Failure of Coagulation
MUDr. Tomáš Stopka Ph.D.
and colleagues from the Institute of
Pathophysiology, Charles University
Plan


Coagulation
Methods

DIC
Therapy

Presentation

I. Coagulation
Initiating the Clotting Process
1. Damaged cells (extrinsic pathway)
display a surface protein called tissue
factor (TF) that binds to activated
Factor 7 (TF-7) to cleave: Factor 10
2. Factor 10 binds and activates Factor
5 (prothrombinase) convertíng
prothrombin (also known as Factor II)
to thrombin
3. Thrombin proteolytically cleave
fibrinogen (Factor I) to fibrin.
4. Factor 13 forms covalent bonds
between the soluble fibrin molecules
converting them into an insoluble
meshwork — the clot.
I. Coagulation
Amplifying the Clotting Process
1. The TF-7 complex also activates
Factor 9.
2. Factor 9 binds to Factor 8, a
protein that circulates in the blood
stabilized
by another protein, von Willebrand
Factor (vWF).
3. Complex 9-8-vW activates more
factors: 5,8,10,11
I. Coagulation
LUMEN
Blood clot
The intrinsic
cascade is
initiated when
contact is
made between
blood and
exposed
endothelial
cell surfaces.
WALL
Endothelial demage
Damaged
endothelial cells
display tissue
factor (TF) that
binds to
activated Factor
7 (TF-7) to
cleave: Factor 10
I. Coagulation
Controlling Clotting
Antithrombin III inactivates: prothrombin, factor 9, factor 10

Heparin binds to and enhances antithrombin III.
Protein C and its cofactor Protein S together inhibit thrombin
formation
by inactivating Factor 5 and by inactivating Factor 8. Inherited deficiency
(mutations) of Protein C or Protein S (or FV, Leiden)= thrombophilia
Warfarin (aka coumadin) is an effective vitamin K antagonist.
Vitamin K is a cofactor needed for the synthesis (in the liver) of
factors 2 (prothrombin), 7, 9, and 10, proteins C and S
Deficiency of Vitamin K predisposes to bleeding. Conversely,
blocking the action of vitamin K helps to prevent inappropriate
clotting.
I. Coagulation

Dissolving clots
Plasma plasminogen to the fibrin molecules in
a clot. Nearby healthy cells release tissue
plasminogen activator (TPA), which also binds
to fibrin and, activates plasminogen forming
plasmin. Plasmin (serine protease) proceeds to
digest fibrin, thus dissolving the clot.
I. Coagulation
HEMOCOAGULATION is INTEGRAL PART of INFLAMATORY
RESPONSE
VASCULAR WALL
ENDOTHELIUM
PLATELETS
PLAZMATIC
COAGULATION SYSTEM
I. Coagulation
DISORDERS OF HEMOCOAGULATION = THROMBOSIS AND EMBOLISM
THROMBOSIS
IN MICROCIRCULATION
VENOUS
ARTERIAL
SIGNS
LUNGS
SYSTEMIC
-TISSUE ISCHEMIA
- HEMODYNAMIC FAILURE
EMBOLISM
I. Coagulation

Deep Venous Thrombosis (DVT)
A) asymptomatic : > 50% Lung Embolism.
B) symptomatic: pain (Homans’s sign), oedema, dicoloration and
incr. temperature of the skin

Posthrombotic syndrome
latent, 3 - 15 y after DVT: distension of superf. veins,
lipodermatosclerosis, varices, ulceration.

Lung embolism (LE)
Dyspnoe, tachypnoe, tachykardia, pleuritic chest pain,
distension of the jugular veins, hemoptysis, hemodynamic
instability, hemodynamic failure or death.
I. Coagulation
BLEEDING
SURGERY
traumatic
SMALL,
TRAUMATIC
- sc.,
im.injections
- Easy bruising
Failure of coagulation
DIFUSE
MICROVASCULAR
- purpura - petechia,
ekchymosis (>3 mm)
- organ apoplexia
A) trombocytopenia
B) Desintegration
of microvascular
intima
II. Laboratory
BLEEDING TIME and RESISTANCE OF CAPILARS


