BEHANDLING AF H

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Disseminated Intravascular Coagulation (DIC) and
related disorders in critically ill patients
Arno Zaritsky, M.D. University of Florida
College of Medicine Some slides from
www.dicsepsis.org and www.coumadin.com
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Normal haemostasis is dependent on

• Platelets
• The coagulation system
• The fibrinolytic system
• Endothelial/subendothelial cells
• Blood viscosity
• Blood flow

CoagulationInflammation
AnticoagulantsAntiinflammatoryFibrinolysis
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Case

• A 10-year-old 30 kg boy is involved in an ATV
  accident. He is hypotensive with a distended
  abdomen and severe laceration to his thigh.
• Taken to OR and requires 6 units of pRBC, 2 units
  of FFP and 7 liters of Ringers lactate to manage
  severe bleeding from a laceration to his femoral
  artery, splintered spleen and fractured liver.
• Arrives in the PICU with oozing from wound. He is
  hemodynamically stable HR 110 BP 105/70 and
  breathing spontaneously

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Case

• H/H 9.5/28.5 platelets 43,000 PT 18.6
  seconds/ PTT 48 secs FDP 1.4 Fibrinogen
  124 mg
• Does he have DIC?
• What is DIC?
• How do you diagnose DIC?

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Diagnosis of DIC

• Hemorrhage is often the recognized manifestation
  of DIC,but the initial major problem is
  thrombosis of the micro-vasculature sometimes
  leading to microembolization of multiple organs
• Although DIC is a well recognized clinical
  condition, there is no consensus on its
  definition and diagnostic criteria.
• There is also no method to quantify the severity
  of DIC and to recognize non-overt DIC

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Platelets release ADP and TxA2 generate PL
activating factors and release PAI to limit
thrombolysis TF expression induced on endothelium
and mononuclear cells by endotoxin, TNF, IL-1
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Definition of disseminated intravascular
coagulation

• DIC is an acquired syndrome characterized by the
  intravascular activation of coagulation with loss
  of localization arising from different causes. It
  can originate from and cause damage to the
  microvasculature, which if sufficiently severe,
  can produce organ dysfunction.

Scientific Subcommittee on DIC of the
International Society on Thrombosis and
Haemostasis. July 9, 2001
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DIC
SYSTEMIC ACTIVATION OF COAGULATION

• An acquired syndrome characterized by systemic
  intravascular coagulation
• Coagulation is always the initial event

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Disseminated intravascular coagulation

• Microvasculature is defined as a transport organ
  composed of blood and the vascular structures in
  contact with the blood, including endothelium and
  mononuclear cells (RES/microvasculature)
• Homeostasis is maintained by a COMPLEX balance
  between vascular, RES and blood component factors

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D fragmentsE fragments
Fibrinogen
Prothrombin
Fragment 12
THROMBIN
Fibrino-peptideA B
AntithrombinaPC PS
Plasmin
Fibrin
FXIII FXIIIa
Thrombin-Antithrombincomplex(TAT)
Cross-linkedfibrin
D dimerE fragmentsFDP
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Laboratory Studies

• D-dimer and FDP complex products produced from
  fibrinolysis
• FDP more sensitive D-dimer more specific
• PT extrinsic (I, II, V, VII, X) international
  normalization ratio (INR) better expresses value
• aPTT intrinsic (XII, XI, X, IX, VIII, V, II I)
• TAT Thrombin-antithrombin reflects activation
  of thrombin and inhibitory pathway
• Fragment 12 prothrombin activation

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Symptoms of DIC

• Dysfunction of multiple organs
• The pulmonary microembolism syndrome
• Acute vascular and bronchoconstriction
• Late ARDS
• Acute renal failure
• Oliguria, increasing serum creatinine, hematuria
• Cerebral dysfunction
• Confusion, blurred consciousness, coma
• Cutaneous hemorrhagic necroses
• Failure of liver, endocrine glands etc.

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Causes of DIC (Clinical conditions, I)

• Infections (responsible for 50 of cases)
• Septicaemia
• Gram negative (endotoxin)
• Gram positive (polysaccharides, peptides)
• Viremias
• Varicella
• Hepatitis
• Cytomegalovirus
• HIV

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Causes of DIC

• Trauma
• Crush injuries
• Other trauma with tissue necrosis
• Severe burns
• Extensive surgery
• TBI high concentration of TF
• Obstetric complications
• Amniotic fluid embolism
• Placental abruption
• (Pre)eclampsia
• Dead fetus syndrome

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Causes of DIC

• Hemolysis
• Hemolytic transfusion reactions
• Massive transfusions
• Malaria
• Other severe hemolysis
• Malignant disorders
• Metastatic malignancy
• Tumors producing cancer procoagulant
• Tumor with tissue necrosis

