Bongard Frederic , Darryl Sue. Diagnosis and Treatment Critical Care

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BLEEDING & HEMOSTASIS

417

have been associated with thrombocytopenia following

desmopressin therapy because of increased binding of aber-

rant vWF to platelets. If the response to desmopressin is

unknown and a patient is actively bleeding, factor replace-

ment with blood products is preferable. Desmopressin also

stimulates release of tissue plasminogen activator, so antifib-

rinolytic therapy is often administered simultaneously.

Aminocaproic acid and tranexamic acid are two commer-

cially available antifibrinolytic agents that may be useful for

managing bleeding in patients with a wide variety of bleed-

ing disorders. The use of antifibrinolytics in combination

with desmopressin often eliminates the need for any blood

product administration for patients with vWD or mild

hemophilia A with minor bleeding or after dental proce-

dures. Antifibrinolytic therapy also may be useful as an

adjunct to factor replacement in any inherited coagulation

disorder unless there are contraindications such as hema-

turia, uncontrolled DIC, or use of prothrombin complex

concentrates. For acute bleeding, aminocaproic acid usually

is given as an intravenous infusion at a rate of 1 g/h until

bleeding is controlled (maximum 24 g in 24 hours), followed

by a maintenance dose of 6 g intravenously or orally every 6

hours for 7–10 days. The suggested dose of tranexamic acid

is 10 mg/kg intravenously or 25 mg/kg orally three or four

times a day beginning 1 day before surgery or at the onset of

acute bleeding and to be continued for 2–8 days.

Current Controversies and Unresolved Issues

Current recommendations regarding factor replacement for

inherited coagulation disorders stem primarily from anec-

dotal experience rather than from carefully designed clinical

trials comparing one regimen with another. The optimal

level of factor activity, the precise interval between doses, and

the duration of therapy are somewhat arbitrary and for most

of the rare disorders reflect a lack of clinical experience.

Genetic heterogeneity contributes further to the lack of firm

data to support current recommendations.

Because of the risks of bleeding, infections, and other

transfusion-related complications, elective surgery should be

avoided when possible. There is a body of literature demon-

strating the success of surgery in hemophiliacs and others

with inherited coagulation defects, but clearly, surgery in

such patients poses significant risks and increases the

demand for scarce resources, including blood products.

Current screening for infectious diseases and processing

of factor concentrates to eliminate many (but not all) infec-

tious agents has significantly decreased the risk of transmis-

sion of infectious diseases from plasma-derived products. All

patients with hemophilia and related coagulation disorders

should be vaccinated against hepatitis B. The development of

recombinant factors VIII and IX has contributed to a marked

decrease in virus-associated illnesses in these patients (no

documented cases of HIV and hepatitis B or C since 1985

and 1990, respectively), and human albumin–free products

have been developed to reduce further the possible transmission

of Creutzfeldt-Jakob disease. However, recombinant factors

are two to three times more expensive than plasma-derived

factors, are not always available owing to limited production

capacity, and may be associated with a higher rate of

inhibitor development compared with plasma concentrates.

Hemophilia patients who acquired HIV infection prior to

the widespread availability of screening and purified factors

have been treated successfully with antiretroviral therapy, but

there appears to be an increased risk of spontaneous bleed-

ing in these patients.

The development of inhibitors to factors continues to be

a problem for patients with severe hemophilia; recombinant

factors do not eliminate this risk (estimated at 10–15%).

Recombinant factor VIIa and activated prothrombin com-

plex concentrates (aPCCs) can be used to control hemor-

rhage by bypassing factors VIII and IX in patients with

inhibitors, but both may be associated with thromboem-

bolism. Porcine factor VIII is no longer used owing to con-

tamination with porcine parvovirus. Protein A sepharose

immunoadsorption may transiently lower factor VIII

inhibitors, allowing time for other immunosuppressive ther-

apies to work. Optimal management of inhibitors remains a

challenge in management of severe hemophilia.

Factor IX replacement (recombinant or purified plasma-

derived) can cause anaphylaxis in 5% of patients with severe

hemophilia B. Further replacement therapy in these patients

is risky. Recombinant factor VIIa is the only available thera-

peutic option for these patients.

Research in gene therapy is ongoing for patients with

severe hemophilia A and B. Results from preliminary trials

are promising, but this approach remains experimental.

Gene therapy may not prevent inhibitor development, how-

ever, and patients who are undergoing treatment for HIV

infection or who have hepatitis may not respond to this

approach.



Acquired Coagulation Disorders

ESSENTIALS OF DIAGNOSIS



Absence of a personal (if newly acquired) or family his-

tory of bleeding disorder.



Abnormal screening coagulation tests.



Clinical situation leading to decreased production or

increased destruction of coagulation factors or presence

of an anticoagulant.

General Considerations

Acquired coagulation disorders result from four basic mech-

anisms: vitamin K deficiency, liver disease, consumption of

factors, or inhibition of factor activity or fibrin polymeriza-

tion. Unlike inherited disorders, acquired coagulation disor-

ders are often characterized by multiple factor deficiencies as

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418

well as platelet defects (quantitative and qualitative). In addi-

tion, many of the clinical symptoms and signs result from the

underlying disease process; the coagulopathy is just one of

many processes contributing to the overall clinical picture.

A. Vitamin K Deficiency—Vitamin K is a cofactor necessary

for the synthesis of functional factors II (ie, prothrombin),

VII, IX, and X and proteins C and S. Vitamin K is found in

dietary sources (green vegetables) and is synthesized by bac-

teria in the intestinal lumen. It is fat-soluble, requiring bile

salts for absorption in the intestine. Vitamin K deficiency is

most likely to occur in patients who have disruption of both

dietary and bacterial sources of vitamin K (eg, patients who

are receiving broad-spectrum antibiotics who are not eating),

who have biliary obstruction or fat malabsorption, or who

are taking warfarin derivatives that inhibit metabolism of

vitamin K in the liver and induce a vitamin K–depleted state.