Bleeding time (Duke, 1910)
standard puncture of the ear lobe (Duke, 1910)
2 - 5 min. prolonged in thrombocytopenia (<20
000/uL) OR vonWillebrand disease
Capillary resistance ( Rumpel, Leede)
pressure on the arm 10,5 kPa/10 min
petechia > 5 = increased fragility of capillaries.
(hereditary purpura e.g. Weber-Rendu-Osler).
II. Laboratory
Basic coagulation methods

Thrombin time
-full blood is activated with thrombin to form fibrin fiber
-used for measurement of fibrinogen levels (DIC)
II. Laboratory
Methods for measuring platelets and vWf






(PLT) – normal 150 - 300 000/uL, for surgery optimum
> 100 000 /uL. Thrombocytopenia PLT < 20 000/ uL –
spontaneous bleeding and purpura.
(MPV) - normal 6 - 9 fL, incr. hereditary
trombocytopathy.
Agregometry – photometric, with addition of activator of
platelet aggregation - ADP, thrombin, kolagen. Diagnosis
of hereditary trombocytopaty
Flow cytometry - imunologic.
Anti PLT antibodies – diagnosis of imune-mediated
trombocytopenia
vWf - imunologic or functional tests incl. ristocetin
II. Laboratory
Methods for measuring Coagulation factors
Blood drown into citrate is centrifuged to obtain decalcified plasma


PT – prothrombin time PT (Quickův)
APTT - activated partial thromboplastin time
Statim
 FBG - fibrinogenu plasma levels (normal :2 - 4
g/L). ( FBG acute phase protein)
 FDP - imunologic measurement of degradation
products of fibri(noge)n (normal: < 1000 ug/L),
II. Laboratory
Methods for measuring Coagulation factors

D-dimer - imunologic measurement of FDP
specific for
stabilized fibrin (normal < 500 ug/L). Increased
D-dimer DVT/PE and DIC.

AT - function test to measure antithrombin
activity in plasma (normal 80 - 100% activity of
the control plasma). With heparin part of the
TAT inhibitory complex, deficiency predispose to
thrombophilia or DIC.
II. Laboratory
Methods for measuring Coagulation

Ethanol test – FDP anti-polymeration effect on
fibrin fiber is blocked by ethanol

Euglobulin method of measuring fibrinolytic
activity
Euglobulin fraction of plasma obtained with acetic
acid conatins predominantly plasminogen, in DIC
there is more plasmin and so the test is quicker
(result of increased fibrinolysis).
II. Laboratory
Methods for measuring Coagulation




proteinu C- Act. Protein C resistence, mutation
of FV, mutation of protein S
fibrinolytic system- tPA , inhibitor PAI-1,
plazminogen, inhibitor alfa2AP
Antifosfolipid antibodies - lupus anticoagulans
(LA) : modif. APTT
Individual factors hemofilia A (FVIII), B(FIX),
C (FXI)
II. Laboratory
Protrombin time PT (Quick)

Principle: extrinsic pathway – tissue factor. Blood drawn to
citrate and TF is added. with CaCl2. Time is measured until
the fibrin fiber is formed.

Normal: PTN= 12 - 15 s

Prolonged PT:, deficiency of FV, vit. K dep: FII, VII, X,
deficient FBG, high FDPs

International normalized ratio INR= (PTP/ PTN)ISI
ISI = international index of used tromboplastin (usu > 1).
(max. therapeutic INR = 4,5)
APTT
II. Laboratory

Principle : intrinsic pathway. Blood drawn to citrate and kaolin
(activates inner system) is added with CaCl2. Time is measured until
the fibrin fiber is formed.

Normal APTTN = 27 - 35 s

Used: hemophilia, lupus anticoagulans, heparin therapy (1,5x - 2,5
x).

Prolonged APTT: deficient FII,V, X, - F XII, PreK, HMWK, FXI, FIX , FVIII (hemofilia C, B,A), lupus anticoagulans, low FBG,
high FDP.

