C gene identified. The deficiency can
either be quantitative (type I) or qualitative (type II).
APC, in conjunction with its cofactor, protein S, inactivates FVa and FVIIIa, thus protein C or protein S
deficiency leads to unbalanced activation of these
factors and increased production of thrombin.9 Protein
C or protein S deficiency can also be acquired
secondary to consumption, decreased production, or
excess loss, by similar mechanisms as acquired antithrombin III deficiency.
Secondary HS
Hospitalization, trauma, and surgery. Hospitalization is a risk factor for VTE, likely as a result of
immobilization, with the severity of the illness also
contributing to the risk.17 Patients admitted with major
trauma are at an exceptionally high risk of DVT. A
prospective study of 349 patients with major trauma
identified at least 1 DVT present in 58% of the
patients.18 Patients undergoing surgical procedures
are also at increased risk of VTE, with numerous
associated risk factors, including patient age, a history
of VTE, the type and duration of the surgery, and
comorbid conditions.
Obesity. The cause of venous and arterial hypercoagulability in obese patients is multifactorial.19,20
Increased levels of fibrinogen, FVII, FVIII, von
Willebrand factor, and plasminogen activator inhibitor have been described, however the exact mechanisms predisposing to thrombosis are unclear.19
The body mass index (kg/m2) correlates with risk of
VTE, and increased fat deposition around the abdomen and upper body is associated with arterial
thrombosis.21 In addition, elevated levels of leptin,
a hormone produced by adipocytes, has been shown
to increase the risk of arterial thrombosis.22
Cancer. Patients with cancer are at a higher risk
of VTE and arterial thrombosis, with venous thrombosis as the second leading cause of mortality.23
Venous or arterial thrombosis occurs in 15% to 20%
of patients with cancer.24 The risk of thrombosis is
related to the actual disease and to the associated
treatments and procedures. Elevated levels of fibrinogen, FV, FVIII, FIX, FX, fibrin degradation products,
J AM ACAD DERMATOL
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Secondary (acquired)
Hospitalization
Surgery
Immobilization
Cancer/myeloproliferative
states
Pregnancy
Obesity
Venous thrombosis
Gene mutations:
Factor V Leiden mutation
Prothrombin G20210A
mutation
Deficiencies of anticoagulants
(inherited or acquired):
Antithrombin III deficiency
Protein C deficiency
Protein S deficiency
Medications
Antiphospholipid antibody
syndrome
Acquired
hyperhomocysteinemia
Acquired antithrombin III
deficiency, protein C,
protein S deficiency
Hyperhomocysteinemia
Methyltetrahydrofolate
reductase deficiency
Cystathione-b-synthase
deficiency
Acquired
hyperhomocysteinemia
Cancer/myeloproliferative
states
Secondary
hypercoagulable states:
Hospitalization
Surgery
Immobilization
Pregnancy
Obesity
Rare causes:
Dysfibrinogenemia
Plasminogen deficiency
Tissue factor pathway
inhibitor deficiency
Elevated levels of factor
VIII, IX, or X
Medications
Antiphospholipid
antibody syndrome
J AM ACAD DERMATOL
Interpretation
Gene mutations:
Factor V Leiden
Prothrombin G20210A
MTHFR (677TT genotype) 1 homocysteine level
APLAs:
Lupus anticoagulant panel
- Screening tests: PTT, PTT screen with different
reagent, dRVVT, hexagonal phospholipid screen
- Mixing studies: PTT mixing study, dRVVT
mixing study
- Confirmation tests: dRVVT confirmation,
hexagonal PL confirmation, platelet
neutralization procedure
APLA, Antiphospholipid antibody; dRVVT, dilute Russell viper venom test; HS, hypercoagulable states; MTHFR, methyltetrahydrofolate
reductase; PL, phospholipid; PTT, partial thromboplastin time.
J AM ACAD DERMATOL
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Fig 2. Purpura fulminans (PF). A, Noninflammatory microvascular occlusion. B, PF manifesting as purpura and hemorrhagic bullae from Escherichia coli sepsis. (A, Hematoxylin-eosin
stain; original magnification: 310.)
J AM ACAD DERMATOL
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study, 25% of 844 patients with SVT also had DVT, PE,
or both.98 In the OPTIMEV study, 29% of 788 patients
had DVT.99 Varicose veins are present in 60% to 90%
of patients before developing SVT.100,101 The most
commonly affected vein is the great saphenous vein,
which accounts for 60% to 80% of SVT.101 This
condition is more common in women with an average age of onset at 60 years.101 When SVT is associated with varicose veins, it is less likely to be
complicated by extension into the deep venous
system.102 Superficial thrombophlebitis has been
found in association with anticardiolipin antibodies,
protein C or S deficiency, FV Leiden mutation,
prothrombin mutation, and antithrombin III deficiency.103-107 One study showed FV Leiden mutation
was present in 14.3% of patients presenting with
superficial thrombophebitis.106
J AM ACAD DERMATOL
Antiplatelet medications
Aspirin
Clopidogrel
Ticlopidine
Prasugrel
Dipyridamole
Pentoxifylline
Anticoagulants
Unfractionated heparin
LMWH:
Enoxaparin
Dalteparin
Reviparin
Tinzaparin
Nadroparin
Parnaparin
Cyclo-oxygenase inhibitor
Adenosine diphosphate
receptor inhibitors
Adenosine deaminase
inhibitor
Phosphodiesterase
inhibitor
Potentiates action
of antithrombin III
Potentiates action
of antithrombin III
CONCLUSION
Primary and secondary HS are associated with
cutaneous manifestations, including purpura, PF, LR,
LV (atrophie blanche), anetoderma, SVT, and
chronic venous ulcers. The dermatologist can
J AM ACAD DERMATOL
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