127 Disseminated Intravascular Coagulation

Question 1

The organs most frequently involved by diffuse microthrombi

Answer 1

Lungs and kidneys

Followed by the brain, heart, liver, spleen, adrenal glands, pancreas, and gut

Acute tubular necrosis is more frequent than renal cortical necrosis

Question 2

The most important mediators responsible for the imbalance in DIC

Answer 2

Cytokines

Question 3

The most important interface in which the interaction between inflammation and coagulation takes place

Answer 3

Endothelium of the capillary bed

Question 4

Constitutes a sine qua non for most patients with DIC

Answer 4

Endothelial perturbation

Question 5

Plays a central role in the initiation of inflammation-induced coagulation in DIC

Answer 5

Tissue factor (TF)

TF becomes exposed to blood upon disruption of the vascular integrity, or when cells present in the circulation, such as monocytes, are triggered to express TF.

Question 6

The in vivo expression of TF is dependent on what cytokine

Answer 6

Interleukin (IL)-6

Question 7

Other cytokines generated during inflammation, impair the physiologic anticoagulant pathways.

Answer 7

Tumor necrosis factor (TNF)-α and IL-1

Question 8

Thrombin generated by the TF pathway amplifies both clotting and inflammation through the following activities:

Answer 8

• (a) it activates platelets, giving rise to platelet aggregation and augmenting platelet functions in coagulation;
• (b) it activates factors VIII, V, and XI, yielding further thrombin generation;
• (c) it activates proinflammatory factors via protease-activated receptors (PARs) on inflammatory cells;
• (d) it activates factor XIII to factor XIIIa, which crosslinks fibrin clots;
• (e) it activates thrombin-activatable fibrinolysis inhibitor (TAFI), making clots resistant to fibrinolysis; and
• (f) it increases expression of adhesion molecules, such as L-selectin, thereby promoting the inflammatory effects of leukocytes

Question 9

Serves as an “off switch” for further thrombin generation

Answer 9

Activation of Protein C by Thrombin

Paradoxically, at low concentrations, thrombin exhibits both antiinflammatory and anticoagulant effects because it binds to thrombomodulin and activates protein C to the activated form

Question 10

The effects of fibrinogen on mononuclear cells seem to be mediated by

Answer 10

Toll-like receptor–4

It is also the receptor of endotoxin.

Question 11

Procoagulant activity is regulated by three important anticoagulant pathways:

Answer 11

• AT
• Protein C system
• TFPI

Question 12

Main inhibitor of thrombin and factor Xa

Answer 12

AT

• Without heparin, AT neutralizes coagulation enzymes in a slow, progressive manner.
• Heparin induces conformational changes in AT that result in at least a 1000-fold enhancement of AT activity.
• Thus, the clinical efficacy of heparin is attributed to its interaction with AT.

Question 13

Acts with its cofactor protein S and degrades the essential cofactors Va and VIIIa, and hence, is an effective anticoagulant

Answer 13

APC

Question 14

Increased plasma levels of what complement factor results in a relative protein S deficiency during inflammatory diseases

Answer 14

C4bBP

Question 15

Factor V or factor VIII

Sepsis can also cause resistance toward APC because of a substantial increase in __________levels.

Answer 15

Factor VIII

Question 16

The main inhibitor of the TF–factor VIIa complex and factor Xa

Answer 16

TFPI

Question 17

ROLE OF NATURAL ANTICOAGULANT PATHWAYS

(Increased or Decreased) during Inflammation/Sepsis

AT:
Glycosaminoglycans:
Zymogen protein C:
Thrombomodulin:
Plasma levels of C4bBP:
EPCR:
Factor VIII:

Answer 17

AT: decrease
Glycosaminoglycans:decrease
Zymogen protein C: decrease
Thrombomodulin: decrease
Plasma levels of C4bBP: increase
EPCR: decrease
Factor VIII: increase

Question 18

Inhibits platelet activation and aggregation, blocks neutrophil tethering to blood vessels, and decreases endothelial cell production of various cytokines and chemokines

Answer 18

Prostacyclin

The antiinflammatory effects of APC are mediated by the EPCR.

AT cause induction of prostacyclin release from endothelial cells

Question 19

In DIC, fibrinolysis is initially activated but subsequently inhibited, because of an increased release of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells.

These effects are mediated by

Answer 19

TNF-α and IL-1

TAFI, like PAI-1, may play a role in impeding fibrinolysis and in augmenting formation of microvascular thrombi.