Vitamin K stores also may be depleted in patients with acute

or chronic liver disease. By unclear mechanisms, certain

antibiotics—particularly certain cephalosporins—and high

doses of aspirin are known to induce a deficiency of vitamin

K–dependent coagulation factors that is reversible with

administration of vitamin K. Cholestyramine, mineral oil,

and other cathartics may interfere with vitamin K absorption

when taken for a prolonged period. Normal newborns have

low levels of vitamin K–dependent factors that fall further

during the first few days of life. Deficiency of vitamin K

results in progressive depletion of all the vitamin K–dependent

factors as they are metabolized. Factor VII has the shortest

biologic half-life and is depleted first, followed by proteins

C and S and then factors IX, X, and II. Bleeding owing to vita-

min K deficiency is uncommon unless the deficiency is severe

(PT >25–30 seconds) or vascular injury is present.

B. Liver Disease—Coagulation disorders associated with

liver disease are complex. With the exception of vWF and

factor VIII, all the coagulation factors and other regulatory

proteins (eg, α

-antiplasmin, proteins C and S, and

antithrombin) are synthesized in hepatocytes. The liver is

also the site of clearance of activated coagulation factors and

degradation products of fibrin and fibrinogen and is respon-

sible for regeneration of vitamin K after it participates in

synthesis of the vitamin K–dependent coagulation factors.

Liver disease from any cause may result in multiple abnor-

malities, including decreased synthesis of all the coagulation

factors (with the exception of factor VIII), abnormal synthe-

sis of factors and proteins (eg, dysfibrinogenemia), abnormal

vitamin K metabolism resulting in functional vitamin K defi-

ciency, impaired fibrin polymerization owing to increased

fibrin degradation products, and accelerated fibrinolysis. In

addition, thrombocytopenia (owing to multiple mecha-

nisms, including inadequate synthesis of thrombopoietin in

the liver and hypersplenism, among others), defective

platelet function, or both may complicate severe liver disease.

Advanced cirrhosis is often associated with abnormalities of

blood vessels (eg, esophageal and gastric varices) and other

defects (eg, gastritis, ulcer disease, and esophageal tears),

which are the major sites of bleeding in patients with liver

disease. Hemostatic abnormalities exacerbate bleeding from

these sites and contribute to epistaxis, ecchymoses, and

increased bleeding with invasive procedures. In general, the

presence of a coagulopathy is a sign of advanced liver disease,

although passive congestion of the liver owing to right-sided

heart failure may be associated with coagulation distur-

bances without irreversible liver dysfunction.

C. Consumption of Coagulation Factors—Consumption

of coagulation factors may result from massive internal or

external blood loss or from DIC. Occasional patients who

have massive blood loss will develop a clinically significant

deficiency of multiple hemostatic factors, but DIC is the

most typical condition associated with consumption of coag-

ulation factors.

DIC occurs as a result of abnormal activation of coagula-

tion because of vascular injury, direct release of procoagulant

materials into the circulation, or both. There also may be

decreased quantity or function of naturally occurring antico-

agulants (ie, thrombomodulin–protein C pathway) in

patients with sepsis-associated DIC or in patients following

resuscitation for cardiac arrest. Consumption of coagulation

factors and platelets is accompanied by secondarily acceler-

ated fibrinolysis and results in a generalized bleeding ten-

dency associated with mucosal bleeding, ecchymoses, and

oozing from sites of vascular trauma, including venipuncture

and surgical sites. Fibrin deposition in the microcirculation

may contribute to some of the clinical sequelae of DIC, such

as tissue hypoxia. Rarely, purpura fulminans complicates

DIC. As a result of widespread arterial and venous thrombo-

sis, patients with purpura fulminans may have skin necrosis

and gangrene of the distal extremities and digits. The condi-

tions in which DIC occurs are complex (Table 17–5), with

multiple pathophysiologic mechanisms contributing to the

overall outcome of patients. DIC itself contributes to

multiple-organ-system failure and death in patients with

severe systemic disorders, particularly sepsis. Localized con-

sumption of coagulation factors and platelets owing to mas-

sive internal bleeding may mimic DIC but is not associated

with intravascular fibrin generation or generalized fibrinoly-

sis. In this situation, depletion of coagulation factors and

platelets may be accompanied by elevated circulating fibrin

degradation products and may result in a serious bleeding

tendency, but it is not associated with microvascular throm-

bus formation. Primary systemic fibrinolysis is extremely

rare and results in rapid destruction of fibrin clots, destruc-

tion of circulating fibrinogen, and consumption of plas-

minogen and its inactivators. Systemic fibrinolysis

accompanies DIC and may contribute significantly to clini-

cal bleeding. Primary fibrinolysis can be confused with DIC

but usually is not associated with thrombocytopenia and

generalized consumption of coagulation factors.

D. Inhibitors of Coagulation—Infrequently, inhibitors of

coagulation develop and may result in a serious bleeding

diathesis. Inhibitors directed against factor VIII are encountered

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BLEEDING & HEMOSTASIS

419

most frequently as a complication of treatment for severe

hemophilia A and also may be associated with pregnancy,

collagen vascular diseases, malignancy, or certain drug reac-

tions. Inhibitors may occur as an isolated condition. The

abrupt development of factor V inhibitors following surgical

procedures has been reported and may cause unexpected

severe postoperative bleeding. These inhibitors appear to be

related to the use of topical bovine thrombin preparations con-

taining bovine factor V intraoperatively that may crossreact

with human factor V. Inhibitors to other coagulation factors,

including vWF and factor XIII, have been described. These

inhibitors are immunoglobulins with neutralizing activity

directed against specific factors and result in a clinical picture

consistent with a factor deficiency state. Other types of

inhibitors include substances that inhibit fibrin polymerization

without immunologic specificity for the fibrin molecule (eg,

fibrin degradation products or myeloma proteins). The lupus

anticoagulant typically prolongs the aPTT and therefore may

be confused with factor deficiencies or other inhibitors, but it is

not associated with bleeding. Heparin is a therapeutic inhibitor

of coagulation, accelerating the rate of antithrombin-mediated

inactivation of thrombin and other coagulation factors that act

as serine proteases (ie, factors VII, IX, and X).

