Download ACQUIRED COAGULATION FACTOR DISORDERS

ACQUIRED COAGULATION
FACTOR DISORDERS
Majid vafaie
MD
Acquired Hemorrhagic Disorders
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Drug-Induced Bleeding
Disseminated Intravascular Coagulation
Liver Disease
Vitamin K Deficiency
Massive Transfusion Coagulopathy
Acquired Inhibitors of Coagulation Proteins
• Many drugs have been associated with
abnormal platelet function, although not all
result in bleeding manifestations.
• The major classes include anti-inflammatory
agents,antibiotics, cardiovascular drugs,
psychotropic drugs,anticonvulsants, and
anticoagulants.
• Aspirin is the most common example; it acts
by irreversibly acetylating a serine residue at
the active site of cyclooxygenase
• whereas other nonsteroidal antiinflammatories (e.g.,ibuprofen, naproxen) are
reversible inhibitors
• B-Lactam antibiotics can interfere with
platelet function through binding to the
platelet membrane
• Calcium channel blockers, such as
nifedipineand tricyclic antidepressants,
• such as amytriptyline can give rise to
decreased platelet aggregation responses but
are unlikely to result in clinical bleeding.
Valproic acid induced coagulopathy
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thrombocytopenia
platelet dysfunction
acquired vonWillebrand'sdisease
decreased VK-dependent clotting factors
hypofibrinogenemia
decreased factor XIII levels
• Therapeutic anticoagulants (heparin, lowmolecularweight-heparin [LMWH], warfarin).
• Platelet receptor antagonists (lIb/IlIa
inhibitors,e.g., abciximab, eptifibatide,
tirofiban; adenosine diphosphate receptor
antagonists, e.g., clopidogrel) are increasingly
being used in patients with congenital heart
disease
• discontinuation of the offending drug should
resolve the hemorrhagic manifestations
• Administration of VK will in most cases rapidly
reverse warfarin-induced bleeding
• Alternatively, (FFP) can be used to replace Vk
dependent clotting factors rapidly
• Recombinant factor VIla (rVlIa) has proved
effective at rapidly reversing warfarin-induced
coagulopathy
• Transfusions of fresh platelets are indicated in
patients with life-threatening or unremitting
bleeding as a result of drug-induced platelet
dysfunction.
• In cases of minor bleeding in which
the drug cannot readily be discontinued (e.g.,
anticonvulsants),desmopressin has been used
with some success
Vitamin K Deficiency
• The normal full-term infant is born with levels
of factors II, VII, IX and X that are low by
• adult standards (Table 13-3).
• The coagulation factors fall even lower over
the first few days of life, reaching their nadir
on about the third day
• This is due to the low body stores of vitamin
K at birth.
• As little as 25 μg vitamin K can prevent this fall
in activity of the vitamin Kdependent clotting
factors.
• The vitamin K content of cow’s milk is about 6
μg/dl and that of breast milk 1.5 μg/dl.
• It is a combination of low initial stores and
subsequent poor intake of vitamin K that
occasionally produces an aggravation of the
coagulation defect causing primary
hemorrhagic disease of the newborn
• Vitamin K deficiency results in hemorrhagic
disease between the second and fourth days of
life
• is manifested by gastrointestinal
hemorrhage, hemorrhage from the umbilicus, or
internal hemorrhage (classic hemorrhagic
disease of the newborn).
• Bleeding attributable to this cause is responsive
to parenteral vitamin K therapy; for this reason
parenteral vitamin K is routinely administered to
newborns
• In premature infants of low birth weight, both
the vitamin K stores and the level of
coagulation factors are even lower than in
term infants.
• The response to vitamin K is slow and
inconsistent, suggesting that the immature
liver has reduced synthetic capability
• Maternal ingestion of certain drugs may cause
early hemorrhagic disease of the newborn as
a result of neonatal hypoprothrombinemia
due to a reduction in factors VII, IX and X.
• These drugs include oral anticoagulants and
anticonvulsants (phenytoin, primidone and
phenobarbital
• Late hemorrhagic disease of the newborn occurs
from one week after birth until 6 months of life
due to the absence of adequate vitamin K
prophylaxis at birth, malabsorption, liver disease,
or idiopathically
• Consider investigating for biliary atresia, alpha 1
antitrypsin deficiency if hemorrhagic disease of
the newborn occurs after adequate vitamin K
prophylaxis at birth.
Hepatic Dysfunction
• Any transient inability of the newborn’s liver
to synthesize necessary coagulation factors,
even in the presence of vitamin K, can result
in hemorrhagic disease that is nonrespon to
vitamin K therapy
• Hepatic dysfunction as a result of immaturity,
infection, hypoxia, or underperfusion of the
liver can all result in transient inability of the
liver to synthesize coagulation factors
• This is more prominent in small premature
infants.
• The sites of bleeding in these cases are usually
pulmonary and intracerebral with a high
mortality
• In liver disease vitamin K-dependent factors
and factor V and fibrinogen are
• In liver disease vitamin K-dependent factors
and factor V and fibrinogen are usually
decreased, fibrin split products may be
elevated due to impaired clearance
• In contrast, factor VIII levels are usually
normal.
• There is no response to vitamin K.
• There is usually a clinical response to clotting
factor replacement therapy, using fresh frozen
plasma and cryoprecipitate (replacement
guidelines are the same as those
• outlined in Table 13-7).
Disseminated Intravascular
Coagulation
• Disseminated intravascular coagulation is characterized by
the intravascular consumption of platelets and plasma
clotting factors
• Widespread coagulation within the vasculature results in
the deposition of fibrin thrombi and the production of a
hemorrhagic state when the rapid utilization of platelets
and clotting factors results in levels inadequate to maintain
hemostasis.
