Disseminated Intravascular Coagulation  

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Coagulation and fibrinolysis in its most severe derangement.

Critically ill children in the ICU may  develop the catastrophic thrombotic and proteolytic syndrome of DIC as a final common pathway complicating  their underlying illness.

Lets first review the normal coagulation and fibrinolysis mechanisms.

Important  Points

ü      Surface activated intrinsic system consisting of factors XII, XI, IX, VIII is tested by activated-partial thromboplastin time (PTT)

ü      Tissue Factor activated extrinsic system is tested by prothrombin time (PT)

ü      Thrombin is a very potent platelet aggregator. It cleaves fibrinopeptides A and B from fibrinogen to form fibrin monomers which spontaneously polymerize into fibrin

ü      Fibrin polymers are stabilized by factor XIII

ü      Vitamin K is critical : It is needed for carboxylation of inactive synthesized prothrombin (factor II) as well as factors VII, IX, X, protein C, protein S

 Fibrinolysis

 ü      Thrombin when bound to the endothelial receptor thrombomodulin loses its ability to clot fibrinogen, aggregate platelets and activate factor V

 ü      Thrombin instead activates protein C which inactivates factor V and VIII, it also increases tPA levels

 ü      Endothelial Cell:

Ø     Generates heparin like molecules à binds antithrombin III à has 75% antithrombin activity, inhibits Xa, IXa, XIa and XIIa

Ø     Heparin combines with heparin cofactor II decreasing coagulation

Ø     Endothelial cell also generates tPA à cleaves plasminogen to plasmin à lyses fibrin clot à thus proteolysis is confined to clot surface

Ø     Action of plasmin is inhibited by alpha 2 antiplasmin

TO DISCUSS WHAT HAPPENS IN DIC

Pathophysiology

Ø     The basic problem in DIC is that the processes of  thrombosis and fibrinolysis are no longer controlled.

Ø     The endothelial cell normally contributes importantly to the maintenance of blood flow and the prevention of inadvertent coagulation by producing

  ü      prostacyclin,

 ü      by exhibiting thrombomodulin on the cell surface

 ü      and supplying heparin like molecules that interact with antithrombin III and heparin cofactor II.

Ø     When perturbed by endotoxin in vitro

ü      endothelial cell synthesizes tissue factor, thus, promoting the assembly and activation of the prothrombinase complex.

ü      Thrombomodulin may be lost from the endothelial cell surface and decrease protein C activation.

ü      Moreover, the perturbed endothelial cell may synthesize thromboxane rather than prostacyclin, promoting platelet aggregation and adhesion

Ø     In addition, activated protein C is consumed in DIC. Activated protein C may protect the host during an inflammatory challenge and its loss may thus further major organ damage during DIC.

Ø     Also, ATIII and HCII may be consumed in the attempt to localize the pathologic widespread microthrombosis seen in DIC. The exhaustion of these modulating proteins will lead to worsening of thrombosis.

Ø     Once activated, thrombin has manifold effects. However, the activation of factors V and VIII and platelets by thrombin leads to their subsequent degradation àà In pathologic overactivation of thrombin, therefore, these components (platelets, V, VIII) will be consumed further contributing to hemostatic failure.

The widespread platelet activation and abnormal endothelial cell modulation of thrombosis will derange fibrinolysis as well as thrombosis. The activation of thrombosis in DIC is countered by secondary fibrinolysis .

Secondary Fibrinolysis

Ø     Thrombin in directly leads to the activation of tPA and the generation of plasmin. Plasmin hydrolyses fibrinogen and fibrin into the fibrin degradation products (FDP) that themselves add to the hemostatic failure in DIC.