Clinical Features

The clinical history, physical examination, and screening lab-

oratory abnormalities are usually sufficient to determine the

nature of the coagulation defect.

A. Symptoms and Signs—Patients with acquired coagula-

tion disorders occasionally may have spontaneous bleeding

but more commonly have excessive bleeding with surgical or

other invasive procedures or exacerbations of bleeding from

GI or other sites. Other clinical features reflect the underly-

ing disorder. Patients with liver disease may have bleeding

from esophageal varices as well as signs of hepatic dysfunc-

tion. In DIC, bleeding is a common finding, but ongoing

coagulation may be manifested as intravascular thrombosis

with skin necrosis and gangrene (ie, purpura fulminans).

Features of the disease causing DIC—particularly sepsis—

may predominate.

B. Laboratory Findings (See Table 17–6)—The PT and

the aPTT may be prolonged in all the acquired coagulation

defects as a result of multiple factor deficiencies. A 1:1 dilu-

tion test that fails to correct the abnormal PT or aPTT indi-

cates the presence of an inhibitor (including heparin and

lupus anticoagulants). Complete correction of the prolonged

PT and aPTT within 24 hours of administration of intra-

venous vitamin K confirms the presence of vitamin K defi-

ciency; vitamin K administration therefore is both diagnostic

and therapeutic. The diagnosis of DIC is based on the pres-

ence of prolonged PT and aPTT, thrombocytopenia, and ele-

vated fibrin degradation products or D-dimer in the

presence of an appropriate underlying condition.

Hypofibrinogenemia may be present in very severe cases,

but—because fibrinogen is an acute-phase reactant—fib-

rinogen levels are often normal. None of these tests is sensi-

tive or specific enough to determine conclusively whether

DIC is present. Circulating fibrin monomers (protamine sul-

fate test) and degradation products of cross-linked fibrin (D-

dimer test) confirm the presence of increased thrombin or

plasmin generation, and both are usually present in DIC;

they also may be positive occasionally in patients with liver

disease. Laboratory findings also vary as the condition of the

patient changes. Despite numerous attempts to standardize

the diagnostic criteria for DIC, DIC remains a clinical diag-

nosis, and assessment of the consequences of DIC is the

most critical aspect of management.

Coagulation defects owing to liver disease may be con-

fused with DIC because of the presence of accelerated fibri-

nolysis, decreased clearance of fibrin and fibrinogen

degradation products, thrombocytopenia, and prolongation

of both the PT and the aPTT. Therefore, differentiating DIC

from the coagulopathy of severe liver disease may be difficult,

and clinical experience is required to interpret the often

complex laboratory abnormalities. Schistocytes may be

found on peripheral blood smear; when present, DIC must

be distinguished from microangiopathic hemolytic anemia.

This disorder, which can be due to thrombotic thrombocy-

topenic purpura–hemolytic uremic syndrome, chemother-

apy, malignant hypertension, and the HELLP (hemolysis,

elevated liver enzymes, low platelets) syndrome, results from

endothelial injury with subsequent platelet activation,

thrombin generation, and fibrinolysis. Thrombocytopenia,

Cause Examples

Infections Bacterial sepsis (gram-negative and

gram-positive), viremia, rickettsiae,

malaria, tuberculosis

Trauma Massive tissue injury, head trauma, fat

embolism, burns

Malignancy Adenocarcinomas, acute leukemia

Obstetrical complications Abruptio placentae, amniotic fluid

embolism, retained dead fetus, septic

abortion, placenta previa, eclampsia

Vascular disorders and

prosthetic devices

Giant hemangioma (Kasabach-Merritt

syndrome), aortic aneurysm

Toxins Snake venoms, drugs

Immunologic disorders Severe allergic reaction, hemolytic

transfusion reaction, transplant

rejection

Metabolic disorders Hypotension, hypoxia, hyperthermia,

hypothermia, cardiac arrest

Table 17–5. Causes of disseminated intravascular

coagulation (DIC).

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420

hemolytic anemia, and fragmented red blood cells are the

hallmarks of microangiopathic hemolytic anemia, without

prolongation of coagulation times in most cases.

Differential Diagnosis

Inherited coagulation defects, thrombocytopenia, platelet

dysfunction, and accelerated fibrinolysis all may result in

bleeding at sites of vascular injury. Prolonged screening

coagulation tests may be abnormal owing to technical error

(including obtaining blood samples through heparinized

lines or inadequate quantity of blood in the tube) because of

inhibitors that do not cause bleeding (eg, lupus anticoagu-

lant) and deficiencies of factors that are not important for in

vivo hemostasis (eg, the contact factors, factor XII, high-

molecular-weight kininogen, and prekallikrein). Finally,

impaired surgical hemostasis, mucosal abnormalities, and

primary vascular abnormalities may result in clinical bleed-

ing regardless of coagulation status.

Treatment

Treatment of the underlying disease state, avoidance of inva-

sive procedures, and replacement of deficient factors during

acute bleeding episodes are the mainstays of treatment.

Vitamin K

(phytonadione), 1–10 mg orally or subcuta-

neously (not intramuscularly), should be administered to

patients at risk for vitamin K deficiency as both a diagnostic

and therapeutic strategy. The American College of Chest

Physicians recommends different dosing ranges of vitamin K

depending on the elevation of the PT and the bleeding status

or risk of the patient. Weekly administration (10 mg) reduces

the risk of vitamin K deficiency in patients who are poorly

nourished, receiving antibiotics, or who have malabsorption.

Intravenous vitamin K administration works more rapidly

but rarely may cause severe allergic reactions. Larger doses

may be required to reverse massive overdoses of warfarin.

Fresh-frozen plasma administration is necessary to correct

multiple factor deficiencies, but this treatment may be compli-

cated by the large volume required to achieve adequate hemo-

static levels, especially if factors are being consumed rapidly.

