American Journal of Emergency Medicine (2006) 24, 460 – 467

www.elsevier.com/locate/ajem

Review

Acute thrombotic disorders

Joanne G. Kuntz MDa, Justin D. Cheesman MDa, Robert D. Powers MD, MPHa,b,*

a
Division of Emergency Medicine, University of Connecticut School of Medicine, Farmington, CT 06030, USA
b
Department of Emergency Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA

Received 3 January 2006; accepted 14 January 2006

Abstract The acquired hypercoagulable states are responsible for a broad range of thrombotic and
thromboembolic disorders. Symptoms and signs of acute ischemia or organ dysfunction will lead
many of these patients to seek care in EDs. Proper diagnosis and therapy must be based on an
understanding of epidemiology and pathophysiology. Immediate anticoagulation with heparin may not
always be the treatment of choice; careful analysis of clinical and laboratory parameters is necessary to
arrive at the safest and most effective course of action. Newer anticoagulants, including low-
molecular-weight heparins and nonheparin compounds, are changing the therapeutic approach to many
of these disorders.
D 2006 Elsevier Inc. All rights reserved.

1. Introduction thrombosis (DVT) in a recently hospitalized patient with

acute coronary syndrome can have grave consequences
Normal hemostasis is ensured by a balance between the when heparin-induced thrombocytopenia with thrombosis
inhibitors of coagulation and the activation of coagulation syndrome has precipitated the clot.
factors. Imbalances or deficiencies of anticoagulant proteins Given that many patients with coagulation disorders will
allow the activation process to proceed abnormally, leading present to EDs with acute symptoms, emergency physicians
to thrombotic disorders manifested as intravascular clotting. should be familiar with recent advances in the understand-
The clinical presentation of these disorders is variable; it ing of these disorders, as well as the indications for therapy
would include a postoperative patient with a simple with conventional and newer treatment modalities.
uncomplicated distal deep vein thrombosis or a pregnant
woman with thrombotic thrombocytopenic purpura (TTP)
causing intrauterine fetal demise. 2. Systemic thrombotic disorders
In many instances, the diagnosis is evident, and therapy
with anticoagulants is routine. However, certain complex Generally speaking, all systemic thrombotic disorders
syndromes demand a detailed understanding of the patho- can be attributed to the presence of a hypercoagulable state.
physiology and careful consideration of therapy. Intuitive Hypercoagulability is defined as a bstate of heightened
treatments such as empiric heparin for deep venous activity of the coagulation systemQ or thrombophilia [1]. The
differential diagnosis of the patient presenting with an acute
intravascular thrombosis is quite broad and can be initially
* Corresponding author. University of Connecticut School of Medi- divided into inherited and acquired hypercoagulable states.
cine, USA. Primary, or inherited, hypercoagulable states often result

0735-6757/$ – see front matter D 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.ajem.2006.01.009
Acute thrombotic disorders 461

