Dr Budi Enoch

COAGULATION
DISORDERS
 Deficiencies of coagulation factors have been recognized for
centuries.
 Patients with genetic deficiencies of plasma coagulation factors
exhibit life-long recurrent bleeding episodes into joints, muscles,
and closed spaces, either spontaneously or following an injury.
 The most common inherited factor deficiencies are the
hemophilias, X-linked diseases caused by deficiency of factor (F)
VIII (hemophilia A) or factor IX (FIX, hemophilia B).
 Rare congenital bleeding disorders due to deficiencies of other
factors, including FII (prothrombin), FV, FVII, FX, FXI, FXIII,
and fibrinogen are commonly inherited in an autosomal
recessive manner (Table 116–1). Advances in characterization of
the molecular bases of clotting factor deficiencies have
contributed to better understanding of the disease phenotypes
and may eventually allow more targeted therapeutic approaches
through the development of small molecules, recombinant
proteins, or cell and gene-based therapies.
 Commonly used tests of hemostasis provide the initial
screening for clotting factor activity, and disease
phenotype often correlates with the level of clotting
activity.
 An isolated abnormal prothrombin time (PT) suggests
FVII deficiency, whereas a prolonged activated partial
thromboplastin time (aPTT) indicates most commonly
hemophilia or FXI deficiency).
 The prolongation of both PT and aPTT suggests
deficiency of FV, FX, FII, or fibrinogen abnormalities.
The addition of the missing factor at a range of doses
to the subject's plasma will correct the abnormal
clotting times; the result is expressed as a percentage
of the activity observed in normal subjects.
 HMW
K