The quantity of fresh-frozen plasma administered must be

individualized, but in general, 30–40% of plasma volume (eg,

1000–1200 mL) is required to achieve adequate levels of all the

deficient factors; this amount must be readministered every

6–8 hours to maintain adequate levels of factor VII. Many

patients will not tolerate such a high volume of fresh-frozen

plasma replacement, so only partial correction may be possi-

ble—yet, if increased consumption of factors is present, even

more frequent administration may be needed.

A. Liver Disease—Management of liver disease complicated

by bleeding is difficult owing to the presence of multiple

Laboratory Abnormality

Vitamin K

Deficiency

Liver Disease DIC

Specific Factor

Inhibitors

Lupus

Inhibitors

Primary

Fibrinolysis

PT prolonged + + + +

∗

(+)

aPTT prolonged + + + +

∗

1:1 dilution does not correct +

†

Thrombin time prolonged + + +

Thrombocytopenia + + (+)

FDP elevated + + + +

D-dimers present (+) +

Protein C/S decreased + + (+)

Antithrombin decreased + +

Red blood cells Targets,

macrocytes

Schistocytes,

microspherocytes

Hypofibrinogenemia (+) (+)

∗

Pattern of clotting time prolongation depends on specific factor to which inhibitor is directed.

†

May require incubation.

Key: + common; (+) occasional

Table 17–6. Laboratory diagnosis of acquired coagulopathies.

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BLEEDING & HEMOSTASIS

421

pathologic processes. Factor replacement with fresh-frozen

plasma, platelet concentrates for thrombocytopenia, and cry-

oprecipitate for severe hypofibrinogenemia is a reasonable

intervention for serious bleeding but must be accompanied

by attempts to correct vascular and mucosal defects that

often are the main reasons for bleeding. The volume of fresh-

frozen plasma required to completely reverse prolonged clot-

ting times is substantial (>1000 mL), which limits its efficacy.

Prothrombin complex concentrate provides essential coagu-

lation factors in a much smaller volume, but because it is

associated with increased thromboembolic complications

and DIC (particularly with severe liver disease owing to

decreased clearance of activated clotting factors present in

the complex), it should be used only in life-threatening

bleeding. Vitamin K

administration (10–20 mg) may

improve the PT and aPTT in some patients and should be

tried. Desmopressin may shorten the bleeding time in some

patients with platelet dysfunction complicating cirrhosis, but

its efficacy has not been determined for control of bleeding

in liver disease. Treatment with desmopressin may exacer-

bate hyponatremia and hypotension and should be used with

caution. Antifibrinolytic agents have been advocated for

patients with evidence of accelerated fibrinolysis, but their

safety and efficacy in patients with advanced liver disease

have not been proved.

B. Disseminated Intravascular Coagulation—Patients

with DIC have diverse underlying conditions (see Table

17–5) and heterogeneous complications (both hemorrhagic

and thrombotic). Management should be directed primarily

at the underlying disorder. If serious bleeding is present, or if

an invasive procedure is required, factor replacement with

fresh frozen plasma to shorten the PT to within 2–3 seconds

of normal, cryoprecipitate to maintain fibrinogen levels

greater than 100 mg/dL, and platelet concentrates to raise the

platelets to greater than 50,000/μL should be attempted, but

these efforts may be compromised by short survival of the

hemostatic factors. Prophylactic administration of factors

and platelets in the absence of bleeding is not effective, and

coagulation factor concentrates should be avoided because

activated factors present in the concentrate may increase

intravascular coagulation.

Interruption of the primary pathologic coagulation of

DIC with heparin is controversial. DIC complicating acute

leukemia may be associated with marked bleeding owing to

impaired platelet production and may necessitate the use of

low-dose heparin (eg, 5–10 units/kg per hour) to achieve

adequate platelet counts with platelet concentrates, although

controlled studies have demonstrated that heparin adminis-

tration increases platelet transfusion requirements without

decreasing complications associated with DIC. Patients with

solid tumors and chronic DIC are more likely to experience

thrombotic complications than bleeding and may benefit

from long-term administration of heparin. Patients with

overt thromboembolism or purpura fulminans should be

treated with heparin, but because of an increased risk of

adrenal hemorrhage, the initial dose should be relatively low

and adjusted based on clinical response. Although secondary

fibrinolysis often contributes to the bleeding diathesis,

antifibrinolytic agents generally are contraindicated in the

presence of DIC because of the potential for unopposed

intravascular coagulation, which may result in significant

thrombotic complications. If marked symptomatic fibrinol-

ysis is present and there is no evidence of thrombotic com-

plications, however, antifibrinolytic therapy may be

attempted in combination with low-dose heparin to control

bleeding.

C. Circulating Inhibitors—Circulating inhibitors pose sub-

stantial difficulties in management of the bleeding patient.

As in patients with hemophilia A with factor VIII inhibitors,

strategies include high-dose factor replacement, decreasing

the titer of the inhibitor by immunosuppression or plasma-

pheresis, or using factors that bypass the need for the factor

being inhibited (eg, use of activated prothrombin complex

concentrates or recombinant factor VIIa). When high con-

centrations of fibrin and fibrinogen degradation products

are present, treatment of the underlying process (eg, sepsis-

induced DIC) is more useful than specific hemostatic ther-

apy. Myeloma proteins that inhibit fibrin polymerization

should be definitively treated with chemotherapy, but

plasmapheresis may be used as a temporizing measure.

Current Controversies and Unresolved Issues

Despite our understanding of the multiple processes that con-

tribute to bleeding in patients with liver disease, management

of bleeding has not been subject to careful clinical study to

determine optimal treatment strategies. Recombinant factor

VIIa (rFVIIa) has been shown to improve outcome from

acute variceal bleeding in a small preliminary trial, but its pre-

cise role in the management of bleeding in liver disease has

not been defined by clinical studies. The use of thrombopoi-

etin to improve thrombocytopenia is under investigation.

DIC is a syndrome that occurs in diverse clinical condi-

tions and is usually diagnosed on the basis of a combination

of laboratory abnormalities in the appropriate situation.