Question 20

The most devastating effect of excessive generation of superoxides and associated free radicals may be their role in

Answer 20

Inducing endothelial apoptosis, which exacerbates capillary leak

Question 21

TRUE OR FALSE

LPS-induced DIC so prominently displays tissue infarction leading to multiorgan dysfunction (eg, sepsis) compared with DIC that is predominately induced by TF exposure (eg, head trauma)

Answer 21

TRUE

LPS-induced DIC so prominently displays tissue infarction leading to multiorgan dysfunction (eg, sepsis) compared with DIC that is predominately induced by TF exposure (eg, head trauma)

mas malala sepsis than trauma

LPS infusion increased both NO and endothelin remarkably, whereas TF infusion increased NO more than did LPS but did not stimulate endothelin significantly.

Question 22

TRUE OR FALSE

The occurrence of schistocytes in the blood film is uncommon in patients with DIC

Answer 22

FALSE

The occurrence of schistocytes in the blood film is not uncommon in patients with DIC

so common!

Patients with DIC may also display signs of thrombotic microangiopathy, causing further consumption of platelets, and nonimmune hemolysis.

Question 23

A crucial factor in the pathogenesis of this enhanced platelet–vessel wall interaction is

Answer 23

Release of (ultra-large) von Willebrand factor multimers

Von Willebrand factor is an acute phase protein and markedly upregulated and released during systemic inflammation.

Question 24

Account for approximately two-thirds of DIC cases in the major series

Answer 24

Infectious diseases and malignant disorders

Infectious diseases: purpura fuminans

Question 25

# TRUE OR FALSE Patients with chronic DIC usually exhibit major skin and mucosal bleeding.

Answer 25

TRUE Patients with **chronic DIC** usually exhibit only **minor** skin and mucosal bleeding. ## Footnote **Acute DIC** frequently is heralded by hemorrhage into the **skin** at multiple sites.

Question 26

# TRUE OR FALSE Thrombosis of major veins and arteries and pulmonary embolism occur but are rare.

Answer 26

TRUE Thrombosis of **major** veins and arteries and pulmonary embolism occur but are **rare**. ## Footnote Extensive organ dysfunction can result from **microvascular thrombi** or from **venous and/or arterial thromboembolism**

Question 27

The major causes of renal dysfunction in DIC

Answer 27

* Renal cortical ischemia induced by microthrombosis of afferent glomerular arterioles * Acute tubular necrosis related to hypotension

Question 28

# TRUE OR FALSE No single laboratory test is sensitive or specific enough to allow a definite diagnosis of DIC

Answer 28

TRUE No single laboratory test is sensitive or specific enough to allow a definite diagnosis of DIC

Question 29

One of the best parameters for **detection of ongoing DIC**

Answer 29

Soluble fibrin in plasma

Question 30

Conditions associated with elevated FDPs

Answer 30

Trauma, recent surgery, inflammation, or venous thromboembolism ## Footnote The specificity of high levels of FDPs is therefore limited

Question 31

Marker that is elevated in patients with DIC, but this poorly distinguishes patients with DIC from patients with venous thromboembolism, recent surgery, or inflammatory conditions.

Answer 31

D-dimer

Question 32

International Society on Thrombosis and Haemostasis (ISTH) score indicative of DIC

Answer 32

5 or more

Question 33

ISTH Score

Answer 33

* Presence of an underlying disorder known to be associated with DIC (no = 0, yes = 2) * **Platelet count** (>100 = 0; <100 = 1; <50 = 2) * Level of **fibrin markers** (soluble fibrin monomers/ fibrin degradation products) (no increase: 0; moderate increase: 2; strong increase: 3) * Prolonged **prothrombin time** ( < 3 s = 0; >3 s but < 6 s = 1; >6 s = 2) * **Fibrinogen** level (>1.0 g/L = 0; <1.0 g/L = 1)

Question 34

Test that has advantage of providing an idea of platelet function as well as fibrinolytic activity

Answer 34

Thromboelastography (TEG)

Question 35

The most common causes of DIC

Answer 35

Bacterial infections ## Footnote Clinically overt DIC may occur in **30% to 50%** of patients with **gram-negative** sepsis.

