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DisseminatedIntravascular Coagulation

D I C

Hemostasis and Coagulation ConferenceMeredith Lann, MD

Dec 1, 2005

What is DIC?

• A syndrome characterized by systemic intravascular activation of coagulation and widespread deposition of fibrin in the circulation leading to overwhelming consumption of coagulation factors

• Dx is suggested by clinical presentation, confirmed by laboratory studies

• Always secondary to an underlying process

Clinical presentation of DIC

Bleeding 64%

Renal dysfunction 25%

Hepatic dysfunction 19%

Respiratory dysfunction 16%

Shock 14%

Thromboembolic event 7%

CNS involvement 2%

Conditions associated with DIC• Sepsis/severe infection• Trauma• Organ destruction (eg, severe pancreatitis)• Malignancy (solid tumors, hematologic)• Obstetrical calamities (amniotic fluid embolism,

abruptio placentae)• Vascular abnormalities (Kasabach-Merritt Syndrome,

large vascular aneurysms• Severe hepatic failure• Severe toxic or immunologic reactions (snake bites, rec

drugs, transfusion rxns, transplant rej.)

Conditions associated with DIC

From Wada H. Disseminated intravascular coagulation. Clinica Chemica Acta 2004 Jun; 344(2): 13-21.

Significance of DIC• Constitutes

approximately 1% of all hospital admissions in U.S.

• Mortality is 40 - 80% (trauma, sepsis, burn)

• Independent risk factors for death: age, organ failure, hemostatic abnormalities

80%

1%

Scoring Systems for Diagnosis

Fujita M, et al. Protein C Inhibitor as an Anti-DIC agent – Mechanism and modification. Current Medicinal Chemistry: Cardiovascular and Hematological Agents. 2004 Mar 2(1): 21-27.

Alternative scoring systems

• Simple calculation that can be computed quickly at the bedside

• Accurate, effective• Minimize lab tests• Provide prognostic value• Account for dynamic nature of evolving

disease example: Kinasewitz et al 2005

Pathophysiology of clinical manifestations of DIC

www.uptodate.com

Variations of DIC – Overt• Overt/Acute DIC

– Easier to diagnose, clear criteria/scoring systems exist

– Uncompensated state with levels of hemostatic components

– Clinical findings: bleeding, oozing, petechiae, purpura. Microthrombosis 60-75% (ARF, resp failure,liver failure, necrotic skin lesions

Variations of DIC – Non-overt• Non-overt/Chronic DIC

– Difficult to dx as no clear criteria – Compensated state that is prone to develop in

certain medical conditions such as disseminated malignancy, advanced liver disease, immunologic disorders

– Coag studies may be normal– Normal or clotting factors (esp if APR)– Recommend following SERIAL tests to

evaluate the course (progressive, resolving, chronic)

Acute v Chronic DIC

www.uptodate.com

Lab tests in DIC – what do they really mean?

platelet count - thrombin activation and clearance, destruction, endotoxemia-induced suppression

D-Dimer - secondary lysis of crosslinked fibrin PT, aPTT – reduction of clotting factors fibrinogen – thrombin converts to fibrin thrombin clotting time – inhibition of fibrin

polymerization by FDPs

No one single test…• D Dimer is more sensitive than FDPs• High negative predictive value• good screening test• Formerly only +/-, newer quantitative test is more

helpful• Monoclonal antibody or ELISA

Lehman CM et al. Am J Clin Pathol 2004;122:178-184www.uptodate.com

Pre-DIC

• Difficult to dx• Allows for earlier Rx• Sensitive tests: TAT complex, PPIC, SF and

D-Dimer • In 2002 ISTH subcommittee proposed

global coagulation tests, PC and AT activity, TAT complex levels, aPTT biphasic waveform (but was not adopted)

Biphasic Transmittance Waveform in the aPTT

Coagulation Assay• Change in light

transmittance due to formation of Ca+

+dependent complex of CRP with VLDL

• Indicates greater capacity to generate THROMBIN From Toh CH et al. Blood, Sep 2002; 100: 2522 - 2529.

•

Normal Hemostasis- Thrombogenesis

http://www.frca.co.uk/images/clotting_cascade.gif

PTAPTT

Normal Hemostasis - Fibrinolysis

http://upload.wikimedia.org

Derangements of hemostasis in DIC – activation of coagulation

• Abundant presence of TF or inflammatory mediator

• Activation of extrinsic pathway leads to TF-FVIIa complex formation

• Role of sytemic inflammatory mediators• Continues down cascade, eventual THROMBIN

generation• State worsened by consumption of clotting

factors, secondary fibrinolysis

• Tissue Factor Pathway Inhibitor insufficency- less inhibition of TF/FVIIa complex

• Antithrombin system ( levels of AT)– Consumption by

complex formation– Degraded by elastases– Impaired synthesis– Capillary leakage

Protein C system ( levels of PC or capacity of APC)– Enhanced consumption– Impaired liver synth.– Vascular leakage– Activation of cytokine

network (TNF-alpha) results in TM and free Protein S

Derangements at control pathways

Impact on anticoagulant mechanisms during sepsis

Levi M. Disseminated Intravascular Coagulation: What’s New? Critical Care Clinics 2005 Jul; 21(3): 449 – 467.