Several confirmatory laboratory tests have been proposed as

essential for the diagnosis, but the lack of a “gold standard”

combined with lack of standardization for the newer tests has

resulted in conflicting data on their usefulness. Management

of DIC is directed primarily against the underlying condi-

tion, but interventions to interrupt the state of pathologic

coagulation and fibrinolysis seem to be logical because these

processes may contribute significantly to the pathologic

state. Nevertheless, it has been difficult to demonstrate a clear

benefit of anticoagulation or antifibrinolytic therapy in any

situation complicated by DIC above and beyond that of

aggressive supportive care and treatment of the underlying

disease, with the possible exceptions of purpura fulminans

and thromboses associated with solid tumors. The use of

rFVIIa to treat bleeding associated with DIC may increase

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422

thrombotic sequelae and is not recommended by the manu-

facturer. However, control of refractory bleeding with rFVIIa

without thrombotic complications has been reported in sev-

eral patients with DIC. The use of activated protein C has

been shown to reduce hospital mortality in patients with

severe sepsis; however, this benefit was seen in patients both

with and without DIC. It is not known whether this benefit

is due to its anti-inflammatory properties, profibrinolytic

properties, or antithrombotic properties. Other strategies

aimed at interrupting important steps in the pathogenesis of

DIC such as the use of antithrombin concentrate and

inhibitors of the tissue factor pathway are under investiga-

tion for treatment of DIC. Antifibrinolytic therapy has

proven to be useful in the management of some of the inher-

ited coagulation disorders as an adjunct to factor replace-

ment. Because the acquired coagulation disorders are often

more complex, disruption of fibrinolysis has been attempted

infrequently. Potential complications of such therapy, such as

unmasking an underlying thrombotic diathesis, have limited

its role in the management of acquired coagulation disor-

ders. There is some evidence, however, that patients with

severe liver disease may have excessive fibrinolysis as a major

contributor to bleeding. Future studies to determine the effi-

cacy and safety of antifibrinolytic therapy are necessary

before it can be recommended.



Inherited Platelet Dysfunction

ESSENTIALS OF DIAGNOSIS



Lifelong history of easy bleeding.



Prolonged bleeding time out of proportion to platelet

count.



Normal platelet count or mild thrombocytopenia.



Normal coagulation times.

General Considerations

Platelets are involved in multiple aspects of normal hemosta-

sis. Defects in platelet membrane constituents, granules,

metabolism, or coagulant function give rise to defective

adhesion, aggregation, secretion, or procoagulant activity

(Table 17–7). These disorders are generally rare, usually fol-

low autosomal recessive inheritance patterns, and result in

varying degrees of bleeding associated with prolongation of

the bleeding time or defective or absent platelet aggregation

in response to platelet agonists. The most severe defects have

onset in the neonatal period or in early childhood with

ecchymoses, epistaxis, and other mucosal bleeding, but

milder defects may be manifest only after surgery or trauma.

Thrombocytopenia is present in some platelet disorders and

may contribute to the bleeding tendency. Other congenital

abnormalities (eg, albinism) also may be present.

Clinical Features

A clinical history of lifelong bleeding, accompanied by a pro-

longed bleeding time in the presence of normal platelet

count (or mild thrombocytopenia), PT, and aPTT, should

suggest the possibility of an inherited platelet disorder. A

peripheral smear made from fresh non-anticoagulated blood

may uncover morphologic platelet abnormalities or absence

of platelet aggregation. Platelet aggregation studies using a

wide variety of platelet agonists (including ristocetin) are

helpful for identifying the specific defect. Confirmation of

the specific diagnosis may require specialized studies avail-

able only in research laboratories.

Differential Diagnosis

A prolonged bleeding time in the absence of a history of clini-

cal bleeding is unreliable as an indicator of platelet dysfunction

or as a predictor of future bleeding. In the presence of bleeding,

a prolonged bleeding time may suggest the diagnosis of vWD

or an acquired disorder of platelet function (eg, uremia, drug

therapy, cardiopulmonary bypass, or myeloproliferative disor-

ders) rather than an inherited defect. Mucosal bleeding, ecchy-

moses, and posttraumatic bleeding may result from severe

coagulation disorders, accelerated fibrinolysis, thrombocytope-

nia, or vascular injury or from multiple hemostatic defects.

Adult onset of a severe bleeding tendency makes the diagnosis

of an inherited disorder of platelet function very unlikely.

Treatment

Serious bleeding usually requires transfusion of normal

platelets. Alloimmunization to HLA antigens and to platelet-

specific antigens may result in refractoriness to platelet trans-

fusions, so efforts to decrease alloimmunization are

Function Disorder

Adhesion Bernard-Soulier syndrome (GP Ib deficiency)

von Willebrand disease.

Aggregation Glanzmann’s thrombasthenia (GP IIb/IIIa deficiency)

Afibrinogenemia

∗

Secretion/

signal

transduction

Gray platelet syndrome (alpha granule deficiency)

Storage pool deficiency (delta granule defects)

Arachidonic acid pathway abnormalities

Defective calcium mobilization

Wiskott-Aldrich syndrome (defective cytoskeletal

regulation)

Procoagulant

activity

Decreased platelet factor III activity

Scott syndrome (asymmetry of platelet phospholipids)

∗

Defect is extrinsic to platelet but affects platelet function, with

exception of platelet-type von Willebrand disease.

Table 17–7. Inherited disorders of platelet function.

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BLEEDING & HEMOSTASIS

423

recommended (eg, limiting transfusions to life-threatening

situations, use of leukocyte-poor platelet preparations, or

administration of HLA-matched platelets). For unclear rea-

sons, some defects respond to therapy with desmopressin.

Antifibrinolytic agents (eg, aminocaproic acid or tranexamic

acid) may be useful for control of minor mucosal bleeding or

as adjuncts to platelet transfusions. Hormonal suppression of

menses is indicated for control of menorrhagia. Antiplatelet

agents are contraindicated, and surgical procedures should

be avoid whenever possible. Antifibrinolytic agents (eg,

epsilon-amino caproic acid and tranexamic acid) may be

helpful for controlling bleeding, as they do in inherited coag-

ulation disorders.