Ø     Plasmin also hydrolyses V, VIII, IX, and XI

Ø     In a feedback loop that may be of particular importance in sepsis-induced DIC, plasmin degrades activated factor XII (XIIa). XIIa fragments, as well as XIIa, generates bradykinin

Ø     Bradykinin strongly stimulates the release of tissue plasminogen activator

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Clinical Settings For DIC

 1.  Infection

A.   Gram negative

a. Endotoxin

i. Activates Kallikren-kinins  (e.g.,  bradykinin)

ii. Activates factor XII, platelets

iii. Endothelial damage

iv. Activates factor VII [monocyte tissue factor production)

B. General mechanisms

a. Direct endothelial damage

b. Antigen-antibody complexes

i. Platelet activation

c. Direct platelet activation

d. Venous / vascular stasis           

2.  Tumor

A. I,eukemia

a.   Acute promyelocytic leukemia

i.                    Factor VII-like activity

B. Solid tumors

a. X activating activity (especially in rnucinous adeno-carcinoma)

b. Endothelial injury and prothrombinase assembly

3.  Severe head injury

A.   Tissue thromboplastin activity

4.  Obstetric

A. Abruption

B. Retained dead fetus

5.    Neonatal

A. Necrotizing enterocolitis

B. Respiratory distress syndrome

6.  HUS

7.  Giant hemangioma

8.  Miscellaneous

A. Shock [anaphylaxis, heat stroke, etc. )

B.   Snakebite

C.   Transfusion reactions

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Description Of  Clinical Syndromes

Sepsis

q       Any sepsis syndrome can lead to DIC however the most characteristic are Gram-negative infections associated with endotoxin release.

q       Endotoxin can directly injure the vessel wall, exposing the subendothelium.

q       The exposed subendothelial surface can initiate contact activation of the coagulation cascade  and endotoxin can directly activate factor XII

q       Pathologic over activation of the contact system may also lead to neutrophil activation and release of their contents, furthering tissue injury.

q       Endotoxin also stimulates the synthesis of tissue factor activity by monocytes, which can then activate X in the presence of VIIa.

Both gram-negative bacteria and other infectious organisms can induce DIC through mechanisms other than endotoxin-mediated effects. These include:

q       Direct endothelial damage

q       The leukocytes may further cause damage by releasing mediators, including proteolytic granular enzymes, superoxides, and sulfated muco-polysaccharides,  that  nonenzymatically  precipitate fibrin monomer

     q       Antigen-antibody complexes may form, leading to platelet injury

q       In fact, organisms may attach to the platelet surface, leading to direct platelet injury.

q       Overall, sepsis-related DIC is a fulminant process whose predominant clinical manifestation is hemorrhage

q       Nonetheless, it is important to remember that widespread microthrombosis leading possibly to organ ischemia is an ongoing process. This is dramatically evident in purpura fulminans

q       Intravascular occlusion of the terminal arterioles in the skin gives rise to sharply demarcated areas of hemorrhagic necrosis, which may coalesce if larger vessels are subsequently occluded

·        Digit or even limb gangrene may supervene

·        Renal damage varying from glomerular injury to cortical necrosis may also occur

·        A confusional state, convulsions, or coma may be furthered by microvascular occlusion in what may be an underperfused brain

·        Pulmonary injury and gastrointestinal ulceration may also result from clots in small vessels

DIC Assoclated with Tumors

q       In adults, DIC associated with cancer is most often a chronic, low-grade, primarily thrombotic process seen most frequently in mucinous adenocarcinomas. Pancreatic carcinoma leading to migratory thrombophlebitis is the classic example

q       The mucin may have X-activating activity

q       Some malignant cells can also assemble the prothrombinase  complex

Severe Head Injury

q       Brain tissue is known to be a  potent thromboplastin

q       In fact. it is the thromboplastin used in the laboratory evaluation of the classic extrinsic  pathway.

q       Severe brain injury may therefore, release thromboplastic substances into the  circulation, where they initiate coagulation

Obstetric Accidents

q       Tissue thromboplastic material may also be released into the circulation after a dead  fetus has been retained for longer than 2 weeks

q       In placenta abruptio, clotting factors may be consumed at the site of the retroplacental clot, but thromboplastic material from degenerating placental tissue may also enter the circulation

NeonataI IIIness

q       Birth depression (defined as a 1-min Apgar score of less than 3 and a 5-min Apgar score of less than 7) and sepsis are the most common etiologies of DIC in the newborn

q       Necrotizing enterocolitis, may also lead to either thrombocytopenia or DIC. The release of thromboplastic material from the injured bowel wall may be etiology

q       Obstetric problems such as toxemia and third trimester bleeding figure prominently in neonatal as well as maternal DIC

 Hemotytic Uremic Syndrome

q       Thrombocytopenia is usually more prominent than DIC, and thrombosis, particularly in the renal microvasculature and perhaps in the brain also, is more important than hemorrhage

q       The verotoxin, in particular, may act by inducing a plasma factor that causes platelet aggregation by use of glycoproteins IIB and IIIA

q       Microvascular occlusion in cerebral vessels is particularly pronounced in TTP, a closely related if not identical syndrome in adults.

