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Failure of C oagula tion. MUDr. Tomáš Stopka Ph.D. and colleagues from the Institute of Pathophysiology, Charles University. Pl a n. Coagulation Methods DIC T h erap y Presentation. I. Coagulation. Initiating the Clotting Process

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Failure of c oagula tion

Failure ofCoagulation

MUDr. Tomáš Stopka Ph.D.

and colleagues from the Institute of Pathophysiology, Charles University

Pl a n

  • Coagulation

  • Methods

  • DIC

  • Therapy

  • Presentation

I coagulation
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 c oagula tion
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 coagulation1
I. Coagulation


Blood clot


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.

I coagulation2

Heparin binds to and enhances antithrombin III.

Warfarin (aka coumadin) is an effective vitamin K antagonist.

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.

I c oagula tion1
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 coagulation3
I. Coagulation







I c oagula tion2
I. Coagulation












I c oagula tion3
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 yafter 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 c oagula tion4
I. Coagulation



- sc., im.injections

- Easy bruising



- purpura - petechia,

ekchymosis (>3 mm)

- organ apoplexia


A) trombocytopenia

B) Desintegration of microvascular intima


Failure of coagulation

Ii laboratory
II. Laboratory


  • 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 laboratory1
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 laboratory2
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 laboratory3
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


  • 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.

Ii laboratory4
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 (normal80 - 100% activity of the control plasma). With heparin part of the TAT inhibitory complex, deficiency predispose to thrombophilia or DIC.

Ii laboratory5
II. Laboratory

Methods for measuring Coagulation

  • Ethanol test – FDP anti-polymeration effect on fibrin fiber is blocked by ethanol

  • Euglobulinmethod 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 laboratory6
II. Laboratory

Methods for measuring Coagulation

  • proteinu C- Act. Protein C resistence, mutationof FV, mutationof protein S

  • fibrinolytic system- tPA , inhibitor PAI-1, plazminogen, inhibitor alfa2AP

  • Antifosfolipid antibodies- lupus anticoagulans (LA) : modif. APTT

  • Individual factorshemofilia A (FVIII), B(FIX), C (FXI)

Ii laboratory7
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)

Ii laboratory8
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.

  • NormalAPTTN = 27 - 35 s

  • Used:hemophilia, lupus anticoagulans, heparintherapy (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 laboratory9













































II. Laboratory

Hemofilia A

Hemofilia B

Hemofilia C



Ii laboratory10
II. Laboratory














Iii dic



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

Iii dic1


Intravascular coagulation

Conditions associated with dic

Heat stroke




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)


Insufficiency of major organs (Liver, Kidney)

Diabetes mellitus



Severe prolonged hypotension (including shock)

Severe volume depletion

Impaired blood flow to a major organ

Conditions Associated with DIC

What are fdps and d dimers and how do they relate to 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.


  • 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.

What are FDPs and D-dimers and how do they relate to DIC?

What are fdps and d dimers and how do they relate to dic1
What are FDPs and D-dimers and how do they relate to DIC?


  • 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.

Iii dic2


  • 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 dic3


  • 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 dic4

  • PLT

  • FBG

  • DD

  • AT

    Repeat every 3-4h

Iii dic5

1 Hypercoagulation


2 Hypocoagulation

Bleeding and thrombosis in microcirculation

3 Massive fibrinolysis

Bleeding and multiorgan failure (MOF)

4 Death

Thrombotic thrombocytopenic purpura
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.

Researchers pinpoint cause of deadly blood clotting disorder
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.

Iii dic6


Blockade of activated coagulation 

  • 1 Heparin

    • 5-10 IU/kg/h

    • bolus 2500 IU, inf. Up to 10 000 IU/24h

  • LMWH

Iii dic7


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 dic8



  • 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 dic9



  • 5 Erythrocytes

  • 6  PLT

    • 1 unit/10kg

Iii dic10



  • 1 shock

  • 2  volume

  • 3 acidobasic and ionts

  • 4 ATB

  • 5 Surgical

Iii dic11

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
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
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
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 presentation1
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 presentation2
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.

Selected disorders that may be associated with dic
Selected Disorders ThatMay 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)


  • 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.


  • 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.


  • 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
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
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

  • 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
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.

Case 2 presentation
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 presentation1
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 presentation2
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.

Specific therapies
Specific Therapies

  • Platelet and Coagulation Factor Infusion

  • Heparin

Platelet and coagulation factor infusion
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.


  • 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
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 therapies1
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 therapies2
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
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 dic1
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.)*


Schistocytes on the Peripheral Blood Smear

DIC - Gangrene in patient with meningococcal sepsis


Subdermal bleeding at IV site following a bite by Hoplocephalus stephensi

Disseminated intravascular coagulation dic
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).