Current Controversies and Unresolved Issues

Optimal therapy of inherited platelet disorders is hampered

by the infectious risk of platelet concentrates and by the risk

of alloimmunization to HLA antigens and platelet-specific

antigens that renders further transfusions ineffective. The

risk of antibody formation is highest in patients with mem-

brane protein defects because of the presence of these pro-

teins on normal platelets. Bone marrow transplantation can

completely correct the bleeding tendency in patients with

inherited platelet disorders but remains experimental

because of potential lethal toxicity. Desmopressin releases

vWF and factor VIII from the endothelium, but it also may

shorten the bleeding time in some patients with a wide vari-

ety of platelet disorders independent of vWF and factor VIII

levels; its mechanism of action in these intrinsic platelet dis-

orders has not been established. Corticosteroid therapy prior

to surgery may improve hemostasis via an effect on vascular

integrity and may be indicated for control of bleeding in

patients with inherited platelet disorders who have no con-

traindications to steroid use.



Acquired Platelet Dysfunction

ESSENTIALS OF DIAGNOSIS



Mucosal bleeding, ecchymoses, or excessive surgical

bleeding in the absence of thrombocytopenia.



Abnormal bleeding time.



Normal coagulation times.



Clinical condition or medication associated with platelet

dysfunction.

General Considerations

Acquired platelet dysfunction may result from defects in

platelet adhesion, aggregation, secretion, or procoagulant

function. Drugs, liver or renal disease, cardiopulmonary

bypass, antiplatelet antibodies, acquired vWD, dysproteine-

mias, and myeloproliferative or lymphoproliferative disorders

(acute and chronic) may be associated with impairment of

platelet function, as measured by the bleeding time or by

abnormal tests of platelet aggregation. The clinical impor-

tance of the laboratory abnormalities in these diverse clinical

conditions is not always clear. Bleeding depends not only on

the severity of the defect but also on the presence of vascular

injury and other hemostatic defects. Typical manifestations

reflect impaired platelet function with mucocutaneous

bleeding and excessive posttraumatic bleeding. Petechiae are

rare unless thrombocytopenia is also present. Spontaneous

soft tissue hematomas and joint bleeding are rare.

Thromboxane A

is an important mediator of platelet

secretion and aggregation. Aspirin irreversibly acetylates and

inactivates cyclooxygenase, thus preventing the production of

prostaglandins, including thromboxane A

. Most individuals

who take aspirin will have a slight prolongation of baseline

bleeding time that may persist for several days, but marked

prolongation or clinical bleeding owing to platelet dysfunc-

tion is rare at doses used in most clinical situations, although

chronic use may be accompanied by easy bruising and

mucosal bleeding. Patients with other hemostatic defects,

however, may experience marked prolongation of bleeding

time and clinical bleeding if they take aspirin. Increased GI

tract bleeding is common in patients chronically taking high

doses of aspirin, but this is due to its irritant effect on the

mucosa rather than its effect on platelet function. The effect

of aspirin on bleeding following major surgery or invasive

procedures is controversial. While other nonsteroidal anti-

inflammatory agents reversibly inhibit cyclooxygenase, these

rarely prolong the bleeding time or induce clinical bleeding

even in patients with severe coagulation defects.

Dextran is used occasionally for its antiplatelet effect in

preventing postoperative deep vein thrombosis without

increasing postoperative blood loss. Ticlopidine and clopido-

grel are newer antiplatelet agents that inhibit ADP-induced

platelet aggregation and prolong the bleeding time, and these

occasionally may cause increased mucosal bleeding or bruis-

ing. Both agents appear to have irreversible effects on platelet

function, requiring 7 days for normal platelet function to

appear after withdrawal of the drugs (see Table 39–2).

Platelet glycoprotein IIb/IIIa inhibitors are used for treat-

ment of acute coronary ischemia, usually in combination

with anticoagulants or fibrinolytic agents, and work by pre-

venting fibrinogen-mediated platelet aggregation. β-lactam

antibiotics given at high doses for a prolonged period of time

may affect platelet function and can cause bleeding. However,

most patients with overt bleeding have multiple contributing

problems and can be managed without discontinuing the

antibiotic. Many other drugs have been linked to prolonga-

tion of the bleeding time but rarely result in clinical bleeding.

Renal failure is frequently associated with abnormal

platelet function, as measured by the bleeding time and by

platelet aggregation tests. Impaired platelet function appears

to result from biochemical alteration of intrinsically normal

platelets, although the precise mechanisms have not been



CHAPTER 17

424

elucidated. Severe anemia seen with renal failure can con-

tribute to prolongation of the bleeding time. Bleeding mani-

festations attributed to uremia include purpura, epistaxis,

and menorrhagia, but the risk of bleeding does not correlate

well with laboratory assessment of platelet function. With

adequate dialysis and generally improved care of uremic

patients in the past 25 years, bleeding may not be increased

significantly compared with those without renal failure.

Cardiopulmonary bypass induces both thrombocytope-

nia and transient platelet dysfunction. Platelet activation

while the platelets circulate through the bypass circuit results

in a state of functional “refractoriness” that usually reverses

within the first few postoperative hours. Multiple mecha-

nisms appear to be responsible for the observed changes

in platelet membranes, granule content, and functional

activity following bypass. Modest transient coagulation factor

deficiencies—owing mainly to hemodilution coupled with

heparin and protamine use—may result in prolongation of

coagulation times. Bleeding following cardiopulmonary

bypass therefore may result from multiple defects in hemo-

stasis, including inadequate surgical hemostasis.

Acquired hematologic disorders cause platelet dysfunc-

tion through production of intrinsically abnormal platelets

(eg, myeloproliferative disorders, myelodysplastic syn-

dromes, acute leukemias, or hairy cell leukemia), or through

production of abnormal substances that interfere with

platelet function (eg, immunoglobulins in myeloma or

Waldenström’s macroglobulinemia; rarely, immune-

mediated thrombocytopenia), or from abnormalities in vWF

(acquired vWD, seen in aortic stenosis, myeloproliferative

and lymphoproliferative disorders, collagen vascular dis-

eases, and angiodysplasia). Clinical bleeding is more often

the result of associated hemostatic defects or other hemato-

logic abnormalities, such as severe anemia, thrombocytope-

nia, marked leukocytosis, or hyperviscosity. Thrombotic

sequelae also may result from abnormal platelet function,

particularly in the myeloproliferative disorders.