aPTT : activated partial thromboplastin time

PT: prothrombin time
 Acquired deficiencies of plasma coagulation
factors are more frequent than congenital
disorders; the most common disorders include
hemorrhagic diathesis of liver disease,
disseminated intravascular coagulation (DIC),
and vitamin K deficiency.
 In these disorders, blood coagulation is
hampered by the deficiency of more than one
clotting factor, and the bleeding episodes are
the result of perturbation of both primary
(coagulation) and secondary (e.g., platelet and
vessel wall interactions) hemostasis
 The development of antibodies to coagulation
plasma proteins, clinically termed inhibitors, is a
relatively rare disease that often affects hemophilia
A or B and FXI-deficient patients on repetitive
exposure to the missing protein to control bleeding
episodes.
 Inhibitors also occur among subjects without
genetic deficiency of clotting factors (e.g., in the
postpartum setting as a manifestation of underlying
autoimmune or neoplastic disease or idiopathically).
Rare cases of inhibitors to thrombin or FV have been
reported in patients receiving topical bovine
thrombin preparation as a local hemostatic agent in
complex surgeries
Disseminated
Intravascular
Coagulation
 Disseminated intravascular coagulation
(DIC) is a clinicopathologic syndrome
characterized by widespread
intravascular fibrin formation in response
to excessive blood protease activity that
overcomes the natural anticoagulant
mechanisms.
 There are several underlying pathologies
associated with DIC
 The most common causes are bacterial sepsis, malignant
disorders such as solid tumors or acute promyelocytic
leukemia, and obstetric causes.
 DIC is diagnosed in almost one-half of pregnant women with
abruptio placentae, or with amniotic fluid embolism.
 Trauma, particularly to the brain, can also result in DIC.
 The exposure of blood to phospholipids from damaged tissue,
hemolysis, and endothelial damage are all contributing factors
to the development of DIC in this setting.
 Purpura fulminans is a severe form of DIC resulting from
thrombosis of extensive areas of the skin; it affects
predominantly young children following viral or bacterial
infection, particularly those with inherited or acquired
hypercoagulability due to deficiencies of the components of
the protein C pathway.
 Neonateshomozygous for protein C deficiency also present
high risk for purpura fulminans with or without thrombosis of
large vessels.
 The central mechanism of DIC is the uncontrolled
generation of thrombin by exposure of the blood to
pathologic levels of tissue factor (Fig. 116-3).
 Simultaneous suppression of physiologic anticoagulant
mechanisms and abnormal fibrinolysis further accelerate the
process.
 Together, these abnormalities contribute to systemic fibrin
deposition in small and midsize vessels. The duration and
intensity of the fibrin deposition can compromise the blood
supply of many organs, especially the lung, kidney, liver,
and brain, with consequent organ failure.
 The sustained activation of coagulation results in
consumption of clotting factors and platelets, which in turn
leads to systemic bleeding. This is further aggravated by
secondary hyperfibrinolysis.
Clinical Manifestations
 DIC are related to the magnitude of the imbalance of
hemostasis, to the underlying disease, or to both. The
most common findings are bleeding ranging from
oozing from venipuncture sites, petechiae, and
ecchymoses to severe hemorrhage from the
gastrointestinal tract, lung, or into the CNS.
 In chronic DIC, the bleeding symptoms are discrete
and restricted to skin or mucosal surfaces.
 The hypercoagulability of DIC manifests as the
occlusion of vessels in the microcirculation and
resulting organ failure. Thrombosis of large vessels
and cerebral embolism can also occur.
 Hemodynamic complications and shock are common
among patients with acute DIC. The mortality ranges
from 30 to >80% depending on the underlying disease,
the severity of the DIC, and the age of the patient.
 The diagnosis of clinically significant DIC is based
on the presence of clinical and/or laboratory
abnormalities of coagulation or thrombocytopenia.
 The laboratory diagnosis of DIC should prompt a
search for the underlying disease if it is not already
apparent.
 There is no single test that establishes the diagnosis
of DIC. The laboratory investigation should include
coagulation tests [aPTT, PT, thrombin time (TT)] and
markers of fibrin degradation products (FDPs), in
addition to platelet and red cell count and analysis of
the blood smear. These tests should be repeated over
a period of 6–8 hours because an initially mild
abnormality can change dramatically in patients
with severe DIC.
 Common findings include the prolongation of PT and/or
aPTT; platelet counts 100,000/L 3, or a rapid decline in
platelet numbers; the presence of schistocytes
(fragmented red cells) in the blood smear; and elevated
levels of FDP.
 The most sensitive test for DIC is the FDP level.
 DIC is an unlikely diagnosis in the presence of normal
levels of FDP. The D-dimer test is more specific for
detection of fibrin—but not fibrinogen—degradation
products and indicates that the cross-linked fibrin has
been digested by plasmin. Because fibrinogen has a
prolonged half-life, plasma levels diminish acutely only
in severe cases of DIC.
 High-grade DIC is also associated with levels of
antithrombin III or plasminogen activity <60% of normal.
Treatment
 The morbidity and mortality associated with
DIC are primarily related to the underlying
disease rather than the complications of the DIC.
 The control or elimination of the underlying
cause should therefore be the primary concern.
 Patients with severe DIC require control of
hemodynamic parameters, respiratory support,
and sometimes invasive surgical procedures.
Attempts to treat DIC without accompanying
treatment of the causative disease are likely to
fail.
 Management of Hemorrhagic
Symptoms
 The control of bleeding in DIC patients with
marked thrombocytopenia (platelet counts
<10,000–20,000/L3) and low levels of coagulation
factors will require replacement therapy.
 The PT (>1.5 times the normal) provides a good
indicator of the severity of the clotting factor
consumption.
 Replacement with FFP is indicated (1 unit of FFP
increases most coagulation factors by 3% in an
adult without DIC).
 Low levels of fibrinogen (<100 mg/dL) or brisk
hyperfibrinolysis will require infusion of cryoprecipitate
(plasma fraction enriched for fibrinogen, FVIII, and vWF).
 The replacement of 10 U of cryoprecipitate for every 2–3 U
of FFP is sufficient to correct the hemostasis.
 The transfusion scheme must be adjusted according to the
patient's clinical and laboratory evolution. Platelet
concentrates at a dose of 1–2 U/10 kg body weight are
sufficient for most DIC patients with severe
thrombocytopenia.
 Clotting factor concentrates are not recommended for
control of bleeding in DIC because of the limited efficacy
afforded by replacement of single factors (FVIII or FIX
concentrates), and the high risk of products containing
traces of aPCCs that further aggravate the disease
 Coagulation Disorders
Associated with Liver Failure
 The liver is central to hemostasis because it is the site of
synthesis and clearance of most procoagulant and
natural anticoagulant proteins and of essential
components of the fibrinolytic system.
 Liver failure is associated with a high risk of bleeding
due to deficient synthesis of procoagulant factors and
enhanced fibrinolysis.
 Thrombocytopenia is common in patients with liver
disease, and may be due to congestive splenomegaly
(hypersplenism), or immune-mediated shortened
platelet lifespan (primary biliary cirrhosis).
 In addition, several anatomic abnormalities secondary
to underlying liver disease further promote the
occurrence of hemorrhage
 Treatment with FFP is the most effective to correct hemostasis in
patients with liver failure.
 Infusion of FFP (5–10 mL/kg; each bag contains 200 mL) is
sufficient to ensure 10–20% of normal levels of clotting factors but
not correction of PT or aPTT. Even high doses of FFP (20 mL/kg)
do not correct the clotting times in all patients.
 Monitoring for clinical symptoms and clotting times will determine
if repeated doses are required 8–12 h after the first infusion.
Platelet concentrates are indicated when platelet counts are
<10,000–20,000/L3 to control an ongoing bleed or immediately
before an invasive procedure if counts are <50,000/L 3.
 Cryoprecipitate is indicated only when fibrinogen levels are less
than 100 mg/mL; dosing is six bags for a 70-kg patient daily.
Prothrombin complex concentrate infusion in patients with liver
failure should be avoided due to the high risk of thrombotic
complications. The safety of the use of antifibrinolytic drugs to
control bleeding in patients with liver failure is not yet well defined
and should be avoided
Terima Kasih