from quantitative or qualitative coagulation protein disor- in complex management challenges that will require a
ders. These include factor V Leiden mutation, prothrombin multidisciplinary approach. Specific therapy will depend
gene mutation, elevated levels of fibrinogen, protein C or S on the nature of the event and the underlying etiology.
deficiencies, and antithrombin deficiency. Secondary, or
acquired, hypercoagulable states can cause significant 2.1.2. Antiphospholipid syndrome
disease on their own or provide the trigger for a thrombotic Antiphospholipid syndrome was previously called blupus
event when superimposed on a primary disorder [1,2]. anticoagulant syndrome.Q The former is a more descriptively
The risk for thrombosis in primary disorders is predict- accurate name for 2 reasons. Although it can be associated
able and related to the degree of the inherited defect and the with lupus, the syndrome may also be seen in individuals
role that the defect plays in hemostasis. In contrast, who do not have a collagen vascular disease. More
quantification of risk in the acquired states is difficult, as importantly, the antibodies actually induce a procoagulant
the pathophysiology is variable, and due to differing state in vivo; the blupus anticoagulantQ label refers to in vitro
abnormalities in any or all of the classic causes of properties of no clinical relevance. Antiphospholipid anti-
thrombosis described by Virchow. These include abnormal- bodies have been identified in 5% to 10% of healthy
ities in blood flow, abnormalities in blood composition, and individuals. The mechanism whereby the antibodies induce
abnormalities of the vessel wall. This review will address a hypercoagulable state is not clear, but likely involves
the acquired hypercoagulation disorders most likely to be antibody-protein complexes and their influence on platelet
encountered in emergency practice and also describe activation and other hemostatic factors [4,5].
available therapies. Manifestations of the syndrome are characterized by
arterial thrombosis in about one third of the cases, with
2.1. Acquired hypercoagulable states most of these involving the cerebrovascular circulation.
Venous thrombosis occurs in the remainder of the cases,
2.1.1. Pregnancy and oral contraception typically presenting as DVT and PE. The spectrum of clinical
The normal physiologic changes associated with preg- manifestations includes TIA, multi-infarct dementia, renal
nancy bring about a progressive shift to a hypercoagulable artery occlusion, and mesenteric and coronary artery
state that is at its peak in the peripartum period. insufficiency. Obstetric complications are troublesome, with
The puerperium, defined as the 6-week period after repeated miscarriages and fetal growth retardation being the
delivery, is associated with a higher rate of thrombosis than most prominent [4,5].
pregnancy itself. Hormonal changes caused by oral contra- Treatment of thrombotic complications associated with
ceptive use produce similar physiologic circumstances. In antiphospholipid syndrome includes anticoagulation with
pregnancy, the placenta introduces thrombin into the utero- heparin. Patients have a prolonged PTT at baseline, so low-
placental circulation. Placental plasminogen activator inhib- molecular-weight heparins (LMWHs) may be used to avoid
itor type 2 further shifts the hemostatic balance by blunting the pitfalls associated with interpreting the PTT. The
fibrinolysis. Stasis and mechanical interruption of venous syndrome is especially problematic in young women because
return associated with the gravid uterus contribute to the no established treatment has been identified to prevent
prothrombotic state, as can vessel injury sustained during recurrent fetal loss.
vaginal or cesarean delivery [1].
Risk factors for thrombosis in pregnancy include 2.1.3. Malignancy
increasing age, cesarean delivery, prolonged immobiliza- More than a century ago, Armand Trousseau described
tion, obesity, and prior thromboembolism. Further risk is the association between neoplasms and thrombosis in a
noted in those women with a coexisting primary hyperco- series of patients. Since that time, scientists have been trying
agulable state, multiparity, prolonged bed rest or immobi- to understand the relationship between the two. It is not
lization, or previous DVT [1]. Venous thrombosis and known whether every neoplasm is an independent risk
pulmonary embolism (PE) are the most common thrombotic factor for a prothrombotic state. Investigation of thrombosis
manifestations of pregnancy and oral contraceptive use. in malignancy is inevitably confounded by the influence of
Pregnancy alone is associated with a 6-fold increased risk of antineoplastic therapy on hemostasis.
venous thromboembolic disease (VTE) [3]. Surgical procedures and some of the chemotherapy used
Systemic anticoagulation is the mainstay of therapy for in the treatment of cancer increase the likelihood of
thromboembolic disease in pregnancy and the puerperium. thrombosis independent of the risk imposed by the cancer
As warfarin is contraindicated before delivery, anticoagulant itself. Fibronopeptide A levels have been shown to increase
therapy for DVT or PE during pregnancy is limited to during infusion of certain chemotherapeutic agents, leading
heparins. Thrombolytic therapy is contraindicated in preg- to a conversion of fibrinogen to fibrin, with presumed
nancy and the immediate postpartum period. Although most increased risk of thrombosis immediately thereafter [6].
episodes of DVT and VTE associated with pregnancy occur Delayed thrombosis after infusion of certain cytotoxic, anti-
in the puerperium, significant thrombotic and thromboem- metabolic, and hormonal chemoagents has been thought to
bolic events occurring before term or fetal viability result result from a decrease in circulating anticoagulant proteins
462 J.G. Kuntz et al.