Shortened APTT: thrombophilia
II. Laboratory
Disorder
Trombocytopenia
PLT
L
Hemofilia A N
Hemofilia B N
Hemofilia C N
vW-disease N
LA
N
BT APTT
PT
TT
FBG
P
N
N
N
P
N
N
N
N
N
N
N/P
N
N
N
N
N
N
N
N
N
N
N
N
N
P
P
P
N/P
P
II. Laboratory
Disorder
PLT
BT APTT
PT
TT
FBG
FV-def.
N
N
P
P
N
N
FII-def.
N
N
P
P
N
N
FVII-def.
N
N
N
P
N
N
Vit.Kdef./OA N
N
P
P
N
N
FBG-def.
N
N
P
P
P
L
Heparin
N
P/N P
N/P P
N
III. DIC
Definition
Secondary
Disorder of Coagulation with pro-thrombotic
phase followed by severe bleeding phase (as a
result of consumption of coagulation factors).
III. DIC
Ethiopathogenesis
Intravascular coagulation
Conditions Associated with DIC










Heat stroke
Sepsis
Viremia
Pancreatitis
Neoplasia (Diffuse and local)
Parasitic Infections
Intravascular Hemolysis
Immune-mediated Diseases
Exposure to venom/toxins
Massive tissue injury (including
burns, crush trauma, and
surgical procedures)








Obstetric Complications
Insufficiency of major organs
(Liver, Kidney)
Diabetes mellitus
Acidosis
Polycythemia
Severe prolonged hypotension
(including shock)
Severe volume depletion
Impaired blood flow to a major
organ
What are FDPs and D-dimers and
how do they relate to DIC?
DIC



Activation of the coagulation
cascade results in increased levels
of circulating thrombin and
plasmin.
Thrombin cleaves fibrinopeptides
A and B from fibrinogen, leaving
soluble fibrin monomers as the end
product (Figure 1).
Activation of factor XIII results in
polymerization of these fibrin
monomers into insoluble cross-
•Increased levels of circulating plasmin
causes clot lysis and degradation of
fibrinogen and the soluble fibrin
monomers.
•Plasmin cleaves fibrinogen into
fragments X,Y,D, and E, known as
fibrinogen degradation products
(FDPs).
•Plasmin also cleaves insoluble crosslinked fibrin polymers into x-oligomers.
The main x-oligomers are known as
d-dimers.
What are FDPs and D-dimers and
how do they relate to DIC?
FIBRIN


Monoclonal antibodies have been
generated which recognize the
cross-linked domain of d-dimers
as an antigenic target. These
antibodies are used in all available ddimer assays.
Quantitative tests for d-dimers are
available, including enzymatic
immunoassays (ELISA) and
immunoturbidometric systems.
III. DIC
NORM








PLT 150 - 300 000 x 10 exp9 /l
APTT 30 - 35 s
AT 80 - 140 %
TT 14 - 16 s
FBG 2.5 - 5 g/l
FM (ethanol test)
DD < 500 ng/ml
FDP
III. DIC
DIC










PLT low
APTT short or prolonged
AT low
TT prolonged
FBG low
FM (etanol test) positive
plasminogen low
DD positive
FDP positive
euglobulin lysis norm. - prolonged
III. DIC




PLT
FBG
DD
AT
Repeat every 3-4h
III. DIC
1 Hypercoagulation
Silent
2 Hypocoagulation
Bleeding and thrombosis in microcirculation
3 Massive fibrinolysis
Bleeding and multiorgan failure (MOF)
4 Death
Thrombotic Thrombocytopenic Purpura
Peripheral
smear
showing
microangiopathic hemolytic features
with numerous RBC fragments
(helmet cells/schistocytes). Marked
thrombocytopenia is evident.
Renal biopsy showing hyaline thrombi
in the glomerulus and small arterioles.
von Willebrand factor protein multimer
analysis
on
agarose
gel
electrophoresis. Lane 1. - normal
plasma. Lane 2. - patient plasma when
symptomatic. Multimer pattern is
similar to the control plasma. Lane 3. patient plasma after response to
pheresis. Note the presence of ultralarge high molecular weight multimers.
Researchers Pinpoint Cause of Deadly Blood-Clotting Disorder

Several earlier studies had implicated a clotting-related protein known as
von Willebrand factor (VWF) in the disorder. These studies found that the
blood of patients with TTP showed an abnormally large form of the VWF
protein that had not been cleaved into two smaller sizes, as is normally the
case. Thus, said Ginsburg, many scientists believed that a defect in a proteinclipping enzyme known as a protease might be responsible for the disorder.