Question 36

Characterized by deep tissue infection, vascular collapse, vascular leakage, and multiorgan dysfunction

Answer 36

Group A Streptococcus toxic shock syndrome ## Footnote A streptococcal **M protein** forms complexes with **fibrinogen**, and these complexes bind to β2 integrins of neutrophils leading to their activation

Question 37

A fulminant gram-negative infection characterized by extensive hemorrhagic necrosis, DIC, and shock

Answer 37

Meningococcemia ## Footnote More frequent gram-negative infections associated with DIC are caused by **Pseudomonas aeruginosa, E coli, and Proteus vulgaris.**

Question 38

Occurs in patients with sepsis-induced DIC and is associated with a high incidence of acute renal failure

Answer 38

Severe secondary deficiency of a disintegrin-like metalloprotease with thrombospondin type 1 repeats (ADAMTS13)

Question 39

Can cause DIC accompanied by renal cortical and dermal necrosis.

Answer 39

Staphylococcus aureus bacteremia ## Footnote Related to an **α-toxin** that activates platelets and induces IL-1 secretion by macrophages

Question 40

Syndrome in **asplenic** patients with **streptococcus pneumoniae and meningococcal infections**

Answer 40

Waterhouse-Friderichsen syndrome

Question 41

Has been reported in patients with infections and either **hereditary thrombophilias or acquired antibodies to protein S**

Answer 41

Purpura fulminans associated with DIC

Question 42

The most striking coagulation test abnormality in severe COVID-19 patients

Answer 42

Abnormally high D-dimer level ## Footnote Patients with D-dimer levels more than sixfold the upper limit of normal were found to have an **increased need for mechanical ventilation** and a significantly **higher risk of death.** The clinical presentation of the COVID-19 coagulopathy is **mostly prothrombotic** with a high incidence of overt venous (and possibly arterial) thromboembolism

Question 43

# TRUE OR FALSE COVID 19 is associated with severe thrombocytopenia.

Answer 43

FALSE COVID 19 is associated with **mild** thrombocytopenia. ## Footnote Most patients with COVID-19 have a platelet count between **100 and 150 x 109/L**; lower platelet counts are rarely (<5%) seen. A low platelet count in COVID-19 **has not been associated with an adverse outcome** (although very low platelet counts can be an exception)

Question 44

All patients with **COVID-19 that are admitted** to the hospital should receive ___________ prophylaxis

Answer 44

Heparin ## Footnote The clinical presentation of the COVID-19 coagulopathy is mostly **prothrombotic**, with a high incidence of overt venous (and possibly arterial) thromboembolism, and patients do not have many hemorrhagic complications

Question 45

A severe, often lethal form of DIC in which extensive areas of the **skin** over the **extremities** and **buttocks** undergo **hemorrhagic necrosis**.

Answer 45

Purpura fulminans ## Footnote * Affects **infants and children** predominantly and occasionally adults. * Onset can be within **2 to 4 weeks of a mild infection** such as scarlet fever, varicella, or rubella, or can occur during an acute viral or bacterial infection in patients with **acquired or hereditary thrombophilias affecting the protein C inhibitory pathway**. * Are acutely ill with fever, hypotension, and hemorrhage from multiple sites; they frequently have typical laboratory signs of DIC

Question 46

# TRUE OR FALSE Patients with solid tumors and DIC are more prone to thrombosis than to bleeding, whereas patients with leukemia and DIC are more prone to hemorrhage.

Answer 46

TRUE Patients with **solid tumors and DIC are more prone to thrombosis** than to bleeding, whereas patients with **leukemia and DIC are more prone to hemorrhage**.

Question 47

Identified as one of the most important **proinflammatory** cytokines that is able to induce **TF expression** on cells.

Answer 47

IL-6 ## Footnote Inhibition of IL-6 results in an inhibition of endotoxin-stimulated activation of coagulation

Question 48

Changes in **fibrinolysis and microvascular physiologic anticoagulant pathways** are mostly dependent on

Answer 48

TNF-α ## Footnote Other cytokines that participate in the systemic activation of coagulation are **IL-1β and IL-8**, whereas **antiinflammatory** cytokines, such as **IL-10**, are able to **inhibit DIC**.

Question 49

**Microangiopathic hemolytic anemia frequently is induced by DIC** in patients with malignancies and is particularly severe in patients with widespread intravascular metastases of

Answer 49

Mucin-secreting adenocarcinomas ## Footnote Interactions of P- and L-selectins with mucin from mucinous adenocarcinoma can induce formation of platelet microthrombi

Question 50

Risk factors and additional triggers of DIC that can aggravate thromboembolism and bleeding:

Answer 50

* Advanced age * Stage of the disease * Use of chemotherapy or antiestrogen therapy

Question 51

Type of leukemia in which DIC is present in more than **90%** of patients at the time of diagnosis or after initiation of remission induction.

Answer 51

Acute promyelocytic leukemia (APL) ## Footnote **All-transretinoic acid** may **induce thrombotic complications** as it stimulates blasts to differentiate, whereby they can release prohemostatic triggers.