antithrombin III, protein C, and protein S. The decrease in The DIC associated with APL frequently resolves within 4 to
these proteins, although not clearly understood, may be due 8 days after initiation of all-trans retinoic acid. Anticoag-
to the hepatotoxic nature of some agents [6]. ulant therapy in APL should be reserved for patients who
The most common thrombotic manifestations in patients demonstrate clinical thrombosis and laboratory features
with malignancy are DVT and PE. However, certain malig- of DIC [8].
nancies can have a rather unusual characteristic thrombotic 2.1.5. Hypercoagulable states
picture. When these specific events are recognized, the Hyperviscosity of the blood may be caused by ab-
physician should consider the presence of an underlying normalities in plasma or cellular components. As viscosity
malignancy if it has not already been diagnosed. The classic increases, normal laminar flow is disrupted, resulting in
syndrome of migratory thrombophlebitis of upper and lower microvascular stasis and diminished perfusion. If left
extremities is strongly linked to adenocarcinomas; Trous- untreated, thrombosis ensues. Increased plasma viscosity
seau described its association with pancreatic cancer. These is most commonly seen in disease states with increased
patients are at particular risk for recurrent thromboembo- levels of gamma globulins. Waldenstrom’s macroglobuli-
lism, which is typically not prevented by warfarin. Long- nemia is responsible for the majority of cases, with
term therapy with LMWH is recommended [7]. multiple myeloma accounting for the bulk of the remain-
Certain other cancers, notably Hodgkin disease and renal der. The presence of increased numbers of red cells, white
cell carcinoma, are associated with bacute-phase reactionsQ cells, or platelets can produce a procoagulant state, as
brought on in part, by cytokines tumor necrosis factor and can the altered red cell morphology seen in sickle cell
interleukin 2. Tumor necrosis factor can down-regulate the disease [2,10].
expression of thrombomodulin on vascular endothelial cells, The clinical features of hyperviscosity include bleeding
thus limiting the full anticoagulant effects of protein C. This from mucous membranes, visual abnormalities, and neuro-
may increase the risk of thrombosis [6]. logic disturbances such as headache, dizziness, somnolence,
Physicians should maintain a broad differential diagnosis seizure, and coma. Cardiopulmonary findings including
in patients who present with limb ischemia, as routine hypoxemia, CHF, myocardial ischemia, and respiratory
surgical interventions could be hazardous if the cause of the failure have all been reported. Associated thrombotic events
thrombosis remains unrecognized. Patients with cancer are include DVT and VTE [9].
occasionally subject to peripheral arterial occlusion from Unlike other hypercoagulable states, the altered mental
nonthrombotic, embolic phenomena, including those arising status and other clinical features seen in hyperviscosity
from heart valves in nonbacterial endocarditis. This disor- syndromes may be completely reversible with treatments
der, also called marantic endocarditis, consists of sterile such as phlebotomy and intravenous fluids, chemotherapy
deposits of alternating layers of fibrin and platelets on heart or plasmapheresis. Hyperviscosity syndromes do not gen-
valves. These may be small, and unlike bacterial endocar- erally require anticoagulant therapies [2,10].
ditis, are not necessarily associated with physical or
echocardiographic findings. Their presence should be 2.1.6. Thrombotic microangiopathies
suspected in patients with systemic embolic signs in the The thrombotic microangiopathies are a group of
absence of a heart murmur and a normal echocardiogram. At syndromes characterized by small-vessel thrombosis, micro-
autopsy, it has been shown that up to 75% of cases are angiopathic hemolytic anemia, thrombocytopenia, and
associated with a malignancy [6]. organ failure. The most common of these disorders,
hemolytic uremic syndrome (HUS) and TTP, were once
2.1.4. Leukemia considered 2 distinct disease entities. In consideration of
Acute promyelocytic leukemia (APL), a subtype of acute their extensive pathophysiologic overlap, they are now
myelocytic leukemia, is characterized by b a profound dis- termed the HUS/TTP syndrome [11].
ruption of hemostasisQ [8]. The coagulopathy seen in APL has This disease complex has diverse causes, but endothelial
a laboratory profile similar to that seen in disseminated damage and platelet aggregation dominate the pathogenesis.
intravascular coagulation (DIC). Clinically, bleeding tenden- These cause vascular thrombosis, obstruction, and vasocon-
cies predominate. Abnormalities are due to the intrinsic striction, precipitating distal ischemia. The thrombi are
characteristics of the leukemic cells, which are able to directly composed predominantly of platelet aggregates with scant
activate the clotting cascade. The cells produce 2 tumor- fibrin. It is believed that the differences in the clinical
associated procoagulants: (1) tissue factor, which complexes manifestations of TTP and HUS are due to different
with factor VII and activates factors IX and X; and (2) cancer distribution of microvascular lesions. Investigators continue
procoagulant, which activates factor X independent of factor to work to identify specific serum factors responsible for the
VII. These cells also have plasminogen activators. alterations in hemostasis seen in HUS/TTP and to determine
All-trans retinoic acid has proven to be an effective whether they are primary or secondary to endothelial