Laboratory Abnormalities

Therapy

q       The mainstay of therapy in DIC is treatment of the underlying disease

q       The most clear-cut example of the efficacy of such therapy is in obstetric disorders, in which evacuation of the uterine contents removes the thrombotic stimulus and allows for rapid normalization of hemostasis

q       Antithrombin therapy: Elimination of the thrombotic initiators is more difficult in sepsis or other shock states, in which there may be diffuse vascular damage. Antithrombin therapy, therefore, has been suggested as an adjunct to treatment of the underlying disorders. This has classically been heparinization

q       Heparin: Unfortunately, the main side effect of heparin is hemorrhage, so that heparin has been a controversial medication for use in DIC

Nonetheless, there are specific indications for heparin therapy

o       In purpura fulminans, fibrin deposition in small vessels is of major pathologic significance, and heparin therapy may improve outcome

o       End-organ dysfunction, such as brain, kidney, heart, or lung dysfunction, due, at least in part, to microthrombi is a controversial indication for heparinization

o       Heparin may also normalize coagulation in acute promyelocytic leukemia by interfering with the action of the tissue factor-like activity in the granules

q       Topical nitroglycerin: Recent developments in the treatment of DIC include topical nitroglycerin therapy

                                {that was found helpful in a report of two children with purpura fulminans who were unresponsive to other therapy (heparin, systemic vasodilation, and sympathetic blockade)}

q       Antithrombin III: A second therapy.that has been available in Europe and Japan for some time now is antithrombin III concentrate infusion

q       Low Molecular Weight Heparin: A third therapy of potential use is low molecular weight fractions of heparin They have anti-Xa and antithrombin activity with perhaps a lower risk of hemorrhage

q       Protein C: Protein C may protect the host from the lethal effects of overwhelming infection. This is still under trial

q       Other investigational antithrombin agents:

§        A synthetic thrombin inhibitor, MD-S05

§        Gabexate, or Foy,  a synthetic antithrombin that also inhibits the kallikrein and complement systems

§        Human monoclonal antibody against endotoxin

§        In the neonate, exchange transfusion has been advocated

q       Platelets: Platelets may be rapidly sequestered, unfortunately. One unit of platelets per 5 kilograms body weight is estimated to raise the platelet count 5O,OOO / microliter

q       Prothrombin concentrates containing factors II, VII, IX, and X have also been used

q       FFP: FFP can be used. although the volume required may be a problem. FFP in a dose of 10-15 ml/kg supplies all factors in limited concentration

q       Cryoprecipitate: One unit of cryoprecipitate per 5 kilograms body weight will raise the fibrinogen concentration by about 75 mg / dl

q       This replacement should also be undertaken in victims of snake bite, along with the administration of specific antivenom.

____________________________________________________________________________

To Summarize The Guidelines Of Therapy In DIC               

1.         Interrupt the process

a.   Treat the underlying disease

2.         Replacement

a.   Platelets: 1 unit / 5 kg body weight

b.   Plasma:10-15 ml / kg body weight

c.   Cryoprecipitate (fibrinogen source):  1 bag / 5 kg body weight

3.         Pharmalogical Interentions

a.         Heparin:

i.    Purpura fulminans

ii.   ? Acute promyelocytic leukemia

b.         Topical nitroglycerin

i.    Purpura fulminans

c.         Investigational

i.    Antithrombin III infusions

ii.   Synthetic antithrombins

iii. Heparin fragments

iv.  Protein C infusions

v.   Antimediator therapy

a.   HA-lA vs. endotoxin

b.   Mutant ai-antitrypsin vs. kallikrein-kinin

c.   vs. Tumor necrosis factor

i.    Monoclonal antibodies

ii.   Soluble receptors

d.   vs. Interleukin-1

i.    Monoclonal antibodies

ii.   Receptor antacsnnictc

4.         Exchange Transfusion

Thank You.

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