Question 52

The most immediate triggers of DIC in trauma

Answer 52

* Extensive exposure of TF to the blood circulation * Hemorrhagic shock

Question 53

What, then, should be the approach to patients with liver disease and bleeding without an apparent local cause?

Answer 53

First, possible **underlying causes of DIC** should be considered and identified, and then a **hemostatic profile** should be examined at **frequent intervals** to detect any dynamic changes that may be helpful in recognizing DIC.

Question 54

Tests that may help establish the diagnosis of DIC in a patient with liver disease.

Answer 54

* Sensitive assays that reflect thrombin generation (TAT complex and prothrombin fragments 1.2) or concomitant thrombin and plasmin generation (D-dimer) * Finding a normal or decreased level of factor VIII

Question 55

A syndrome characterized by a rise in body temperature to higher than **42 C**, which follows collapse of the thermoregulatory mechanism

Answer 55

Heat stroke ## Footnote The possible triggers of DIC in patients with heat stroke include **endothelial cell damage and TF released from heat-damaged tissues.**

Question 56

# HEMANGIOMAS Treatment of choice for hemangioma

Answer 56

Glucocorticoids

Question 57

# HEMANGIOMAS Treatment of choice for hemangioma in **life-threatening** circumstances after **failure of glucocorticoid therapy**

Answer 57

Radiotherapy and interferon-α

Question 58

Pregnancy predisposes patients to DIC for at least four reasons:

Answer 58

1. Pregnancy itself produces a hypercoagulable state, manifested by evidence of **lowgrade thrombin generation,** with **elevated levels of fibrin monomer complexes and fibrinopeptide A** 2. During labor, l**eakage of TF from placental tissue** into the maternal circulation causes a hypercoagulable state 3. Pregnancy is associated with r**educed fibrinolytic activity** because of **increased plasma levels of PAI-1**; and 4. Pregnancy is associated with a **decline in the plasma level of protein S** | taas F78 ## Footnote DIC may be difficult to diagnose during pregnancy because of the **high initial levels of coagulation factors such as fibrinogen, factor VIII, and factor VII**. **Thrombocytopenia may be particularly helpful in determining whether DIC is present, provided other causes of thrombocytopenia are excluded.**

Question 59

Treatment of choice for placental abruption

Answer 59

Rapid volume replenishment and evacuation of the uterus ## Footnote Transfusion of **cryoprecipitate, fresh-frozen plasma, and platelets** should be given when profuse bleeding occurs. However, in the absence of severe bleeding, administration of blood components may not be necessary because **depleted coagulation factors increase rapidly after delivery**.

Question 60

# TRUE OR FALSE Patients predisposed to amniotic fluid embolism are multiparous women whose pregnancies are postmature with large fetuses and women undergoing a tumultuous labor after pharmacologic or surgical induction.

Answer 60

TRUE Patients predisposed to amniotic fluid embolism are **multiparous** women whose pregnancies are **postmature with large fetuses** and women undergoing a **tumultuous labor after pharmacologic or surgical induction**.

Question 61

# TRUE OR FALSE HELLP syndrome occurs more often in whites, multiparous women, and women older than 35 years.

Answer 61

TRUE HELLP syndrome occurs more often in **whites**, **multiparous women, and women older than 35 years**.

Question 62

Organisms that are common causes of sepsis during pregnancy

Answer 62

Gram-negative bacteria, group A streptococci, and Clostridium perfringens

Question 63

**Acute fatty liver of pregnancy** is a rare disorder that occurs during the

Answer 63

Third trimester of pregnancy ## Footnote Characterized by severe liver dysfunction, renal failure, hypertension, and signs of DIC

Question 64

In 15% to 20% of cases, acute fatty liver of pregnancy is associated with fetal homozygosity or compound heterozygosity for _______________ deficiency.

Answer 64

Long-chain acyl-coenzyme A dehydrogenase (LCAD) deficiency ## Footnote Infants born with LCAD deficiency fail to thrive and are prone to liver failure and death. LCAD is one of four enzymes taking part in β-oxidation of fatty acids in mitochondria.

Question 65

Characterized by severe liver dysfunction, renal failure, hypertension, and signs of DIC

Answer 65

Acute fatty liver of pregnancy ## Footnote The typical histologic feature is **microvesicular fatty infiltration** of the liver.