treatment of this condition by inducing terminal differenti- damage [11,12].
ation of the promyelocytes. This maturation prevents pro- Classic, or childhood, HUS is very well characterized,
duction of the procoagulants and corrects the coagulopathy. with as many as 75% of cases occurring after intestinal
Acute thrombotic disorders 463

infection with Escherichia coli type 0157:H7. The offend- Table 1 Major disorders associated with disseminated
ing bacteria produce a toxin that has a variety of effects on intravascular coagulation
the endothelium, platelets, erythrocytes, and monocytes,
Obstetric complications
resulting in the characteristic microangiopathy. The effects ! Placental Abruption
are most apparent in the kidneys, with acute and sometimes ! Retained products of conception
chronic renal failure ensuing. ! Septic abortion
The clinical picture is one of the immediate onset of ! Amniotic fluid embolism
bleeding, predominantly gastrointestinal, with oliguria, ! Eclampsia
hematuria, and hemolytic anemia. Some of the children Infections
have neurologic disturbances as well [11-13]. ! Sepsis/SIRS
Idiopathic HUS/TTP syndrome is more commonly re- ! Meningococcemia
ferred to as TTP. The classic clinical pentad of TTP includes ! Rocky Mountain spotted fever
(1) fever, (2) neurologic symptoms, (3) microangiopathic he- ! Fungemia
molytic anemia, (4) thrombocytopenia purpura, and (5) the ! Malaria
presence of thrombi in glomerular capillaries and afferent Neoplasms
arterioles. Although hemolytic anemia is a universal feature, ! Carcinomas of pancreas, prostate, lung, and stomach
all 5 classic findings are present in only 40% of cases. ! Acute promyelocytic leukemia
Thrombotic thrombocytopenic purpura is seen more often in Massive tissue injury
women, with most of the patients younger than 40 years. ! Trauma
The diagnosis rests on evidence of microangiopathic hemo- ! Burns
lytic anemia and thrombocytopenia in the absence of DIC ! Extensive surgery
or other known causes of thrombotic microangiopathy. ! Snakebite
Differentiating HUS/TTP from DIC can be exceedingly ! Vasculitis
difficult, as there is significant overlap in both the clinical and ! Heat Stroke
laboratory findings. Some data suggest that an initial Adapted from: Cotran RS, Kumar V, Collins T. Robbins Pathologic Basis
schistocyte count of greater than 1% strongly suggests the of Disease. 6th ed. Philadelphia: WB Saunders; 1999. p. 985 - 8.
diagnosis of TTP. In idiopathic TTP, neurologic manifes-
tations are the dominant feature. Renal involvement is seen in The clinical signs and symptoms of DIC are as variable as
only about 50% of patients. In contrast to DIC, activation of the associated underlying diseases. Minimum criteria re-
the coagulation cascade in HUS/TTP is not of primary quired for the diagnosis include evidence of hemorrhage,
importance, and the standard coagulation tests are usually thrombosis, or both. These symptoms should occur in an
normal [12]. appropriate clinical setting and be accompanied by specific
If untreated, TTP is often fatal. However, mortality has laboratory findings. The prothrombin time and activated
gone from 90% to 17% with the advent of plasmapheresis in partial thromboplastin time are often prolonged, but may also
conjunction with corticosteroid and antiplatelet therapy. be normal or even short because of the presence of circulating
Despite the fact that the associated thrombocytopenia may activated clotting factors. Assays for fibrin degradation
result in platelet counts of less than 10 000, it is important to products are typically positive. Treatment of DIC is most
recognize that avoiding platelet transfusion is crucial [12,13]. often directed at the underlying causative pathology, with
There are reports of clinical deterioration, even death, after aggressive supportive measures used concurrently [15,16].
platelet transfusion. Up to 60% of women who develop TTP
associated with pregnancy will relapse, often in association 2.1.8. Heparin-induced thrombocytopenia
with subsequent pregnancies, infection, or surgery [14]. Heparin-induced thrombocytopenia (HIT) is defined as a
fall in the platelet count to less than 150 000 or a decrease in a
2.1.7. Disseminated intravascular coagulation patient’s pretreatment platelet count by at least 50% after
Disseminated intravascular coagulation, also called initiation of heparin therapy. Platelet destruction in HIT is due
consumptive coagulopathy or defibrination syndrome, is a to an antibody directed against complexes of heparin and
systemic thrombohemorrhagic disorder. It is seen in factor IV, which leads to platelet activation via platelet FccIIa
association with well-defined clinical situations and labora- receptors, sensitizing them to immunoglobulin G. Heparin-
tory evidence of a procoagulant state. Disseminated intra- induced thrombocytopenia is the most common cause of drug-
vascular coagulation is a disorder that is seen as the final induced thrombocytopenia in hospitalized patients, found
common pathway for a host of unrelated diseases or con- in up to 5% of individuals receiving heparin therapy [17,18].
ditions (Table 1). What these diseases all have in common is In contrast to many other thrombocytopenic states,
their ability to activate thrombin and plasmin, triggering a patients with HIT rarely bleed. More commonly, HIT leads
cascade of reactions that result in intravascular clotting. to a systemic thrombotic syndrome that is both limb and life
High mortality is due to ischemic organ failure precipitated threatening. Platelet activation and antibody-mediated en-
by disruption of normal circulation [15]. dothelial injury are the predominant pathophysiologic
464 J.G. Kuntz et al.

