1. Failure of Coagulation
MUDr. Tomáš Stopka Ph.D.
and colleagues from the Institute of Pathophysiology, Charles University

2. Plan
Coagulation
Methods
DIC
Therapy
Presentation

3. 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.

4. 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

5. I. Coagulation LUMEN Blood clot WALL Endothelial demage
Damaged endothelial cells display tissue factor (TF) that binds to activated Factor 7 (TF-7) to cleave: Factor 10
The intrinsic cascade is initiated when contact is made between blood and exposed endothelial cell surfaces.

6. I. Coagulation Controlling Clotting
Antithrombin III inactivates: prothrombin, factor 9, factor 10
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
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.
Heparin binds to and enhances antithrombin III.
Warfarin (aka coumadin) is an effective vitamin K antagonist.

7. 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.

8. I. Coagulation VASCULAR WALL ENDOTHELIUM PLATELETS PLAZMATIC
HEMOCOAGULATION is INTEGRAL PART of INFLAMATORY RESPONSE
VASCULAR WALL
ENDOTHELIUM
PLATELETS
PLAZMATIC
COAGULATION SYSTEM

9. I. Coagulation ARTERIAL LUNGS SYSTEMIC EMBOLISM THROMBOSIS
DISORDERS OF HEMOCOAGULATION = THROMBOSIS AND EMBOLISM
THROMBOSIS
IN MICROCIRCULATION
VENOUS
ARTERIAL
SIGNS
-TISSUE ISCHEMIA
- HEMODYNAMIC FAILURE
LUNGS
SYSTEMIC
EMBOLISM

10. I. Coagulation Deep Venous Thrombosis (DVT) Posthrombotic syndrome
A) asymptomatic : > 50% Lung Embolism.
B) symptomatic: pain (Homans’s sign), oedema, dicoloration and incr. temperature of the skin
Posthrombotic syndrome
latent, 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.

11. I. Coagulation BLEEDING SMALL, TRAUMATIC - sc., im.injections
- Easy bruising
DIFUSE
MICROVASCULAR
- purpura - petechia,
ekchymosis (>3 mm)
- organ apoplexia
SURGERY
A) trombocytopenia
B) Desintegration of microvascular intima
traumatic
Failure of coagulation

12. II. Laboratory Bleeding time (Duke, 1910)
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).

13. II. Laboratory Thrombin time
Basic coagulation methods
Thrombin time
-full blood is activated with thrombin to form fibrin fiber
-used for measurement of fibrinogen levels (DIC)

14. II. Laboratory
Methods for measuring platelets and vWf
(PLT) – normal /uL, for surgery optimum > /uL. Thrombocytopenia PLT < / uL – spontaneous bleeding and purpura.
(MPV) - normal 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

15. II. Laboratory PT – prothrombin time PT (Quickův)
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), ELISA or aglutination semiq. methods.

16. II. Laboratory D-dimer - imunologic measurement of FDP specific for
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 % activity of the control plasma). With heparin part of the TAT inhibitory complex, deficiency predispose to thrombophilia or DIC.

17. 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).

18. 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)

19. 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= 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)

20. II. Laboratory
APTT
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 = 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

21. II. Laboratory L P N Hemofilia A N P Hemofilia B N P Hemofilia C N P
Disorder
PLT BT
APTT PT TT
FBG
Trombocytopenia L P N
Hemofilia A N P
Hemofilia B N P
Hemofilia C N P
vW-disease N P
N/P LA N P
N/P

22. II. Laboratory FV-def. FII-def. N N P P N N FVII-def. Vit.Kdef./OA
Disorder PLT BT APTT PT TT FBG
FV-def.
FII-def.
FVII-def.
Vit.Kdef./OA
FBG-def.
Heparin
N N P P N N
N N P P N N
N N N P N N
N N P P N N
N N P P P L
N P/N P N/P P N

23. III. DIC Definition Secondary
Disorder of Coagulation with pro-thrombotic phase followed by severe bleeding phase (as a result of consumption of coagulation factors).

24. III. DIC
Ethiopathogenesis 
Intravascular coagulation

25. 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

26. What are FDPs and D-dimers and how do they relate to DIC?
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 cross-linked fibrin polymers into x-oligomers. The main x-oligomers are known as d-dimers.
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-linked fibrin clots.

27. 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 d-dimer assays.
Quantitative tests for d-dimers are available, including enzymatic immunoassays (ELISA) and immunoturbidometric systems.

28. III. DIC NORM PLT 150 - 300 000 x 10 exp9 /l APTT 30 - 35 s
AT     %
TT     s
FBG    g/l
FM (ethanol test)   
DD    < 500 ng/ml
FDP   

29. 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

30. III. DIC
PLT
FBG DD AT
Repeat every 3-4h

31. III. DIC 1 Hypercoagulation 2 Hypocoagulation 3 Massive fibrinolysis
Silent
2 Hypocoagulation
Bleeding and thrombosis in microcirculation
3 Massive fibrinolysis
Bleeding and multiorgan failure (MOF)
4 Death

32. 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 ultra-large high molecular weight multimers.

33. 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 protein-
clipping 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.

34. III. DIC Therapy: Blockade of activated coagulation 1 Heparin LMWH
5-10 IU/kg/h
bolus 2500 IU, inf. Up to IU/24h
LMWH

35. III. DIC Therapy: Blockade of activated coagulation
2 AT (Antitrombin III, Kybernin P)
If less 60%, target~ %
bolus
KI unknown
Half life 3-4 d, during sepsis hours

36. 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

37. III. DIC
Therapy: 
Substitution 
5 Erythrocytes
6  PLT
1 unit/10kg

38. III. DIC Therapy: OTHER 1 shock 2 volume 3 acidobasic and ionts 4 ATB
5 Surgical

39. III. DIC

40. 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

41. 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

42. 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)

43. Current Management of DIC
At present, diagnosis requires a set of blood tests; therapy focuses on reversing the underlying disorder and providing supportive treatment.

44. 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.

45. 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 g/L (normal, <40) and the plasma antithrombin III level was 28% (normal, ).

46. 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.

47. The pathogenesis of DIC

48. Selected Disorders That May Be Associated with DIC
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)

49. 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.

50. 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.

51. 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.

52. 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.

53. 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.

54. 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.

55. 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 low-molecular weight substances, causing oedema. If the process is wide-spread, a capillary leak syndrome may result.

56. 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.

57. 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, sec; PT, sec. Fibrin degradation product levels were very high (>1600 µg/L; normal <40), and the antithrombin III level was 30%.

58. 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.

59. Diagnosis of DIC Result Test Markedly decreased Platelet count
Prothrombin time
Increased
Activated partial thromboplastin time
Fibrin degradation products
Markedly increased
Fibrinogen
Normal or decreased
Antithrombin III
Protein C

60. Specific Therapies
Platelet and Coagulation Factor Infusion
Heparin

61. 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.

62. 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 ( U/hr).
Recent studies show that low-molecular-weight heparin can be used as an alternative to unfractionated heparin.

63. 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.

64. 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.

65. 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.

66. 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

67. 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.)*

68. DIC Schistocytes on the Peripheral Blood Smear
DIC - Gangrene in patient with meningococcal sepsis
Schistocytes on the Peripheral Blood Smear

69. DIC
Subdermal bleeding at IV site following a bite by Hoplocephalus stephensi

70. 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).

71. The E N D