Changes in secondary fibrinolysis in DIC

• Fibrinolysis starts clearly after coagulation is activated

• Fibrin deposition/endotoxemia stimulates release of plasminogen activators (tPA)

• Leads to PLASMIN generation• Plasmin “chews up” fibrin

FDPs • Suppressed by PAI-1 ( in sepsis)

DIC in sepsis

Gram neg sepsis LPS endotoxin initiates

an inflammatory reaction

Stimulates TLR, interacts with CD14 inc production of NF-kB

levels of CYTOKINES (IL-1, TNF), ELASTASE and CRP

Gram pos sepsisPeptidoglycan initiates

inflammatory reaction, much like LPS

production of CYTOKINES (IL-1, TNF) as well as TF

http://www.conceptdraw.com/http://www.nature.com/

Fujita M et al. Protein C Inhibitor as an Anti-DIC agent – Mechanism and modification. Current Medicinal Chemistry: Cardiovascular and Hematological Agents. 2004 Mar 2(1): 21-27.

Mechanisms for

pathogenesis of DIC in

sepsis

Possible future lab tests – Thrombogenic effects in DIC

• Low TAT complex (binds, inhibits FIXa, FXa)

• Prothrombin fragment 1+2 (F1.2)

• Soluble fibrin monomer• APC-PC inhibitor

complex

• TF levels (free, leuk)• TFPI-factor complexes• TF mRNA

Upside: high sens, specDownside:Expensive, require

sophisticated equipmentOften have long turnaround

time

Possible future lab tests – Fibrinolytic effects of DIC

• PAI-1 levels • GE-XDP • PPIC (also PAP), not

as useful as anticipated• tPA• AT, PC levels

(prognostic value)

Unfortunately these tests may not be realistic

-?Fluctuating course

-?tech difficult, more expensive, less sensitive than current tests

Treatment of DIC

• Aggressive treatment for underlying condition• Support with blood products • Follow serial labs• Therapeutic heparin or argatroban (HIT) if risk/

evidence of thrombosis (this is debatable)• Recombinant activated Protein C (both anti-

inflammatory and anti-coagulant effects)

Clinical Trials - APC

PROWESS, 2001 Bernard GR, et al. performed RCT – based on premise that suppression of the protein C system may contribute to DIC

Phase II RCT - APC in patients with severe sepsis reduced D-Dimer, IL-6

Phase III - stopped early as it showed huge reduction in mortality in the treated patients as(RRR 19.4% (24.7% v 30.8%)

-Subgroup analysis showed benefit in virtually all subgroups (age, type, site, disease severity)

Clinical Trials – Antithrombin

Previous bench studies showed AT TF, IL-6 in LPS-stimulated mononuclear cells, HUVECs, WB

KYBERSEPT 2001, Warran BL et al.

RCT showed high-dose ATIII in patients with severe sepsis resulted in increased mortality (38.9% v 38.7%)

Clinical Trials - TFPI

OPTIMIST 2003, Abraham E et al.

In previous mouse models TFPI appeared to protect against the onset of DIC/sepsis

Phase II for recombinant TFPI (tifacogin) supported this

Phase III however showed increased mortality (34.2% v 33.9%)

Therapies under construction

Theoretically the following should work:Rx directed against TF

TFPI, inactivated FVIIa, recomb NAPc2Restoring anticoagulant pathways

AT concentrates (animal studies, Kybersept trial)antifibrinolytics –

gabexate mesilate, nafamostat mesilate (x-ind)Selectively inhibit granulocyte elastase

sivelestat sodium hydrate

Summary

DIC is a syndrome where widespread thrombosis due to underlying condition leads to consumption of coagulation factors, as well as derangement of various control pathways, puts the patient at risk of clotting complications and/or bleeding diathesis.

Treatment aims to improve the causative condition and support the patient.

Many people are working towards improvement in diagnosis and treatment of this condition.

References• Levi M. Disseminated Intravascular Coagulation: What’s New? Critical Care Clinics 2005 Jul; 21(3):

449 – 467.• Wada H. Disseminated intravascular coagulation, review. Clinica Chemica Acta 2004 Jun; 344(2): 13-

21.• Goodnight SH, Hathaway WE. Disorders of Hemostasis and Thrombosis, 2nd ed. Mc-Graw Hill, Inc

2001• Kinasewitz GT, Zein JG, Lee G, Nazir SA, Taylor FB. Prognostic Value of a simple evolving

disseminated intravascular coagulation score in patients with severe sepsis. Critical Care Medicine 2005 Oct; 33(10): 2214-2221.

• Lehman CM, Wilson LW, Rodgers GM. Analytic Validation and Clinical Evaluation of the STALIATEST Immunoturbidimetric D-Dimer Assay for the Diagnosis of Disseminated Intravascular Coagulation. Am J Clin Pathol 2004;122:178-184

• Fujita M, Izutani W, Takahashi K. Protein C Inhibitor as an Anti-DIC agent – Mechanism and modification. Current Medicinal Chemistry: Cardiovascular and Hematological Agents 2004 Mar 2(1): 21-27.

• Toh CH, Samis J, Downey C et al. Biphasic transmittance waveform in theAPTT coagulation assay is due to the formation of a Ca-dependent complex of C-reactive protein with very-low–density lipoprotein and is a novel marker of impending disseminated intravascular coagulation. Blood, Sep 2002; 100: 2522 - 2529.

• DIC, Cause or Consequence of an unfavourable outcome in Sepsis? Summaries from a Satellite Symposium sponsored by bioMerieux at the XIXth Congress of the ISTH. Birmingham, UK, July 2005

• www.uptodate.com, www.biomerieux.com

Questions?

Thank you.