processes, leading to venous and arterial thrombosis. several procoagulant factors, mainly thrombin (factor IIa)
Although venous thromboembolism is the most common and factor Xa. Unfortunately, it also binds to many other
clinical manifestation of HIT, a wide range of associated plasma proteins that are not involved with anticoagulation,
arterial thromboses including myocardial infarction and resulting in decreased bioavailability and substantial vari-
ischemic limb damage also occur [17]. ability in anticoagulant response. A loading dose is required
Thrombocytopenia is usually noted at 5 to 12 days af- to occupy these sites so that sufficient free heparin is
ter initiation of therapy, although delayed-onset HIT up to available to bind to the target antithrombin III. Heparin
40 days after heparin has been described [19]. ED providers therapy requires frequent monitoring of the activated partial
need to have a heightened suspicion of HIT in any recently thromboplastin time (aPTT) to assess level of anticoagula-
hospitalized patient who presents with new or relative tion. When dosed to achieve aPTT at 1.5 to 2.5 times
thrombocytopenia, or a thrombotic or thromboembolic event. the control level, it has been demonstrated to be effective in
The diagnosis is made by demonstrating the presence of the initial treatment of DVT. Some investigators have
circulating antibodies via enzyme-linked immunosorbent suggested that attaining an adequate level of anticoagula-
assay or other specific blood test. Empiric initiation of tion within 24 hours of starting heparin anticoagulation is
heparin in a patient recently hospitalized is unwise, as crucial. This recommendation is based on data from a study
reexposure to heparin can precipitate significant illness in a in which 13 of 14 patients who failed to reach a therapeutic
sensitized patient. Unfortunately, thrombocytopenia is a poor aPTT within 2 hours of starting heparin anticoagulation
proxy for the presence of heparin allergy in ED patients, and developed recurrent venous thromboembolism within the
there is no rapid test readily available [20]. Clinicians must subsequent 3 months [25,26]. The use of weight-based
maintain a high level of vigilance and consider alternatives to nomograms assists in getting to desired levels rapidly [27].
heparin when appropriate. The effect of heparin can be rapidly reversed by infusion of
It was thought initially that treatment of HIT could be protamine sulfate.
limited to cessation of heparin. However, it has been shown
2.2.2. Low-molecular-weight heparin
that more than 50% of these patients continue to be at risk
The LMWHs are increasingly replacing UFH because of
for developing thrombosis [18]. No specific laboratory test
advantages in administration and lower complication rates.
or underlying clinical setting can predict which patients with
The compounds dalteparin, enoxaparin, and tinzaparin are
HIT are at risk for thrombotic complications [21].
derived by chemical or enzymatic depolymerization of
Recommendations for treatment include immediate
UFH. The reduced mass of these molecules markedly
cessation of all heparin exposure and initiation of alternative
diminishes binding to extraneous plasma proteins. Their
anticoagulation therapy. Currently, there are only 2 Food
anticoagulant effect is consistent and reliable, so routine
and Drug Administration–approved therapies for antico-
monitoring and dosage adjustments are typically not
agulation in HIT. These are recombinant hirudin, a
required. Low-molecular-weight heparins have a higher
polypeptide derived from leech saliva, and argatroban, a
bioavailability and longer half-life than UFH, allowing
small synthetic molecule. Both have demonstrated similar
subcutaneous use as a fixed dose once or twice daily. They
efficacy [22,23], although between 44% and 74% of patients inactivate thrombin to a lesser extent than UFH and have
with HIT treated with hirudin have been shown to develop fewer hemorrhagic complications. Allergic and thrombotic
drug-specific antibodies, which may interfere with its complications, such as heparin-induced thrombocytopenia,
activity. This necessitates careful monitoring of patients also occur at a much lower frequency. Low-molecular-
during therapy to avoid the complications these antibodies weight heparins are excreted primarily in the kidney, so
may cause. No clinically significant antibodies have been laboratory monitoring and dose adjustment may be needed
identified in argatroban-treated patients with HIT [24]. Low- in patients with impaired renal function. The anticoagulant
molecular-weight heparin may cross-react with unfractio- effects of LMWHs are only partially reversed by protamine,
nated heparin (UFH) after HIT occurs and should not be and there is no more specific antidote.
used for treatment. Warfarin should not be used for acute The pharmacokinetic and anticoagulant profiles of the
HIT because it is has been associated with a syndrome of individual LMWHs are distinct, and no published data are
venous limb gangrene if initiated early. available regarding their comparative efficacies. Enoxaparin
is probably the most extensively studied LMWH. In the
2.2. Anticoagulant and thrombolytic therapies MEDENOX trial, 40 mg/d was administered subcutaneous-
In circumstances where specific therapy is indicated, cli- ly in hospitalized patients older than 40 years with acute
nicians have several choices for pharmaceutical intervention. medical illnesses. Enoxaparin significantly reduced the
incidence of VTE compared with placebo in these patients
2.2.1. Unfractionated heparin [28]. Although there was also a 2.5% reduction in overall
Unfractionated heparin has been the mainstay for initial mortality in the enoxaparin group, this reduction was not
anticoagulant therapy for many decades. A large-molecular- statistically significant. The incidence of bleeding and
weight compound, it binds to antithrombin III and inhibits thrombocytopenia with enoxaparin was not significantly
Acute thrombotic disorders 465