One of the keys to identifying the gene mutations that underlie TTP was the development of a precise assay for
detecting VWF protease activity. Han-Mou Tsai, a senior author of the Nature paper, and colleagues at
Montefiore Medical Center and Albert Einstein College of Medicine developed the assay and applied it to blood
samples that were provided by members of four families that had an inherited form of TTP. The assays clearly
revealed that within these families, those who had TTP showed low VWF protease activity, while carriers of the
disease showed medium levels of protease activity, and unaffected individuals showed normal levels.

Using results from the assay as a guide, Gallia G. Levy, lead author of the Nature article, performed linkage
analyses of the family members and determined which of known genomic markers were inherited with the
disease gene. These studies enabled her to narrow down the region containing the disease gene to a specific
region of chromosome 9.

Levy then obtained the full gene sequence and proceeded to test the other patients for mutations in the gene,
which they named ADAMTS13. Levy subsequently identified a dozen mutations in the gene among the patients,
accounting for nearly all the cases of TTP. According to Ginsburg, Levy’s findings open the way to understanding
how and why the ADAMTS13 protease cleaves VWF and how the failure to cleave the protein causes disease.
III. DIC
Therapy:
Blockade of activated coagulation

1 Heparin
5-10 IU/kg/h
 bolus 2500 IU, inf. Up to 10 000 IU/24h


LMWH
III. DIC
Therapy:
Blockade of activated coagulation

2 AT (Antitrombin III, Kybernin P)




If less 60%, target~ 100 - 150%
500 - 1000 bolus
KI unknown
Half life 3-4 d, during sepsis hours
III. DIC
Therapy:
Substitution

3 Fresh frozen plasma
 15 ml/kg if APTT more than 1.5 R

4 Fibrinogen
 If less than 1.0 g/l (maximally 2g/24h)
 2 - 4 g in infusion
III. DIC
Therapy:
Substitution

5 Erythrocytes

6 PLT
 1 unit/10kg
III. DIC
Therapy:
OTHER





1 shock
2 volume
3 acidobasic and ionts
4 ATB
5 Surgical
III. DIC
Acute DIC
DIAGNOSIS
Clinical findings
Multiple bleeding sites
Ecchymoses of skin, mucous membranes
Visceral hemorrhage
Ischemic tissue

Laboratory abnormalities
Coagulation abnormalities: prolonged prothrombin time, activated
partial thromboplastin time, thrombin time; decreased fibrinogen
levels; increased levels of FDP (eg, on testing for FDP, D dimer)
Platelet count decreased as a rule but may be falling from a higher
level yet still be normal
Schistocytes on peripheral smear

Chronic DIC
DIAGNOSIS
Clinical findings
Signs of deep venous or arterial thrombosis or embolism

Superficial venous thrombosis, especially without varicose
veins
Multiple thrombotic sites at the same time
Serial thrombotic episodes
Chronic DIC

Laboratory abnormalities
Modestly increased prothrombin time in some patients
Shortened or lengthened partial thromboplastin time
Normal thrombin time in most patients
High, normal, or low fibrinogen level
High, normal, or low platelet count
Increased levels of FDP (eg, on testing for FDP, D dimer)
Evidence of molecular markers* (eg, thrombin-antithrombin
complexes, activation markers on platelet membranes,
prothrombin fragment F1+2)
Current Management of DIC

At present, diagnosis requires a set of blood
tests; therapy focuses on reversing the
underlying disorder and providing supportive
treatment.
Case 1 Presentation