Clinical Features

A. Symptoms and Signs—Mucosal bleeding, ecchymoses, or

excessive posttraumatic or surgical bleeding in the absence of

thrombocytopenia or abnormal coagulation times should sug-

gest the possibility of an acquired defect of platelet function.

B. Laboratory Findings—In most cases, the underlying

condition of the patient and medication use are obvious, and

minimal laboratory evaluation is needed to confirm the pres-

ence of platelet dysfunction. The bleeding time is a readily

available in vivo test of platelet function that will identify

most patients with significantly abnormal platelet function.

In vitro platelet aggregation studies require significant tech-

nical experience for reliable results and should be reserved

for patients with bleeding suggestive of platelet dysfunction

and an unexplained prolongation of the bleeding time—or a

very suggestive history of bleeding without prolongation of

the bleeding time. Bleeding time and platelet aggregation

studies are influenced by multiple factors, and while they are

useful for diagnosis in patients with significant bleeding, they

are not reliable indicators of the risk of future bleeding.

Differential Diagnosis

Inherited disorders of platelet function usually are readily dif-

ferentiated from acquired disorders by the presence of a long

history of bleeding and the absence of underlying conditions

associated with acquired platelet dysfunction. Mucosal bleed-

ing, ecchymoses, or excessive posttraumatic and surgical

bleeding may result from severe coagulation disorders,

thrombocytopenia, excessive fibrinolysis, vascular injury, or

multiple hemostatic defects. Prolongation of the bleeding

time may result from severe anemia, thrombocytopenia,

improper technique, or insignificant platelet dysfunction, and

in the absence of bleeding suggestive of platelet dysfunction,

it is not a reliable indicator of future risk of bleeding.

Treatment

Impaired platelet function in the absence of clinical bleeding

usually requires no specific therapy even when invasive pro-

cedures are performed. If bleeding is present, or if the nature

of an invasive procedure is such that any increased risk of

bleeding is unacceptable, a number of therapeutic options

are available depending on the underlying cause of the

platelet dysfunction. Withdrawal of aspirin or other suspect

drugs is usually adequate for management of drug-induced

platelet dysfunction. Desmopressin may be useful for man-

agement of bleeding in patients with a wide variety of disor-

ders of platelet function, including uremia, cardiopulmonary

bypass, and liver disease. Cryoprecipitate infusions and cor-

rection of severe anemia with red blood cell transfusions or

epoetin alfa (ie, erythropoietin), aggressive dialysis, and con-

jugated estrogens are other strategies for controlling bleeding

in uremic patients with platelet dysfunction. Aprotinin is a

plasmin inhibitor that reduces significant postoperative

bleeding following cardiopulmonary bypass and also may

decrease bleeding after liver transplantation.

Platelet transfusions are indicated in the treatment of

severe bleeding when platelet dysfunction is due to drugs,

cardiopulmonary bypass, or acquired intrinsic abnormalities

of platelets (eg, leukemias, myelodysplasias, and myeloprolif-

erative disorders) but are not helpful for management of

bleeding in uremia. Avoidance of aspirin and other

antiplatelet agents, correction of vascular defects, and treat-

ment of the underlying disease process are the most impor-

tant strategies for prevention and treatment of bleeding

associated with platelet dysfunction.

Current Controversies and Unresolved Issues

The bleeding time has enjoyed widespread use as a screening

test for patients requiring surgical procedures and as a diag-

nostic test in bleeding patients. The bleeding time may be

affected by technique, the site and depth of the incision, the



BLEEDING & HEMOSTASIS

425

presence of anemia, and characteristics of the supporting

connective tissues regardless of the functional status of the

platelets. A recent review of hundreds of studies of bleeding

time produced no convincing evidence that the bleeding

time is a useful predictor of bleeding in any clinical situation.

Its main value is in diagnosing conditions associated with

impaired platelet function, but even when platelet dysfunc-

tion is present, the bleeding time does not correlate well with

clinical bleeding.

Desmopressin acetate has proved to be useful in shorten-

ing the bleeding time in a wide variety of platelet disorders,

and it may decrease clinical bleeding as well. Conflicting

reports on its efficacy and a lack of understanding of its

mechanism of action in diverse diseases have limited its

widespread use. In addition, a few case reports have sug-

gested that desmopressin may contribute to thrombotic

complications, particularly in elderly patients with cardio-

vascular disease. Antifibrinolytic agents may prove to have a

role as adjuncts to other therapies for treatment of acquired

platelet disorders, but the potential for thrombotic complica-

tions must be appreciated when considering their use.



Thrombocytopenia

ESSENTIALS OF DIAGNOSIS



Mucocutaneous bleeding; petechiae in severe cases.



Decreased platelet count.



Absence of other hemostatic defects.



Associated condition leading to thrombocytopenia.

General Considerations

Thrombocytopenia may result from decreased production,

increased destruction or utilization, or sequestration of

platelets in the spleen (Table 17–8). Decreased production

usually affects all hematopoietic cells and rarely results in

isolated thrombocytopenia. Mechanical destruction of

platelets is often accompanied by evidence of hemolysis with

anemia, reticulocytosis, and red blood cell fragmentation on

peripheral blood smear, as well as clinical manifestations of

the underlying disease process. Immunologic destruction of

platelets may occur as an isolated problem (eg, autoimmune

thrombocytopenic purpura) or may result from drugs, trans-

fusions, or disease states associated with the production of

autoantibodies (eg, chronic lymphocytic leukemia, systemic

lupus erythematosus, or HIV infection). Splenomegaly from

any cause may result in thrombocytopenia and is often

accompanied by anemia and leukopenia.

Clinical Features

The history and physical examination with attention to

bleeding symptoms, medication usage, splenomegaly, and

symptoms and signs of underlying disorders often will reveal

clues to the diagnosis.