different from that of placebo. Many published studies have Table 3 Considerations in home treatment for DVT
documented that LMWHs are at least as effective and safe
Medical exclusions
as UFH for DVT management [29]. Investigators have
! Concurrent pulmonary embolism (PE)
concluded that LMWHs reduced thromboembolic compli-
! Serious co-morbid condition
cations, clinically important bleeding, and mortality when ! Cancer, infection, stroke
compared with UFH [30]. Brewer [31] considered efficacy, ! Prior DVT or PE
safety, cost, and convenience to determine that LMWHs ! Contraindications to anticoagulation
were clinically superior to UFH. Guidelines for treatment of ! Familial bleeding disorder
VTE using LMWH are shown in Table 2. ! Known deficiency of antithrombin III, protein C,
Because LMWH can be given subcutaneously once or protein S
twice daily without the need for monitoring anticoagulant ! Pregnancy
status, its use in the outpatient or home setting is an Social exclusions
attractive alternative to inpatient care. Two clinical trials ! No phone
have confirmed that LMWH administered primarily at ! Lives far from hospital
home for the treatment of DVT is as effective and safe as ! Unable to understand instructions or comply with follow-up
UFH administered in the hospital [32,33]. Additional ! Family or patient resistance to home therapy
studies evaluated the feasibility of outpatient adminis- Mechanics and protocols
tration of LMWH and determined that more than 80% of ! LMWH for a minimum of 5 days and until INR of 2-3 from
patients with DVT and PE could be effectively treated at warfarin therapy
home and could perform self-injection safely [34,35]. ! Warfarin started on first day of therapy
Patients who were excluded from outpatient therapy were ! Must be able to monitor INR
those with phlegmasia, massive PE, high risk for major ! Patients to return immediately for shortness of breath,
bleeding or an active bleed, or additional morbidity re- hemorrhage, or clinical worsening
quiring hospitalization. Adapted from Arch Intern Med 1996;156:851-6 and N Engl J Med
1996;334:682-7.
It is evident that outpatient LMWH treatment can be
effectively implemented in real-world settings. Ideally,
protocols in the ED should include criteria for patient
selection, initiation of LMWH and warfarin therapy, patient 2.2.3. Warfarin
and caregiver education, and specific follow-up. Some Warfarin is an oral agent that blocks the synthesis of the
patients with suspected DVT can be sent home on LMWH vitamin K–dependent clotting factors prothrombin, VII, IX,
to await subsequent imaging studies. Considerations for and X. Because it takes some time to act, the consensus
outpatient treatment of DVT are outlined in Table 3; this among investigators is that warfarin and heparin should be
modality is less costly than inpatient administration of UFH initiated at the same time, preferably while the patient is
or LMWH [36 -40]. undergoing objective diagnostic testing [41,42]. Heparin
anticoagulation should overlap with warfarin for a minimum
of 4 to 5 days. Beginning warfarin at the estimated daily
maintenance dose is associated with less bovershootQ of the
Table 2 Guidelines for using LMWH in VTE target INR range, reduces the risk of bleeding, and reduces
Disease suspected the risk of an early fall in protein C levels when compared
! Obtain baseline aPTT, PT, CBC with a larger initial dose [43].
! Check for contraindications to heparin therapy The standard duration of oral anticoagulation after an
! Give LMWH and order imaging study initial DVT or PE has been 3 to 6 months. Because of the
Disease confirmed high rate of recurrent VTE after discontinuation of anti-
! Start LMWH* coagulation and recent published data that suggest better
! Start warfarin 5 mg on day 1 and adjust subsequent dose outcomes with long-term prophylaxis therapy, investigators
according to INR are reevaluating the length of oral anticoagulation therapy in
! Check platelet count between days 3 to 5 patients with DVT [44 - 46].
! Stop LMWH after at least four days of combined therapy
when INR N2.0 for 2 consecutive days 2.2.4. New anticoagulants
! Continue warfarin for 3 months (goal INR 2.5) New classes of agents are unrelated to the heparins; they
include the factor Xa inhibitor fondaparinux and the direct
*Dalteparin 200 IU/kg SC qd or 100 IU/kg SC every 12 hours; thrombin inhibitors lepirudin, argatroban, and ximelagatran.
max daily dose 18,000 IU
Fondaparinux is a pentasaccharide with a greater inhibitory
Enoxaparin 1 mg/kg SC every 12 hours or 1.5 mg/kg SC daily
activity against factor Xa than heparin or LMWH. Unlike the
Tinzaparin 175 IU/kg SC daily
heparins, fondaparinux does not affect platelet function and
Adapted from: Hyers TM, et al. Chest 2001;119(Suppl 1):176S-193S
does not react with heparin PF4 antibodies, thus reducing the
and Nutescu EA. Am J Man Care 2003;9(5 Suppl):S103-14.
risk of HIT [47,48]. It is administered subcutaneously once
466 J.G. Kuntz et al.