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Causes of DIC

• Vascular abnormalities
• Giant hemangioma
• Heriditary teleangiectasis
• Prosthetic devices
• Aortic balloon assist devices
• Denver shunts
• Other conditions
• Pancreatitis
• Acute liver necrosis
• Transplant rejection
• Heat stroke

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Criteria for overt DIC

• Must have a condition associated with DIC
• Platelet count (gt100K 0 lt100K 1 lt50K 2)
• Increased fibrinolysis-related marker (eg. FDP,
  soluble fibrin no increase 0 moderate 2
  strong increase 3)
• PT (lt3 secs0 gt3 but lt 6 sec 1 gt6 sec2)
• Fibrinogen (gt 100 mg0 lt100 mg1)
• If score gt 5, compatible with overt DIC repeat
  daily. If lt5 suggestive of non-overt DIC. Repeat
  daily

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Criteria for non-overt DIC

• More complex and less agreement
• Consider measurement of AT, protein C and TAT
  complexes in addition to previous criteria.
• Also need to recognize that DIC is different
  depending on the time course of the disease
  process

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Systemic hyperactive disorders of hemostasis
TTP Thrombotic Thrombocytopenic
PurpuraHELLP Hemolysis, Elevated Liver enzymes,
Low PlateletsHUS Hemolytic Uremic Syndrome
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Course of DIC Accelerating factors
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Treatment of DIC

• Stop the triggering process .
• The only proven treatment!
• Supportive therapy
• No specific treatments
• Plasma and platelet substitution therapy
• Anticoagulants
• Physiologic coagulation inhibitors

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Heparin

• Acts by binding to AT leading to confirmational
  change.
• The AT-heparin complex inhibits IIa most potently
• Xa is next most potently inhibited and does not
  require simultaneous binding by heparin
• Also inhibits IXa, XIa, and XIIa.
• Binding to AT is through unique penta-saccharide
• Only one-third of heparin molecules can bind to
  AT-III

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Heparin
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Heparin

• Once AT is bound to the serine protease site, it
  releases heparin
• Released heparin can then bind to another AT
• The binding of AT to its target is covalent
• Heparin pharmacokinetics larger molecules are
  cleared more quickly

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Treatment of DIC Heparin

• Heparin has an immediate antithrombotic effect
  but its value in the treatment of DIC is doubtful
  because
• Heparin increases the effect of a number of
  proteases from neutrophil granulocytes and
  bacteria
• Heparin aggregates activated platelets
• Heparin inhibits antithrombin-induced release of
  prostacyclin from endothelial cells by binding to
  glycosaminoglycans
• Heparin requires adequate concentrations of AT,
  which is often depeleted in DIC

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Antithrombin In Sepsis

• Multicenter trial to determine if high-dose AT
  within 6 hours of sepsis onset improved survival
  (KyperSept Trial)
• Double-blind, placebo controlled trial
• 2314 adult patients randomized to 30,000 units AT
  over 4 days or 1 albumin
• Overall 28-day mortality was 38.9 in AT group
  vs. 38.7 in placebo
• In subgroup who did not receive heparin (n698),
  AT group (37.8 vs. 43.6 (p.08)
• ATheparin increased serious bleeding (23.8 vs.
  13.5 placebo)

JAMA 2001 2861896-78 (October 17)
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Randomised trials on antithrombin in patients
with sepsis or evidence of DIC
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Treatment of DIC Antithrombin

• Determine antithrombin activity
• The antithrombin activity is increased to 100
  by infusion of (100 - AT) X (kg body weight)
  IU i.v.
• Determine the antithrombin level every 46 hrs
  and repeat infusion when necessary
• If acute determination of antithrombin is not
  available, treatment can be initiated with a
  dose of 50 X (kg body weight) IU i.v.
• Simultaneous use of heparin increases the
  bleeding tendency

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Activated protein c
Faust et al. Dysfunction of endothelial protein c
activation in severe meningococcal sepsis. NEJM
2001 345408
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Activated Protein C
XaVIIaVaVIIIa
Endothelial Cell
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Activated Protein C

• 164 center study of patients with severe sepsis
• Known or suspected sepsis
• gt3 signs of systemic infection w/in 24 h
• Sepsis-induced organ dysfunction for lt24 h
• Begin therapy within 24 h of entry criteria
• aPC infused for 96 h
• 1728 randomized 1690 received drug or placebo
• 75 on ventilator and 75 on vasopressor
• blood cultures in 32.5

Bernard et al. NEJM 2001 344699-709.
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Activated Protein C

• 259/840 (30.8) versus 210/850 (24.7) died at 28
  days (p0.005)
• ARR 6.2 NNT 16
• Normal PC concentration
• 28/105 (26.7) vs 14/90 (15.6) survived

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Summary

• DIC is complex process often non-overt
• Recognition based on clinical condition and
  laboratory studies
• Treatment based on reversing underlying cause
• Heparin not helpful AT may be helpful, but
  activated Protein C is useful in DIC complicating
  septic shock