A 56-year-old man was admitted to the emergency
department after a car accident.
•He had several bone fractures, a cerebral contusion, and hemodynamic instability caused
by a ruptured spleen.
•Emergency splenectomy and aggressive administration of fluids restored hemodynamic
stability, and the patient was transferred to the intensive care unit (ICU).
A few hours later, profuse extravasation was noted from
the abdominal drains,
endotracheal tube,
and puncture sites of all intravascular lines.
Case 1 Presentation



Laboratory tests showed a rapidly falling
hemoglobin level and a platelet count of
25,000/µL.
The activated partial thromboplastin time (aPTT)
was 44 sec (normal, <28) and the prothrombin
time (PT) was 29 sec (normal, <12.5).
The level of fibrinogen degradation products was
360-520 g/L (normal, <40) and the plasma
antithrombin III level was 28% (normal, 80-120).
Case 1 Presentation

Based on these findings, the diagnosis was DIC secondary
to severe trauma. Surgical exploration revealed diffuse
oozing of blood at the site of the operation, but only partial
surgical hemostasis could be achieved.

The patient was given supportive treatment with:
large infusions of fresh frozen plasma
 platelet concentrates.

The bleeding stopped 48 hours later. Coagulation parameters
eventually returned to normal and the subsequent clinical
course was uneventful.
The pathogenesis of DIC
Selected Disorders That
May Be Associated with DIC

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Malignancy (solid tumors, myeloproliferative,
lymphoproliferative) Obstetric emergencies (amniotic fluid
embolism, abruptio placentae)
Organ destruction (severe pancreatitis)
Sepsis/severe infection (any microorganism)
Severe hepatic failure
Severe toxic or immunologic reactions (snake bites, recreational
drugs, transfusion reactions, transplant rejection)
Trauma (polytrauma, neurotrauma, trauma resulting in fat
embolism)
Vascular abnormalities (Kasabach-Merritt syndrome, large
vascular aneurysms)
Infection.

Bacterial infection, in particular septicemia, is commonly
associated with DIC. However, systemic infections with
other microorganisms, such as viruses and parasites, also
may lead to DIC.

Components of the microorganism's cell membrane
(lipopolysaccharide, or endotoxin) or bacterial exotoxins
(e.g. staphylococcal alpha-toxin) may cause a generalized
inflammatory response characterized by systemic
production of cytokines, mainly by activated mononuclear
cells and endothelial cells.

The cytokines are responsible for the derangement of the
coagulation system in DIC.
Trauma

Head trauma in particular is strongly associated
with DIC; both local and systemic activation of
coagulation may be detected after such an event.

The increased risk of DIC after head trauma is
understandable in view of the relatively large
amount of tissue factor in the cerebral
compartment.
Cancer




Both solid tumors and hematologic malignancies may be
complicated by DIC.
The mechanism by which the coagulation system becomes
deranged is poorly understood. However, most studies
implicate tissue factor, perhaps expressed on the surface
of tumor cells.
A distinct form of DIC is frequently encountered in
patients with acute promyelocytic leukemia; it is
characterized by a severe hyperfibrinolysis superimposed
on an activated coagulation system.
Although clinical bleeding predominates in such cases,
disseminated thrombosis is found at autopsy in a
considerable number of patients.
Obstetric Emergencies




Acute DIC occurs in obstetric complications such as amniotic fluid
embolism and abruptio placentae.
Amniotic fluid can activate coagulation in vitro, and in abruptio
placentae, the degree of placental separation correlates with the
severity of DIC, suggesting that leakage of thromboplastinlike
material from the placental system triggers DIC in these patients.
The most common obstetric complication associated with activation
of coagulation is preeclampsia. Severe preeclampsia may also be
complicated by :
HELLP syndrome (hemolysis, elevated liver enzymes, and low
platelets). The latter, however, is characterized by a microangiopathic
hemolytic anemia with secondary changes in the coagulation system.
It is related to, but clearly distinct from, DIC.
Vascular Disorders

Large aortic aneurysms or giant hemangiomas
(Kasabach-Merritt syndrome) may result in local
activation of coagulation factors.

The activated local factors can ultimately overflow to
the systemic circulation and cause DIC; more
commonly, systemic depletion of coagulation factors
and platelets results from local consumption.