daily and does not require laboratory monitoring. The 3. Summary

incidence of clinically significant bleeding during treatment
with fondaparinux is similar to that of LMWH [49]. The acquired hypercoagulable states are responsible for a
Direct thrombin inhibitors target sites on the thrombin broad range of thrombotic and thromboembolic disorders.
molecule responsible for substrate recognition and/or Symptoms and signs of acute ischemia or organ dysfunction
cleavage. As they do not attach to the fibrin-binding site, will lead many of these patients to seek care in EDs. Proper
they can bind both unbound and fibrin-bound thrombin, diagnosis and therapy must be based on an understanding of
preventing both thrombus initiation and propagation. epidemiology and pathophysiology. Immediate anticoagu-
Lepirudin binds almost irreversibly to thrombin and has lation with heparin may not always be the treatment of
been associated with bleeding problems. There is no choice; careful analysis of clinical and laboratory parameters
antidote available to reverse this effect. It is administered is necessary to arrive at the safest and most effective course
intravenously or subcutaneously and is eliminated renally. of action. Newer anticoagulants, including low-molecular-
Argatroban binds reversibly to thrombin and may thus be weight heparins and nonheparin compounds, are changing
safer than lepirudin. It is administered intravenously and the therapeutic approach to many of these disorders.
hepatically metabolized. Both lepirudin and argatroban
require monitoring of the PTT to assess anticoagulant
activity. Direct thrombin inhibitors are not associated with Acknowledgments
the development of HIT.
Ximelagatran is an oral direct thrombin inhibitor in phase This study was supported in part by an unrestricted
III clinical trial development. Positive attributes of ximela- editorial grant through GSK Pharmaceuticals.
gatran include oral administration, predictable pharmacoki-
netics and pharmacodynamics, a broad therapeutic window,
no routine monitoring, no significant drug interactions,
fixed dose administration, and similar bleeding profile References
compared with placebo [50,51].
[1] Schafer AI, Levine MN, Konkle BA, et al. Thrombotic disorders:
2.2.5. Fibrinolytic/thrombolytic therapy diagnosis and treatment. Hematology 2003. Am Soc Hematology
In contrast to anticoagulants, which only prevent further 2003;520 - 39.
[2] Bauer KA. b Hypercoagulable States Q, Chapter 127. In: Hoffman R,
clotting, thrombolytic agents act to dissolve thrombi and Benz EJ, Shattil SJ, et al, editors. Hematology: basic principles and
restore circulation. These medications convert circulating practice. 4th ed. Philadelphia7 Elsevier; 2005.
plasminogen into plasmin, which in turn degrades the fibrin [3] Letsky EA, de Swiet M. Maternal hemostasis: coagulation problems
structure of clots. Available agents include urokinase, of pregnancy. In: Loscalzo J, Schafer AI, editors. Thrombosis and
streptokinase, alteplase (tissue plasminogen activator), and hemorrhage. Boston7 Blackwell Scientific Publications; 1994. p. 965.
[4] deGroot PG, Derksen RH. Pathophysiology of the antiphospholipid
reteplase (recombinant tissue plasminogen activator). They syndrome. J Thromb Haemost 2005;3(8):1854 - 60.
are used infrequently for the treatment of venous thrombi [5] Sammaritano LR. Antiphospholipid syndrome: review. South Med J
and are generally reserved for those patients with massive 2005;98(6):617 - 25.
PE, ileofemoral, and upper-extremity DVT. Thrombolytics [6] Linenberger ML, Wittkowsky AK. Thromboembolic complications
have not been shown to decrease mortality in these patients of malignancy. Part 1: risks. Oncology (Williston Park) 2005;19(7):
853 - 61.
[52]. The ED use of thrombolytics typically involves [7] Linenberger ML, Wittkowsky AK. Thromboembolic complications of
immediate intervention in coronary and cerebral artery malignancy. Part 2: management. Oncology (Williston Park) 2005;
insufficiency, although early use in severe venous throm- 19(7):1077 - 84.
botic or embolic disease should be considered. [8] Sirulnik LA, Stone RM. Acute promyelocytic leukemia: current
Streptokinase and urokinase are usually given as strategies for the treatment of newly diagnosed disease. Clin Adv
Hematol Oncol 2005;3(5):391-7, 429.
infusions over 24 hours or more. Although streptokinase [9] Gertz MA, Fonseca R, Rajkumar SV. Waldenstrom’s macroglobuli-
produces more rapid resolution of symptoms and better nemia. Oncologist 2000;5:63.
preservation of venous valve integrity when compared with [10] Kwaan HC, Bongu A. The hyperviscosity syndromes. Semin Thromb
heparin, physicians are reluctant to use this agent for Hemost 1999;25:199.
treatment of DVT because there is a 3-fold risk of [11] Mayer SA, Aledort LM. Thrombotic microangiopathy: differential
diagnosis, pathophysiology, and therapeutic strategies. Mt Sinai J Med
significant bleeding [52 -54]. Alteplase is given as a front- 2005;72(3):166 - 75.
loaded infusion over 90 or 120 minutes. Reteplase, a [12] Ruggenenti P, Lutz J, Remuzzi G. Pathogenesis and treatment of
second-generation thrombolytic with a longer half-life, is thrombotic microangiopathy. Kidney Int Suppl 1997;58:S97 -S101.
given as a single bolus or 2 boluses administered 30 minutes [13] Kakishita E. Pathophysiology and treatment of thrombotic thrombo-
apart. Reteplase and alteplase are faster-acting agents and cytopenic purpura/hemolytic uremic syndrome. Int J Hematol
2000;71(4):320 - 7.
are the preferred treatments for PE. Thrombolytics carry a [14] Shamseddine A, Chehal A, Usta I, et al. Thrombotic thrombocyto-
1% to 2% risk of intracranial bleeding, so their potential penic purpura and pregnancy: report of four cases and literature
benefits should be weighed against bleeding risk. review. J Clin Aphar 2004;19:5 - 10.
Acute thrombotic disorders 467