Question 66

Newborns have a limited capacity to cope with triggers of DIC for several reasons:

Answer 66

* (a) their ability to clear soluble fibrin and activated factors is reduced; * (b) their fibrinolytic potential is decreased because of a low plasminogen level; and * their capacity to synthesize coagulation factors and inhibitors is limited ## Footnote Criteria for diagnosis of DIC in newborns are different from those for diagnosis in adults.

Question 67

Physiologic hemostatic findings common in newborns

Answer 67

* Low levels of the vitamin K–dependent factors, * Reduced AT and protein C levels * Prolonged thrombin time

Question 68

The most common manifestation of DIC in newborns

Answer 68

Bleeding from multiple sites

Question 69

Most life-threatening condition in newborns

Answer 69

Intracranial hemorrhage

Question 70

# TRUE OR FALSE The survival of patients with DIC depends on vigorous treatment of the underlying disorder to alleviate or remove the inciting injurious cause.

Answer 70

TRUE The survival of patients with DIC depends on vigorous **treatment of the underlying disorder** to alleviate or remove the inciting injurious cause.

Question 71

Plasma or platelet substitution therapy should not be instituted on the basis of laboratory results alone; it is indicated only in patients with

Answer 71

**Active bleeding** and in those requiring an **invasive procedure** or who are at **risk for bleeding complications** ## Footnote One of the major challenges of infusion of fresh-frozen plasma in these dire circumstances is the propensity of the **added volume**, which is necessary to correct the coagulation defect, to **exacerbate capillary leak.** **Coagulation factor concentrates**, such as prothrombin complex concentrate, may partially overcome this obstacle but do not contain essential factors, such as factor V.

Question 72

**Cryoprecipitate** can be used to rapidly raise the **fibrinogen and factor VIII levels**, particularly when bleeding is part of the DIC and fibrinogen level is less than ___ g/L.

Answer 72

Less than 1 g/L ## Footnote Cryoprecipitate has at least **four to five times the mass of fibrinogen per milliliter** of infusate compared with fresh-frozen plasma. **Fresh-frozen plasma** contains fibrinogen in sufficient amounts for treatment of patients with **mild to moderate hypofibrinogemia.**

Question 73

Replacement therapy for **thrombocytopenia** should consist of **5 to 10 units of platelet concentrate** or **single-donor apheresis-derived platelets** to raise the platelet count to **20–30 x109/L** and, in patients who need an invasive procedure, to ________ x 109/L.

Answer 73

50 x 109/L

Question 74

Administration of **heparin** is beneficial in some categories of **chronic DIC**, such as

Answer 74

* Metastatic carcinoma * Purpura fulminans * Aortic aneurysm (before resection) * Treating thromboembolic complications in large vessels and before surgery ## Footnote Continuous infusion of heparin **500–750 U/h** without a bolus injection

Question 75

**Heparin** administration may be helpful in patients with **acute DIC**

Answer 75

* When intensive blood component replacement fails to improve excessive bleeding * When thrombosis threatens to cause irreversible tissue injury (eg, acute cortical necrosis of the kidney or digital gangrene) * Hyperacute DIC cases, such as mismatched transfusion, amniotic fluid embolism, septic abortion, and purpura fulminans ## Footnote IV bolus injection of **5000–10,000 U** heparin may be given **simultaneously with replacement therap**y with blood products

Question 76

Theoretically, the most logical anticoagulant agent to use in DIC is directed against

Answer 76

TF ## Footnote Potential agents include **recombinant TFPI**, **inactivated factor VIIa**, and **recombinant nematode anticoagulant protein c2 (NAPc2)**, a potent and specific inhibitor of the ternary complex of TF–factor VIIa and factor Xa.

Question 77

# TRUE OR FALSE Patients with DIC must be treated with antifibrinolytic agents such as ε-aminocaproic acid or tranexamic acid.

Answer 77

FALSE Patients with DIC should not be treated with antifibrinolytic agents such as ε-aminocaproic acid or tranexamic acid. ## Footnote Because these drugs block fibrinolysis that preserves tissue perfusion in patients with DIC

Question 78

Conditions wherein the use of fibrinolytic inhibitors can be considered

Answer 78

DIC accompanied by **primary fibrino(geno)lysis**, as in some cases of APL, giant hemangioma, heat stroke, amniotic fluid embolism, some forms of liver disease, and metastatic carcinoma of the prostate ## Footnote Provided: * (a) the patient is bleeding profusely and has not responded to replacement therapy and * (b) excessive fibrino(geno)lysis is observed, ie, rapid whole blood clot lysis or a very short euglobulin lysis time. In such circumstances, **use of antifibrinolytic agents should be preceded by replacement of depleted blood components and continuous heparin infusion**