The ensuing clinical condition may be difficult to
distinguish from DIC.
Microangiopathic hemolytic anemia




Microangiopathic hemolytic anemia is a group of disorders that
includes:
thrombotic thrombocytopenic purpura, hemolytic uremic syndrome,
chemotherapy-induced microangiopathic hemolytic anemia, malignant
hypertension, and HELLP syndrome.
A common pathogenetic feature appears to be endothelial damage,
which promotes platelet adhesion and aggregation, thrombin
formation, and impaired fibrinolysis.
Although some characteristics of microangiopathic hemolytic anemia
and the resulting thrombotic occlusion of small and mid-size vessels
(leading to organ failure) may mimic the clinical presentation of DIC,
these disorders in fact represent a distinct group of diseases.
Early events in sepsis
1) The intital toxic stimuli, such as
endotoxin (LPS), triggers production
of proinflammatory cytokines (TNF,
IL-1) and monocyte adherence to
endothelial cells.
2) TNF and IL-1 also activates
neutrophils and endothelial cells for
increased adherence. All activated
cells release secondary inflammatory
mediators, including cytokines.
3) Activation of platelets and
increased production of
procoagulants by endothelial cells
may trigger microthrombosis. In
some cases, disseminated
intravascular coagulation (DIC) may
occur with life-threatening tissue
ischemia.
4) Vessel dilation caused by free radicals,
histamine, prostaglandins, prostacyclin, and the
kinin and tachykinin family of molecules,
combined with the effects of cytokines on the
endothelial cells, contribute to increased
vascular permeability for fluids and lowmolecular weight substances, causing
oedema. If the process is wide-spread, a
capillary leak syndrome may result.
Case 2 Presentation

A 71-year-old woman was admitted to the ICU with sepsis
complicated by hemodynamic and respiratory instability.

Four days earlier, she had undergone a
duodenopancreatectomy for pancreatic carcinoma.

Fever, chills, and abdominal pain developed on the fourth day,
and a computed tomographic scan showed an intra-abdominal
abscess.

The diagnosis was septic shock complicated by respiratory
failure, which was caused by adult respiratory distress
syndrome.
Case 2 Presentation

The patient was treated with intravenous fluids and
vasopressors, intubation and mechanical ventilation, surgical
drainage of the abscess, and intravenous antibiotics.

Acute renal failure and hepatic insufficiency supervened
during the next several days. Moreover, the patient's
respiratory status deteriorated; the cause was determined to be
a large pulmonary embolism.

Laboratory tests showed persistent thrombocytopenia (platelet
count, 30,000-40,000/µL) and prolonged global clotting times:
aPTT, 40-45 sec; PT, 20-25 sec. Fibrin degradation product
levels were very high (>1600 µg/L; normal <40), and the
antithrombin III level was 30%.
Case 2 Presentation



Based on those findings, DIC secondary to sepsis
was diagnosed.
The patient received supportive treatment with
intravenous heparin and antithrombin III
concentrate (50-70 U/kg), with a goal of producing
greater than normal plasma concentrations.
After 10 days in the ICU, the patient gradually
recovered and all organ function normalized. One
month after her operation, she was discharged from
the hospital in good condition.
Diagnosis of DIC
Test
Result
Platelet count
Markedly decreased
Prothrombin time
Increased
Activated partial thromboplastin time
Increased
Fibrin degradation products
Markedly increased
Fibrinogen
Normal or decreased
Antithrombin III
Markedly decreased
Protein C
Markedly decreased
Specific Therapies


Platelet and Coagulation Factor Infusion
Heparin
Platelet and Coagulation Factor Infusion


Although low levels of platelets and coagulation factors may
increase the risk of bleeding in patients with DIC, plasma or
platelet transfusions should not be given on the basis of
laboratory test results alone; they are indicated only in patients
with active bleeding and in those who require an invasive
procedure or are otherwise at risk for bleeding.
The suggestion that administration of blood components might
exacerbate DIC has never been proved in clinical or
experimental studies. The efficacy of treatment with plasma or
platelets has not been confirmed in randomized controlled trials;
however, it appears to be a rational therapy in patients who are
bleeding or at risk for bleeding because of significant depletion
of these elements.
Heparin