A. Symptoms and Signs—Mucocutaneous bleeding is the

most common bleeding manifestation of thrombocytopenia.

Petechiae usually occur only with severe thrombocytopenia

and may reflect the platelet’s essential role in the mainte-

nance of endothelial tight junctions. Spontaneous soft tissue

hematomas and hemarthroses are distinctly unusual. The

risk of serious bleeding depends on the cause and severity of

the thrombocytopenia, the presence of other hemostatic

defects or vascular injury, and the condition of the patient. In

general, patients with thrombocytopenia owing to consump-

tion, destruction, or splenic sequestration are at less risk for

serious bleeding than patients with decreased production of

platelets because decreased platelet survival results in pro-

duction of a younger, more functional population of

platelets. The most feared complication of severe thrombo-

cytopenia is CNS hemorrhage, which is rare unless the

platelet count is less than 10,000/μL and there are other pre-

disposing factors, such as leukemic infiltration, marked

leukocytosis, or other vascular injury. Bleeding manifesta-

tions associated with various degrees of thrombocytopenia

are shown in Table 17–9.

B. Laboratory Findings—Review of the complete blood

count and peripheral blood smear is essential to evaluate asso-

ciated abnormalities in other blood cell lines and to exclude

the possibility of pseudothrombocytopenia owing to in vitro

platelet clumping in the presence of EDTA anticoagulant.

Other instances of artifactual thrombocytopenia may be due

to platelet satellitism around neutrophils or may occur when

many giant platelets are present that may not be counted as

platelets by automated cell counters. Isolated thrombocytope-

nia is most often the result of immunologic destruction of

platelets but may be found in some patients with mild hyper-

splenism, acute alcohol intoxication, or early acute leukemia

and in the rare patient with isolated amegakaryocytic throm-

bocytopenia. The presence of fragmented red blood cells sug-

gests the possibility of intravascular mechanical trauma to

cells, as seen with DIC, thrombotic thrombocytopenic

purpura–hemolytic uremic syndrome, eclampsia (ie, HELLP

syndrome), or mechanical prosthetic heart valves. Abnormal

white blood cells may indicate the presence of leukemia or

lymphoma. The combination of nucleated red blood cells and

immature white blood cells in the peripheral smear, a leuko-

erythroblastic picture, suggests the possibility of bone marrow

infiltration from myelofibrosis or metastatic carcinoma.

Macrocytosis and pancytopenia should suggest the possibility

of vitamin B

or folate deficiency.

The PT and aPTT should be determined to detect condi-

tions such as DIC or thrombocytopenia associated with liver

failure. Bone marrow biopsy and aspiration are useful for

evaluation of platelet production and should be performed

when the diagnosis is not certain or if confirmation of a spe-

cific diagnosis (eg, leukemia, aplastic anemia, or metastatic

carcinoma) is essential to proper management.



CHAPTER 17

426

Decreased Production Increased Destruction or Utilization

Marrow infiltration or replacement

Leukemia, lymphoma, metastatic carcinoma

Aplastic anemia

Myelofibrosis

Granulomatous disease

Toxic or environmental exposures

Alcohol

Radiation

Chemotherapy

Chemicals

Thiazide diuretics

Ineffective hematopoiesis

Vitamin B

or folate deficiency

Myelodysplastic syndromes

Paroxysmal nocturnal hemoglobinuria

Infections

Viral: HIV, hepatitis, cytomegalovirus

Fungal: histoplasmosis

Acid fast organisms:

M tuberculosis,

M avium-intracellulare.

Bacterial sepsis

Acquired amegakaryocytic thrombocytopenia

Congenital thrombocytopenia

Thrombocytopenia–absent radius syndrome

Wiskott-Aldrich syndrome

May-Hegglin anomaly

Bernard-Soulier syndrome

Alport syndrome

Neonatal rubella or CMV infection

Maternal thiazide use

Mechanical

Abnormal heart valves

Vascular devices

Disseminated intravascular coagulation

Vasculitis

Cardiopulmonary bypass

Thrombotic thrombocytopenic purpura

Hemolytic uremic syndrome

Renal transplant rejection

Giant cavernous hemangioma (Kassabach-Merritt syndrome)

Fat embolism

Burns (>10% body surface)

Snake bite (crotalid)

Sequestration (hypersplenism, hypothermia)

Massive transfusion

Immunologic

Drug-induced antibodies or immune complexes

Systemic lupus erythematosus

Antiphospholipid antibody syndrome

Neoplastic diseases (chronic lymphocytic leukemia,

Hodgkin’s disease)

Posttransfusion purpura

Neonatal alloimmune thrombocytopenia

Viral-associated (HIV, infectious mononucleosis,

cytomegalovirus)

Pregnancy

HELLP syndrome (hemolysis, elevated liver enzymes,

low platelets associated with eclampsia)

Autoimmune thrombocytopenia

Probably immune

Malaria

Bacterial sepsis

Artifactual thrombocytopenias: Anticoagulant-dependent platelet clumping, pseudothrombocytopenia, platelet

satellitism, giant platelets.

Table 17–8. Causes of thrombocytopenia.

Platelet count (per μL) Clinical manifestations

>100,000 No increase in bleeding

50,000–100,000 Minimal bleeding even with surgery unless platelet dysfunction is present

30,000–50,000 Increased bleeding with surgery or trauma

∗

20,000–30,000 Occasionally associated with easy bruising or other minor spontaneous bleeding

∗

10,000–20,000 Epistaxis, petechiae, menorrhagia, gum bleeding

<10,000

Increased gastrointestinal blood loss, spontaneous life-threatening bleeding

†

(eg, intracranial hemorrhage, hematuria,

melena, hematemesis)

∗

Minimal in patients with immune thrombocytopenia or other consumptive disorders.

†

Life-threatening hemorrhage ususally occurs only with underlying vascular defect or if a second hemostatic defect is present

(including aspirin ingestion).

Table 17–9. Bleeding manifestations associated with thrombocytopenia.