• The accumulation of fibrin in the microcirculation leads to
mechanical injury to the red cells, resulting in erythrocyte
fragmentation and microangiopathic hemolytic
anemia
• Widespread activation of the coagulation
cascade rapidly results in the depletion of
many clotting factors as fibrinogen is
converted to fibrin throughout the body
Two important
mechanisms
• The generation of thrombin results in
intravascular coagulation and rapidly falling
• platelet count, fibrinogen and FV, FVIII and
FXIII levels
• Paradoxically, in vitro bioassays for these
factors may be elevated owing to generalized
activation of the coagulation system
• Concurrently, plasminogen is converted to its
enzymatic form (plasmin) by t-PA.
• Plasmin digests fibrinogen and fibrin
(secondary fibrinolysis) into fibrin split
products (FSPs), resulting in clot lysis.
• Diagnosis of DIC relies on presence of a welldefined clinical situation associated with a
thrombo-hemorrhagic disorder.
Diagnostic test
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Increased PT and (aPTT)
Decreased fibrinogen
Decreased platelet count
Fibrin degradation (elevated fibrin degradation
products, elevated D dimmers)
Presence of fragmented red blood cells (e.g.,
schistocytes, triangle cells, helmet cells, burr cells)
Increased PF4 (platelet factor 4)
Increased FPA (fibrinopeptide A)
Decreased FV, FVIII, FXIII
low-grade DIC
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Kasabach–Merritt syndrome
Chronic inflammatory disorders
Arteriovenous fistulae
Vascular prosthesis
Glomerulonephritis
Low-grade DIC has the potential to accelerate
into fulminant DIC
laboratory
findings
• Presence of fragmented red blood cells
• Usually normal or mildly decreased platelet
count
• Normal or mildly increased PT/APTT
• Normal or mildly decreased fibrinogen
• Usually increased FSPs
• Usually increased PF4
• Usually increased FPA levels.
Treatment of low-grade DIC
• Treatment of the underlying disease
responsible for triggering low-grade DIC
• Antiplatelet therapy:
• Aspirin (5–10 mg/kg/day)
• Dipyridamole (3–5 mg/kg/day).
Massive Transfusion Coagulopathy
• Uncontrolled bleeding can be a clinical
problem associated with the management of
trauma and surgical patients and often
necessitates transfusion of large amounts of
blood and blood derivatives
• Massive transfusion has commonly been
defined as replacing at least one blood volume
in 24 hours
• Patients with this degree of bleeding are at
risk for defective hemostasis related to the
transfusions, in addition to the underlying
precipitating trauma or surgical insult
• The resulting bleeding diathesis may be
complex and include evidence of DIC,
depletion of hemostatic factors through blood
loss, tissue injury, and consumption of factors,
dilutional coagulopathy secondary to
aggressive blood component resuscitation,
hypothermia, platelet dysfunction, and
excessive fibrinolysis.
• rVIIa has demonstrated effectiveness in
patients with bleeding associated with
massive transfusion who were refractory
to conventional treatments
Acquired Inhibitors of
Coagulation Proteins
• Acquired Inhibitors to Factor VIII
• Acquired Inhibitors to Factor IX
• Acquired Inhibitors As a Result of Exposure to
Bovine Thrombin
• Acquired von Willebrand's Syndrome
• Acquired Inhibitors to Prothrombin
Hemorrhagic Lupus Anticoagulant Syndrome
• Anti-factor VIII autoantibodies are rare in
children but can result in severe bleeding and
significant morbidity
• These antibodies are associated with
underlying medical conditions in half of those
affected, including malignancy, autoimmune
disease, Iymphoproliferative disorders, or
drugs (e.g., penicillin)
• Patients can exhibit bleeding symptoms
ranging from easy bruising to intracranial
hemorrhage
• Laboratory screening studies will show a
prolonged APTT that does not fully correct
upon mixing with normal plasma in a 1 : 1
mix ("inhibitor screen")
• Hemostasis can be achieved with high doses
of factor VIII concentrates,activated
prothrombin complex concentrates, and
rVIIa
Acquired Inhibitors to Factor IX
• Few cases of spontaneous factor IX inhibitors
have been reported in nonhemophiliacs, and
most adult cases have been related to
underlying systemic disorders such as
systemic lupus erythematosus (SLE), hepatitis,
multiple sclerosis, rheumatic fever, collagen
vascular disease,postpartum status, and
prostatectomy.
• Treatment has included any combination of
corticosteroids, gamma globulin, or
cyclophosphamide, with rapid resolution of
the inhibitor
• Recombinant factor IX and rVIIa can be
considered for the acute management of
bleeding
Acquired von Willebrand's
Syndrome
• Acquired von Willebrand's syndrome (AVWS)
is a rare bleeding disorder with clinical and
laboratory findings similar to those of
inherited von willebrand's disease
• AVWS usually occurs in individuals with no
personal or family history of von Willebrand's
disease and is accompanied by bleeding
symptoms in about three quarters of patients
• Iymphoproliferative and myeloproliferative
disorders, solid tumors, immunologic and
cardiovascular disorders, and other
miscellaneous conditions,
including drug associations
• AVWS has also been reported in children,
primarily associated with congenital heart
disease,collagen vascular diseases, Wilms'
tumor, hypothyroidism,and certain drugs
• Drug-associated AVWS has been described in
up to 20% of pediatric patients taking
valproic acid