Experimental studies have shown that heparin can at least partly inhibit
the activation of coagulation in DIC secondary to sepsis and other
causes.
In addition, patients with DIC need prophylaxis against venous
thromboembolism.
The benefit of heparin has been shown in a small, uncontrolled series of
patients with DIC but has never been demonstrated in controlled clinical
trials. The safety of heparin in patients with DIC who are prone to
bleeding is often debated, but clinical studies have not shown that
heparin significantly worsens bleeding complications in this group.
Altogether, heparin is probably useful in patients with DIC, particularly
in those with clinically overt thromboembolism or extensive fibrin
deposition, such as purpura fulminans or ischemia in the extremities.
Heparin is usually given in a relatively low-dose, continuous infusion
(300-500 U/hr).
Recent studies show that low-molecular-weight heparin can be used as
an alternative to unfractionated heparin.
Experimental Therapies


Theoretically, the most logical anticoagulation
therapy in patients with DIC is an agent that is
directed against tissue factor activity.
Indeed, inhibitors of the tissue factor pathway
have been developed and ongoing clinical
studies are evaluating their efficacy and safety in
DIC.
Experimental Therapies


Restoration of physiologic anticoagulation pathways might be an
appropriate therapeutic option in DIC. Antithrombin III is one
of the most important natural inhibitors of coagulation; patients
with DIC almost invariably have an acquired deficiency of the
substance.
Administration of supraphysiologic concentrations of
antithrombin III has produced promising results in clinical trials
involving patients with sepsis or septic shock, with or without
DIC. Some trials showed a modestly (but statistically
insignificant) reduced mortality in patients treated with
antithrombin III. A metaanalysis of the trials showed that
mortality decreased from 56% to 44% (odds ratio, 0.63; 95%
confidence interval, 0.39 to 1.0). A large, randomized, controlled
multicenter trial of supraphysiologic doses of antithrombin III
in patients with sepsis is currently under way, and its outcome
will more definitively determine the place of antithrombin III
treatment in sepsis and DIC.
Experimental Therapies


Another promising treatment is recombinant activated
protein C.
This compound is now being evaluated in large
multicenter trials in patients with sepsis, DIC, or both.
In view of the pivotal role of protein C as inhibitor of
the coagulation cascade and its postulated role as an
important mediator of inflammation, activated protein
C may be a good candidate for supportive treatment of
patients with DIC.
Treatment options for DIC

Acute DIC
Without bleeding or evidence of ischemia
No treatment
With bleeding
Blood components as needed
Fresh frozen plasma
Cryoprecipitate
Platelet transfusions
With ischemia
Anticoagulants (see "with thromboembolism" below) after
bleeding risk is corrected with blood products
Treatment options for DIC

Chronic DIC
Without thromboembolism
No specific therapy needed but prophylactic drugs
(eg, low-dose heparin, low-molecular-weight
heparin)
may be used for patients at high risk of thrombosis
With thromboembolism
Heparin or low-molecular-weight heparin, trial of
warfarin
sodium (Coumadin). (If warfarin is unsuccessful,
long-term use
of low-molecular-weight heparin may be helpful.)*
DIC
DIC - Gangrene in patient with
meningococcal sepsis
Schistocytes on the Peripheral
Blood Smear
DIC
Subdermal bleeding at
IV site following a bite
by Hoplocephalus
stephensi
Disseminated intravascular coagulation (DIC).
Patient with Postvaricella purpura
fulminans showing extent of necrotic
lesions
Leg after skin grafting
14 year old otherwise healthy male who three weeks after primary varicella infection developed large
painful lesions on his leg. (Fig 1). Laboratories evaluation showed evidence of disseminated intravascular
coagulation (DIC). Plasma free protein S level was below 5% with other factors only mildly decreased
(consistent with his DIC).
Patient was treated with heparin and plasma infusion which resulted in stabilization of his lesions. For his
presumed autoimmune protein S deficiency he received immunoglobulin. Over the course of the next
several months his protein S levels increased back into the normal range but his skin lesions required
extensive grafting (fig 2 and 3).
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