[15] Levi M. Disseminated intravascular coagulation: what’s new? Crit embolism with low molecular weight heparin: a comparison of
Care Clin 2005;21(3):449 - 67. patients self-injection with home care injection. Arch Intern Med
[16] Franchini M, Manzato F. Update on the treatment of disseminated 1998;158:1809 - 12.
intravascular coagulation. Hematology 2004;9(2):81 - 5. [36] Hull R, Raskob G, Rosenbloom D, et al. Treatment of proximal vein
[17] Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombosis with subcutaneous low molecular weight heparin vs
thrombocytopenia in patients treated with low-molecular-weight intravenous heparin. An economic perspective. Arch Intern Med
heparin or unfractionated heparin. N Engl J Med 1995;332:1330 - 5. 1997;157:289 - 94.
[18] Warkentin TE, Kelton JG. A 14-year study of heparin-induced [37] Tillman DJ, Charland SL, Witt DM, et al. Effectiveness and economic
thrombocytopenia. Am J Med 1996;101:502 - 7. impact associated with a program for outpatient management of acute
[19] Rice L, Attisha WK, Drexler A, et al. Delayed onset heparin-induced deep vein thrombosis in a group model health maintenance
thrombocytopenia. Ann Intern Med 2002;136:210 - 5. organization. Arch Intern Med 2000;160:2926 - 32.
[20] Howell MD, Powers RD. Utility of thrombocytopenia as a marker for [38] Spyropoulos AC, Hurley JS, Ciesla GN, et al. Management of acute
heparin allergy in ED patients. Am J Emerg Med 2006 [in press]. proximal deep vein thrombosis: pharmacoeconomic evaluation of
[21] Boshkov LK, Warkentin TE, Haywood CPM, et al. Heparin-induced outpatient treatment with enoxaparin vs inpatient treatment with
thrombocytopenia and thrombosis: clinical and laboratory studies. Br unfractionated heparin. Chest 2002;122:108 - 14.
J Haematol 1993;84:322 - 8. [39] O’Brien B, Levine M, Willan A, et al. Economic evaluation of
[22] Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin outpatient treatment with low molecular weight heparin for proximal
provides safe and effective anticoagulation in patients with heparin- vein thrombosis. Arch Intern Med 1999;159:2298 - 304.
induced thrombocytopenia: a prospective study. Circulation 1999;99: [40] Hull RD, Pineo GF, Raskob GE. The economic impact of treating
73 - 80. deep vein thrombosis with low molecular weight heparin: outcome of
[23] Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in therapy and health economic aspects. Haemostasis 1998;28(Suppl 3):
patients with heparin-induced thrombocytopenia. Arch Intern Med 8 - 16.
2003;163:1849 - 56. [41] Mohiuddin SM, Hilleman DE, Destache CJ, et al. Efficacy and safety
[24] Walenga JM, Ahmad S, Hoppensteadt D, et al. Argatroban therapy of early versus late initiation of warfarin during heparin therapy in
does not generate antibodies that alter its anticoagulant activity in acute thromboembolism. Am Heart J 1992;123:729 - 32.
patients with heparin-induced thrombocytopenia. Thromb Res [42] Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous
2002;105:401 - 5. thromboembolic disease. Chest 1992;102:408S - 25S.
[25] Hull RD, Raskob GE, Brant RF, et al. Relationship between time to [43] Harrison L, Johnston M, Massicotte MP, et al. Comparison of 5-mg
achieve the lower limit of the APTT therapeutic range and recurrent and 10-mg loading doses in initiation of warfarin therapy. Ann Intern
venous thromboembolism during heparin treatment for deep vein Med 1997;126:133 - 6.
thrombosis. Arch Intern Med 1997;157:2562 - 8. [44] Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-
[26] Hull RD, Rascob GE, Hirsch J, et al. Continuous intravenous heparin intensity warfarin therapy for the prevention of recurrent venous
compared with intermittent subcutaneous heparin in the initial thromboembolism. N Engl J Med 2002;348:1425 - 34.
treatment of proximal vein thrombosis. N Engl J Med 1986;315: [45] Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral
1109 - 14. anticoagulation therapy after a second episode of venous thrombo-
[27] Elliot CG, Hiltunen SJ, Suchyta M, et al. Physician-guided treatment embolism. N Engl J Med 1997;336:393 - 8.
compared with a heparin protocol for deep vein thrombosis. Arch Int [46] Kearon C, Gent M, Hirsh J, et al. A comparison of three months of
Med 1994;154:999 - 1004. anticoagulation with extended anticoagulation for a first episode of
[28] Samama MM, Cohen AT, Darmon J-Y, et al. A comparison of idiopathic venous thromboembolism. N Engl J Med 1999;340:901 - 7.
enoxaparin with placebo for the prevention of VTE in acutely ill [47] Messmore Jr HL, Griffin B, Fareed J, et al. In vitro studies of the
medical patients. N Engl J Med 1999;341:793 - 800. interaction of heparin, low molecular weight heparin and heparinoids
[29] Leizorovicz A. Comparison of the efficacy and safety of low with platelets. Ann N Y Acad Sci 1989;556:217 - 32.
molecular weight heparins and unfractionated heparin in the initial [48] Ahmad S, Jeske WP, Walenga JM, et al. Synthetic pentasaccharides do
treatment of deep vein thrombosis: an updated meta-analysis. Drugs not cause platelet activation by anti-heparin platelet factor 4 anti-
1996;(529 Suppl 7):30 - 7. bodies. Clin Appl Thromb Hemost 1999;5:259 - 66.
[30] Lensing AW, Prins MH, Davidson BL, et al. Treatment of deep [49] Bauer KA, Eriksson BI, Lassen MR, et al. Fondaparinux com-
venous thrombosis with low-molecular-weight heparins. A meta- pared with enoxaparin for the prevention of venous thromboembo-
analysis. Arch Int Med 1995;155:601 - 7. lism after elective major knee surgery. N Engl J Med 2001;345:
[31] Brewer D. Should low-molecular-weight heparins replace unfractio- 1305 - 10.
nated heparin as the agent of choice for adults with deep venous [50] Eriksson H, Wahlender K, Lundstrom T, et al. Extended secondary
thrombosis? J Fam Pract 1998;47:185 - 92. prevention with the oral direct thrombin inhibitor ximelagatran for
[32] Levine M, Gent M, Hirsh J, et al. A comparison of low molecular 18 months after 6 months of anticoagulation in patients with venous
weight heparin administered primarily at home with unfractionated thromboembolism: a randomized, placebo-controlled trial. Blood
heparin administered in the hospital for proximal deep-vein thrombo- 2002;100:81a [abstract].
sis. N Engl J Med 1996;334:677 - 81. [51] Nutescu EA, Wittkowsky AK. Direct thrombin inhibitors for anti-
[33] Koopman MM, Prandoni P, Piovella F, et al. Treatment of venous coagulation. Ann Pharmacother 2004;38:99 - 109.
thromboembolism with intravenous unfractionated heparin adminis- [52] Witty LA, Krichman A, Tapson VF. Thrombolytic therapy for venous
tered in the hospital as compared with subcutaneous low molecular thromboembolism. Utilization by practicing pulmonologists. Arch
weight heparin administered at home. N Engl J Med 1996;334:682 - 7. Intern Med 1994;154:1601 - 4.
[34] Harrison L, McGinnis J, Crowther M, et al. Assessment of outpatient [53] Sherry S. Thrombolytic therapy for deep vein thrombosis. Semin
treatment of deep-vein thrombosis with low molecular weight heparin. Intervent Radiol 1985;2:331 - 7.
Arch Intern Med 1998;158:2001 - 3. [54] Rogers L, Lutcher C. Streptokinase therapy for deep vein thrombosis:
[35] Wells PS, Kovacs MJ, Bormanis J, et al. Expanding eligibility for a comprehensive review of the English literature. Am J Med 1990;
outpatient treatment of deep venous thrombosis and pulmonary 88:389 - 95.